approach to lymphadenopathy

1. By: Dr Sana Shaikh, Resident

2.  A previously well 9 y/o girl was transferred to a tertiary paediatric centre after 15
days of fever and lymphadenopathy.
 Her symptoms started with fever and headache, resulting in several visits to her
family doctor and eventually a prescription for cefprozil. Despite antibiotic
therapy, the fever persisted, with increasing malaise and the development of
‘lumps’ on the left side of her neck.
 She was brought to her local emergency room on day 9 of her illness.

3.  Assessment in the ED noted the above symptoms plus a complaint of myalgias,
particularly when her temperature was at its highest. She also described
persistent ‘backache’ localized to her spine. The review of her systems noted the
absence of rashes, gastrointestinal symptoms, weight loss, anorexia or other
constitutional symptoms.
 Medical history: was unremarkable, noting only attention-deficit hyperactivity
disorder treated with methylphenidate.
 She had no known allergies, and her immunizations were up to date.
 The patient lived at home with her parents, sister and pet cat. All members of her
family were well, with no contributory medical history, and none of whom had
similar symptoms. She had not travelled recently, nor had tuberculosis or other
sick contacts.

4.  On initial examination:
- Child was thin with a temperature of 38.8°C.
- 0.5 cm lymph node in her left posterior auricular chain, and several shotty lymph nodes
bilaterally.
- Her physical examination was otherwise normal.
 Labs:
- CBC: WBC of 14.2×109/L (neutrophils 50%, bands 18%, lymphocytes 25% and monocytes 6%)
- ESR : elevated at 105 mm/h
- CRP :76 mg/L.
- The remainder of her complete blood count, electrolytes, liver enzymes, lactate dehydrogenase
and urinalysis were within normal limits. Her blood cultures, monospot, rheumatoid screening
and spine x-rays were all negative, as were her serological tests for cytomegalovirus and
toxoplasmosis.

5.  She remained febrile over the next five days, with her temperature spiking to
40°C
 The only new finding was progression of the lymphadenopathy in her left-sided
cervical nodes.
 Further diagnostic evaluation was done..A laboratory test definitively made the
diagnosis.

6.  Bartonella serology was performed revealing a strongly positive titre of 1:2048.
This remarkably positive result confirmed the suspicion of Bartonella henselae
infection.
 B henselae is a Gram-negative bacillus that typically causes infection after a
scratch or bite from a kitten younger than one year of age. In 90% of CSD cases,
cat exposure is reported.
 In typical CSD, which constitutes 90% of cases, the only symptoms are regional
lymphadenopathy proximal to the inoculation site, and mild constitutional
symptoms, which may include low-grade fever, malaise and fatigue.
*To identify infectious agents, a thorough history often reveals clues to the
diagnosis. In the present case, the family cat was actually a kitten that was prone
to biting and scratching.

7. Once the diagnosis was confirmed, and considering the
duration and persistence of fever, it was decided to
image the abdomen for splenic and/or liver involvement
with a CT scan.
Despite having no hepatomegaly, there was
disseminated liver involvement.
Because the patient had
been experiencing
myalgia and bone pain
in her spine, a bone scan
was performed, which
showed focally increased
uptake in several
vertebrae. MRI was
performed because it is a
more specific tool for
osteomyelitis diagnosis
and follow-up.

8.  Child was started on azithromycin and rifampin.
 Despite obvious regression of her lymphadenopathy, she continued to have spiking
fevers for the next week.
 Gentamicin was then added, and fever subsided within 48 h. Following 14 days of
gentamicin, and a total of six weeks of antibiotic therapy, the patient had complete
resolution of her infection.

