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Fever of unknown origin

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Niloofarsadaat Eshaghhosseiny, MD[2] Yarlagadda Harshitha, MD[3]

Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; fever/pyrexia of obscured/undetermined/uncertain/unidentifiable/unknown focus/origin/source; fever/pyrexia without a focus/origin/source; FUO; PUO


Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; FUO; PUO; pyrexia of unknown origin

Overview

Fever of unknown origin (FUO) was formally defined for the first time by Petersdorf and Beeson: “fever above 38.3° C (100.9° F) on several occasions, persisting without diagnosis for at least three weeks in spite of at least one week’s investigation in hospital.ʺ[1]

Durack and Street made four different categories of fever of unknown origin in 1991:

  1. Classic FUO
  2. Nosocomial FUO
  3. Neutropenic FUO
  4. HIV related FUO[2]

References

  1. ↑ Auwaerter, Paul G; Wright, William F (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infectious Diseases. 7 (5). doi:10.1093/ofid/ofaa132. ISSN 2328-8957.
  2. ↑ Auwaerter, Paul G; Wright, William F (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infectious Diseases. 7 (5). doi:10.1093/ofid/ofaa132. ISSN 2328-8957.
Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Fever of unknown origin was something that had confused clinicians for a longer time but there was no formal definition for it until Petersdorf and Beeson gave first formal definition for it almost sixty years ago. Their definition was widely accepted however with advancement of medical knowledge their definition was revisited by Durack and street in 1991 which is still used widely.[1]

Historical Perspective

Discovery

  • Fever of unknown origin was for the first time defined by Petersdorf and Beeson in 1961 in their article on fever of unknown origin after they studied many cases.
  • Their definition excluded many acute self limiting causes of fever and provide a road map for further work.
  • Working on the outstanding work of Petersdorf and Beeson , Durack and street revisited this definition in 1991 making four categories of FUO.
  • They made these categories based on the etiologies of FUO which are still accepted widely.[2]

Landmark Events in the Development of Treatment Strategies

  • After the medical science advanced more sophisticated diagnostic tools were invented it was possible to find out the exact cause of FUO.
  • Once the cause was known it was possible to direct treatment towards the exact cause this made the prognosis of disease good, decreased complication and reduced use of unnecessary drugs.[3]

References

  1. ↑ Wright WF, Auwaerter PG (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infect Dis. 7 (5): ofaa132. doi:10.1093/ofid/ofaa132. PMC 7237822 Check |pmc= value (help). PMID 32462043 Check |pmid= value (help).
  2. ↑ Vanderschueren, Steven; Knockaert, Daniël; Adriaenssens, Tom; Demey, Wim; Durnez, Anne; Blockmans, Daniël; Bobbaers, Herman (2003). “From Prolonged Febrile Illness to Fever of Unknown Origin”. Archives of Internal Medicine. 163 (9): 1033. doi:10.1001/archinte.163.9.1033. ISSN 0003-9926.
  3. ↑ Mulders-Manders C, Simon A, Bleeker-Rovers C (2015) Fever of unknown origin. Clin Med (Lond) 15 (3):280-4. DOI:10.7861/clinmedicine.15-3-280 PMID: 26031980

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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Based upon the work of Petersdorf and Beeson, Durack and Street classified fever of unknown origin(FUO) into four distinct categories in 1991:[1]

  1. Classic FUO
  2. Neutropenic FUO
  3. HIV related FUO
  4. Nosocomial FUO[2]

Classification

Classic FUO[3]

  • Fever above 38.3° C (100.9° F)
  • For more than three weeks
  • No diagnosis after work up for at least three visits in outdoor or three days of stay in hospital.

Neutropenic FUO

  • Fever above 38.3° C (100.9° F)
  • Absolute neutrophil count not more than 500 cells per mm³
  • Minimum diagnostic work up for at least three days.

HIV associated FUO

  • Known HIV case
  • Fever above 38.3° C (100.9° F)
  • Time span of more than four weeks for non hospitalized while 3 days for hospitalized patients.

Nosocomial FUO

  • Patient in hospital for at least 24 hours
  • Absence of fever or incubating fever at admission
  • Minimum diagnostic workup for at least three days.

