Approach to fever

( including pyrexia of
unknown origin)
Presenter: Dr. Angeline Ooi Ying Ying
Supervisor: Dr. Ho SY
What is Pyrexia of unknown origin
(PUO)
 PUO refers to a prolonged febrile illness without an established aetiology
despite intensive evaluation and diagnostic testing.
 Fever higher than 38.3ºC on few occasions
 Duration at least three weeks
Approach to PUO

 GOOD History & Physical examination

 Complete blood count, including differential and platelet count
 Blood cultures (3 sets ,different sites, interval at least few hours
between each; before antibiotics)
 Routine blood chemistries, including liver enzymes and bilirubin
 If liver tests are abnormal, hepatitis A, B, and C serologies
 Urinalysis, microscopic examination, and urine culture
 Chest radiograph
 If any signs or symptoms point to a particular organ, further testing,
imaging, and/or biopsy should be pursued.
 Approach to PUO

 Gastrointestinal tract system

 Central nervous system
 Infective acute gastroenteritis (AGE)
 Meningitis  Intraabdominal abscess
 Respiratory system  Appendicitis
 Diverticulitis
 Upper/lower respiratory tract infection  Cholecystitis
(URTI/LRTI)  Cholangitis
 Tuberculosis (TB)  Liver abscess
 Cardiovascular
 Infective endocarditis system
 Rheumatic fever
 Genitourinary system  Systemic fever
  Urinary tract infection  Dengue fever
 Malaria
  Intrarenal abscess  Leptospirosis
  Pyelonephritis  Toxoplasmosis
 Psittacosis
  Pelvic inflammatory disease (PID)
 Others
 Malignancy eg Carcinoma of liver
 Hematological system
(HCC), kidney (RCC)
  Acute myeloid lymphoma (AML)  Thyroid storm
  Chronic myeloid lymphoma (CML)

 Skin or connective tissue

  Rheumatoid arthritis
  Systemic lupus erythematosus
History taking

 Fever
o duration (how many days)
o high / low grade fever (measured temperature?)
o any chills/rigor?
o pattern of fever (continuous, intermittent)
o relieved by paracetamol?
o precipitating factor - history of dental/GIT/GUT procedure prior to onset of
fever?
Associated symptoms
 Meningitis
o Fever, neck stiffness, seizures, headache, nausea, vomiting, photosensitivity, confusion,
sleepiness
 URTI
o Sore throat, cough, runny nose
 Infective endocarditis
o History of dental/GIT/ GUT procedure , anaemic symptoms, renal symptoms –
haematuria, proteinuria, rashes
 Tuberculosis
o Haemoptysis, night sweats, loss of appetite, loss of weight, TB contact
 Associated symptoms
 UTI
o Urinary frequency, urgency, dysuria, haematuria
o Back pain (pyelonephritis)
 Genitourinary
o Dyspareunia, abdominal pain, per vaginal bleed, foul smelling discharge, penile
discharge
 Skin
o Itchiness, rash (maculopapular, vesicle)
o site of rash
 Systemic fever (tropical diseases)
o Dengue (any rash, arthralgia, live in dengue endemic area, recent fogging, travel
history)
o Malaria (history of jungle trekking/ travel to endemic area, pattern of fever)
o Leptospirosis (contact with rodents, swimming in river)
o Toxoplasmosis (contact with cat)
o Psittacosis (contact with birds)
 Connective tissue disease
o RA
 Morning stiffness (>1 hr >6 weeks) before maximal improvement
 Arthritis (>3 joints >6 weeks)
 Symmetrical joints involvement
 Small joints of hands
 Rheumatoid nodules
 Radiographic changes (erosion)
o SLE
 arthritis
 oral ulcers, malar rash, discoid rash, exaggerated photosensitivity
 haematological disorder
 immunological disorder, serositis (pleuritis, pericarditis)
 CNS disorder (seizure)
 Hematological malignancy
o Anaemic symptoms: lethargy, dyspnea, palpitation, syncope
o Any recurrent infection
 Other malignancies
o constitutional symptoms: lymph node enlargement, weight loss, fatigue,
malaise
Etiologies

 Infection
 noninfectious inflammatory diseases
 Malignancy
 Others’
 Geographical factors
Infections

■ Tuberculosis
■ Abscess
■ Osteomyelitis
■ Bacterial endocarditis
■ Others
Connective tissue disease

 RA
 SLE
■ Adult Still’s disease
■ Giant cell arteritis
■ Polyarteritis nodosa
■ Takayasu's arteritis
■ Granulomatosis with polyangiitis
■ Mixed cryoglobulinemia
Malignancies

■ Non-Hodgkin’s lymphoma
■ Other lymphoma
■ Leukemia
■ Myelodysplastic syndromes
■ Multiple myeloma
■ Renal cell carcinoma
■ Hepatocellular carcinoma or metastasis
Drugs

