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Pediatric Curriculum

Sahai, S. “Lymphadenopathy”. Pediatrics in Review 34 (5). 2013.

LYMPHADENOPATHY

Objectives

•  Define lymphadenopathy

•  Consider various investigations in the work-up for lymphadenopathy

•  Know the differential diagnosis for localized and

generalized lymphadenopathy

•  Recognize “red flags” associated with noninfectious causes of lymphadenopathy

Background •  Lymphadenopathy – An abnormality in size and

consistency of lymph nodes •  Lymphadenitis – Lymphadenopathy that occurs

from infectious and other inflammatory processes

•  Generalized Lymphadenopathy – Involves 2 or more noncontiguous regions

•  Lymph node enlargement is a common finding on

physical exam in children •  Infections are the most common cause of lymph

node enlargement

• Primary Lymphoid Organs: (Sites for generation of B and T lymphocytes)

- Bone marrow - Thymus

• Secondary Lymphoid Organs:

- Lymph nodes - Spleen - Mucosa-Associated Lymphoid Tissue (MALT)

• Tonsils • Appendix • Solitary lymphoid nodules • Peyer patches of the ileum

Test Your Knowledge

•  Which of the following lymph nodes is considered enlarged in a child?

A.  Axillary lymph node 1cm B.  Cervical lymph node 1.5cm C.  Inguinal lymph node 1.5cm D.  Epitrochlear lymph node 0.5cm

The Answer

The normal size for lymph nodes in children is as follows:

- Axillary region – Up to 1cm - Cervical region – Up to 1cm

- Inguinal region – Up to 1.5cm

- Epitrochlear region – Up to 0.5cm B

The Case

•  A 4 year old girl presents to the ER with a 1 week history of fever and progressive neck swelling on the right

•  The area of swelling is tender to palpation, slightly erythematous, mobile, ~3cm in diameter

•  She is previously well

History

What would you ask?

History

•  Preceding symptoms (ie URTI, sore throat, etc) •  Localizing signs or symptoms (ie stomatitis may be

associated with mandibular nodes) •  Duration: Days or weeks •  Constitutional or Associated Symptoms: Fever,

Weight loss, Night sweats, Fatigue, etc •  Exposures: Cat exposure, Uncooked meat

(toxoplasmosis), Tick bite (lyme disease) •  Medications: ie Phenytoin, Isoniazid •  Travel history •  Sick contacts

Physical Exam

What would you look for?

Physical Exam

•  Vitals (HR, RR, Temp), Weight, Pallor •  H&N – Ears, Throat (tonsils), Discharge from Eyes/Nose •  Resp – ?Equal A/E, Cough, Wheeze, SOB when lying flat •  Abdo – HSM, Masses •  MSK – Swelling, Erythema, Pain •  Skin – Rashes, Bite marks, Scratches •  Lymph Nodes – Head & Neck, Supraclavicular,

Deltopectoral, Axillary, Epitrochlear, Inguinal, Popliteal (see graph in next slides) •  Location, Size, Number, Fluctuance, Tenderness,

Mobility

Lymph Nodes of the Head and Neck and Their Drainage Areas

Lymph Node Regions in the Body and the Areas They Drain

clues in cases of chronic lymphadenopathy. Poor weightgain may be present when the lymphadenopathy iscaused by infections such as TB or human immunode-ficiency virus (HIV) or by lymphoma.

Examination of Lymph Nodeand Lymphatic Organs

The size of the enlarged lymph nodeaids in determining the need for fur-ther evaluation. Lymph nodes largerthan 2 cm are more likely to harbora more serious disease process. Thenumber of lymph nodes and the con-sistency, fluctuance, tenderness, mo-bility, and presence of mattingshould be noted. Lymphadenitis ischaracterized by swelling of lymphnodes in conjunction with pain, skinchanges in the form of erythemaand edema, and tenderness. All otherareas of potential lymph node en-largement should be examined. Thepresence of liver and spleen enlarge-ment should be evaluated.

It is important to examine thedrainage area in cases of localizedlymphadenopathy. A careful head,neck, and oropharyngeal examina-tion may reveal a primary focus of in-fection. The presence of rash andpetechiae may help to make the diag-nosis. Conjunctival injection without

exudates may be present in patients with Kawasaki disease.Exudative conjunctivitis is present in infection with Barto-nella, adenovirus, and Francisella tularensis (tularemia).Bone and joint tenderness should be looked for.

Figure 2. Lymph node regions in the body. Reproduced with permission from: McClain, KL, FletcherRH. Causes of Peripheral Lymphadenopathy in Children. In: UpToDate, Basow DS (Ed), UpToDate,Waltham, MA 2013. Copyright 2013. UpToDate Inc. For more information, visit www.uptodate.com.

