Patients with fever not meeting these criteria, and specifically those admitted to the hospital with neither an apparent site of infection nor a noninfectious diagnosis, may be considered to have fever without localizing signs.

Abscesses:

Abdominal, brain, dental, hepatic, pelvic, perinephric, rectal, subphrenic,psoas

Infections:
Bacterial

1. Brucellosis
2. Salmonella
3. Tuberculosis
4. Bartonella henselae (cat-scratch disease)
5. Francisella tularensis,Listeria monocytogenes
6. Rat-bite fever (Streptobacillus moniliformis; streptobacillary form)
7. Others -Mycoplasma pneumoniae ,Yersiniosis, Actinomycosis , Campylobacter , Meningococcemia (chronic) -rarely
8. Localized infections- Cholangitis ,Infective endocarditis ,Mastoiditis , Osteomyelitis,Pneumonia ,Pyelonephritis ,Sinusitis

Spirochetes

1. Borrelia burgdorferi(Lyme disease),Relapsing fever (Borrelia recurrentis)
2. Leptospirosis
3. Rat-bite fever (Spirillum minus; spirillary form of rat-bite fever)
4. Syphilis

Fungal diseases
Blastomycosis (extrapulmonary) ,Coccidiodomycosis (disseminated) ,Histoplasmosis (disseminated)
Chlamydia (Lymphogranuloma venereum,Psittacosis)
Rickettsia (Ehrlichia canis ,Q fever,Rocky Mountain spotted fever ,Tick-borne typhus)

Viruses
CMV, Hepatitis viruses ,HIV, IM (Epstein-Barr virus)

Parasitic Diseases
Amebiasis , Giardiasis ,Babesiosis ,Malaria ,Toxoplasmosis
Trichinosis ,Trypanosomiasis ,Visceral larva migrans (Toxocara)

Rheumatologic diseases

1. Behçet disease
2. Juvenile dermatomyositis
3. JRA
4. Rheumatic fever
5. SLE
6. Hypersensitivity diseases-Drug fever,Hypersensitivity pneumonitis ,Pancreatitis ,Serum sickness ,Weber-Christian disease

Neoplasms

1. Atrial myxoma
2. Cholesterol granuloma
3. Hodgkin disease
4. Inflammatory pseudotumor
5. Leukemia
6. Lymphoma
7. Neuroblastoma
8. Wilms tumor

Granulomatous diseases

1. Crohn disease
2. Granulomatous hepatitis
3. Sarcoidosis

Familial-hereditary diseases

1. Anhidrotic ectodermal dysplasia
2. Fabry disease
3. Familial dysautonomia
4. Familial Mediterranean fever
5. Hypertriglyceridemia
6. Ichthyosis
7. Sickle cell crisis

Miscellaneous

1. Chronic active hepatitis
2. Diabetes insipidus (non-nephrogenic and nephrogenic)
3. Factitious fever
4. Hemophagocytic syndromes
5. Hypothalamic-central fever
6. Infantile cortical hyperostosis
7. Inflammatory bowel disease
8. Kawasaki disease
9. Periodic fevers
10. Poisoning
11. Pulmonary embolism , Thrombophlebitis ,
12. Thyrotoxicosis

Undiagnosed fever
Persistent, Recurrent, Resolved

Diagnostic Approach:

A careful history and physical examination is the first step in evaluating a patient with fever of unknown origin.
History:
Fever
o Duration, height and pattern, measurement technique
o Appearance of the child during the febrile episode
o Whether or not the fever responds to antipyretic drugs

Lack of response to NSAIDs may indicate a non-inflammatory condition as the cause of the fever
o Associated sweating
Fever, sweating and heat intolerance may indicate hyperthyroidism
Fever, heat intolerance and absence of sweating is suggestive of ectodermal dysplasia