■ 1/3 of hospitalized patients suffer from adverse drug reactions, including

"drug fever."
■ Allergic or idiosyncratic reaction or by affecting thermoregulation by drugs
■ Eosinophilia and rash accompany drug fever in 25 % of cases;
■ Absence of these should not preclude a search for a possible offending drug
 The diagnosis of drug fever is made by a trial of stopping the suspected
drug (with occasional rechallenge).
■ Most patients will defervesce within 72 hours although some may not
recover for weeks.
■ Clearance of offending drug derivatives may be delayed if the derivatives
become bound or haptenated on long-lived host proteins
 Antimicrobials (sulfonamides, penicillins, nitrofurantoin, vancomycin,
antimalarials)
 H1- and H2-blocking antihistamines
 Antiepileptic drugs (barbiturates and phenytoin)
 Iodides
 Nonsteroidal antiinflammatory drugs (including salicylates)
 Antihypertensive drugs (hydralazine, methyldopa)
 Antiarrhythmic drugs (quinidine, procainamide)
 Antithyroid drugs
 Contaminants such as quinine that accompany injected cocaine or
heroin
 A number of drugs rarely cause fever, such as digoxin and
aminoglycosides.
Disordered heat homeostasis

 Hypothalamic dysfunction d/t damage to brain (eg, massive stroke or

anoxic brain injury)
 Abnormal heat dissipation (from skin conditions such as ichthyosis-
impaired sweat glands).
 Hyperthyroidism (metabolic disease)
Dental abscess

 Apical dental abscesses are a rare cause of persistent fever that can be
overlooked by the patient and physician.
 Most individuals defervesced following removal of the decayed teeth,
with or without antimicrobial therapy.
 Other conditions linked to oral disease include brain abscesses,
meningitis, mediastinal abscesses, and endocarditis
Concurrent infections

 multiple concurrent opportunistic infections in PUO patients with AIDS

particularly when CD4 counts are very low.
■ Ie: cytomegalovirus, Mycobacterium avium complex, Pneumocystis jirovecii,
endemic fungi (eg, Histoplasma capsulatum), and gastrointestinal protozoa (eg,
Cryptosporidium, Microsporidium).
■ Other types of immunocompromised hosts may also present with PUO caused
by more than one infection
■ babesiosis, Lyme disease, and anaplasmosis/ehrlichiosis, have varying
incubation periods and different susceptibilities to antimicrobials, may infect
concurrently or serially and present as PUOs or relapsing fever syndromes.
■ Q fever, leptospirosis, psittacosis, tularaemia, and melioidosis.
■ secondary syphilis, chronic meningococcaemia, visceral leishmaniasis,
Whipple's disease, and yersiniosis.
Alcoholic hepatitis

 characteristic signs and symptoms = fever, hepatomegaly, jaundice,

and anorexia.
 Fever is typically modest (< 38.3 C)
 Typical laboratory abnormalities
 AST > ALT ratio >2.0
Other causes

 Venous thrombosis and thromboembolism,

 Hyperthyroidism and subacute thyroiditis
 Phaeochromocytomas
Factitious fever

 psychiatric condition
 secondary gain.
 evidence of self-mutilation, had multiple hospitalizations, invasive
diagnostic tests (eg, cardiac catheterization), and surgery.
 The response to psychiatric intervention is discouraging

 manipulation of thermometers- but less with modern digital

thermometers
Investigations

 Esr
 Crp
 3 blood cultures, from different sites several hours apart (before
antibiotics)
 Rheumatoid factor
 Creatine kinase (CK)
 Heterophile antibody test in children and young adults
 Antinuclear antibodies
 Serum protein electrophoresis
 HIV
Identify sites of involvement
 CT scan or MRI of the Chest, Pelvis, Abdomen
 Bone marrow biopsy
Other investigations

 Lumbar puncture > biochemistry, specific panels (ie viral panel, VDRL),
cultures
 Fungal cultures (histoplama, coccidiomycosis)
 Tuberculosis culture/mycobacterium cultures
 Thick and thin films for malaria
 Biopsies: lymph nodes, pleural, liver, temporal artery, bone marrow
 Echocardiogram : to look for vegetation
 PET CT scan: if suspect malignancy
 Drugs with antipyretic effects may delay or obscure early symptoms
and signs of specific diseases-
 ■ Acetaminophen ■ NSAIDS ■ Steroids
THANK YOU

References
■ Drenth JP, van der Meer JW. Hereditary periodic fever. N Engl J Med 2001;
345:1748.
■ Society of Critical Care Medicine (SCCM) and the European Society of
Intensive Care Medicine (ESICM)