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Fever of Unknown Origin

Path and Micro

Allison Simpson

on 27 November 2012

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Transcript of Fever of Unknown Origin

• Fever is a consequence of the response of the anterior hypothalamus to inflammatory mediators (IL1, IL6, IFN,TNF) and these are released by monocytes and macrophages.
• There is some evidence as well that fever can be caused by interleukin-1 induced prostaglandin E2
• These mediators increase normal body temperature and therefore shivering and chills are induced by the nervous system
• Antipyretics act by resetting the thermal set point by reducing production of prostaglandin E
• Aspirin, Acetaminophen, and NSAIDs are all effective drugs and should be administered until the primary cause of the fever has been treated Fever of Unknown Origin By: Eethar Nourein, Huma Rohan, Alycia Sam, Ilana Shapera, Allison Simpson, Marijana Skok, Murad Zaman, Daniel Zettler Definition: The "normal" body temperature average is 98.6 F OR36 C .
The term FUO carries specific criteria :

1-Patient that has illness that lasted 3 weeks.
2-fever of over 101 F or 38C on several occasions
3-no diagnosis after routine workup for 3 days in hospital. Mechanism to Fight Fever: Factors Contributing to FUO 3 Major Etiologic Factors: 1. Infections
2. Neoplasms
3.Autoimmune Diseases Infections: Abscesses (*dental)
Osteomyelitis of mandible and/or air sinuses
Subacute bacterial endocarditis (may be induced by dental treatment)
Biliary system infection (path followed by bile from liver to duodenum)
TB (*miliary)
Rickettsial infection
Parasites, fungus, chlamydia, spirochetes, Epstein Barr virus, cytomegalovirus Neoplasms: Lymphoma *most common neoplastic cause of FUO in elderly
Hodgkin’s lymphoma may present with recurrent episodes of febrility (Pel-Ebsten fever pattern)
Primary Hepatoma
Solid tumor of the liver whose origin is within the liver; tumors which metastasize to the liver are unlikely to cause fever
Atrial myxoma
Tumor of atria; fragments of tumor may dislodge and causes embolisms (mimics subacute bacterial endocarditis) Autoimmune Diseases: Still’s disease (juvenile rheumatoid arthritis)
Typically presents in young individuals with a pattern of symptoms including sore throat, fading macular rash and arthralgias
Physicians may misinterpret these findings as a bacterial infection and prescribe ineffective antibiotics
Hypersensitivity Angiitis
Inflammation of blood or lymph vessels
May be caused by Streptococcal infection, from drugs, or other ingested/inhaled chemicals
Polymyalgia rheumatica/temporal arteritis
Visual deterioration and complaints of temporal headache
Polyarteritis nodosa
Serious illness involving vasculitis of small and medium sized arteries which are irreversibly damaged by immune cells
Mixed connective tissue disease
Condition where immune system is self destructive
Subacute thyroiditis
Thyroid gland swelling typically following URTI (upper respiratory tract infection)
Systemic Lupus Erythmatosus
With the advent of improved diagnostic testing (DNA markers), SLE is readily diagnosed within a couple of weeks of fever onset Minor Etiologic Factors: Granulomatous Diseases
Diseases which exhibit granulomatous inflammation e.g. Tuberculosis
Regional Enteritis
Inflammation of small intestine
Familial Mediterranean Fever
Hereditary, involving repeated fevers and inflammation of various areas of the body
Drug Fever
Several drugs are capable of inducing FUO including ibuprofen, antihistamines, barbiturates and penicillins
Pulmonary Emboli
Factitious Fever
Patient purposely exposes themselves to infectious material (e.g. stool or saliva) via injection; typically young female healthcare workers or those prone to self-mutilation Patient Examination •Past medical history- History of TB, TB exposure,or positive PPD
•Family history- to exclude genetic disorders such as cyclic neutropenia and familial Mediterranean fever.
•Epidemiology history- animal exposure, home environment, occupational exposure.
•Travel history- areas endemic for malaria, other parasites, typhoid, coccidiomycosis, histoplasmosis, and tick-borne illnesses.
•List of all medications- OTC & natural to exclude the possibility of drug fever Diagnostic Workup 1. Skin Tests