References

  1. ↑ Wright WF, Auwaerter PG (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infect Dis. 7 (5): ofaa132. doi:10.1093/ofid/ofaa132. PMC 7237822 Check |pmc= value (help). PMID 32462043 Check |pmid= value (help).
  2. ↑ Hayakawa K, Ramasamy B, Chandrasekar PH (2012). “Fever of unknown origin: an evidence-based review”. Am J Med Sci. 344 (4): 307–16. doi:10.1097/MAJ.0b013e31824ae504. PMID 22475734.
  3. ↑ Hayakawa K, Ramasamy B, Chandrasekar PH (2012). “Fever of unknown origin: an evidence-based review”. Am J Med Sci. 344 (4): 307–16. doi:10.1097/MAJ.0b013e31824ae504. PMID 22475734.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; FUO; PUO; pyrexia of unknown origin

Overview

The exact pathogenesis of FUO is not fully understood in many cases where the exact etiology is not known. However in cases where etiology is known its pathophysiology depends upon etiology.[1]


References

  1. ↑ Wright WF, Auwaerter PG (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infect Dis. 7 (5): ofaa132. doi:10.1093/ofid/ofaa132. PMC 7237822 Check |pmc= value (help). PMID 32462043 Check |pmid= value (help).
Causes

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Naresh Mullaguri, M.B.B.S. [2]

Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; FUO; PUO; pyrexia of unknown origin

Overview

Classic FUO may be caused by infection, neoplasia, inflammatory , miscellaneous diseases, and undiagnosed illness.Common causes of neutropenic FUO include bacterial, fungal and viral infection.Causes of nosocomial FUO are related to hospital setting such as drugs, infections acquired during hospitalization and complications that occur during and after surgery.This may due to acute infection from HIV itself earlier or later due to opportunistic bacterial, fungal and viral infections such as mycobacteria, toxoplasma etc.


Causes

Etiology is different for different categories of FUO:

Classic FUO

  1. Malignancies such as Hodgkin and non-Hodgkin lymphoma, myeloproliferative disorders, colorectal carcinoma and carcinoma of liver.
  2. Infections such as intrabdominal and pelvic abscesses, inflammation of the endocardium, tuberculosis, cat scratch disease, CMV and EBV infections.
  3. Inflammatory causes such as autoimmune diseases (systemic lupus erythematosus, Rheumatoid arthritis) and polymyalgia rheumatica.[1]
  4. Miscellaneous such as Medication/drug fever,Hyperthyroidism Hematoma,Chronic pulmonary.[2]

Neutropenic FUO

These are mostly caused by bacterial, fungal and viral infection because of the decreased neutrophil count.[3]

HIV associated FUO

This may due to acute infection from HIV itself earlier or later due to opportunistic bacterial, fungal and viral infections such as mycobacteria, toxoplasma etc.[4]

Nosocomial FUO

Causes of nosocomial FUO are related to hospital setting such as drugs, infections acquired during hospitalization and complications that occur during and after surgery.[2]


References

  1. ↑ Hayakawa, Kayoko; Ramasamy, Balaji; Chandrasekar, Pranatharthi H. (2012). “Fever of Unknown Origin: An Evidence-Based Review”. The American Journal of the Medical Sciences. 344 (4): 307–316. doi:10.1097/MAJ.0b013e31824ae504. ISSN 0002-9629.
  2. ↑ 2.0 2.1 Wright WF, Auwaerter PG (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infect Dis. 7 (5): ofaa132. doi:10.1093/ofid/ofaa132. PMC 7237822 Check |pmc= value (help). PMID 32462043 Check |pmid= value (help).
  3. ↑ Hayakawa, Kayoko; Ramasamy, Balaji; Chandrasekar, Pranatharthi H. (2012). “Fever of Unknown Origin: An Evidence-Based Review”. The American Journal of the Medical Sciences. 344 (4): 307–316. doi:10.1097/MAJ.0b013e31824ae504. ISSN 0002-9629.
  4. ↑ Hayakawa, Kayoko; Ramasamy, Balaji; Chandrasekar, Pranatharthi H. (2012). “Fever of Unknown Origin: An Evidence-Based Review”. The American Journal of the Medical Sciences. 344 (4): 307–316. doi:10.1097/MAJ.0b013e31824ae504. ISSN 0002-9629.
Differentiating Fever of unknown origin from other Diseases

Differentiating Fever of unknown origin from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; FUO; PUO; pyrexia of unknown origin

Overview

  1. Fever can be the presenting symptom with many diseases, it is therefore important to differentiate fever of unknown origin from all those diseases which present with fever.
  2. Because of the broad range of differential diagnosis they can be grouped into four categories based on their etiology.

