Fever of Unknown Origin (FUO) poses diagnostic challenges with prolonged fever despite assessment. The article highlights FUO types, diagnostic approaches, and the role of thorough patient evaluation for effective management.

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When a patient has a fever without a clear cause at first, doctors often refer to it as a fever of unknown origin (FUO). Nonetheless, the majority of feverish diseases either go away before a diagnosis can be established or acquire distinctive features that help with a diagnosis.

The term "FUO" describes a protracted febrile illness that, despite thorough assessment and diagnostic testing, lacks a known cause.

Numerous decades have seen the collection of large case series of FUO, which help in the approach to patients with FUO and give insight into how FUO patterns change over time in response to new diagnostic methods.

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FUO types and definitions

A general definition of fever that lasts longer than usual self-limiting diseases (such as common viral infections) without a clear cause and after an acceptable assessment by a skilled doctor is provided by a practising practitioner.

A specific description of FUO has eluded the efforts of several clinical researchers, despite their best efforts. FUO definitions that are proposed usually consist of three parts:

Fever is defined as a temperature greater than 38.3˚C (100.9˚F) in the majority of FUO research, while definitions vary from 38.0˚C (100.4˚F) to 38.5˚C (101.3˚F). Experts have more recently suggested a cut-off temperature for FUO of >38.0˚C (100.4˚F) rather than >38.3˚C (100.9˚F) since the peak normal temperature in healthy persons is 38.0˚C.

The majority of definitions stipulate that several diagnostic procedures must be carried out before a fever is classified as having an "unknown origin." The required tests might vary, but they usually consist of specific radiographic imaging as well as standard laboratory tests (such as a urinalysis and full blood count).

FUOs are separated into the following groups:

Classic FUO: In most studies, classic FUO is defined as a temperature >38.3˚C (100.9˚F) recorded on several occasions for >3 weeks, despite an appropriate initial inpatient or outpatient evaluation.

Clinically speaking, even if a patient doesn't fit the aforementioned criteria, we often treat them as if they had FUO. For example, we may define a fever as any temperature higher than 38.0˚C (100.4˚F) or stipulate that it should last for two weeks rather than three. Furthermore, some patients may fit the criteria for FUO even though they may not have had a basic workup. In these situations, we often combine elements of the initial workup done on patients with confirmed FUO with the basic workup required to confirm the diagnosis of FUO. Ultimately, the decision to diagnose and proceed with a workup for a typical FUO rests on clinical judgment.

Healthcare-related FUO: Certain infectious and noninfectious causes of fever may affect patients who are receiving medical treatment or have recently been exposed to it. When dealing with such patients, FUO is often split according to the patient's hospitalisation status—that is, whether they are in the ICU, out of the ICU, or have just had surgery.

FUO in immunocompromised patients: Patients with impaired immune systems are susceptible to a variety of opportunistic illnesses in addition to more prevalent ailments.

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Basic assessment and management

A systematic approach is advised, regardless of the clinician's definition of FUO.

1. Evaluation pace: Since many patients with typical FUO have experienced persistent fevers, they may receive initial or follow-up outpatient examinations rather than being admitted to the hospital.

However, hospitalisation is acceptable to expedite diagnostic tests or offer prompt empirical therapy for patients who are critically unwell or believed to be in danger of a life-threatening disease.

2. Protocol-driven evaluation: While some experts recommend avoiding a regular battery of tests, others support the adoption of an organised protocol-based approach to testing (e.g., having a minimum set of studies conducted for all patients with FUO). There was not enough data, according to a systematic review and meta-analysis, to favour one strategy over another.

Generally, we use a protocol-based approach and add other tests to the procedure if the patient's history and physical examination point to a certain diagnosis.

Getting a history: In the assessment of FUO, a thorough history must be obtained. Our experience indicates that early gaps in the patient's history are often the reason for delays in identifying the source of FUO.

We also try to get a collateral history from the patient's family member or partner. They could remember details that the patient forgot or suppressed. Furthermore, the spouse's past might be significant (for instance, if the partner wears work clothes home from a slaughterhouse where animals harbouring Q fever are kept).

