Fever of Unknown Origin - Sochinf · Fever of Unknown Origin •No standard definition in children •Reasonable Definition: Unexplained fever (> 38° C or 100.4° F) persisting for

Pediatrics

Fever of Unknown

Origin in Pediatrics

Sheldon L. Kaplan, MD

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Fever of Unknown Origin

•No standard definition in children

•Reasonable Definition:

Unexplained fever (> 38° C or 100.4° F) persisting

for > 2 weeks despite a careful history, physical

examination and initial laboratory assessment

including urine culture and chest radiograph

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Diagnosis of FUO and Prolonged Fever in 146

Children from 1990 to 1996.

Arkansas Children’s Hospital

Category No. (%) of children

Established Diagnosis 84 (57.5)

Infectious Disease 64 (43.8)

Autoimmune 11 (7.5)

Malignancy 4 (2.7)

Other 5 (3.4)

Jacobs and Schutze Clin Infect Dis 1998

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Infectious Disease Etiologies in 64 Children with

FUO and Prolonged Fever from 1990-1996.

Arkansas Children’s Hospital

•EBV 22

•Osteomyelitis 14

•Bartonellosis 7

•UTI 6

•Enterovirus 2

•CMV 4

•HIV 1

•Tularemia 4

•Ehrlichiosis 3

•Blastomycosis 1

Jacobs and Schutze Clin Infect Dis 1998

History in FUO Evaluation

Activity

Weight loss or gain

Rash

Musculoskeletal

Abdominal complaints

Area of residence

Travel

Drugs

Contacts

Ingestion

Pets & other animal

exposure

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Physical Examination Clues for FUO

•Skin rash (JRA), petechiae (IE)

•Lymphadenopathy (EBV, CMV, Cat scratch disease, lymphoma)

•Heart murmur (IE)

•Hepatosplenomegaly (RE infections, cat scratch disease, abscess, malignancy)

•Abdominal mass (malignancy, abscess, IBD)

•Joint effusions (JIA, IBD, SLE)

•Bone pain - osteomyelitis

•Eye findings C/W autoimmune disease

•Mucous membranes - ulcers (IBD)

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Evaluation of Children with FUO

CBC, ESR, CRP

U/A and urine culture

PPD

Uric Acid and LDH

Serologies: EBV, Bartonella henselae, HIV (if risk factors)

Blood culture

CXR

Abdominal Ultrasound

Daily temperature recordings at home

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Cat-Scratch DiseaseTransmission

•Young cats < one year old are more likely to have high grade B. henselae bacteremia (>103 cfu/mL) than older cats.

•Younger cats may also be more likely to be infested with fleas

•Flea-borne transmission of B. henselae from cat to cat is efficient but no evidence flea is a vector for humans.

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Hepatosplenic Cat Scratch Fever

•Exposure to kittens usual

•prolonged fever, +

abdominal pain, usually

well in between fever

•may observe papule or

scratches,

lymphadenopathy

•hepatosplenomegaly and

tender to liver palpation

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Hepatosplenic Cat Scratch Fever

•Liver ultrasound or abdominal CT scan shows

characteristic lesions (single or multiple)

•Antibody to Bartonella henselae present

•May respond to rifampin + azithromycin or

aminoglycoside therapy

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Hepatosplenic Cat-Scratch

Disease in Children at TCH•19 cases reviewed with + serology from CDC and typical U/S or CT findings

•Age range: 2.3 to 11.7 years old

•All with history of cat exposure

•9 evaluated for FUO, 6 referred for FUO + abdominal pain

•Duration of fever from onset to Dx was 7 to 56 days (mean: 22 days)

•After fever, abdominal pain was the second most common complaint

•Weight loss in 8 children (1 to 4 kg)

Arrisoy et al Clin Infect Dis 1999;28:778-84

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Hepatosplenic Cat-Scratch

Disease in Children at TCH•All hospitalized a mean of 4.6 days (range:1-13 days)

•13 treated with rifampin alone, 3 with rifampin+ gentamicin or TMP-SMX

•After rifampin initiated, improvement was noted within 1 to 5 days-mean was 2.6 days

•Most common rifampin dose was 20 mg/kg/day in 2 divided doses for 14 days

Arrisoy et al Clin Infect Dis 1999;28:778-84

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Cat-Scratch Disease at TCH

September 2000-August 2001

•32 children identified through positive serology performed at CDC; 14 hospitalized

•Median age was 6 years (range: 2-15 y)

•Half of the children presented in the months of July through September.

