Kembara Xtra - Medicine - Fever of Unknown Origin (FUO)

Kembara Xtra - Medicine - Fever of Unknown Origin (FUO)

​Introduction 
Definition according to the classic criteria: >38.3°C fever for at least 3 weeks with no clear cause after 1 week of hospitalization and observation.
More than half of cases have unknown causes. Fever of unknown origin (FUO) is typically caused by one of three mechanisms: infection, cancer, or a systemic rheumatic or connective tissue illness.


Incidence in Epidemiology
It is unclear how often this occurs.
Prevalence
As imaging and biomarker analyses continue to develop, it becomes increasingly challenging to define fever with undetermined origin (real FUO). As a result, the frequency of unexplained fever is not known.


Causes and Mechanisms of Illness 
True FUO are unusual; more often than not, FUO is really an unusual manifestation of a more prevalent medical problem.
The range of possible explanations is broad.
– In high-income countries, the leading causes are noninfectious inflammatory disorders. Temporal arteritis, polymyalgia rheumatica, and rheumatoid arthritis are frequent triggers.
Infection — Abscesses in the abdomen or pelvis — Amebic hepatitis — Infections caused by catheters — Cytomegalovirus — Abscesses in the teeth — Endocarditis/pericarditis — HIV (advanced stage) — Mycobacterial infection (frequently with advanced HIV)
Pyelonephritis/renal abscess - Osteomyelitis
Infections of the sinuses, wounds, and other body sites
Cancers of the gastrointestinal tract and other neoplasms; atrial myxoma
Renal cell carcinoma; hepatocellular carcinoma; lymphoma; myeloma; solid tumors

Diseases of the connective tissue are a type of noninfectious inflammation.
Systemic lupus erythematosus - Granulomatous illness - Rheumatoid arthritis - Adult onset still's disease
Diseases like Crohn's, Sarcoidosis, and Vasculitis
Other Causes: Giant Cell Arteritis Polymyalgia Rheumatica 
- Alcoholic hepatitis - a cerebrovascular accident - cirrhosis - medication - allopurinol - captopril - carbamazepine - cephalosporins - cimetidine - clofibrate - erythromycin - heparin - hydralazine - hydrochlorothiazide - isoniazid - methyld Endocrine Disruption
- Causes related to work that aren't real fevers
Pulmonary embolisms/deep vein thrombosis Thermoregulatory abnormalities Periodic fever
Even after exhaustive testing, the source of a patient's fever is not determined in as many as 20% to 30% of cases.

Recent travel (malaria, enteric fevers), exposure to biologic or chemical agents, HIV infection (especially acute infection and severe stages), the elderly, drug misuse, immigration, and young (usually female) health care professionals (factitious fever) are all factors that increase the likelihood of contracting a disease. 

Factors Relevant to the Elderly

Systemic rheumatic illnesses (such as polymyalgia rheumatica and giant cell arteritis), sarcoidosis, intra-abdominal abscess, urinary tract infection, tuberculosis (TB), and endocarditis are common infectious causes of FUO in the elderly. Patients older than 65 years often get FUO due to drug-induced fever or malignancies (especially hematologic tumors).

Concerns Related to Children

One-third are unnamed viral diseases that typically resolve on their own.
Fifty percent of all cases of FUO in children are contagious. The next most common are collagen vascular disease and cancer.

In older children and teenagers, IBD is a common cause of FUO.

Diagnosis 
A thorough history, physical examination, and relevant laboratory testing should form the basis of the first line of treatment. Based on the findings, we can decide what more testing is necessary.

History Giving Fever Onset and Course Constitutional Symptoms (Fever, Chills, Night Sweats, Muscle Aches, and Loss of Appetite) (Infectious Etiology) Inflammatory etiology for arthralgia, myalgia, and fatigue
- Weakness, nocturnal sweats, and loss of appetite leading to weight loss (neoplastic etiology).
Past medical history including but not limited to: chronic infections, abdominal diseases, transfusion history, malignancy, psychiatric illness, and recent hospitalization; Past surgical history including but not limited to: type of surgery, postoperative complications, and indwelling foreign material; Past medication history including but not limited to: over-the-counter and herbal remedies
Social history: travel, animal exposure (e.g., pets, occupational, farms), living environment, sexual activity, recreational drug use; medical history: inherited conditions, periodic fever syndromes, and recent febrile illnesses in close connections

Caution 
Collect information on your recent trips, mental health, jobs, sexual activity, medications, and recreational drug use.

Analyses in the Clinic 
The skin, eyes, lymph nodes, liver, and spleen are common sites for highly diagnostic physical examination findings. 
You can find useful hints in:
Testicular examination; Lymph node examination; Skin and nail bed examination for clubbing, nodules, lesions, and erosions; Focal papilledema; Temporal artery tenderness; Oral-mucosal lesions; Cardiac auscultation for bruits and murmurs; Pulmonary exam: consolidation or effusion; Abdominal palpation for masses or organomegaly and tenderness or peritoneal signs; Rectal examination for blood,
Changes in physical symptoms (like those seen with endocarditis) can be picked up with the use of repeated examinations.


