PUO

Pyrexia of Unknown Origin

Dr. Kazi Shamim Al MamunHMO, Medicine Unit - I

Chittagong Medical College and Hospital

ALTERATION OF BODY TEMPERATURE:

“Normal” body Temperature

Fever

Hyperpyrexia

Hyperthermia

NORMAL BODY TEMPERATURE

The normal body temperature is said to be 37°C (98.6°F) but the maximal normal temp. range from 37.2°C (98.6°F) at 6 am to 37.7°C (99.9°F) at 4 pm.

The rectal temp. are generally 0.4°C (0.7°F) higher than oral reading.

Fever is a protective response to infectious & Injury.Elevated temp. enhances the body’s innate defense by

making condition less favorable for infectious microorganism to thrive by:-

1. Elevated temp decreases the levels of Iron in blood stream, thus inhibiting their growth.

2. People with fever tends to eat less and rely more on protein & fat sources for energy, which decreases blood sugar level upon which bacteria normally thrive.

3. There are some bacteria/ microorganism. That are heat sensitive and do not grow well at elevated body temp.

FEVER: Also known as “Pyrexia” or a Febrile response and archaically known as ‘argue’, is a medical symptom.

Fever is caused by resetting of the hypothalomus ‘set point’ by PG’s a process mediated by cytokins, this elevated thermoregulatory “set point means that the previous “normal body temp.” would be considered hypothalamic.

HYPERTHERMIA: is a uncontrolled increase in body temp that exceeds the body’s ability to lose heat without an elevation of the hypothalamic “set point”.

PYREXIA OF UNKNOWN ORIGIN (PUO)

DEFINITION: Petersdorf and Beeson defined pyrexia of unknown origin (PUO) in 1961. It is defined as:

1. A temperature greater than 38.3°C on several occasions.2. More than 3 weeks of illness.3. Failure to reach a diagnosis after 1 week of inpatient

investigation.

Definitions: (Arnow and Flaherty, 1997)

Fever that does not resolve spontaniously in the period expected for self-limited infection and whose cause cannot be ascertained despite considerable diagnostic effort”.

“A prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing” – Up To Date

New definition / Classification developed by Durack & Street:

2 weeks of fever and 3 days of inpatients investigation or 3 outpatient visits without finding a source of fever.

CLASSIFICATION OF PUO:

Category of PUO Definition Common etiologies

1. Classic Temperature >38.3˚C

(100.9˚F)

Duration of >3 weeks

Evaluation of at least 3 outpatient visits or 3 days in hospital

Infection, malignancy, Collagen vascular disease

2. Nosocomial Temperature >38.3˚CPatient hospitalized >= 24 hours but no fever or incubating on admission

Evaluation of at least 3 days

Clostridium difficile entercolitis, drug-induced PE, Septic thrombophlebitis, sinusitis

3. Immune deficient (neutropenic)

Temperature >38.3˚CNeutrophil count <=500 per mm³

Opportunnistic bacterial infections, aspergilloisis, candidiasis, herpes virus

4. HIV-associated Temperature >38.3˚C, duration of >4 weeks for outpatients, > 3 days for inpatients, HIV infection confirmed.

Cytomegalo virus, mycobacterium aviumintracellulare complex, pneumocystitis carinii pneumonia, drug induced, kaposi’s sarcoma lymphoma

Infection (30%) Sepsis

Abscess : Intra abdominal, cholecysititis / cholangitis

Urinary tract infection:

Prostatitis

Dental and sinus infections

Bone and joint infections Imported infections, e.g.. Malaria, dengue, brucelloiss Enteric fevers Endocarditis (HACEK)

AETIOLOGY OF PUO

Malignancy (20%) Lymphoma and myeloma Leukaemia Solid tumours (renal, liver, colon, stomach, pancreas)

Connective tissue disorders (15%) Vasculitic disorders (incl. Polyarteritis nodosa and

rheumatoid disease with vasculitis) Temporal arteritis/polymyalgia rheumatica Stystemic lupus erythematosus (SLE) Still’s disease Polymysositis Rheumatic fever

Miscellaneous (20%) Inflammatory bowel disease Liver disease: cirrhosis and granulomatous hepatitis Sarcoidosis Drug reactions Atrial myxoma Thyrotoxicosis Hypothalamic lesions Familial Mediterranean fever

No diagnosis or resolves spontaneously (15%)

Ten leading causes of classic PUO among adults at community hospitals in the United States

Cause % of totalLymphoma 16Collagen vascular disease 16Abscess 13Undiagnosed cause 09Solid tumor 08Thrombosis or haematoma 07Granulomatous disease, nonmycobacterial 05Endocarditis 05Mycobacterial disease 05Viral disease 05Remaining causes 11

100Source: Adapted from Kazanjian 1992

A Prospective study of 100 cases. Kajariwal D et al. JPGM 2001; 47: 104-7

Infection esp. TB 53%

Neoplasms 17%

Collagen Vascular Disease 11%

Miscellaneous 5%

Undiagnosed 14%

EVALUATION & APPROACH TO DIAGNOSIS:

1. History taking and Physical Examination:

i. Onset : Sudden in pneumonia, pyelitis, influenza etc.

