Fever of Unknown Origin - DONE Flashcards
FUO =
Fever of unknown origin
Who defined fever of unknown origin?
FUO was defined by Petersdorf and Beeson in 1961
What is the definition of fever of unknown origin?
- Temperatures >38.3°C on several occasions
- A duration of fever of >3 weeks
- Failure to reach diagnosis despite 1 week of inpatient investigation
What are the classification of FUO?
- Classic FUO
- Nosocomial FUO
- Neutropenic FUO
- FUO associated with HIV infection
Classic FUO:
- Temperatures >38.3°C on several occasions
- A duration of fever of >3 weeks
- Failure to reach diagnosis despite; 3 outpatient visits or 3 days int he hospital without elucidation of a cause or 1 week of “intelligent and invasive” ambulatory investigation
Nosocomial FUO:
- A temperature of >=38.3°C develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission
- 3 days of investigation, including at least 2 days´ incubation of cultures, is the minimum requirement for this diagnosis
Neutropenic FUO:
- A temperature of ≥ 38.3 °C on several occasions
- In a patient whose neutrophil count is <500/uL or is expected to fall to that level in 1-2 days
- A diagnosis is invoked is a specific cause is not identified after 3 days of investigation, including at least 2 days´ incubation of cultures
HIV-associated FUO
- A temperature of >=38,3 ° on several occasions over a period of > 4 weeks for outpatients or> 3 days for hospitalized patients with HIV infection
- this diagnosis is invoked if appropriate investigation over 3 days, including 2 days´ incubation of cultures, reveal no source
What are the causes of Classic FUO?
- Infections
- Neoplasms
- Habitual Hyperthermia
- Collagen vascular /Hypersensitivity Diseases
- Granulomatous Diseases
- Miscellaneous Conditions
- Inherited and Metabolic Diseases
- Thermoregulatory Disorders
- Factious Fevers
What is the definition of pyogenic infection (google)?
Infection characterized by severe local inflammation, usually with pus formation, generally caused by pyogenic bacteria.
Give examples of localized pyogenic infections:
- Appendicitis
- Cat-scratch disease
- Cholangitis
- Cholecystitis
- Dental abscess
- Diverticulitis/abscess
- Lesser sac abscess
- Liver abscess
- Mesemteric lymphadenitis
- Osteomyelitis
- Pancreatic abscess
- Pelvic inflammatory disease
- Perinephric/intrarenal abscess
- Prostatic abscess
- Renal malacoplakia
- Sinusitis
- Subphrenic abscess
- Suppurative thrombophlebitis
- Tuboovarian abscess
Give examples of systemic bacterial infections:
- Bartonellosis
- Brucelosis
- Campylobacter infection
- Cat-scratch disease/bacillary angiomatosis
- Gonococcemia
- Legionnaires’ disease
- Leptospirosis
- Lisreriosis
- Lyme disease
- Melioidosis
- Meningococcemia
- Rat-bite fever
- Relapsing fever
- Salmonellosis
- Syphilis
- Tularemia
- Typhoid fever
- Vibriosis
- Yersinia infection
Give examples of intravascular infections:
- bacterial aortitis
- bacterial endocarditis
- vascular catheter infection
Give examples of Mycobacterial infections:
- M. avium/M. intracellulare infections
- Other atypical mycobacterial infections
- Tuberculosis
Give examples of Chlamydial infections:
- Lymphogranuloma venereum
- Psittacosis
- TWAR (Chlamydophila pneumoniae)
Psittacosis (google):
Psittacosis—also known as parrot fever, and ornithosis is a zoonotic infectious disease caused by a bacterium called Chlamydia psittaci and contracted from infected parrots, such as macaws, cockatiels and budgerigars, and pigeons, sparrows, ducks, hens, gulls and many other species of bird.
Other bacterial infections:
- Actinomycosis
- Bacillary angiomatosis
- Nocardiosis
- Whipple’s disease
Whipple’s disease (google):
Whipple’s disease is a rare, systemic infectious disease caused by the bacterium Tropheryma whipplei.