History of current sickness: The fever and any accompanying symptoms should be the main topics of discussion in the history of the current disease. Paying attention to the time link between these related symptoms is typically beneficial. A patient who first has a fever, then jaundice or joint swelling, for instance, is probably going to get a different diagnosis than one who first experiences fever, then jaundice or joint symptoms.

Fever history: Details to gather regarding the patient's fever include the date of the first fever episode, the highest temperature they have ever recorded in a day, and the length and frequency of their fever episodes.

3. The meaning of fever: It is crucial to understand that fluctuations in temperature are common and that different specialists have different opinions about what constitutes a fever (traditionally defined as >38.3˚C [100.9˚F], while a more recent definition of >38.0˚C [100.4˚F] has been advocated).
4. Temperature trends: Fever patterns have been used in the past to try to focus the differential diagnosis of FUO. As mentioned previously, certain fever patterns have not been shown to be sensitive or specific enough to narrow the differential.

The literature mentions two types of fever patterns: Pel-Ebstein patterns, which are fevers that cyclically increase and then decrease over a period of one to two weeks and are associated with Hodgkin's lymphoma, and tertian and quartan fever patterns, which are fevers that occur every 48 or 72 hours, respectively, and are linked to malaria.

5. Method of temperature measurement: It's critical to ascertain the patient's method of taking their temperature and if any witnesses can attest to the findings at home. Some patients mistakenly believe they have a fever due to subjective symptoms (sweats, chills, etc.); these patients need to be counselled to take a thermometer reading before receiving further testing.

Oral or tympanic membrane thermometers work well enough, but rectal temperature is the most accurate. Nonetheless, there are significant differences in the quality of tympanic membrane (TM) thermometers sold commercially. Because of the wide range of findings, axillary, infrared, contact, and noncontact forehead thermometers are not advised. Additional information on measuring temperature is accessible on a separate basis.

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Associated signs and symptoms

Extra symptoms of the disease might appear during feverish episodes or could not be directly related to the fevers.

The following symptoms are linked to febrile episodes:

1. Distinctions: Shaking chills, sometimes known as rigours, may have a variety of reasons, including medication responses to biologics, chimeric antigen receptor (CAR)-T cell treatment, and infection aetiologies, including bacteremia.
2. Diaphoresis, exhaustion, and malaise: These vague symptoms are often linked to fevers of any cause and may even be present in some people who are not really feverish.
3. Evanescent rash during fever: If a rash develops on the trunk, arms, or legs during a fever and goes away as the fever passes, it may be a sign of adult-onset Still's illness
4. Additional symptoms: At the time of the first presentation, a thorough evaluation of all systems should be conducted. Particular symptoms, particularly when clustered together, might aid in narrowing the focus of the FUO workup. For example, fever, mouth ulcers, and rash together should raise the possibility of acute HIV syndrome. As previously mentioned, the order in which new symptoms appear might be helpful in diagnosing conditions.

Past medical history: Since numerous illnesses are risk factors for ailments that are known to cause FUO, a complete medical history should be collected.

Some instances are as follows:

1. Infectious endocarditis is associated with certain disorders, such as artificial heart valves and congenital or ventricular heart disease.
2. Basis risk for TB is altered by prior exposure to or history of tuberculosis, BCG vaccination, positive tuberculin skin test (TST), or positive interferon-gamma release assay (IGRA) test.
3. Orthopaedic or other metal implant histories: they may be the locations of sneaky infections.
4. Immunocompromising condition: Individuals with serious immunocompromising conditions are treated and classified differently from those with traditional FUO.

Lung silicosis: A risk factor for TB.

1. Previous history of cancer: Indicates a risk of recurring or metastatic cancer.
2. Previous STIs: STIs increase the chance of getting them again or developing new ones.
3. The use of injection drugs raises the risk of several diseases, such as HIV, viral hepatitis, TB, and endocarditis.

Renal cell cancer is predisposed to Von Hippel-Lindau disease.

Many drugs have the potential to induce fever. Any prescription and OTC drugs, cannabis, herbal supplements, over-the-counter pharmaceuticals, home remedies, and any other medically prescribed substances should all be included in the patient's medication history.

In order to guarantee accurate and comprehensive information, we often urge patients to bring their prescriptions to the appointment.

