Pyrexia of Unknown Origin

PUO or FUO
Dr.T.V.Rao MD

1/19/2013

Dr.T.V.Rao MD

What is the normal human body temperature?

A. 37.5 C B. 98.6 F C. Each human being is a unique individual, and therefore, normal temperature cannot be defined.

1/19/2013

Dr.T.V.Rao MD

What is the normal human body temperature?

A. 37.6 C B. 98.6 F C Each human being is a unique individual, and therefore, normal temperature cannot be defined.

1/19/2013

Dr.T.V.Rao MD

Normal Body Temperature

For healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8 0.4C (98.2 0.7F) Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M. The maximum normal oral temperature is 37.2C (98.9F) at 6 A.M. and 37.7C (99.9F) at 4 P.M. These values define the 99th percentile for healthy individuals.
1/19/2013 Dr.T.V.Rao MD

Mackowiak, et al., JAMA 1992;268:1578

Definition
Fever > 38.3 on several occasions Fever lasting more than 3 weeks No diagnosis despite 1 week of inpatient workup
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Terminology
Old Definition:
1. Fever higher than 38.3oC on several occasions. 2. Duration of fever 3 weeks 3. Uncertain diagnosis after one week of study in hospital

New Definition:

Eliminated the in-hospital evaluation requirements 3 outpatient visits, or 3 days in hospital. Ambulatory as well as in 1/19/2013 Dr.T.V.Rao MD hospital

Historical Causes of FUO

Hippocrates: excess of yellow bile Middle Ages: demonic possession (encephalitis?) 18th Century: Friction associated with the flow of blood through the vascular system and from fermentation and putrefaction occurring in the blood and intestines
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Definition Expansion
1. Classical PUO 2. Nosocomial PUO 3. Neutropenia PUO 4. HIV-Associated 5. Transplant
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Categories of FUO
Feature Nosocomial Neutropenic HIV-associated Classic

Patients situation

Hospitalized, acute care, no infection when admitted

Neutrophil count Confirmed HIVeither <500/L or positive expected to reach that level in 1-2 days

All others with fevers for 3 weeks

Duration of illness while investigated

Examples

3 daysb

3 daysb

3 daysb (or 4 weeks as outpatient)

3 daysb or 3+ outpatient visits

Infections, malignancy, inflammatory diseases, drug fever

Septic thrombophlebitis, sinusitis, C. difficile colitis, drug fever

Perianal infection, MAIc infection, aspergillosis, TB, noncandidemia Hodgkins lymphoma, drug fever

require temperatures of 38.3C (101F) on several occasions. bIncludes at least 2 days incubation of microbiology cultures. cM. avium/M. intracellulare.
aAll

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Modified Dr.T.V.Rao Durack, AC Street, in JS Remington, MN Swartz (eds): 9 from DT MD Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.

Pattern of Fever

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Etiologies of PUO
Infection: Three major causes Abscess .. especially occult .. Intracellular organisms. (salmonella mycobacterium, brucella) Intravascular SBE
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True Fever
Occurs when IL-1, IL-6, TNF- or other cytokines are released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the bodys set point. The anterior hypothalamus maintains an inherent set point near 36C(98.6F). Normal circadian rhythm, which is highest(up to 2C, 3F) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.

Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
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Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, Cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection

Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

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Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, Cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis

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Bacterial Pyrogens
Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNF.

Staphylococcus aureus enterotoxins

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Infectious Causes of FUO

Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, Legionellosis Salmonellosis (including typhoid fever), Listeriosis, ehrlichiosis, Actinomycosis, nocardiosis, Whipples disease Fungal (candidaemia, cryptococcosis, sporotrichosis, Aspergillosis, Mucormycosis, Malassezia furfur) Malaria, Babesiosis, toxoplasmosis, schistosomiasis, fascioliasis, Toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19
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Miscellaneous Causes of FUO

Complex partial status epilepticus, cerebrovascular accident, brain tumor, encephalitis Drug fever, Sweets syndrome, familial Mediterranean fever Gout, pseudo gout Kawasakis syndrome, Kikuchis syndrome Crohns disease, ulcerative colitis, sarcoidosis, granulomatous hepatitis Deep vein thrombosis Atelectasis?
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Bacterial Pyrogens
Staphylococcus aureus toxic shock syndrome toxin (TSST)
Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNF and TNF, and interferon (IFN)-gamma in large amounts