Gradual – Typhoid, typhus, pulmonary TB

ii. Rigors : Malaria, filaria, UTI, cholangitis, Hepatic abscess, septicemia, etc.

iii. Headache : Meningitis, typhoid at onset, encephalitis, ICSOL & dengue.

iv. Body ache : Dengue, viral fever, secondary syphilis, rat bite fever etc.

v. Sweating : Malaria, miliary TB, rheumatic fever, hepatic abscess

vi. Delirium : Typhoid, septicemia meningitis, pneumonia etc.

vii. Wt. loss : TB, Chronic suppurative disease like empyema, lung abscess, thyrotoxicosis, polyarthritis

other symptoms like association diarrhoea, vomiting, sore throat, urinary frequency helps in diagnosis.

PAST HISTORY:

History of RF, VHD, TB of any form, syphilis, filariasis etc.

PERSONAL HISTORY:

Residence in endemic area in kalazar, Mediterrarean fever, Trypanosomeasis

Inquiry of Alcoholic intake & Sexual habit.

Dietary habit: Raw or poorly cooked meat Raw milk

Occupation- Weil’s disease

Travel history/Recreational habits:

Seasonal: Epidemic in rainy season e.g.- Malaria, Dengue.

Exposure in hot weather: Heat stroke

Recent drug history: e.g.- Penicillin, Cephalosporin,

Methyldopa, Antitubercular,

Steroid.

I/V drug use/Abuse

Immunization history

Contact with domestic or wild animals or birdsBrucellosis (cattle)Psittacosis (Birds)Leptospirosis (rats & dogs)Rat bite fever

Contact with persons with TB or other family member having infections.

Family history: Arthritis, Rash, Collagen vascular disease.

Pyrexia of Unknown origin causes by age:

I Causes: Age < 6 years old:

A. Infections (65%)

B. Neoplastic disease (8%)

C. Autoimmune disease (8%)

D. Miscellaneous (13%)

E. No Diagnosis (6%)

II Causes: Age 6 to 14 years old:

A. Infections (38%) B. Neoplastic disease (4%) C. Autoimmune disease (23%) D. Miscellaneous (17%) E. No Diagnosis (19%)

III Causes: Age > 14 years old: A. Infections (36%) B. Neoplastic disease (19%) C. Autoimmune disease (13%) D. Miscellaneous (25%) E. No Diagnosis (7%)

II Causes: Age > 65 years old: A. Connective tissue disease (30%)

1. Temporal arteritis2. Polymyalgia rheumatica

B. Infection (25%) C. Cancer (12%) D. No diagnosis (8%) E. Reference.

Incubation Periods:

I. Incubation < 10 days

A. Travelers Diarrhea

B. Dengue fever (common)

C. Yellow fever

D. Spotted fever

E. Meningococcemia

II. Incubation < 21 days

A. Leptospirosis B. Viral hemorrhagic fever

C. Malaria (common) D. Enteric fevers

1. Typhoid Fever (common)

2. Paratyphoid

E. Typhus F. East African Trypanosomiasis

III. Incubation > 21 days

A. HIV

B. Hepatitis-A (common) & others hepatitis

C. Malaria (common, symptoms may be delayed)

D. TB

E. Amoebic liver abscess

F. Brucellosis

G. Leishmaniasis

Physical examination:Should be repeated on regular basisShould be done meticulouslyAxillary temp. is unreliableRectal (preferable) temp. should be measuredOral temp. can be measured.

Physical Examination:

1.Temperature: Type of fever

i. Intermittent- with high peaks,

Malaria, acute pyelonephritis, septicemia, filariasis

ii. Continuous- within range of 2F typhoid, miliary TB, pneumonias

iii. Periodic or undulating- Hodgkin’s, relapsed typhoid, brucellosis

iv. Double rise- Kalazar, malaria, liver abscess, & Ecoli infections.