Table 1. Differential Diagnosis of Lymph Node EnlargementLesion Description Location

Cystic hygroma(lymphangioma)

A compressible painless soft mass thattransilluminates; may increase in sizeduring upper respiratory infections

Supraclavicular and posterior to thesternocleidomastoid on the left side, butmay extend to other areas such as thefloor of the mouth and axilla

Branchial cleft cyst Recurrent swelling that may be infected;may have a sinus or pit

Lateral neck with sinus along anteriorborder of the lower 2/3 of thesternocleidomastoid

Thyroglossal duct cyst May present with infection and moveswith tongue protrusion and swallowing

Midline at the level of the thyrohyoidmembrane; communicates with the baseof the tongue. Occasionally may be feltlateral to the midline

Cervical rib Hard, bony feel SupraclavicularThyroid nodule Painless firm to hard Midline in thyroid areaSternocleidomastoidfibroma

Soft mass in the sternocleidomastoid,torticollis with chin pointing to theopposite side of hematoma

Inferior portion of sternocleidomastoid

Epidermoid cyst Superficial, smooth Suprasternal

blood disorders lymphadenopathy

Pediatrics in Review Vol.34 No.5 May 2013 219

Workup

What would you order?

Workup •  Bloodwork

•  CBC+diff, CRP, Blood culture •  Specific serology – EBV, HIV, CMV, Parvovirus, Bartonella,

etc •  LDH, Uric Acid, Liver Enzymes (if worried about

malignancy/infiltrative process)

•  Ultrasound •  Assess for abscess and size of nodes

•  Chest and/or Neck X-Ray (consider) •  Assess for mediastinal widening, Hilar lymph node

enlargement, Calcifications (TB)

•  Fine Needle Aspiration (consider) •  Excisional Biopsy (consider)

When to Consider Possible Lymph Node Biopsy

• Size • >2cm • Increasing over 2 weeks OR no decrease in size of node after 4 weeks

• Location • Supraclavicular lymph node

• Consistency • Hard, Matted, Rubbery

• Associated Features • Fever, Weight loss, HSM, CXR suggestive of lymphoma

Differential Diagnosis:

Localized Lymphadenopathy

Table 3. Sites of Local Lymphadenopathy and Associated DiseasesCervical

Oropharyngeal infection (viral, group A streptococcal, staphylococcal)Scalp infectionMycobacterial lymphadenitis (tuberculosis and nontuberculous mycobacteria)Viral infection (EBV, CMV, HHV-6)Cat scratch diseaseToxoplasmosisKawasaki diseaseThyroid diseaseKikuchi diseaseSinus histiocytosisAutoimmune lymphoproliferative disease

Anterior auricularConjunctivitisOther eye infectionOculoglandular tularemiaCat scratch diseaseFacial cellulitisOtitis mediaViral infection (especially rubella, parvovirus)

SupraclavicularMalignancy or infection in the mediastinum (right)Metastatic malignancy from the abdomen (left)LymphomaTuberculosis

EpitrochlearHand infection, arm infection*Cat scratch diseaseLymphoma[†]

SarcoidSyphilis

InguinalUrinary tract infectionVenereal disease (especially syphilis or lymphogranuloma venereum)Other perineal infectionsLower extremity suppurative infectionPlague

Hilar (not palpable, found on chest radiograph or CT)Tuberculosis[†]

Histoplasmosis[†]

Blastomycosis[†]

Coccidioidomycosis[†]

Leukemia/lymphoma[†]

Hodgkin disease[†]

Metastatic malignancy*Sarcoidosis[†]

Castleman diseaseAxillary

Cat scratch diseaseArm or chest wall infectionMalignancy of chest wallLeukemia/lymphomaBrucellosis

AbdominalMalignanciesMesenteric adenitis (measles, tuberculosis, Yersinia, group A Streptococcus)

This table was published in Practical strategies in pediatric diagnosis and therapy, 2nd ed, by Kliegman RM, Greenbaum LA, Lye PS, p 864, Copyright Elsevier, 2004.CMV!cytomegalovirus; CT!computed tomography; EBV!Epstein-Barr virus; HHV-6!human herpesvirus 6.*Unilateral. †Bilateral.








SarcoidSyphilis



Histoplasmosis[†]

Blastomycosis[†]
















SarcoidSyphilis



Histoplasmosis[†]

Blastomycosis[†]











Up to 80% of acute unilateral cervical lymphadenitis inchildren younger than age 5 years are due to infectionswith Staphylococcus aureus and Streptococcus pyogenes. An-tibiotic therapy is directed at antibiotics that will coverS pyogenes and methicillin-resistant S aureus. Childrenolder than age 5 years who have dental or periodontal dis-ease will require coverage also for anaerobic bacteria. Pa-tients who have high fever, poor oral intake, pain, and thepotential for airway compromise from retropharyngeal in-volvementmay require hospitalization. Identification of bac-teria may be done through a culture from a primary site suchas the pharynx or skin. Antibiotics are administered for 10days or for 5 additional days after resolution of symptoms,whichever is longer. Improvement may be noted in 2 to 3days, although complete resolutionmay require a fewweeks.

