Disclosure Statement. Evaluation of Lymphadenopathy in Children. Objectives. Definitions. Anatomical Lymph Node Regions. What Is Normal?

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1 Disclosure Statement Evaluation of Lymphadenopathy in Children Chimerix, Inc.: Clinical Endpoint Committee Member Rachel C. Orscheln, MD Associate Professor of Pediatrics Division of Pediatric Infectious Diseases Washington University and St. Louis Children s Hospital Objectives To review normal lymph node findings in children To discuss causes of lymph node enlargement To review the evaluation of lymphadenopathy in children Definitions Localized or regional: Enlargement of lymph nodes within contiguous anatomic regions Generalized: Enlargement of more than two noncontiguous lymph node regions Acute: Present for < 3 weeks Chronic: Present for > 6 weeks Anatomical Lymph Node Regions Occipital Preauricular Submaxillary and submental Cervical Supraclavicular Mediastinal Axillary Epitrochlear Inguinal Iliac Popliteal Abdominal Pelvic What Is Normal? Lymph nodes are palpable in most normal children 34% of neonates 45-57% of children 1 month to 6 years Most frequent site of enlargement: Cervical Occipital Submandibular Post-auricular Axillary Inguinal Clin Pediatr. 2004; 42:

2 What Is Abnormal? Normal lymph nodes in infants typically <1.2 cm in longitudinal diameter Normal lymph nodes in children < 1.6 cm in longitudinal diameter Supraclavicular lymph nodes typically not found in healthy children Size Matters Lymph nodes measuring > 2.0 cm are more often associated with a more significant disease process Concerning features: Increasing in size over 2 weeks Not decreasing in size in 4-6 weeks Not returned to baseline in 8-12 weeks Clin Pediatr. 2004; 42: Neild and Kamut, Clin Pediatr. 2004; 43: Causes of Lymph Node Enlargement Proliferations of cells intrinsic to the node Lymphocytes Monocytes Histiocytes Plasma cells Infiltration of lymph node Inflammatory cells Malignant cells Clinical Scenerios Acute Bilateral Cervical Lymphadenitis Acute Unilateral Lymphadenitis Cervical Axillary Inguinal Chronic Localized or Generalized Lymphadenopathy Clin Pediatr. 2004; 42: Acute Bilateral Cervical Lymphadenitis Most commonly reaction to infection: Viral infection Respiratory viral infection Rhinovirus Adenovirus Influenza Parainfluenza RSV hmpv Enteroviruses or Parechoviruses EBV CMV HSV HHV-6 Group A beta hemolytic Streptococcus sp. (GAbHS) Pediatri Clin N Am, 2013; 60: GAbHS Pharyngitis Clinical presentation: Tonsillopharyngeal erythema +/- exudates Enlarged, tender anterior cervical lymph nodes Swollen uvula Palatal petechiae Diagnosis: Testing should be performed on those WITHOUT signs of URI (cough and rhinorrhea) RADT and culture Treatment: Penicillin or amoxicillin 2

3 Recurrent Bilateral Cervical Adenitis Recurrent viral illnesses of childhood Recurrent streptococcal pharyngitis Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) PFAPA Clinical findings (first described in 1987): High fever, occurring every 2-12 weeks and lasting 3-6 days Mouth sores (aphthous stomatitis) in 70% of patients Sore throat (pharyngitis) Swollen glands (adenitis) Other associated features: Headache Nausea and vomiting Abdominal pain Poor response to acetaminophen (Tylenol ) or ibuprofen (Motrin ) Laboratory finding: Increased WBC, ESR, CRP PFAPA Treatment Steroids: (1 to 2 mg/kg/dose) results in a dramatic resolution of the fever in up to 90% of children Cimetidine (20-40mg/kg/day divided BID): 30-40% of patients treated with cimetidine may have a reduction in the episodes of fever Montelukast (4-5 mg/day): 68% of patients responded Tonsillectomy: 80-90% of patients treated with tonsillectomy may have a reduction in their episodes of fever Prognosis No long term effects Acute Unilateral Lymphadenitis Typical bacterial adenitis GAbHS Staphylococcus aureus including MRSA Anaerobic bacteria Cat Scratch Disease Tularemia Mycobacterial infection Histoplasmosis Actinomycosis Typical Bacterial Adenitis Clinical presentation: Tender unilateral adenopathy which may be fluctuant and have overlying erythema Fever frequently present Infectious etiologies: Group A beta hemolytic Streptococcus sp. Staphylococcus aureus including MRSA Diagnosis: Rapid streptococcal testing and culture Blood culture if indicated Imaging as directed by clinical findings (US or CT scan) Treatment: b-lactam antibiotic or clindamycin Cat Scratch Disease Causative organism: Bartonella henselae Fastidious, slow growing gram-negative bacillus Incubation period: 1-3 weeks after exposure Transmission: Scratch of cat Bite of infected cat flea Epidemiology: Kittens are most likely to be bacteremic Fall and winter is most common time for presentation Children < 15 years of age most commonly affected Redbook,