Differential diagnosis

Infectious

These patients mostly have a history of hospitalization, surgical procedures, contact with infected person or travel to an endemic place.[3][4]

Examples include:


Malignant

They are mostly accompanied by loss of weight, decrease in appetite, lymph node enlargement and aquagenic pruritic mostly occurring after hot shower.

Examples include:


Autoinflammatory/Rheumatologic

Mostly they have multi organ involvement and lymphadenopathy along with joint symptoms may be present.[5][6]

Examples include:

Miscellaneous

Mostly does not belong to any of the above.

Examples include:

    Disease History Physical examination Laboratory or radiological findings
    Subacute Bacterial endocartitis Recent dental procedures, Joint pain, decrease weight, Night sweats, back pain
    		Heart murmur, splinter hemorrhages, Janeway lesions, Roth spots, enlarged spleen.
    		Elevated WBCs, decreased platelets, Elevated ESR , presence of Cryoglobulins
    Abscess GI, genitourinary, Pelvic procedure or infection , fever, chills, decrease weight, night sweats.
    		RUQ tenderness ( subphrenic Abscess),hepatomegaly (hepatic abscess), splenomegaly ( splenic abscess), tenderness on DRE ( pelvic abscess).
    		Elevated WBCs and ESR, elevated platelets, Positive CT/MRI findings
    Tuberculosis of CNS Previous tuberculosis, Altered mental status, Headace
    		Morning temperature spikes, relative bradycardia, Abducens palsy.
    		CSF: Increased lymphocytes, increased RBCs, decreased glucose, increased lactate, positive AFB stain and Culture.
    EBV infection Exposure to saliva ( kissing disease ) , upper respiratory tract infection
    		Enlarged lymph nodes, palatal petechiae, enlarged tonsils, enlarged spleen.
    		Positive monospot test, decreased WBCs, decreased lymphocytes, atypical lymphocytosis, positive PCR, positive IgM EBV VCA titers, enlarged spleen, increased LFTs.
    CMV infection Exposure to body fluids or blood transfusion
    		Enlarged lymph nodes, palatal petechiae, enlarged tonsils, enlarged spleen.
    		Negative monospot test, decreased WBCs, decreased lymphocytes, atypical lymphocytosis, positive PCR, increased IgM, increased LFTs
    HIV infection Exposure to body fluids (blood, breast milk, semen and vaginal secretions), IV drug abuse, weight loss, night sweats .
    		Generalized lymphadenopathy, pharyngeal and palatal petechiae.
    		Decreased lymphocytes, decreased platelets, positive HIV serology and PCR , increased viral load.
    Toxoplasmosis Exposure to cat feces or consumption of uncooked meat, joint pain.
    		Chorioretinitis, enlarged lymph nodes, enlarged spleen.
    		Atypical lymphocytes, increased IgM titers ( toxoplasma serology), Positive MRI/CT scan finding in brain ( ring enhancing lesions ).
    Ehrlichiosis/ Anaplasmosis Recent insect (Tick) exposure, Headache, muscle aches, fatigue,
    		Relative bradycardia, enlarged spleen.
    		Decreased WBCs, decreased platelets, inclusions in Monocytes (Ehrlichiosis ) and Granulocytes (Anaplasmosis ), positive serology.
    Leptospirosis Exposure to water contaminated with animal (Rodents) urine, common in surfers, Flu like symptoms, Headache.
    		Calf tenderness, Photophobia, Jaundice, conjunctival suffusion without exudate, enlarged liver.
    		Increased WBCs, Decreased platelets, increased LFTs, Increased creatinine kinase, positive serology.
    Brucellosis Exposure to animals or contaminated dairy products (milk, cheese), Headache, muscle aches, fatigue,
    		Muscle (Thigh) tenderness, Spine tenderness, enlarged lymph nodes, enlarged spleen.
    		Positive serology, increased LFTs , Atypical lymphocytes, positive blood culture.
    Histoplasmosis Cave exploration, Mississippi and Ohio river valleys location, weight loss, night sweats
    		Palatal/tongue ulcers, enlarged spleen, enlarged liver.
    		Decreased WBCs, decreased platelets, increased LFTs, positive serum and urine antigen test.
    Q fever Exposure to cattle/sheep amniotic fluid, night sweats, weight loss, prosthetic heart valve.
    		Relative bradycardia, heart murmur, enlarged spleen.
    		Decreased platelets, increased LFTs, positive PCR
    SLE Young female, joint pain, recurrent infections, fatigue, headache, hair loss, anemia
    		Multiple mucosal ulcers, malar rash, enlarged lymph nodes, enlarged spleen, Osler nodes, Roth spots, heart murmur (endocarditis),
    		Pancytopenia, increased ANA, increased C reactive protein, increased ferritin, positive ds DNA, decreased complement.
    Giant cell temporal arteritis Old age, amaurosis fugax, jaw pain, headache (unilateral), muscle aches. .
    		temporal artery nodules and tenderness, jaw tenderness, pallor of optic disc.
    		Elevated ESR, positive imaging findings, positive biopsy (granulomatous inflammatory).
    Poly arteritis nodosa Fever, weight loss, fatigue, abdominal pain, black stools, rashes, livedo reticularis, neurologic problems, edema.
    		Increased blood pressure, skin purpura.
    		Elevated ESR, increased creatinine, positive hepatitis B serology, fibrinoid necrosis on biopsy.
    Takayasu arteritis Headache, joint pain, weight loss, edematous face, claudication, skin nodules, neurologic deficits
    		Unequal B.P in arms, bruits over larger arteries.
    		Elevated ESR, positive imaging findings, positive biopsy (granulomatous inflammatory).
    Sarcoidosis Arthritis, headache, eye problems, hearing problems, peripheral neuropathy, parotitis, skin nodules.
    		Enlarged lymph nodes, erythema nodosum, facial nerve palsy, Argyll Robertson pupil, uveitis, enlarged liver.
    		Decreased WBCs, decreased platelets, increase Eosinophils, hypercalcemia, hypercalciuria, increased ACE levels in blood.
    Hodgkin lymphoma Radiation exposure, fever, night sweats, fatigue, bone pain, pruritis.
    		Enlarged lymph nodes, enlarged liver, enlarged spleen,
    		lymphopenia, eosinophilia, increased basophils, increased LDH, positive CT/MRI, Reed Sternberg cells on lymph node biopsy.
    CNS Malignancies Headache, vomiting, altered mental status, seizures.
    		Cranial nerves abnormalities, optic disc swelling
    		Positive CT/ MRI of brain, CSF increased protein and RBcs
    Hepatocellular Carcinoma Abdominal pain, family history, alpha 1 anti trypsin deficiency, Cirrhosis, Chronic Hepatitis Band C infection.
    		Enlarged Liver, ascites, abdominal tenderness
    		Increased LFTs, Increased AFP, increased ALP, Malignant cells on biopsy, positive imaging.
    Chronic lymphocytic leukemia fever, weight loss, night sweats
    		Enlarged lymph nodes, enlarged spleen.
    		Elevated ESR, positive coombs test, Smudge cells on blood smear, Leukocytosis.