Lymphadenitis may be complicated by an abscess forma-tion in up to 25% of patients and surgical intervention withincision and drainage may be necessary.

SUBACUTE AND CHRONIC PRESENTATIONS. The morecommon causes of subacute and chronic lymphadenopa-thy in children are as follows:

A t y p i c a l m y c o b a c t e r i a llymphadenitis. In the United

States, 70% to 95% of mycobacteriallymphadenitis is due to atypical my-cobacteria. Nontuberculous atypi-cal mycobacteria are acquired fromenvironmental source; they exist assaprophytes in water and soil. Sub-mandibular lymphadenopathy is themost common presentation. Fiftypercent of patients who have nontu-berculous lymphadenitis develop anabscess. Sinus tract formation mayoccur in 10% of these patients. Iden-tification of the bacteria along witha drug susceptibility profile is helpfulin management. Atypical mycobacte-ria respond poorly to antibiotics andthese infections require surgical exci-sion. If surgery cannot be performed,a 3- to 6-month course of antibioticsis recommended. Clarithromycin orerythromycin combined with rifabutinor ethambutol may be effective.

Tuberculous lymphadenitis. Thepresence of 2 of the following 3 cri-teria has 92% sensitivity in identifyingtuberculous lymphadenitis. The cri-teria are (1) a positive PPD skin test

result, (2) an abnormal chest radiograph, and (3) contactwith a person who has infectious TB. The PPDmay be pos-itive in atypical mycobacterial infection. Tuberculouslymphadenitis requires treatment with multiple antituber-culous antibiotics for 18 months. Surgical treatment is re-quired rarely.

Cat scratch disease. This infection results from entry ofBartonella henselae through a scratch in the skin. Exposureto a kitten and the resultant skin papule may have been for-gotten by the time lymphadenopathy develops 5 days to 2months later. Most lymphadenopathy occurs in the axillarygroup (50%), followed by the cervical group. Constitutionalsymptoms such as low-grade fever, malaise, and anorexiamay be associated. This infection can be confirmed by serol-ogy. The condition resolves spontaneously in 1 to 3months.Although the benefit of antibiotic therapy is questionable inlocalized disease, azithromycin is known to cause a rapid res-olution of lymph node swelling. Systemic involvement canlead to hepatitis, encephalitis, endocarditis, and osteomyeli-tis. Antibiotics used for systemic infection with Bartonellaare rifampin, ciprofloxacin, gentamicin, trimethoprim, sulfa-methoxazole, clarithromycin, and azithromycin.

Table 6. Lymphadenitis-Causing BacteriaBacteria Clinical features

ACUTEStreptococcus pyogenes Associate tonsillopharyngitisGroup B Streptococcus Infants, unilateral facial or

submandibular swellingAnaerobic such as Bacteroides species,Peptococcus species, Propionibacteriumacnes, and Fusobacterium nucleatum

May have associated dental andgingival disease

Francisella tularensisPasteurella multocida May occur after animal bites or

scratchYersinia pestis Flea bites on head and neck in

western United StatesHaemophilus influenzae type BRare gram-negative bacilli, pneumococcus,Group C streptococci, Yersiniaenterocolitica, Staphylococcusepidermidis, alpha hemolyticstreptococci

SUBACUTEAtypical mycobacterium species such asavium-intracellulare (common),scrofulaceum, kansasii (common),fortuitum, haemophilum

Rapid onset nodal enlargement,overlying skin becomeserythematous, thin andparchment like

Mycobacterium tuberculosis High risk groups like immigrantpopulations, travel or residence inendemic areas

Bartonella henselae History of contact with kittens, largesingle lymph node enlargement,systemic involvement


224 Pediatrics in Review Vol.34 No.5 May 2013

Differential Diagnosis:

Generalized Lymphadenopathy

InvestigationsAfter a careful history and physical examination, it is pos-sible to narrow the differential diagnosis of lymphadenop-athy. Laboratory evaluation may aid in narrowing thediagnosis of both chronic and generalized lymphadenopa-thy. In the presence of an acute localized lymphadenopa-thy, when a focus of infection has not been identified andthe lymph nodes raise suspicion of a bacterial infection,a trial of antibiotics may be given before embarking onan extensive evaluation. The antibiotics chosen should pro-vide coverage for both Staphylococcus aureus and group AStreptococcus. When Bartonella is suspected, it is reasonableto add azithromycin. Laboratory and imaging studies maybe necessary if a lymph node does not regress after treat-ment or after resolution of the associated acute symptoms.