•20-classic CSD with fever and regional adenopathy

•5-prolonged fever w/o organ involvement

•4-hepatosplenic CSD with fever

•3-other (encephalitis, endocarditis, vertebral osteomyelitis)

MMWR 2002;51:212-4

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•Hospital San Juan de Dios, Universidad de Chile,

Santiago

•January 2004 to December 2011

•24 children with positive Bartonella henselae

serology who had a bone scan

•4 admitted with FUO

Donoso et al. Clin Nucl Med 2013;38:936-939

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•Congenital heart defects such as ventricular septal defect,

aortic valve abnormalities, and tetralogy of Fallot are common

underlying conditions; increasing proportion of cases have

had corrective or palliative surgery with or without prosthetic

material implanted.

•IE in the absence of CHD is often associated with central

indwelling venous catheters.

•In approximately 8% to 10% of pediatric cases, IE develops

without structural heart disease or other identifiable risk

factors and usually involves infection of the aortic or mitral

valve secondary to Staphylococcus aureus bacteremia

Baltimore et al. Circulation 2015;132:1487-1515

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Clinical Manifestations of Infective

Endocarditis in Children

•Malaise-55%

•Anorexia/weight

loss-31%

•Fever-90%

•Heart failure-30%

•Arthralgia-24%

•Neurologic-18%

•Gastrointestinal-16%

•Chest pain-9%

Textbook of Pediatric Infectious Diseases 2013

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Clinical Manifestations of Infective

Endocarditis in Children

•Splenomegaly-55%

•Petechiae-33%

•Embolic lesions-28%

•New or changing

heart murmur-24%

•Clubbing-14%

•Osler nodes-7%

•Roth spots-5%

•Janeway lesion-5%

•Splinter

hemorrhages-5%

Textbook of Pediatric Infectious Diseases 2013

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Selected Laboratory Findings of

Bacterial Endocarditis in Children

Laboratory Finding Average (%) Range (%)

Positive blood culture

87 68-98

Elevated erythrocyte

sedimentation rate80 71-96

Low hemoglobin (anemia)

44 19-79

Positive rheumatoid factor

38 25-55

Hematuria 35 28-47

Feigin & Cherry 7th Edition

Textbook of Pediatric Infectious Diseases

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Organism Average (%) Range (%)

Streptococci

Viridans 40.3 17-72

Enterococci 4.0 0-12

Pneumococci 3.3 0-21

β-Hemolytic 2.7 0-8

Other 1.1 0-16

Staphylococci

Staphylococcus aureus

23.8 5-40

Coagulase-negative 4.7 0-15

Gram-negative aerobic bacilli

4.0 0-15

Fungi 1.1 0-12

Miscellaneous bacteria 2.4 0-10

Culture-negative 12.6 2-32

Etiologic Agents of Bacterial Endocarditis in Children

Feigin & Cherry 7th Edition

Textbook of Pediatric Infectious Diseases

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Salmonella typhi

•12.5 million cases / yr worldwide

‐10-540 cases / 100,000 in developing countries

‐0.2-3.7 cases / 100,000 in western Europe, US, and Japan

•US

‐28% patients < 19 years

‐62-81% foreign travel

•Mexico, India, Philippines, Pakistan, El Salvador and Haiti

•Indian subcontinent has the highest incidence of typhoid among travelers

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Pyogenic Liver Abscess

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Brucellosis

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Brucellosis-Clinical Manifestations

Symptoms Signs

•fever lymphadenpathy

•night sweats hepatosplenomegaly

•malaise arthritis

•weight loss

•anorexia

•arthralgias, myalgias

•headaches

•abdominal pain

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Kawasaki Disease

Infants ≤6 months old on

day ≥7 of fever without

other explanation should

undergo laboratory

testing and, if evidence

of systemic inflammation

is found, an

echocardiogram, even if

the infants have no

clinical criteria..

2012 Red Book

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Hereditary Periodic Fever

Drenth JPH, van der Meer JWM N Engl J Med 2001;345:1748-1757

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Syndrome of Periodic Fever, Pharyngitis,

and Apthous Stomatitis

•usual onset before 5 years

•symptoms occur with striking regularity usually at 4 to 6 week intervals

•attacks characterized by high fever, malaise, chills apthous stomatitis, pharyngitis, headache, and cervical lymphadenopathy

•nausea, vomiting, and abdominal pain may occur

Marshall et al. J Pediatr 1987

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Syndrome of Periodic Fever, Pharyngitis, and