Fever pattern:
o Intermittent:high spike and rapid defervescence-Pyogenic infection ,Can also occur in tuberculosis, lymphoma , JRA
o Remittent:fluctuating peaks and baseline that does not return to normal-Viral infections ,Can occur with bacterial infections, especially endocarditis, sarcoid, lymphoma and atrial myxoma
o Sustained: persist with little or no fluctuation-Typhoid fever, typhus and brucellosis
o Relapsing: afebrile for one or more days in between febrile episodes-Malaria, rat bite fever, Borrelia infection and lymphoma
o Recurrent: episodes of fever of more than six month’s duration-Metabolic defects,CNS dysregulation of temperature control,Periodic disorders such as cyclic neutropenia, hyperimmunoglobulin D syndrome and deficiencies of selected
Rash

Examination of the characteristics and distribution of the rash will help in the diagnosis of the cause.
A maculopapular, petechial, or urticarial rash -bacterial infections or with medication-related fever.
Viral infections -non-specific maculopapular or a petechial rash.
Many inflammatory/vasculitic disorders present with a rash.

Arthralgias –
septic arthritis and osteomyelitis;
viral infections such as infectious mononucleosis, CMV, toxoplasmosis, and tick-borne illnesses (Lyme disease or Rocky Mountain spotted fever);
medication-related reactions; or malignancies

Poor growth, poor appetite, and weight loss are observed with any chronic illness as opposed to a history that is of relatively short duration (e.g., bacterial infections).
Absent tears are observed in autonomic disease.
There may be a history of recent tick or mosquito bite with Lyme disease, Rocky Mountain spotted fever, and malaria infection.
Bone pains are present in osteomyelitis, leukemia, juvenile idiopathic arthritis (JIA), and SLE.
CNS symptoms -encephalitis, bacterial endocarditis, myocarditis, cerebral abscesses, tuberculous meningitis, secondary spread from a malignancy, severe inflammatory disorders (e.g., SLE), and cerebral malaria. Chorea is present with advanced rheumatic fever.
Urinary symptoms of dysuria, frequency, and haematuria accompany UTIs such as cystitis and pyelonephritis.

Associated complaints
o Include past or current complaints
Exposure
o Sick contacts
o Animal exposures

Household pets, domestic animals in the community and wild animals
o Travel history starting at birth

Site of travel
Prophylactic medications and immunizations for travel
Exposure to contaminated food and water while traveling
Exposure to other persons with recent travel
o Tick or mosquito bites
o Consumption of raw or undercooked meat or raw shellfish
o Consumption of dirt (pica)

Ethnic background
o Ulster Scots: nephrogenic diabetes insipidus
o Sephardic Jewish, Armenian, Turkish or Arab descent: familial Mediterranean fever , Ashkenazi Jewish descent: familial dysautonomias

Physical Exam
Careful physical exam which should be performed while the patient is febrile
Special attention to the following areas:
General appearance and vital signs
Skin and scalp
Eyes
Sinuses
Oropharynx
Lymph nodes
Abdomen
Musculoskeletal
Genitourinary

Heart rate-Tachycardia -common with fever, but persistent tachycardia may suggest thyroid storm or endocarditis/myopericarditis.
Respiration-Tachypnoea may be present in pneumonia, or multisystem disorders with lung involvement.
BP measurement
Hypertension-inflammatory/vasculitic disorders, chr pyelonephritis, SLE, and thyroid storm.
Postural hypotension -toxic shock syndromes, medication-related, and autonomic disorders.
Pallor-leukemia, lymphoma, most chronic bacterial infections and inflammatory/vasculitic illnesses, malaria, and tuberculosis.
Jaundice-Present in patients with hepatic abscess and infectious mononucleosis.
Clubbing-Present in patients with endocarditis, inflammatory bowel disease, and tuberculosis.