Group A and B streptococcal toxins

Exotoxins induce human mononuclear cells to synthesize not only TNF but also IL1 and IL-6
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CAUSES CLASSIC PUO

INFECTIVE 20-30% CANCER 10-20% AUTOIMMUNE 15-20% MISC 15-25% UNDIAGNOSED 5-10%
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Classic FUO

Infection Malignancy Collagen vascular diseases

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Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
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Infectious Causes of FUO

Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
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Infectious Causes of FUO

Intraabdominal abscess (liver, splenic, psoas, etc) Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra Intracranial abscess, sinusitis, dental abscess Chronic pharyngitis, tracheobronchitis, lung abscess Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis
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Geography
Malaria Saudi (malaria area)/Africa/India

Brucella Kala-Azar
Leprosy Typhoid Histoplasmosis

Saudi/Gulf Area Yemen/Jazan/Sudan/India

Yemen/Najran India/Pakistan/Egypt/Indonesia USA (West Coast)

N.B.: Ease of Travel Infection All parts of the world. Tuberculosis Liver Abscess All over the world.

AIDS

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Pathophysiology
Meningitis and sepsis are serious etiologies of fever in infants and young children. Neonates' immature immune systems place them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing sepsis.
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Bacterial Pyrogens
Lipopolysaccharide (LPS) endotoxin
Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNF.

Staphylococcus aureus enterotoxins Staphylococcus aureus toxic shock syndrome toxin (TSST)
Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNF and TNF, and interferon (IFN)-gamma in large amounts

Group A and B streptococcal toxins

Exotoxins induce human mononuclear cells to synthesize not only TNF but also IL1 and IL-6

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What are common Causes

The following are among the most common bacterial etiologies of serious bacterial infection in this age group:

Streptococcus pneumoniae Group B streptococci Neisseria meningitidis Haemophilus influenzae type b

Listeria monocytogenes
Escherichia coli
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Consequences of Fever can be confusing

Approximately 2.5-3% of highly febrile children younger than 3 years develop occult bacteremia, which typically is caused by S pneumoniae. Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever.
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History Taking
Family History:
Scrutinized for possible infectious or hereditary disorders
Tuberculosis FMF

Past Medical Condition:

Lymphoma Rheumatic Fever Stills Disease Behcets Disease may recur may recur may recur may recur

Exposure to sexual partner Acute HIV Illicit drug abuse (IV) infective endocarditis, Hepatitis HIV
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Physical Examination
.. Looking for the KEY physical sign . Diagnostic yield 60% in children (50%repeated) Document the Fever:
Significant and persistent for more than ONE occasion.

Analyzing the Pattern:

Neither specific Nor sensitive enough to be considered diagnostic EXCEPT

Tertian & Quarter Pattern Pel-Ebstein Pattern

Pulse-Temp Dissociation
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Malaria Lymphoma/ Tuberculosis Typhoid/ Brucellosis

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Infections
Tuberculosis (especially extrapulmonary) Abdominal abscesses Pelvic abscesses Dental abscesses Endocarditis Osteomyelitis
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Infections
Sinusitis Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus Lyme disease Prostatitis Sinusitis
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Etiologies of PUO
Infection
Tuberculosis: .. Disseminated
The single most common infection in most PUO series except in children and elderly. Usually extrapulmonary or military, or Occurs in the lungs and significant pre-existing lung disease. Pulmonary TB in AIDS is often subtle (normal chest xrays 15 30%). PPD is (+ve) < 50% of TB with PUO. Diagnosis often requires Bx of LN/Liver/Bone marrow. Sputum smear (+) only 25%
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Etiologies of PUO
Abscess:
Usually located in abdomen or pelvis. Secondary to appendicitis or diverticulitis. Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. Amoebic liver abscess is similar to pyogenic amoebic serology is positive > 95% of cases. Splenic abscess is usually secondary to hematogenous seeding. Perinephric or renal abscess is usually secondary to UTI.
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Etiologies of PUO
Bacterial Endocarditis
Culture remains negative in 5% of patient. Culture negative is likely with the following organisms:
Coxiella burnetii no growth. HACEK group incubate blood 7 21 days Brucella } Special media/ Legionelle } long time Mycoplasm/Chlamydia } Fungal usually sterile