Apthous Stomatitis

•leukocytosis and elevated ESR

•resolves spontaneously after 4 to 5 days

•not associated with abscesses, pneumonia,

furunculosis, or neutropenia

•child grows and develops normally

•episodes may recur for several years

Marshall et al. Marshall et al. J Pediatr 1987

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Hemophagocytic Syndrome

•Non-malignant proliferative disorder that affects

the antigen-processing macrophages

•Uncontrolled hemophagocytosis and

upregulation of inflammatory cytokines

•A primary element of the defective immunity is

markedly impaired natural killer (NK) cell

function

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Hemophagocytic Lymphohistiocytosis

HLH Associations

Primary

• Primary HLH is an autosomal recessive

disease that can appear sporadically or as a

familial disorder

Secondary

•Virus: EBV, CMV, Herpes simplex, Hepatitis B,

Rubeola, Parvovirus, Adenovirus, others

•Bacterial Infections including TB and Brucellosis

•Parasites-Malaria, Babesiosis, Leishmaniasis

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Hemophagocytic Lymphohistiocytosis

HLH AssociationsSecondary

•Malignancy:T-cell lymphoma, leukemia

•Immune Deficiency: X-linked lymphoproliferative

Disease, Chédiak-Higashi,

Hypogammaglobulinemia

•Autoimmune: SLE, JRA, Kawasaki disease

•Drugs:Phenytoin

•Prolonged administration of fat-soluble lipids

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Diagnostic Criteria for the Hemophagocytic SyndromeNeed 5 of the following 8 findings

• Fever ≥38.5°C

• Splenomegaly

• Peripheral blood cytopenia, with at least two of the following: hemoglobin <9 g/dL (for

infants <4 weeks, hemoglobin <10 g/dL); platelets <100,000/microL; absolute

neutrophil count <1000/microL

• Hypertriglyceridemia (fasting triglycerides >265 mg/dL) and/or hypofibrinogenemia

(fibrinogen <150 mg/dL)

• Hemophagocytosis in bone marrow, spleen, lymph node, or liver

• Low or absent NK cell activity

• Ferritin >500 ng/mL (the author prefers to consider a ferritin >3000 ng/mL as more

indicative of HLH

• Elevated soluble CD25 (soluble IL-2 receptor alpha) two standard deviations above

age-adjusted laboratory-specific norms

K. McClain UpToDate 2015

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Hemophagocytic Syndrome in

Children with FUO at TCH 1991-2001

Number: 19

Gender: 6 male, 13 female

Ethnicity: 42% Hispanic, 32% Caucasian,

16% Asian, 11% African American

Age: median 17.4 months

range, 7 days to 16 years

Fever duration: median 19 days prior to diagnosis

range, 4 to 41 days

Palazzi et al. Clin Infect Dis 2003

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Hemophagocytic Syndrome in

Children with FUO at TCH 1991-2001

Ferritin: Elevated in 100%, > 4000 µg/L in 95%

Infectious agent: Isolated in 42%, all viral

4 EBV, 4 adenovirus, 2 RSV,

1 parainfluenza 3

Non-infectious cause: 3 patients (SLE, JRA, KD)

Mortality: 75% in children < 12 months of age

36% in children > 12 months of age

53% overall


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Laboratory study Median Range Abnormality (%)

LDH 8008 616-25,132 100

AST 387 35-4690 90

ALT 119 35-805 90

Direct bilirubin 3.8 0.6-9.4 80

Serum sodium 131 125-143 79

Laboratory values in 19 children with HPS

TCH 1991-2001


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CLINICAL FINDINGS

Fever

Hypotension

Respiratory distress

Hepatosplenomegaly

LABORATORY FINDINGS

Anemia

Thrombocytopenia

Neutropenia

Elevated AST/ALT

Elevated bilirubin

Elevated LDH

ORDER

Infectious agents tests

ADDITIONAL LABS

Elevated PT/PTT

Decreased fibrinogen

Ferritin > 4000

FEVER OF UNKNOWN ORIGIN

PURSUE

Bone Marrow Aspiration

(BMA) and Biopsy

If BMA positive for hemophagocytosis

and/or high clinical suspicion

and ferritin >4000,

Start treatment protocol

HOW CAN THE EVALUATION OF A PATIENT

WITH FUO LEAD TO A DIAGNOSIS OF HPS?

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Conclusions

•FUO in children usually related to an infection which varies

with the local epidemiology.

•In a large percentage of patients the fever will resolve

without a specific diagnosis.

•A normal CBC, ESR and CRP are generally reassuring and

suggest a serious condition is unlikely.

•Consider Hemophagocytic syndrome in the differential

diagnosis of FUO in ill children.

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Thank You

Fever of Unknown Origin - Sochinf · Fever of Unknown Origin •No standard definition in children •Reasonable Definition: Unexplained fever (> 38° C or 100.4° F) persisting for

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