Lymphadenopathy
Isolated cervical lymphadenopathy -Kawasaki disease and cat-scratch disease.
Disseminated lymphadenopathy -Infectious mononucleosis, CMV, toxoplasmosis, leukemia, lymphomas, tick-borne illnesses, and some inflammatory/vasculitic illnesses.
Most bacterial infections give rise to regional lymphadenopathy.
The ulceroglandular form of tularaemia typically presents with lymphadenopathy.

Diagnostic Studies
Directed toward likely cause of fever based on information gained from the history and physical
Timing of labs and studies is based on severity of illness
For Serious cases no diagnostic test should be delayed.

CBC
o Anemia: malaria, IE, IBD, SLE or tuberculosis
o Thrombocytosis: Kawaskai disease
o WBC: atypical lymphocytes -viral infection, immature forms -leukemia , Eosinophilia-parasitic, fungal, neoplastic, allergic or immunodeficiency disorders

ESR and CRP: non-specific acute phase reactants and general indicators of inflammation Initial Tests:

Urinalysis and urine culture: UTI is a common source of FUO, sterile pyuria is suggestive of Kawaski disease or genitourinary tuberculosis

Chest X Ray: evaluate for infiltrates or lymphadenopathy

Mantoux test
Serum electrolytes, BUN, creatinine and hepatic enzymes

HIV: significant variability in manifestations of primary HIV infection

Initian Test

1.CBC ,PS,ESR, CRP
2.Aerobic blood C/S, UA, urine C/S,
3.CXR, tuberculin skin test,
4.Electrolytes, BUN, creatinine,
5.hepatic enzymes, HIV serology
Blood cultures: obtain several sets if infective endocarditis is a consideration

Additional Tests are Guided by information obtained with history, physical exam and results of initial testing

Stool studies: culture, ova and parasites in patients with loose stools or recent travel

Bone marrow: most useful in diagnosing malignancy, histiocytic disorders and hemophagocytic disease, not helpful in diagnosing infection

Serologies: targeted approach is indicated
HIV serology for all children with FUO
Syphilis is recommended for neonates, young infants and adolescents
Consider evaluation for EBV, CMV, toxoplasmosis, bartonellosis, brucellosis, tularemia as well as parasitic infections such as strongyloidiasis
Serum ANA: obtain in children over age 5 with family history of rheumatologic disease
Immunoglobulins:serum IgG, IgA and IgM in children with evidence of recurrent or persistent infections and in those with persistent fever and a negative initial evaluation
Molecular testing: (ie PCR) may be useful in specific cases
Ophthalmologic exam can be helpful to evaluate uveitis or leukemic infiltration

Imaging and other evaluations

Abdominal imaging
o Indicated if inflammatory bowel disease is suspected
o Consider if fever may be due to intrabdominal abscess -psoas abscess or cat scratch disease .

Imaging of the nasal sinuses or mastoid is recommended if sinusitis is a possible etiology for FUO

ECG/Echocardiography should be performed if there is concern for infective endocarditis

Biopsy is recommended only when there is evidence of specific organ involvement

Computed Tomography Scanning- If USG fails to help reveal the diagnosis, obtain CT scans of the abdomen in all patients with symptoms suggesting an intra-abdominal process, Intravenous pyelographymay be more sensitive than CT scanning in detecting processes involving the descending urinary tract, but CT scanning is preferred for most other processes of the retroperitoneal space.

Magnetic Resonance Imaging-osteomyelitis, vasculitides.
Endoscopic Examination
Upper and lower gastrointestinal tract, including retrograde cholangiography when indicated or when searching for Crohn disease,Whipple disease, biliary tract disease, and gastrointestinal tumors..
Radionucleotide Studies
Ventilation and perfusion radionucleotide studies to document pulmonary emboli.
A technetium bone scan may be a more sensitive method for documenting skeletal involvement when osteomyelitis is suspected in a patient in whom conventional radiography has shown no compatible changes.
Consider radionucleotide studies using gallium citrate or granulocytes labeled with indium In 111 (111In) for diagnosis of occult abscesses, neoplasms, or soft-tissue lymphomas.
Angiography, Echocardiography
Biopsy