Results from the Lab 

Laboratory and Imaging Initial Tests
Complete blood count, C-reactive protein, erythrocyte sedimentation rate, antinuclear antibody 
Electrolytes, blood urea nitrogen, and creatinine; lactic dehydrogenase; LFT; calcium; and a peripheral blood smear 
Creatine phosphokinase Urinalysis and urine culture Heterophile antibody testing HIV testing Three blood cultures collected from different places within hours without administering medications
 CT or MRI of the abdomen and pelvis (with guided biopsy, if needed) Chest x-ray

Additional Evaluations & Cautious Thoughts
Epstein-Barr virus, hepatitis, syphilis, Lyme disease, Q fever, cytomegalovirus, brucellosis, amebiasis, coccidioidomycosis, and histoplasmosis serologies Rheumatoid factor and antinuclear antibody test
Electrophoresis of serum proteins and ferritin levels
TB testing - Tuberculin skin test TB testing - AFB smear TB testing - sputum and urine cultures for TB TB testing - may not be beneficial if anergic or acute illness
If the result is negative, retest in two weeks.
Thyroid function tests - Interferon- release assay (IGRA) Recommended for people at high risk for tuberculosis infection and/or who have been vaccinated with BCG
PET scans have a high negative predictive value and strong sensitivity (but may have false positives), therefore they are a useful option if an infectious condition, inflammatory process, or tumor is suspected.
If renal obstruction or biliary pathology is suspected, an echocardiogram may be ordered; if endocarditis, atrial myxomas, or pericardial effusion are suspected, an ultrasound of the abdomen and pelvis may be ordered (with guided biopsy, if required). Bone scan for osteomyelitis or metastatic disease; Doppler for deep vein thrombosis/pulmonary embolism suspicion; CT scan of chest for PE suspicion; Indium-labeled leukocyte scanning for inflammation or occult abscess suspicion; 

Tests and Other Methods of Diagnosis
Liver biopsies for probable granulomatous disease 
Biopsies of the temporal artery, particularly in the elderly; biopsies of lymph nodes, muscles, or skin; bone marrow aspiration biopsies with smear, culture, histologic examination, and flow cytometry; biopsies of the lumbar puncture; endoscopy procedures for inflammatory bowel disease (IBD) or sarcoidosis.

In patients with persistent fever, empiric medication is not suggested since it can mask the underlying cause, which can delay identification and, consequently, right treatment options.

 Based on the current clinical evidence, therapeutic trials should be as specific as feasible as a last resort.
Avoid "shotgun" approaches, as they obscure the clinical picture, have unintended consequences, and do not help with diagnosis. Empiric therapy is prudent in a few life-threatening cases where a diagnosis is difficult to make, such as central nervous system or miliary tuberculosis or giant cell arteritis/temporal arteritis.

Drugs as Initial Treatment
Symptomatic antipyretic therapy is a subset of empiric therapy that does not require knowledge of the underlying cause of fever.
Primitive treatments are condition-specific.
There is no proof that fever should be treated separately from other symptoms.
Position Two
Only if the fever is accompanied with localizing symptoms or if the patient's condition worsens can a treatment trial be considered.
Specialists in infectious illness and rheumatology, among others, should be consulted.
The patient's history and the possibility of culture-negative endocarditis warrant an antibiotic trial.
Treatment with antituberculous drugs for those at high risk of contracting tuberculosis before final culture results are in
If temporal arteritis is suspected, a corticosteroid trial should be performed based on the patient's history (after occult cancer has been ruled out).

​Caution 
Relapses can occur after treatment with steroids or if other illnesses (such as tuberculosis) are present but undiagnosed.

Supplemental Therapies
Patients who are febrile have higher energy and hydration needs.

Medical Interventions 
With the development of superior diagnostic tools, exploratory laparotomies are now rarely necessary.

Patients with serious illnesses or those who need an invasive operation may be admitted. This option is reserved for the sick and the disabled.

Constant Patient Supervision
Repeat the patient's history, physical examination, and screening laboratory tests if the cause of the fever is still unknown.

​There is no evidence that following any particular diet will reduce an undetected fever.
Keep the doctor-patient dialogue going as the workup unfolds: The protracted time needed to establish a diagnosis can be frustrating.

The prognosis varies age and cause dependent, with the highest mortality rate seen in patients with HIV.
One year survival rates (including fatalities from any cause) are lower if the diagnosis is delayed, whereas individuals with an unknown source of FUO who have undergone a thorough workup that includes a negative FDG-PET/CT scan may have spontaneous remission.


Inconvenience Level S Varies by Cause
Planning for a Baby
Fetal fever can lead to premature labor and an increased risk of neural tube abnormalities.