4 Clinical presentation: Fever (30%) Tender regional adenopathy which may become fluctuant Innoculation papule at the site of scratch may be seen Cat Scratch Disease Cat Scratch Disease Diagnosis Bartonella serologies Bartonella PCR if tissue is available Treatment Most infections resolve without intervention Azithromycin may speed time to resolution of lymphadenopathy Less common presentations: Hepatosplenic CSD -- Encephalitis Parinauds oculoglandular syndrome --Osteomyelitis Redbook, 2006 Tularemia Causative organism: Francisella tularensis Small, aerobic, catalase-positive, pleomorphic gram-negative coccobacilli Incubation period: 3-6 days (hours-3 weeks) Transmission: Tick bite or Hamster bite? Epidemiology Non-tuberculous mycobacterial infection Most commonly M. avium intracellulaire Natural Reservoir: Ubiquitous in the environment in soil and dust Found in tap water May contaminate food, eggs, dairy products Endemic to the midwestern and southwestern U.S. Nigrovic and Wingerter, Infect Dis Clin N Am, 22(2008), Age 1-4 years Girls > boys No risk factors for TB Epidemiology Pathogenesis Ingestion of organisms: Eating soil Exploratory behavior with contaminated objects Teething Direct inoculation Contaminated medical equipment Abrasions in swimming pools 4

5 Clinical Presentation Insidious onset of painless unilateral lymphadenopathy Fails to respond to typical antibiotics Node is rubbery in character Skin may become red or Photo Courtesy of: Stephanie Attarian violacious Spontaneous drainage may occur Diagnosis Evaluate for risk of TB Place PPD Gamma-interferon release assay if risk factors for MTB Evaluate for other causes: Bartonella infection Tularemia Histoplasmosis Trial of antibiotic therapy Diagnosis Surgical approach FNA Complete excision Pathology Routine culture, fungal culture, AFB culture Surgical excision Antibiotic therapy Combination therapy: Clarithromycin Rifampin Ethambutol Observation Treatment Histoplasmosis Causative organism: Histoplasma capsulatum Natural reservoir: Warm moist soil (high in nitrogen and carbon with low ph) Caves: bat guano Buildings: bird guano Incubation period: 1-3 weeks Clinical presentation: Pulmonary syndrome most frequent Lymphadenopathy Progressive disseminated histoplasmosis Diagnosis: Histoplasmosis antibody screen followed complement fixation and immunodiffusion assay Urine Histoplasmosis antigen Treatment: Itraconazole for severe or prolonged disease Don t Forget Kawasaki Disease Principal Clinical Findings Fever for > 5 days > 4 of the 5 principle features: Changes in the extremities Polymorphous exanthema Bilateral bulbar conjunctivitis Changes in the lips and oral cavity Cervical lymphadenopathy Exclusion of diseases with similar findings 5

6 Cervical Lymphadenopathy Unilateral and confined to the anterior cervical triangle > 1.5 cm in diameter Firm and non-fluctuant Lymph-Node-First Presentation of Kawasaki Disease (NFKD) NFKD represents 9-23% of cases of KD Compared with typical KD: Older age Longer fever Higher inflammatory markers Possible increased risk of IVIG resistance and coronary artery lesions Compared to bacterial adenitis: Higher inflammatory markers Transaminase elevation present Conglomerate of nodes rather than single dominant node Kanegaye, JT, et al. The Journal of Pediatrics, 162: , Diagnosis If > 4 principle features are present, the diagnosis of KD can be made on day 4 of illness KD should be considered in any young child with fever > 5 days with any of the clinical features KD should be considered in any infant < 6 months of age with prolonged fever, even if no principle features are present Evaluation of Suspected Incomplete KD Supplemental Laboratory Criteria Albumin < 3 g/dl Anemia for age Elevated ALT Platelets > 450,000 after 7 days of illness WBC > 15,000/mm 3 UA with > 10 WBC/HPF Treatment of KD Baseline Echocardiography with follow-up at 2 weeks and 6-8 weeks, Evaluate for KD IVIG: 2 g/kg in a single infusion Timing: Should be given within the first 10 (and if possible 7) days of illness Aspirin High dose ASA should be given acutely Until day 14 of illness AND/OR until afebrile for hours Low dose ASA is continued as indicated by risk level Diffuse Lymphadenopathy Differential Diagnosis Infectious Autoimmune Neoplastic 6

7 Diffuse Lymphadenopathy Epstein-Barr Virus Infectious Causes: EBV CMV HIV Toxoplasmosis DNA virus of the herpesvirus group Transmission: primarily through contact with oral secretions Incubation period: days Clinical presentation: May be asymptomatic in young children Infectious mononucleosis Mononucleosis Fever Headache Malaise and fatigue Exudative pharyngitis Lymphadenopathy Hepatosplenomegaly Rash (especially if penicillin is given) Diagnosis: Ancillary lab: CBC cytopenias atypical lymphocytosis CMP transaminase elevation Monospot EBV IgG and IgM EBV PCR EBV Cytomegalovirus (CMV) DNA virus of the herpesvirus group Transmission: Person-to-person through secretions (saliva) and urine Vertical transmission through blood, genital tract (at delivery) or through breast milk Blood transfusion Incubation period: Unknown Manifests 3-12 weeks after blood transfusion Asymptomatic infection Mononucleosis-like syndrome Fever Lymphadenopathy Fatigue Hepatitis CMV Clinical Syndromes Congenital infection Growth retardation, Jaundice Purpura Hepatosplenomegaly Microcephaly Intracranial calcifications Retinitis Sensorineural hearing loss 7

