Fever of Unknown Origin in Pediatrics

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1 Fever of Unknown Origin in Sheldon L. Kaplan, MD

Fever of Unknown Origin No standard definition in children Reasonable Definition: Unexplained fever (> 38 C or 100.

2 Fever of Unknown Origin No standard definition in children Reasonable Definition: Unexplained fever (> 38 C or F) persisting for > 2 weeks despite a careful history, physical examination and initial laboratory assessment including urine culture and chest radiograph Page 2 xxx00.#####.ppt 12/8/2015 6:56:05 PM

4 Diagnosis of FUO and Prolonged Fever in 146 Children from 1990 to 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) Page 4 Jacobs and Schutze Clin Infect Dis 1998 xxx00.#####.ppt 12/8/2015 6:56:05 PM

5 Infectious Disease Etiologies in 64 Children with FUO and Prolonged Fever from Arkansas Children s Hospital EBV 22 CMV 4 Osteomyelitis 14 Bartonellosis 7 UTI 6 Enterovirus 2 HIV 1 Tularemia 4 Ehrlichiosis 3 Blastomycosis 1 Page 5 Jacobs and Schutze Clin Infect Dis 1998 xxx00.#####.ppt 12/8/2015 6:56:05 PM

6 History in FUO Evaluation Activity Weight loss or gain Rash Musculoskeletal Abdominal complaints Area of residence Travel Drugs Contacts Ingestion Pets & other animal exposure

7 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) Page 7 xxx00.#####.ppt 12/8/2015 6:56:05 PM

8 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 Page 8 xxx00.#####.ppt 12/8/2015 6:56:06 PM

9 Cat-Scratch Disease Transmission Young cats < one year old are more likely to have high grade B. henselae bacteremia (>10 3 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. Page 9 xxx00.#####.ppt 12/8/2015 6:56:06 PM

Hepatosplenic Cat Scratch Fever Exposure to

10 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 Page 10 xxx00.#####.ppt 12/8/2015 6:56:06 PM

11 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 Page 11 xxx00.#####.ppt 12/8/2015 6:56:07 PM

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13 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: Page 13 xxx00.#####.ppt 12/8/2015 6:56:07 PM

14 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: Page 14 xxx00.#####.ppt 12/8/2015 6:56:07 PM

15 Cat-Scratch Disease at TCH September 2000-August 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 Page 15 xxx00.#####.ppt 12/8/2015 6:56:07 PM

16 Hospital San Juan de Dios, Universidad de Chile, Santiago January 2004 to December children with positive Bartonella henselae serology who had a bone scan 4 admitted with FUO Donoso et al. Clin NuclPage Med ;38: xxx00.#####.ppt 12/8/2015 6:56:07 PM

17 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 Page 17 Baltimore et al. Circulation 2015;132: xxx00.#####.ppt 12/8/2015 6:56:07 PM

18 Clinical Manifestations of Infective Endocarditis in Children Malaise-55% Arthralgia-24% Anorexia/weight loss-31% Fever-90% Heart failure-30% Neurologic-18% Gastrointestinal-16% Chest pain-9% Textbook of Pediatric Infectious Diseases 2013 Page 18 xxx00.#####.ppt 12/8/2015 6:56:08 PM

19 Clinical Manifestations of Infective Endocarditis in Children Splenomegaly-55% Osler nodes-7% Petechiae-33% Embolic lesions-28% New or changing heart murmur-24% Roth spots-5% Janeway lesion-5% Splinter hemorrhages-5% Clubbing-14% Textbook of Pediatric Page Infectious 19 Diseases 2013 xxx00.#####.ppt 12/8/2015 6:56:08 PM

20 Selected Laboratory Findings of Bacterial Endocarditis in Children Laboratory Finding Average (%) Range (%) Positive blood culture Elevated erythrocyte sedimentation rate Low hemoglobin (anemia) Positive rheumatoid factor Hematuria Feigin & Cherry Page 20 7 th Edition Textbook of Pediatric Infectious Diseases xxx00.#####.ppt 12/8/2015 6:56:08 PM

21 Etiologic Agents of Bacterial Endocarditis in Children Organism Average (%) Range (%) Streptococci Viridans Enterococci Pneumococci β-hemolytic Other Staphylococci Staphylococcus aureus Coagulase-negative Gram-negative aerobic bacilli Fungi Miscellaneous bacteria Culture-negative Feigin & Cherry 7 th Edition Page 21 Textbook of Pediatric Infectious Diseases xxx00.#####.ppt 12/8/2015 6:56:08 PM