Give examples of Rickettsial infections:
- Anaplasmosis
- Ehrlichiosis
- Murine typhus
- Q fever
- Rickettsialpox
- Rocky Mountain spotted fever
- Scrub typhus
Give examples of viral infections:
- Chikungunya fever
- Colorado tick fever
- Coxsackievirus group B infection
- Cytomegalovirus infection
- Dengue
- Epstein-Barr virus infection
- Hepatitis A,B,C,D and E
- HIV infection
- Human herpesvirus 6 infection
- Lymphocytic choriomeningitis
- Parvovirus B19 infection
- Picornavirus infection
Give examples of Fungal infections:
- Aspergillosis
- Blastomycosis
- Candidiasis
- Coccidioidomycosis
- Cryptococcosis
- Histoplasmosis
- Mucormycosis
- Paracoccidioidomycosis
- Pneumocystis infection
- Sporotrichosis
Give examples of Parasitic infections:
- Amebiasis
- babesiosis
- Chagas’ disease
- leishmaniasis
- malaria
- Strongyloidiasis
- Toxocariasis
- Toxoplasmosis
- Trichinellosis
Give examples of malignant neoplasms:
- Colon cancer
- Gall bladder carcinoma
- Hepatoma
- Hodgkin’s lymphoma
- Immunoblastic T-cell lymphoma
- leukemia
- Lymphomatoid granulomatosis
- malignant histiocytosis
- Non-Hodgkin’s lymphoma
- Pancreatic cancer
- renal cell carcinoma
- Sarcoma
Give examples of benign neoplasms:
- Atrial myxoma
- Castelman’s disease
- Renal angiomyolipoma
COLLAGEN VASCULAR/HYPERSENSIVITY DISEASES:
- Adult Still’s disease
- Behcet’s disease
- Erythema multiforme
- Erythema nodosum
- Giant-cell arteritis/polymyalgia rheumatica
- Hypersensivity pneumonitis
- Hypersensivity vasculitis
- Mixed connective-tissue disease
- Polyarteritis nodosa
- Relapsing polychondritis
- Rheumatic fever
- Rheumatoid arthitis
- Schnitzler’s syndrome
- Systemic lupus erythematosus
- Takayasu’s aortitis
- Weber-Christian disease
- Granulomatosis with polyangitis
GRANULOMATOUS DISEASES:
- Crohn’s disease
- Granulomatous hepatitis
- Midline granuloma
- Sarcoidosis
MISCELLANEOUS CONDITIONS:
- Aortic dissection
- Drug fever
- Gout
- Hematomas
- Hemoglobinopathies
- Laennec’s cirrhosis
- PFPA syndrome: periodic fever, adenitis, pharyngitis, aphthae
- Postmyocardial infarction syndrome
- Recurrent pulmonary emboli
- Subacute thyroiditis (de Quervain’s)
- Tissue infarction/necrosis
INHERITED AND METABOLIC DISEASES:
- Adrenal insufficiency
- Cuclic neutropenia
- Deafness, urticaria, and amyloidosis
- Fabry disease
- Familial cold urticaria
- Familial Mediterranean fever
- Hyperimmunoglobulinemia D and periodic fever
- Muckle-Wells syndrome
- Tumor necrosis factor receptor-associated periodic syndrome (familial Hibernian fever)
- Type V hypertriglyceridemia
What are the thermoregulatory disorders divided into?
- central
- peripheral
Give examples of central thermoregulatory disorders:
- Brain tumor
- Cerebrovascular accident
- Encephalitis
- Hypothalamic dysfunction
Give examples of peripheral thermoregulatory disorders:
- Hyperthyroidism
- Pheochondrocytoma
What are the causes of classic FUO?
- Infections
- Neoplasms (malignancies)
- Connective tissue diseases
- Miscellaneous
- Undiagnosed
THERE IS A GRAPH
SLIDE 21
What are the common infectious causes of FUO?
Classic FUO
- Unrecognized abscess (ex: abdominal, perinephric)
- Endocarditis – less common than in past
- Tuberculosis
- Histoplasmosis
- Osteomyelitis
Fastidious definition (google):
- Fastidious organism will only grow when specific nutrients are included in its diet.
- The more restrictive term fastidious microorganism is often used in the field of microbiology to describe microorganisms that will grow only if special nutrients are present in their culture medium.
The HACEK organisms (google):
The HACEK organisms are a group of fastidious gram negative bacteria that are an unusual cause of infective endocarditis, which is an inflammation of the heart due to bacterial infection.
HACEK organisms
Indolent, slow-growing microorganisms:
- Haemophilus aphrophilus
- Aggregatibacter
- Actinobacillus
- Cardiobacterium hominis
- Eiknella corrodens
- Kingella
Difficult to culture organisms:
- Bartonell
- Aspergillus
- Coxiella
- Brucella
Common connective tissue causes of FUO:
Classic FUO
- Adult Still’s disease
- Rheumatoid Arthritis (RA)
- Systemic Lupus Erythematosus (SLE)
- Temporal Arteritis
- Polymyalgia Rheumatica (PMR)
RA =
Rheumatoid Arthritis
SLE =
Systemic Lupus Erythematosus
PMR =
Polymyalgia Rheumatica
Adult Still’s disease:
- fever
- rash
- arthritis
Temporal Arteritis:
- > 50 years old
- headache,
- symptoms of PMR
- high ESR
What are the most common malignancies associated with FUO:
Classic FUO
- Lymphoma (most common cause)
- Leukemia
- Tumors metastatic to the liver
- Renal cell carcinoma
What are the Miscellaneous causes of FUO?
- Factitious Fever (ex: Fraudulent vs. Self-induced)
- Drug fever (ex: Antibiotics, Antihistamines, NSAIDS)
- Familial fever syndromes
- Hemophagocytic syndrome
- Inflammatory Bowel Disease (IBD)
- Pheochromocytoma
- Pulmonary embolism (PE)
- Thrombotic Thrombocytopenic Purpura (TTP)
- Thyroiditis
Familial fever syndromes:
- Familial Mediterranean Fever
- TNF-receptor associated periodic syndrome
- Hyper- IgD syndrome
PE =
Pulmonary embolism
When does the likelihood of an infectious cause decreases?