8 Serology Qualitative PCR Quantitative PCR Laboratory Diagnosis of CMV N Engl J Med 1994;331:649 CMV Treatment: Supportive Ganciclovir is effective Foscarnet and cidofovir are alternatives Prevention: Education Hand hygiene Avoiding exposures HIV HIV Human immunodeficiency virus Transmission: Unprotected sex IVDA Mother-to-child Epidemiology: ~40,000 new diagnosis in the US in 2016 Youth ages years accounted for 26% of new HIV cases in 2010 New infections in youth primarily in gay/bisexual males 60% of youth with HIV do not know they are infected Acute retroviral syndrome (develops 1-4 weeks after infection): Fever Malaise Headache Pharyngitis Gastrointestinal symptoms Lymphadenopathy Rash Symptoms persist for 2-4 weeks Diagnostic tests: HIV RNA viral load days after infection P24 antigen days after infection HIV ½ antibody weeks after infection CAROLYN CHU, MD, MSc, and PETER A. SELWYN, MD, MPH, Am Fam Physician May 15;81(10): HIV Treatment: Reduces infectivity Enhances CD4+ recovery Improves symptoms May reduce reservoir of HIV in the body Toxoplasmosis Toxoplasma gondii Ubiquitous protozoan parasite of warm-blooded animals Cats are the definitive host Transmission: Ingestion of cysts in undercooked meat (heating, freezing, and drying destroys cysts) Fecal oral contamination from cats Mother-to-child Transplant 8

9 Toxoplasmosis Toxoplasmosis Epidemiology: 22.5% of the population > age 12 is infected in the US Up to 95% of population in other regions in the world Incubation period: 1-3 weeks Clinical presentation: Flu-like illness: Fever Malaise Myalgias Tender lymphadenopathy Hepatosplenomegaly Rash May last for weeks than resolve Other clinical syndromes: Ocular disease Eye pain Photophobia Eye tearing Blurred vision Congenital toxoplasmosis Infection in immunocompromised hosts Toxoplasmosis Diagnosis: Toxoplasma IgM (positive in 2 weeks, declines over 6-9 months) Toxoplasma IgG (peaks in 1-2 months) Treatment Treatment is usually not necessary For severe disease: Pyrimethamine and sulfadiazine with leukovorin Miscellaneous Causes of Lymphadenopathy Drugs Serum sickness Post vaccination Rosai-Dorfman disease- sinus histiocytosis with massive lymphadenopathy Kukuchi Fujimoto disease- histocytic necrotizing lymphadenitis Sarcoidosis Autoimmune Juvenile ideopathic arthritis Lupus Mixed connective tissue disease Sjogren syndrome Autoimmune lymphoproliferative disease Neoplastic Lymphoma Leukemia Neuroblastoma Rhabdomyosarcoma Nasopharyngeal carcinoma Metastatic disease 9

10 Evaluation of Lymphadenopathy Evaluation of Lymphadenopathy History: Duration Location Associated symptoms Exposures: Ticks Pets (scratches and bites) TB risk factors Travel Medications and immunizations Physical Exam: Size Location Character Warmth Tenderness Erythema Fluctuance Firmness Adherence Discrete or matted Distribution HEENT Pharyngitis Oral ulcers Dental decay Organomegaly Skin findings: Rash Bruising or petechiae Empiric Treatment for Suspected Bacterial Adenitis Rapid Streptococcal antigen testing and culture Antibiotic therapy directed at Staph and Strep Clindamycin 1 st generation cephalosporins Trimethoprim-sulfa will miss GABHS Additional Evaluation for Localized Lymphadenitis CBC with differential Blood culture (consider if febrile) Ultrasound Bartonella sp. antibody panel Tularemia agglutinins PPD or gamma-interferon release assay Evaluation of Generalized Lymphadenopathy CBC with differential Peripheral smear LDH and uric acid Transaminases Serologies for EBV, CMV, HIV, and toxoplasmosis PPD or gamma-interferon release assay CXR Features Prompting a Biopsy Node size > 2 cm Node increasing in size over 2 weeks No decrease in node size after 4-6 weeks Node not returned to baseline after 8-12 weeks No change with specific antibiotic therapy Abnormal chest x-ray Supraclavicular location Rubbery consistency Systemic signs and symptoms not explained by another illness 10

11 Summary Lymph nodes are palpable in the majority of healthy infants and children. Diagnostic evaluation of lymphadenopathy is directed by the clinical presentation. Biopsy is reserved for chronic or increasing lymph node enlargement. 11