      References

      1. ↑ Cunha, Burke A. (2007). “Fever of Unknown Origin: Focused Diagnostic Approach Based on Clinical Clues from the History, Physical Examination, and Laboratory Tests”. Infectious Disease Clinics of North America. 21 (4): 1137–1187. doi:10.1016/j.idc.2007.09.004. ISSN 0891-5520.
      2. ↑ Cunha, Burke A.; Lortholary, Olivier; Cunha, Cheston B. (2015). “Fever of Unknown Origin: A Clinical Approach”. The American Journal of Medicine. 128 (10): 1138.e1–1138.e15. doi:10.1016/j.amjmed.2015.06.001. ISSN 0002-9343.
      3. ↑ Cunha, Burke A.; Lortholary, Olivier; Cunha, Cheston B. (2015). “Fever of Unknown Origin: A Clinical Approach”. The American Journal of Medicine. 128 (10): 1138.e1–1138.e15. doi:10.1016/j.amjmed.2015.06.001. ISSN 0002-9343.
      4. ↑ Salzberger B, Schneidewind A, Hanses F, Birkenfeld G, Müller-Schilling M (2012). “[Fever of unknown origin. Infectious causes]”. Internist (Berl). 53 (12): 1445–53, quiz 1454-5. doi:10.1007/s00108-012-3173-8. PMID 23111594.
      5. ↑ Kümmerle-Deschner JB (2017). “[Autoinflammatory Diseases as a Differential Diagnosis of Fever of Unknown Origin]”. Dtsch Med Wochenschr. 142 (13): 969–978. doi:10.1055/s-0043-103468. PMID 28672419.
      6. ↑ Mulders-Manders CM, Simon A, Bleeker-Rovers CP (2016). “Rheumatologic diseases as the cause of fever of unknown origin”. Best Pract Res Clin Rheumatol. 30 (5): 789–801. doi:10.1016/j.berh.2016.10.005. PMID 27964789.