Peripheral signs may not be detected. Right-side Endocarditis Lack murmurs self antibiotics growth (-ve).
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Etiologies of PUO
Infection
Tuberculosis: .. Disseminated
The single most common infection in most PUO series except in children and elderly. Usually extra pulmonary or military, or Occurs in the lungs and significant pre-existing lung disease. Pulmonary TB in AIDS is often subtle (normal chest xrays 15 30%). PPD is (+ve) < 50% of TB with PUO. Diagnosis often requires Bx of LN/Liver/Bone marrow. Sputum smear (+) only 25%
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Geography
Malaria Saudi (malaria area)/Africa/India

Brucella Kala-Azar
Leprosy Typhoid Histoplasmosis

Saudi/Gulf Area Yemen/Jazan/Sudan/India

Yemen/Najran India/Pakistan/Egypt/Indonesia USA (West Coast)

N.B.: Ease of Travel Infection All parts of the world.

Tuberculosis
Liver Abscess AIDS All over the world.

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HIV associated PUO

HIV alone TB,M avium/intracelulare Toxoplasmosis CMV ,PCP ,Salmonella Cryptococcus, Histoplasmosis Non Hodgkins Lymphoma Drug induced
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 Chronic leukemia Lymphoma Metastatic cancers Renal cell carcinoma Colon carcinoma Hepatoma Myelodysplastic syndromes Pancreatic carcinoma Sarcomas
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Malignancies

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Autoimmune Conditions with Fever

Adult Still's disease Polymyalgia rheumatic Temporal arteritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel disease Reiter's syndrome Systemic lupus erythematous Vasculitides
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Miscellaneous
Drug-induced fever Complications from cirrhosis Factitious fever Hepatitis (alcoholic, granulomatous, or lupoid) Deep venous thrombosis Sarcoidosis
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Diagnosis
A cost-effective individualized approach is essential in the evaluation of these patients to prevent performing inappropriate tests.
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Minimal Initial Diagnostic Workup For FUO

Comprehensive history Physical examination CBC + differential Blood film reviewed by hematopathologist Routine blood chemistry UA and microscopy Blood (x 3) and urine cultures Antinuclear antibodies, rheumatoid factor HIV antibody CMV IgM antibodies; heterophile antibody test (if c/w mono-like syndrome) Q-fever serology (if risk factors) Chest radiography Hepatitis serology (if abnormal LFTs)
1/19/2013 Dr.T.V.Rao MD

Mourad, et al. Arch Intern Med. 2003;163:545

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Diagnostic Testing
Blind application leads to excessive false tests Complete Blood Count
Anemia if present suggest a serious underlying disease Leukocytosis with bands occult bacterial infection Lymphocytosis & atypical Lymphocyte Infectious mononucleosis Leucopenia and Lymphopenia advanced HIV Leukoerythroblastic Anemia Disseminated TB Thrombocytopenia Malaria/Leukemia Peripheral Blood Malaria
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Diagnostic Testing
Urinalysis, Urine Culture, U/E, LFT ESR
If elevated significant inflammatory process Greatest use in establishing a serious underlying disease, esp. if v. high ESR > 100 mm/h Tuberculosis m myeloma temporal arteritis
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Diagnostic Testing
58% malignancy Lymphoma/myeloma 25%
Infection Endocarditis Giant cell arteritis

High ESR lacks specificity:

Drug Reaction Thrombophlebitis Nephrotic Syndrome } } may cause very high ESR }

Normal ESR significant inflammatory process is absent with exception.

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Diagnostic Testing
CRP-closely associated with inflammatory process
Not invariable components of the febrile response. Usually does not go up with viral infection. * ESR & CRP is elevated in:
1. 2. 3. 4.
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Bacterial Infection Neoplasm Immunological-mediated inflammatory states Tissue infarction

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Diagnostic Testing
Acute Phase Proteins
Proteins Increased Fibrinogen Ferritin Plasminogen Fetoprotein Protein S Cerruloplasmin
New England J Med. 1999, 340.448-454
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Proteins Decreased Albumin Transferrin Alpha-