22 Salmonella typhi 12.5 million cases / yr worldwide US cases / 100,000 in developing countries cases / 100,000 in western Europe, US, and Japan 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 Page 22 xxx00.#####.ppt 12/8/2015 6:56:08 PM

23 Pyogenic Liver Abscess Page 23 xxx00.#####.ppt 12/8/2015 6:56:08 PM

24 Brucellosis Page 24 xxx00.#####.ppt 12/8/2015 6:56:09 PM

25 Brucellosis-Clinical Manifestations Symptoms fever night sweats malaise weight loss anorexia arthralgias, myalgias headaches abdominal pain Signs lymphadenpathy hepatosplenomegaly arthritis Page 25 xxx00.#####.ppt 12/8/2015 6:56:09 PM

26 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.. Page Red Book xxx00.#####.ppt 12/8/2015 6:56:09 PM

27 Hereditary Periodic Fever Drenth JPH, van der Meer JWM N Engl J Med 2001;345: Page 27 xxx00.#####.ppt 12/8/2015 6:56:09 PM

28 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 Page 28 xxx00.#####.ppt 12/8/2015 6:56:09 PM

29 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 Page 29 Marshall et al. Marshall et al. J Pediatr 1987 xxx00.#####.ppt 12/8/2015 6:56:09 PM

30 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 Page 30 xxx00.#####.ppt 12/8/2015 6:56:10 PM

31 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 Page 31 xxx00.#####.ppt 12/8/2015 6:56:10 PM

32 Hemophagocytic Lymphohistiocytosis HLH Associations Secondary 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 Page 32 xxx00.#####.ppt 12/8/2015 6:56:10 PM

33 Diagnostic Criteria for the Hemophagocytic Syndrome Need 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 Page 33 K. McClain UpToDate 2015 xxx00.#####.ppt 12/8/2015 6:56:10 PM

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35 Hemophagocytic Syndrome in Children with FUO at TCH Number: 19 Gender: Ethnicity: Age: Fever duration: 6 male, 13 female 42% Hispanic, 32% Caucasian, 16% Asian, 11% African American median 17.4 months range, 7 days to 16 years median 19 days prior to diagnosis range, 4 to 41 days Palazzi et al. Clin Infect Dis 2003 Page 35 xxx00.#####.ppt 12/8/2015 6:56:10 PM

36 Hemophagocytic Syndrome in Children with FUO at TCH 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 Palazzi et al. Clin Page 36 Infect Dis 2003 xxx00.#####.ppt 12/8/2015 6:56:10 PM

37 Laboratory values in 19 children with HPS TCH Laboratory study Median Range Abnormality (%) LDH , AST ALT Direct bilirubin Serum sodium Palazzi et al. Clin Infect Dis 2003 Page 37 xxx00.#####.ppt 12/8/2015 6:56:10 PM

38 HOW CAN THE EVALUATION OF A PATIENT WITH FUO LEAD TO A DIAGNOSIS OF HPS? FEVER OF UNKNOWN ORIGIN ADDITIONAL LABS CLINICAL FINDINGS Fever Hypotension Respiratory distress Hepatosplenomegaly Elevated PT/PTT Decreased fibrinogen Ferritin > 4000 LABORATORY FINDINGS Anemia Thrombocytopenia Neutropenia Elevated AST/ALT Elevated bilirubin Elevated LDH ORDER Infectious agents tests Page 38 xxx00.#####.ppt 12/8/2015 6:56:11 PM PURSUE Bone Marrow Aspiration (BMA) and Biopsy If BMA positive for hemophagocytosis and/or high clinical suspicion and ferritin >4000, Start treatment protocol

39 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. Page 39 xxx00.#####.ppt 12/8/2015 6:56:11 PM

40 Thank You Page 40 xxx00.#####.ppt 12/8/2015 6:56:11 PM

Warm Autoantibodies in a Patient with Hemophagocytic Lymphohistiocytosis: A Case Report

Warm Autoantibodies in a Patient with Hemophagocytic Lymphohistiocytosis: A Case Report Emily Coberly, MD Department of Pathology and Anatomical Sciences University of Missouri Columbia April 30, 2013