Family history: Infections that cause fevers may either have a clear genetic pedigree or be inherited via family predispositions.

Social history, including exposures: When assessing patients with typical FUO, social history is crucial. A comprehensive social history consists of many different parts, and information provided in the social history often changes the clinical assessment.

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Intimate relationships and their ailments

1. Travelling and residency history: Certain tropical and nontropical illnesses are more prevalent in certain parts of the globe. To pursue an appropriate workup, one must have a grasp of illnesses that are endemic to the locations the patient dwells in or has visited.

Certain infections, including TB, melioidosis, and endemic mycotic illnesses, may lie dormant for years and manifest as fevers years after the first period of travel. These infections can also have months-long incubation periods. This is why it's important to know where patients have lived in the past.

2. Sports, hobbies, and occupational history: A patient's employment history may disclose exposures that increase their risk of developing certain illnesses.
3. Exposed to the outdoors: Certain illnesses may be more susceptible to the outdoors. Examples include the following: caverns (histoplasmosis), dirt (blastomycosis, coccidioidomycosis, leptospirosis), and natural or flood waters (schistosomiasis, melioidosis, leptospirosis, typhoid/enteric fever).

Exposures to animals: Animals are linked to a wide range of illnesses. As mentioned separately, animal exposures include those to pets (cat scratch illness), cattle (brucellosis, Q fever), and wild animals (tularemia from rabbits).

1. Insect exposures: Ticks, lice, fleas, mites, and mosquitoes (such as malaria) are among the insects that may spread illnesses that might result in a persistent fever.
2. Food and drink habits: Countries with little resources are more prone to infections (such as typhoid/enteric fever) that are spread by contaminated food and water. Dairy products that have not been pasteurised, such as milk and cheese, may lead to illnesses such as brucellosis.
3. Past history of drug and cigarette use: Cigarette smoking increases the risk of several cancers. Many infectious and noninfectious febrile disorders, such as endocarditis, acute HIV, hepatitis B and C, interstitial lung disease, sinusitis, drug-induced vasculitis, and others, may result from drug use by any method (injecting, smoking, inhaling, snorting, or skin popping).
4. Sexual history: Information on recent and distant sex, the quantity of sex, gender, and kinds of sex should all be included. Sexually transmitted illnesses such as pelvic inflammatory disease, disseminated gonococcus, and acute HIV may all show symptoms of FUO.
5. Recent healthcare exposure: As will be covered in more detail below, exposure to medical treatment in other nations, especially dental and outpatient care, is linked to many causes of foot and mouth disease (FUO).

Physical assessment: When treating individuals with typical FUO, a comprehensive physical examination is crucial.

Every organ system should be assessed, and any further workup should be guided by the findings of the physical examination. Certain components of the examination that are not often included in a clinician's practice may be required in patients with FUO.

A comprehensive physical examination needs to include the following:

• Temporal arteries
• Ophthalmologic examination (including conjunctivae, fundoscopy)
• Oral cavity (palate, teeth, gums)
• Thyroid
• Lymph nodes (neck, supraclavicular, axillae, groin)
• Lungs
• Heart
• Abdomen (including liver and spleen size, rectal and prostate exam)
• Neurologic examination (including cranial nerves and cognition)
• Joints and spine
• Genitalia (including testes/epididymis and gynecologic pelvic exam in women with pelvic complaints)
• Skin and nails (including wounds under dressings and casts)

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Primary diagnostic examinations

Basic examinations for every patient In all adult cases of typical FUO, we get the tests mentioned below. If the history or examination points to a particular diagnosis or diagnosis, further testing is recommended.

1. Whole blood count with peripheral smear and differential.
2. The whole metabolic panel, calcium included.
3. Liver biochemical tests, such as bilirubin, alkaline phosphatase, and aminotransferases.
4. Two sets of blood cultures were taken from two different venous sites before any antibiotics were administered; we requested that the microbiology laboratory incubate the cultures for a minimum of five days.
5. Urinalysis with reflex to urine culture.

Reflex confirmatory testing in conjunction with HIV antigen/antibody testing. We could think about skipping the HIV test as part of the first workup if we believe the risk of HIV is very low. We also get an HIV viral load in the event that acute HIV syndrome is suspected. Information on HIV testing is available separately.