2. Pulse rate: Relative bradycardia- Typhoid, meningitis, dengue, weil’s disease

3. Anaemia: Malaria, Kalaza, Chronic sepsis

4. Lymph node: Generalized- Hodgkin’s disease, Tb, secondary

syphilis, lymphocytic leukemiaLocalized- Plague, glandular fever.

Lymphogranuloma inguinale

5. Jaundice: With fever- infective hepatitis, weil’s disease, malaria, liver abscess, infectious mononucleosis.

6. Skin: Rashes- Typhoid, meningococcal meningitis, relapsing fever, rat bite fever,

Petechial hemarrhages- septicemia, cerbrospinal meningitis, malignant diphtheria.

7. Clubbing: Lung abscess, bronchiectasis, liver abscess

8. Nails: Transverse white band- undulant fever

9. Arthritis: RF, gout, meningococcemia, leukamia, PAN

10. Herpes labiales: in association with pneumococcal pneumonia, Streptococcal infection, malaria and meningococcemia.

11. Nodules: RF, RA, leprosy, erythema nodosum, PAN

Systemic Examination:Chest findings: Lung abscess, TB

Pneumonia, Ca.Heart: Bact. Endocarditis

Pericarditis Myocarditis

Abdomen:Splenomegaly: Malaria

TyphoidKala-azar SBPDiss. TBLymphoma

Hepatomegaly: MalariaEnteric feverKala-azarLeukemiaLymphomaAmoebic liver abcessHepatocellular Ca.

Renal enlargementa. Chronic pylonephritisb. Ca kidneyc. Obstructive uropathy

Rectal examination:Perianal diseaseLocal sepsis or abscessRectal – CarcinomaProstatic malignancy Prostatitis

Genitalia:UlcerationDischargeTesticular swelling.

Nervous system:Coma Encephalitis Cerebral malariaSigns of meningeal irritation MeningitisFocal Sign Brain abscessCranial nerve palsy TBM

Fundus:Hemorrhage and exudates VasculitisRoths spot EndocarditisChoroids tubercle Milliary/Diss.TB

Disseminated fungal infection.

INVESTIGATIONS:

CBC

Urine analysis

Blood for MP

Dipstick test for falciparum malaria

Stool Microscopy

 X-ray chest P/A

Blood Culture- Typhoid, PT, Septicemia, brucellosis

LFT

Serum for Antibodies: bacterial, viral ,fungal, protozoal

Serological test for syphilis

CSF when suspecting meningitis, encephalitis

Serum Immunoglobulins- EBV & CMV IgG, IgM

COLLAGEN VASCULAR DISEASE & GRANULOLOMATOUS DISEASE:

Tests for ANA & Anti DNA antibodies

Complements

Anti Neutrophil Cytoplasma antibodies

Cryoglobulins, Rheumatoid factor

Thyroid profile for hyperthyroidism

HIV antibody tests

Hepatitis A, B, C viral antibody assay

Imaging Studies:

Abdominal radiographs for calcifications of adrenals

Routine Abdominal Ultrasound

IV urography

CT scans

MRI

Others:

Endoscopic examination

Radionucleotide studies (VPRS, PA etc.)

Positron emission tomography (PET)

Echocardiography

Invasive procedure for abnormal finding:

Lumber puncture

Skin biopsy for rash

Lymph aspiration or biopsy

BMA or biopsy

Liver biopsy

Laparotomy or laparoscopy

TREATMENT

1. Emphasis on continuous observation and physicals examination

2. Direct treatment toward the underlying cause.

3. Routine antipyretic is unacceptable in adult hospitalized patient.

4. Routine use of antibiotic is not recommended for virus infection.

5. Therapeutic trial of antibiotic are very difficult to interpret.

6. Empirical Therapeutic trialAnti MalarialAnti TyphoidalAnti TB, Anti Amoebic.

PROGNOSIS IN PUO

The overall mortality of PUO is 30-40% (age under 55 years: 5%; age over 55 years:30%).

Older patients are more likely to have a malignancy. If no cause is found on exhaustive investigation, the long-term mortality is low.

On long-term follow-up of these patents no single disease features strongly and in most cases the fever settles spontaneously.

About 15% of the patients with PUO have no diagnosis or resolves spontaneously.

CONCLUSION

PUO an Evasive clinical problem & difficult to detect primary care physician first to encounter this condition needs well planned, strategic approach to work-up the patients with this problem.

Understanding etiology incorporating thorough history taking & physical examination with more planned testing can lead to finally discovery and treatment.

In most case, the causes of PUO is a familiar disease with an uncommon presentation rather than a rare disease.

Avoid empirical therapy unless there are some modifiers of disease and special circumstances.

Avoid subtherapeutic dosing and multiple empirical therapies simultaneously.