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      Epidemiology and Demographics

      Epidemiology and Demographics

      Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

      Overview

      Epidemiology of the disease is different for different etiologies of FUO. It also depends on the age of the patient, environmental and occupational exposure, Immune system of patient, Socioeconomic status.

      Infectious causes are more prevalent in Immunocompromised individuals and those living in underdeveloped countries while non infectious causes are more prevalent in immunocompetent individuals and those living in developed countries.[1][2]

      Epidemiology and Demographics

      Epidemiology of the disease is different for different etiologies of FUO. It also depends on the age of the patient, environmental and occupational exposure, Immune system of patient, Socioeconomic status.

      Infectious causes are more prevalent in Immunocompromised individuals and those living in underdeveloped countries while non infectious causes are more prevalent in immunocompetent individuals and those living in developed countries.

      References

      1. ↑ Mulders-Manders C, Simon A, Bleeker-Rovers C (2015) Fever of unknown origin. Clin Med (Lond) 15 (3):280-4. DOI:10.7861/clinmedicine.15-3-280 PMID: 26031980
      2. ↑ Hayakawa K, Ramasamy B, Chandrasekar PH (2012) Fever of unknown origin: an evidence-based review. Am J Med Sci 344 (4):307-16. DOI:10.1097/MAJ.0b013e31824ae504 PMID: 22475734

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      Risk Factors

      Risk Factors

      Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

      Overview

      Since in many cases the definite etiology of FUO is not known therefore its risk factors are uncertain but mostly risk factors that are associated with FUO depends upon the underlying etiology.[1][2]

      Risk Factors

      Following are the risk factors:

      Common Risk Factors

      • Common risk factors in the development of FUO may be environmental, social or familial.
      • Family history
      • Radiation exposure
      • History of prior malignancies
      • Any underlying inflammatory disease
      • HIV infection
      • Alcohol use
      • Travel to endemic place
      • Recent contact with infected person
      • Contact with animals
      • Low socioeconomic status
      • Unvaccinated individual
      • Occupational exposure
      • Recent medications and antibiotics
      • Recreational drugs

      References

      1. ↑ Arnow, Paul M; Flaherty, John P (1997). “Fever of unknown origin”. The Lancet. 350 (9077): 575–580. doi:10.1016/S0140-6736(97)07061-X. ISSN 0140-6736.
      2. ↑ Hayakawa K, Ramasamy B, Chandrasekar PH (2012). “Fever of unknown origin: an evidence-based review”. Am J Med Sci. 344 (4): 307–16. doi:10.1097/MAJ.0b013e31824ae504. PMID 22475734.

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      Screening

      Screening

      Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

      Overview

      There is no recommended routine screening for fever of unknown origin

      Screening

      There is no recommended routine screening for fever of unknown origin

      References

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      Natural History, Complications and Prognosis

      Natural History, Complications and Prognosis

      Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

      Synonyms and keywords: febris continua e causa ignota; febris e causa ignota; febris E.C.I.; FUO; PUO; pyrexia of unknown origin

      Overview

      fever of unknown origin has different etiologies it is therefore important to mention that course, complication and prognosis of disease depends on the underlying etiology. In case of old aged patients or patients with malignancy prognosis is poor.

      Natural History, Complications and Prognosis

      1. The course and prognosis of disease dependent on the underlying cause of FUO.[1][2]
      2. If the cause is found earlier and treatment is directed towards it prognosis is usually good
      3. In patients with neutropenic and HIV related FUO the disease can cause many complication due to their immunocompromised state
      4. Prognosis is poor in case of old age patients or when malignancy is the cause of FUO
      5. In more than 50 % cases cause is unknown despite extensive investigation in such cases prognosis is good.


      References

      1. ↑ Wright WF, Auwaerter PG (2020). “Fever and Fever of Unknown Origin: Review, Recent Advances, and Lingering Dogma”. Open Forum Infect Dis. 7 (5): ofaa132. doi:10.1093/ofid/ofaa132. PMC 7237822 Check |pmc= value (help). PMID 32462043 Check |pmid= value (help).
      2. ↑ Mulders-Manders C, Simon A, Bleeker-Rovers C (2015). “Fever of unknown origin”. Clin Med (Lond). 15 (3): 280–4. doi:10.7861/clinmedicine.15-3-280. PMC 4953114. PMID 26031980.
      Diagnosis

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