Empiric Treatment

Approach Considerations-
Generally avoid empiric treatment with anti-inflammatory medications or antibiotics as an effort to diagnose the patient’s condition.
Empiric antibiotics can mask or delay diagnosis of infections such as meningitis, infectious endocarditis or osteomyelitis

Exceptions:
O Nonsteroidal agents in presumed JIA
O Antituberculosis drugs in critically ill children with possible disseminated TB
O Clinically deteriorating with suspicion of bacteremia or sepsis.
O Immunocompromised
Antibiotics if used should be at targeted disease rather than blancket therapy with 4-5 antibiotics.

In general, empiric therapy has little or no role in cases of classic fever of unknown origin (FUO).Treatment should be directed toward the underlying cause, as needed, once a diagnosis is made.Some studies suggest a few exceptions to this general approach, including the following:
1.Cases that meet criteria for culture-negative endocarditis
2.Cases in which findings or the clinical setting suggests cryptic disseminated TB (or, occasionally, other granulomatous infections)
3.Cases in which temporal arteritis with vision loss is suspected.

Inpatient Treatment-No evidence supports prolonged hospitalization in patients who are clinically stable and whose workup findings are unrevealing.

Outpatient Care-Conduct close follow-up procedures and systematic reevaluation studies to prevent clinical worsening. Guide further workup studies on an outpatient basis.

Patient Transfer-The need for transfer is indicated if (1) the current facility is unable to establish a diagnosis, (2) diagnostic tests are unavailable at the existing facility, or (3) the patient deteriorates clinically.

Several studies have found that prolonged, undiagnosed FUO generally carries a favorable prognosis.

The Best Approach
“ there is no substitute for observing the patient , talking to him and thinking about him”

REFERENCES-

1.Nelson Text Book of Pediatrics 18thEdition

2.Ergönül O, Willke A, Azap A, et al. Revised definition of ‘fever of unknown origin’: limitations and opportunities.J Infect. Jan 2005;50(1)

3.Cunha BA.Fever of Unknown Origin. New York, NY: Informa Healthcare; 2007

4.Pyrexia of Unknown Origin: Approach to management ,Singapore Medical Journal 2005 Vol 36: 204-208)

5.Feigin RD, Shearer WT. Fever of unknown origin in children.Curr Probl Pediatr.1976;6:1ospital.

6.Tolan, R.W. Fever of Unknown Origin: A Diagnostic Approach to This Vexing Problem. Clinical Pediatrics. 2010 49:207

7. medscape-emedicine

• Exanthems – eruption of skin accompanied by inflammation.
• Enanthems – eruption of mucous membrane.

Maculopapular rashes :

• Measles
• Rubella
• Erythema Infectiosum
• Roseola
• Coxsackie
• Echo virus
• CMV and HBV
• Erythema Multiforme due to Herpes virus, EBV, Adeno virus, Chlamydia, Salmonella, Mycobacteria, Histoplasma, Coccidiosis

Nodular rashes :

• Fungal disease
• Atypical Mycobacteria
• Pseudomonas infection
• Erythema Nodosum – Streptococcus, Mycobacteria, Yersinia, HCV, Sarcoidosis, Drugs and IBD

Diffuse erythematous with peeling or desquamation :

• Scarlet fever
• Toxic shock syndrome
• Kawasaki disease(KD)
• Staphylococcal Scalded Skin Syndrome(SSSS)
• Steven-Johnson Syndrome

Vesicobullous rashes :

vesiculobullous rashes

• Varicella
• Herpes virus
• Coxsackie
• Enterovirus
• Meningococcal
• Group A Streptococcal
• Pseudomonas

Petechial and Purpuric rashes :

• Epstein-Barr virus(EBV)
• ECHO virus-9
• Cytomegalo virus(CMV)
• Rickettsial
• Malaria
• Pneumococcal
• Meningococcal
• Listeria