It is axiomatic that, as the duration of fever increases, the likelihood of an infectious cause decreases, even for the more indolent infectious etiologies (e.g. brucellosis, paracoccidiomycosis, malaria due Plasmodium malariae).
Nosocomial FUO (short info):
Patients who have a fever start after at least 24 hours of hospitalization
What are the etiologies of nosocomial FUO:
- Drug fever
- Nosocomial infections
- Post operative complications
- Central fever (stroke)
Neutropenic FUO:
- Neutropenia = < 500 PMNs (absolute)
- Decreased mucosal defense
- Febrile neutropenic patients receive empiric courses of broad spectrum antibiotics and often antifungal agents
How do you treat Febrile neutropenic patients?
Febrile neutropenic patients receive empiric courses of broad spectrum antibiotics and often antifungal agents
Common causes of HIV-Related FUO:
- Mycobacterial disease
- Pneumocystosis (PCP)
- Cytomegalovirus (CMV)
- Histoplasmosis
- Lymphoma
- Drug fever
PCP =
Pneumocystosis
CMV =
Cytomegalovirus
Evaluation of FUO:
- Comprehensive history
- Comprehensive physical examination
- Routine blood tests
- Microscopic urinalysis
- Cultures of blood, urine
- Chest radiograph
- Abdominal (including pelvic) ultrasonography
- Autoantibodies
- Serological tests
- Advanced radiological imaging
- Bone marrow biopsy
- Thick blood smears
- Thin blood smears
- Lymphnode or liver biopsy
- Peritoneal lavage
- Laparoscopic biopsy
- Exploratory laparotomy
Comprehensive history:
- Localizing symptoms?
- Workplace?
- Pets?
- Recent travel?
- History of connective tissue disease (CTD)?
- History of cancer/immunosuppression?
- Medications?
- Drug use?
- Familial fever syndromes?
Comprehensive physical examination:
- temporal arteries
- rectal digital examination
- sinus tenderness
- listen for murmur
- look for stigmata of endocarditis
- splenomegaly
- hepatomegaly
Routine blood tests:
- complete blood count including differential
- CRP
- PCT
- ESR (erythrocyte sedimentation rate) electrolytes
- renal and hepatic tests
- creatine phosphokinase
- lactate dehydrogenase
Microscopic urinalysis:
- luecocyturia
- dysmorphic erytrocytes
- protein
Cultures of blood, urine
Cultures of blood, urine and other normally sterile compartments if clinically indicated, e.g. joints, pleura, cerebrospinal fluid
Autoantibodies:
- ANA
- ANCA
- Reuma factor
Serological tests:
HIV, HBV, HCV, CMV, EBV serology,
and others directed by local epidemiological data
Advanced radiological imaging:
CT, MRI, positron emission tomography (PET) to detect localised infections and occult neoplasms
PET =
positron emission tomography
Thick blood smears…
should be examined for Plasmodium - if malaria suspected
Thin blood smears:
to identify Babesia, Trypanosoma, Leishmania, Leptospira in patients with specific history
Nosocomial FUO Diagnosis:
SKIPPED THE SLIDES ABOUT DIAGNOSIS - YOU HAVE TO STUDY THEEEEEEM-KHELLOOOO
- Consider underlying individual susceptibility of the patient with the potential complications of hospitalization
- More than 50% of patients with nosocomial FUO are infected
- Look for infected foreign bodies, abscesses and hematomas
- Check sites where occult infections may be sequestrated, such as paranasal sinuses of intubated patients or a prostatitis in a man with a urinary catheter
Nosocomial FUO Treatment:
- empirical therapy started if bacteriemia, fungemia, persistently high virus load are a threat
- empirical antibiotic therapy includes vancomycin (MRSA) + broad spectrum gram negative coverage with piperacyllin/tazobactam, imipenem or meropenem
Neutropenic patients…..
- Neutropenic patients are susceptible to focal bacterial and fungal infections, bacteriemic infections, infections involving catheters
- 50-60% of febrile, neutropenic patients are infected and 20% are bacteriemic
Neutropenic FUO common pathogen:
Candida and Aspergillus infections are common
Neutropenic FUO treatment:
Empirical treatment:
vancomycin + ceftazidime/cefepime or carbapenem +/- aminogycoside
HIV-associated FUO
- HIV infection alone may be a cause of fever (e.g. acute retroviral disease)
- FUO in HIV patients has an infectious etiology in > 80% of cases
- drug fever and lymphoma remain important considerations
When no underlying source of FUO is indentified after prolonged observation (>6 months)…….
When no underlying source of FUO is indentified after prolonged observation (>6 months), the prognosis is generally good, however vexing the fever may be to the patient.
- Under such circumstances, debilitating symptoms are treated with NSAIDs and glucocorticoids are the last resort
- Patience, compassion, equanimity, vigilance, and intellectual flexibility are indispensable attributes for the clinician in dealing successfully with FUO