Laboratory EvaluationCOMPLETE BLOOD CELL COUNT WITH DIFFERENTIAL.

Results may show a neutrophilic leukocytosis, which canindicate an acute bacterial infection. A predominantlylymphocytic leukocytosis may be associated with Eb-stein-Barr virus (EBV) infection. Leukocytosis with blastson peripheral smear is indicative of leukemia. Leukopeniawith depression of the hemoglobin level and platelet count

also may be indicative of bone marrow involvement withmalignancy. Lymphopenia may be indicative of HIV infec-tion or congenital immunodeficiency disorders. The eryth-rocyte sedimentation level (ESR) and C-reactive proteinlevel may be used as tools to look for inflammation andinfection and also might help in assessing the patient’s re-sponse to treatment. Lactate dehydrogenase and uric acidlevels provide a screen for rapid cell turnover associatedwithmalignancy. High liver enzyme levels may indicate in-volvement of the liver due to a systemic infection or an in-filtrative process.

Serology may be obtained for evidence of infectionwith EBV, HIV, CMV, and parvovirus. Bartonella serol-ogy and polymerase chain reaction studies may be neededwhen there is more generalized involvement. The purifiedprotein derivative (PPD) test is a useful screen for myco-bacterial infection. Interferon-gamma release assays alsomay be used in place of the tuberculin skin test withPPD. Specific atypical mycobacterial antigen may be usedwhen atypical mycobacterial lymphadenitis is suspected.

Radiologic EvaluationChest radiograph (CXR) is an essential test in the evalua-tion of chronic localized and generalized lymphadenopathyand may reveal the presence of mediastinal widening due

Table 2. Differential Diagnosis of Systemic Generalized LymphadenopathyInfant Child Adolescent

COMMON CAUSESSyphilis Viral infection Viral infectionToxoplasmosis EBV EBVCMV CMV CMVHIV HIV HIV

Toxoplasmosis ToxoplasmosisSyphilis

RARE CAUSESChagas disease (congenital) Serum sickness Serum sicknessCongenital leukemia SLE, JRA SLE, JRACongenital tuberculosis Leukemia/lymphoma Leukemia/lymphoma/Hodgkin diseaseReticuloendotheliosis Tuberculosis Lymphoproliferative diseaseLymphoproliferative disease Measles TuberculosisMetabolic storage disease Sarcoidosis HistoplasmosisHistiocytic disorders Fungal infection Sarcoidosis

Plague Fungal infectionLangerhans cell histiocytosis PlagueChronic granulomatous disease Drug reactionSinus histiocytosis Castleman diseaseDrug reaction

This table was published in Practical Strategies in Pediatric Diagnosis and Therapy. 2nd edition, by Kliegman RM, Greenbaum LA, Lye PS, p 863. CopyrightElsevier, 2004.Author’s note: Hemophagocytic lymphohistiocytosis may also be a cause of generalized lymphadenopathy.CMV!cytomegalovirus; EBV!Epstein-Barr virus; HIV!human immunodeficiency virus; JRA!juvenile rheumatoid arthritis (Still disease); SLE!systemiclupus erythematosus.


220 Pediatrics in Review Vol.34 No.5 May 2013

Red Flags for Malignancy

•  Supraclavicular lymph nodes •  Hard consistency •  Rubbery consistency •  Absence of head and neck infection •  Unexplained fevers > 1 week •  Night sweats •  Weight loss •  Mediastinal widening on CXR •  Hepatosplenomegaly •  Abnormal labs (consistent with leukemia/

lymphoma)

Test Your Knowledge

•  A 2 year old child presents with a 7 day history of high grade fever, irritability, right-sided cervical lymphadenopathy measuring 2cm, non-exudative conjunctivitis, a rash, swelling of hands and feet.

A.  Streptococcal infection B.  Adenovirus C.  Kawasaki Disease D.  Mononucleosis

The Answer

•  Kawasaki Disease is defined as fever > 5 days plus at least four of the following:

1.  Bilateral non-purulent conjunctivitis

2.  Mucosal changes (red fissured lips, strawberry tongue, pharyngeal erythema)

3.  Red edematous hands and feet with eventual desquamation

4.  Polymorphic non-vesicular rash 5.  Cervical lymphadenopathy >1.5cm

(usually unilateral)

C

Summary

•  Lymphadenopathy is common in children and is often benign

•  Infection is the most common cause of lymphadenopathy in children

•  A good history and physical exam will help to narrow the differential diagnosis

•  It is important to recognize the signs of a malignant process in order to initiate an early evaluation

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