• Antinuclear antibodies
• Rheumatoid factor

In young people, heterophile antibody tests (such as the Monospot test) or Epstein-Barr virus antibody testing are recommended. Epstein-Barr virus antibody testing should be carried out if a patient with a negative heterophile antibody test is highly suspected of having associated mononucleosis; in these patients, we would also screen for other possible causes of mononucleosis-syndrome, such as HIV testing, cytomegalovirus immunoglobulin (Ig)G and IgM or viral load, and toxoplasma IgM and IgG.

The C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).

Thick and thin blood smears for malaria. Ferritin. It is recommended to do this test as part of the first testing in locations where malaria is prevalent. If laboratory results or clinical characteristics (such as new anaemia or thrombocytopenia) are consistent with malaria, testing should be considered even in non-endemic locations.

• CT scan with contrast of the pelvis, abdomen, and chest

These examinations provide insights into some of the most prevalent causes of typical FUO as well as severe conditions for which an early diagnosis improves prognosis.

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Initial treatment

As previously said, the location and timing of the patient's initial care and assessment are determined by their clinical presentation.

The majority of patients with traditional FUO get outpatient care. Our first strategy in the outpatient context is as follows:

Fever journal: We recommend keeping a fever journal for any patient experiencing persistent, unexplained fevers. The journal documents the date, time, height, length, and intensity of fevers in addition to the heart rate experienced during such episodes. Documentation of the evaluation technique (e.g., oral vs other sites of measurement), accompanying symptoms, and the administration and timing of any antipyretic drugs should also be done. We recommend taking the temperature three to four times a day (morning, lunch, late afternoon/early evening, and sleep) in patients who have asymptomatic fevers.

Temperatures should be taken using the same equipment, either orally or by TM. Verifying the accuracy of the patient's gadget by comparing it to the clinic thermometer could be useful in some situations.

Fever curves are generic, although as previously mentioned, they may be symptomatic of certain conditions. Additionally, illnesses including enteric fever (e.g., typhoid fever), brucellosis, drug fever, and factitious fever may be indicated by temperature-pulse dissociation, also known as relative bradycardia, which occurs when the heart rate does not rise at the pace predicted with fever.

Stop taking unnecessary prescriptions: Especially for those who are new or have a history of causing fevers, unnecessary medications have to be stopped. Serial withdrawal may be helpful in identifying the offending medicine for individuals taking many drugs that cause fever. The diagnosis of drug fever is supported by the resolution of the fever within two half-lives of the medication, which is typically three to four days.

Deciding whether to use antipyretics:

When the patient is afebrile, it is not recommended to administer antipyretics (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]). This is due to the fact that these medications can obscure critical distinguishing characteristics of the illness and hinder the ability to monitor fever patterns. Unless the patient is in discomfort or has a risk factor for fever-related problems (such as heart disease or seizures), we encourage patients to continue refraining from using antipyretics after a fever has occurred.

Restricted function of glucocorticoids and empirical antibiotics In general, we steer clear of empiric antibiotics and don't give patients empiric glucocorticoids during their first assessment.

1. Empiric antibiotics: In the interim between test findings, individuals suspected of having an infection that could be fatal should receive empiric antibiotics that target the suspected bacteria. Antibiotics are often avoided because they might obfuscate or postpone the detection of severe illnesses (such as meningitis and endocarditis) and disrupt the process of isolating an organism from a culture. Before beginning antibiotics, blood and, if necessary, urine cultures should be acquired to optimise culture findings.
2. Empiric glucocorticoids: In patients with a high suspicion of giant-cell arteritis, corticosteroids are started very once to avoid consequences like stroke or irreversible vision loss. Corticosteroids do not affect the outcomes of planned biopsies, at least not in the first month of treatment; thus, there should be no delay in starting corticosteroids. In the case of non-critical conditions, glucocorticoids are withheld unless it is anticipated that such administration will result in amelioration of the patient's state. Glucocorticoids have the ability to exacerbate infections, conceal cancer, and even change the outcome of cancer biopsy.

There are too many possible aetiologies of FUO to cover in this article due to its vast breadth.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.