2. Cultures

3. Smears An intermediate-strength PPD should be performed in all patients with FUO who do not have a previously documented positive PPD •Blood cultures -part of the initial workup of all patients with significant prolonged fever.
•Urine cultures -obtained and cultured for tuberculosis in addition to more conventional bacteria.
•Sputum culture-In patients with respiratory complaints/chest X-ray abnormalities
•Bone marrow analysis-patients undergoing bone marrow biopsy
•Cerebrospinal fluid (CSF) culture -cases with specific neurologic complaints.
•Biopsy specimens-Aerobic, anaerobic, mycobacteria, and fungal cultures ordered on all culture samples. •Giemsa and Wright stains - malaria, trypanosomiasis, and relapsing fever.
•Wright stain with differential cell count -determines the nature of the inflammatory response.
•Atypical lymphocytes and monocytes- Epstein-Barr virus.
•Elevated peripheral white blood cell counts with a predominance of neutrophils and band forms -Still's disease
•CSF India ink smear and cryptococcal antigen -diagnosis of cryptococcal meningitis. 4. Other Peripheral Blood Tests

5. Imaging Studies

6. Invasive Procedures •Antibody titers should be considered when specific pathogens are part of the differential diagnosis. eg. cytomegalovirus, EBV etc.
•ESR- polymyalgia rheumatica/temporal arteritis and Still's disease. Normal ESR virtually excludes these diagnoses as well as subacute bacterial endocarditis. Tests performed during the initial diagnostic workup:
•Chest X-ray- lymphoma, miliary tuberculosis, nodular lesions, or infiltrates (can be seen in many infectious diseases, connective tissue diseases, and neoplasms)
•Air sinus films or sinus CT scans-sinus infection,tooth abscess•Upper gastrointestinal barium study with small bowel follow-through regional enteritis.
•Ultrasound of the gallbladder and/or an oral cholecystogram- cholecystitis or an enlarged gangrenous gallbladder.
•Intravenous pyelogram- renal tuberculosis, renal stones, polycystic kidney disease, and renal cell carcinoma.
Tests ordered based on signs & symptoms:
•X-rays - joint complaints
•Radionuclide scans/Gallium Scan/FDG- localizing site of chronic infection
•Indium white blood cell scan- abdominal lesions
•Technetium scan -osteomyelitis and tumor metastasis to bone.
•Total-body CT scan: Very EXPENSIVE
•Echocardiography -heart murmur
•Transesophageal echocardiography- cardiac vegetations, myocardial abscess, atrial myxoma
•Ultrasound of the lower abdomen - pelvic lesions •Liver biopsy- granulomatous hepatitis.
•Laparoscopic guided biopsy- abnormalities in the external capsule
•Bone marrow aspiration and biopsy - Leukemia, stage IV lymphoma, TB, mycobacterial fungal infections.
•All biopsy specimens should undergo Brown-Brenn, Ziehl-Neelsen, methenamine silver, PAS, and Dieterle silver staining in addition to routine hematoxylin and eosin staining.
•Frozen sections should be obtained for immunofluorescence staining, and the remaining tissue block should be saved for additional future studies. Treatment: 1. Documentation of fever pattern
‘True fever’
Symptoms include chills, sweating, fatigue, loss of appetite
2. NSAIDS, aspirin and acetaminophen
Tends to be overprescribed by clinicians
Can be taken once a ‘true fever’ has been documented
Analgesic and anti-pyretic effects
Essential to give at regular time intervals in order to reduce symptoms of fever
3. Avoid broad-spectrum antibiotics
Most cases of FUO involve infections:
That are not susceptible to broad-spectrum antibiotics
When indicated, requires antibiotics for prolonged periods in addition to surgical drainage (most clinicians do not prescribe for long enough)
Do not consider using unless specific diagnosis has already been made
4. Systemic glucocorticoids in select cases
Indications include:
Connective tissue diseases
(Temporal arteritis, polymyalgia rheumatica, Still’s disease, some complications associated with lupus erythematosus)
Reduces inflammation and host defense
But can also exacerbate an assortment of infections
Consequences of prolonged use include osteoporosis, diabetes mellitus and aseptic necrosis of hip Prognosis: Dependent on etiological category
For some conditions, a delay in diagnosis is detrimental to the outcome
Intra-abdominal abscess, miliary TB, disseminated fungal infections, pulmonary emboli
For most other conditions, lack of diagnosis after extensive diagnostic workup has a better outcome
Modern day advances
Five-year mortality rate of only 3%

At what time should another round of diagnostic workup be performed?
If fever has lasted for a further four to six months Prevalence in Canada: Systematic review by researchers from University of Toronto
Looked at patient populations from North America, Western Europe and Scandinavia (similar to our own)
Hospitalized patients (2.9%)
Spectrum of the disease:

Some additional considerations/findings:
Deep vein thrombosis and temporal arteritis accounted for 3% and 16-17%, respectively
Undiagnosed patients with FUO spontaneously recovered in 51-100% of cases
Compared to less than 30% in the 1930’s
Relative amount of FUO cases with infections and neoplasms as etiological factors has decreased in last half-decade Lemierre's Syndrome •Lemierre was a French physician and professor microbiology who described the syndrome in 1936
•Also known as postanginal septicemia or necrobacillosis
•Uncommon complication of pharyngitis caused by bacterium Fusobacterium necrophorum (anaerobic, gram-negative pleomorphic bacilli)
•Principal infection site: palatine tonsils and peritonsillar tissue
•Syndrome is characterized by a history of recent pharyngitis followed by ipsilateral internal jugular vein thrombosis and metastatic pulmonary abscesses
•Symptoms are similar to the flu or strep throat (sore throat, fever, lymphadenopathy)
•Most prevalent in adolescents and young adults (average age of 19 years old)
•Slightly higher prevalence in males.
•Mortality rate between 5% and 10% (with significant morbidity)
•With the use of antibiotics in the early treatment of throat infections, there has been a dramatic decrease in the incidence of Lemierre syndrome (fewer than 100 cases have been reported since 1974) Case 1: Patient History - -19 year old Caucasian male
-Presents with 3 week history of fever (approx 104 F), fatigue, anorexia
-Was given IV fluids for dehydration and penicillin/clarithromycin
-Fever persisted Physical Exam - -Temperature: 39.2 C
-Pulse: 88
-Respirations: 20
-BP: 122/60
-Mildly ill-looking
-Body exam normal (no lympthadenopathy, no rashes, no heart murmurs, normal joints/extremities-Lab tests all within normal limits Imaging - -Due to persistent fever and anorexia, an abdominal CT scan was performed
-9 cm diameter abscess found in right lower lobe of liver
-Cutaneous aspiration of pus followed by culture yielded Staphylococcus aureus Comments - -Only after CT imaging and then further testing was it determined that this patient had fever caused by an infection of staph aureus Case 2 Patient History - -63 year old male
-Presents with fevers, chills, fatigue, weight loss, and rigors present for 1 month
-History of hypertension and smoking Physical Exam - -Fever of 39 C
-Vital signs normal
-No lymphadenopathy
-Smears, lab tests, echocardiogram, bone scan normal
-Chest X ray and CT scan normal
-Head CT scan showed lesion on right medial temporal lobe
-MRI of brain confirmed previous findings
-No malignant cells or acid-fast bacilli found in CSF Complications - -Doctors suspected the lesions were either TB or a malignancy, therefore, anti-TB medications were administered and an appointment was made with a local neurology department
-However, a few weeks later (before patient had seen neurologist), patient was re-admitted with hallucinations, personality change, and delusions (in addition to previous symptoms) Outcome - -MRI showed lesions had increased in size
-Biopsy in the area revealed large B-cell lymphoma
-Condition worsened, so he was admitted to ICU
-After his state stabilized, oncologists began performing full brain irradiation
-Patient began to suffer from seizures and pneumonia
-CT scan showed further progression of cerebral lesions
-Condition continued to deteriorate
-Patient dies, 7 months after initially presenting to hospital Comments - -The physicians who published this case report recommend brain imaging if FUO is found with no obvious causes after initial testing and abdominal imaging References Alherabi A. A Case of Lemierre Syndrome. Ann Saudi Med. 2009 Jan-Feb; 29(1): 58–60.

Alt HL, Barker MH. JAMA. Fever of Unknown Origin. 1930; 94(19):1457-1461

Bin Salih S. et al Primary CNS lymphoma presenting as fever of unknown origin., Springer Science/business Media. Riyadh, Saudi Arabia. January 2009

Lemierre A. On certain septicaemia due to anaerobic organisms. Lancet. 1936;I:701–703.

Mourad O, et al. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003 Mar 10; 163(5):545-51. PubMed PMID: 12622601.

Sams WM Jr. Human hypersensitivity angiitis. Immunol Ser. 1989;46:585-604.University of Alabama, Birmingham.

Southwick, Frederick S. Infectious Diseases in 30 days. 1st ed. United States of America. McGraw-Hill; 2003 The End
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