Diagnostic Testing
Blood Testing
Anti-nuclear Antibodies Rheumatoid Factor CMV Antibody IgM Heterophile Antibody Test in children and young adult Tuberculin Skin Test 5 unit ID Thyroid Function Test HIV Screening
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Diagnostic Testing
Imaging Studies: to localize abnormalities for definite tests or treatment
Chest x-ray:
Military shadows disseminated tuberculosis Atelectasis } 1. Liver Hemi diaphragm } Abscess 2. Spleen Pleural Effusion } 3. Pancreatic 4. Subphrenic Mediastinal mass Lymphoma/Tuberculosis/ Sarcoid If CXR is (N) Repeat on weekly basis
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Diagnostic Testing
CT-Scan CT scan chest
Mediastinal mass Tuberculosis/Lymphoma/ Sarcoidosis Dorsal Spine Spondylitis and disc space disease CT-Scan Abdomen very effective to visualize
All types of abscesses Retroperitoneal tumor, lymph node or hematoma

MRI: spleen, lymph node and the brain

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Diagnostic Testing
Serology Test
Brucella Titer CMV & EBV antibody test HIV testing (Elisa screening) ANF

Radio nuclear Scanning

Bone TC-scan osteomyelitis (skeletal) Gallium scan occult inflammation Indium labeled WBC-scan occult abscesses
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Diagnostic Testing
Hepatomegaly or Abnormal LFT
Hepatic Granuloma
Non-caseating: Tuberculosis/Sarcoidosis & Brucellosis Caseating: Tuberculosis

Bone Marrow
Granuloma Tubercle Bacilli Tuberculosis Aplastic Cells Leukemia Leishmania Bodies Kala-Azar Atypical Cells Lymphoma Atypical Plasma Cells M. myeloma

Temporal Artery Giant Cell Arteritis Pleural or Pericardial Extrapulmonary Tuberculosis

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Investigation
Blood culture before the antibiotics Culturing of Urine Sputum culture Stool examination for Bacterial and Parasitic infection.
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Etiologies of PUO
Abscess:
Usually located in abdomen or pelvis. Secondary to appendicitis or diverticulitis. Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. Amoebic liver abscess is similar to pyogenic amoebic serology is positive > 95% of cases. Splenic abscess is usually secondary to haematogenous seeding. Perinephric or renal abscess is usually secondary to UTI.
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Tuberculosis
Sputum examination for AFB
Culturing for AFB Monteux test Tuberculin test X ray of the chest
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Diagnosis
More invasive testing, such as LP or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation. When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful.

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Etiologies of PUO
Factitious Fever
Febrile PUO In one study 9% of cases of PUO False fever: thermometer manipulation using external heat or substitute thermometer. Men use this way physician are rare for this disorder. Increasing somewhat in elderly 115 116 Genuine fever (self induced) Administration of pyrogenic substances (bacterial suspensions) Generally young women with connection to health care often NURSES. 1/19/2013 Dr.T.V.Rao MD 60

Pyrexia of Unknown Origin

The majority of disease remaining after an initial NEGATIVE work-up are:
1. 2. 3. 4. 5. 6. 7. 8.
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Neoplasm Seronegative Collagen Vascular Disease Increasing Tuberculosis Increasing Drug Addition Elderly with Endocarditis HIV with or without infection or malignancy Implanted prosthetic devices Travel New Exposure
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Therapeutic Trials
Limitation and risk of empirical therapeutic trials:
Rarely specific Underlying disease may remit spontaneously false impression of success. Disease may respond partially and this may lead to delay in specific diagnosis. Side effect of the drugs can be misleading.

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Therapeutic Trials
What is the best therapy for PUO patient?
To hold therapeutic trials in the early stage except in:
Patient who is very sick to wait. All tests have failed to uncover the etiology.

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Prognosis
Prognosis is determined primarily by the underlying disease. Outcome is worst for neoplasms. FUO patients who remain undiagnosed after extensive evaluation generally have a favorable outcome and the fever usually resolves after 4-5 weeks.
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Larson et al. Medicine 1982;61:269

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Summary
FUO is often a diagnostic dilemma Infections comprise ~30% of cases Bone marrow biopsies are of low diagnostic yield Diagnostic approach should occur in a step-wise fashion based on the H&P Patients that remain undiagnosed
generally have a good prognosis
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