9.  In the face of fever and lymphadenopathy, consider B henselae, and ask
specifically about cat exposures.
 If B henselae serology is positive, ensure that the infection has not disseminated –
possible for unknown reasons in immunocompetent hosts.
 The evidence for treatment is sparse, and is only warranted in
immunocompromised patients or those with complicated or disseminated disease

10.  "Lymphadenopathy" refers to enlargement of the lymph nodes. The threshold for
enlargement varies with location.
 “Lymphadenitis" refers to enlarged lymph nodes that are inflamed, but it is often
used interchangeably with "lymphadenopathy.“
 Lymphadenopathy is common and usually not clinically important in and of itself.
 However, it can be a manifestation of serious underlying disease.
 The challenge for clinicians is to avoid aggressive evaluation and biopsy of most
children, while making timely, specific diagnoses in children with serious
underlying disease

11. Etiologic categories that lead to lymph node enlargement:
 Immune response to infective agents (bacteria, viruses, fungi)
 Inflammatory cells in infections involving the lymph node
 Infiltration of neoplastic cells carried to the node by lymphatic or
blood circulation (metastasis)
 Localized neoplastic proliferation of lymphocytes or macrophages
(eg, leukemia, lymphoma)
 Infiltration of macrophages filled with metabolite deposits (eg,
storage disorders)

12.  Urgency and extent of evaluation:
- Determined by how ill the patient appears and whether there are clinical features suggestive of
malignancy.
- Peripheral lymphadenopathy in children generally is benign and self-limited
 For those without worrisome features:
- The first stage is to evaluate and treat conditions that appear obvious based upon the history and
examination (eg, throat culture for group A streptococcal pharyngitis, antibodies or specific titers
for EBV or CMV mononucleosis, serology for Bartonella henselae for cat scratch disease).
- If the cause remains uncertain after the initial evaluation  evaluate and/or treat common
causes of generalized or localized lymphadenopathy (according to site) or provide a two-week trial
of antibiotic therapy or a two- to three-week period of observation.
- If the cause remains uncertain after the second stage evaluation and treatment and the
adenopathy has not decreased in size less common causes and causes that require specific
treatment (eg, tuberculosis) are evaluated.
- If after four weeks of observation and/or empiric therapy, the diagnosis remains uncertain and the
lymph node has not regressed in size biopsy may be warranted.
* Evaluation may include blood tests CBC, ESR/CRP, serology, cultures, imaging, a trial of
antimicrobial therapy, and/or lymph node biopsy - depending upon associated symptoms.

13.  Avoidance of glucocorticoids
- Treatment with glucocorticoids must be avoided before a definitive diagnosis is
established.
- Glucocorticoid treatment could mask or delay the histologic diagnosis of leukemia,
lymphoma, or histiocytic disease.
- Treatment with glucocorticoids also may exacerbate an infectious disease.

14.  Systemic symptoms (fever >1 week, night sweats, weight loss)
 Supraclavicular (lower cervical) nodes
 Generalized lymphadenopathy
 Fixed, non-tender nodes in the absence of other symptoms
 Lymph nodes of >1 cm (0.4 inches) with onset in the neonatal period (<1 month of age)
 Lymph nodes >2 cm (0.8 inches) in diameter that have increased in size from baseline or have
not responded to two weeks of antibiotic therapy
 Abnormal chest radiograph, particularly mediastinal mass or hilar adenopathy
 Abnormal CBC and differential (eg, lymphoblasts, cytopenias in more than one cell line)
 Lack of infectious symptoms in the ear, nose, and throat regions
 Persistently elevated ESR/CRP or rising ESR/CRP despite antibiotic therapy

15. Focused on symptoms suggestive of infection (eg, exposures, travel, immunization
status), malignancy (constitutional symptoms, paraneoplastic syndromes), and
medications associated with lymphadenopathy.

17.  General examination — focused on signs of local or systemic disease or infection.
 Weight – Weight loss of >10 percent of body weight may be indicative of malignancy.
 Head, eyes, ears, nose, throat:
Scalp infection – Tinea capitis
Conjunctival injection – Kawasaki disease, leptospirosis
Nasal obstruction or depression of the soft palate – Rhabdomyosarcoma, nasopharyngeal carcinoma
Oropharynx – Dental problems, pharyngitis, herpangina, HSV gingivostomatitis
 Chest – Adventitious sounds may indicate a systemic process (eg, histoplasmosis; asthma, which may be
associated with eosinophilic granulomatosis with polyangiitis (Churg-Strauss)
 Abdomen – Hepatosplenomegaly (systemic process such as EBV, CMV, brucellosis, HIV, syphilis, neoplastic
disease, rheumatologic disease); abdominal mass (eg, neuroblastoma)
 Skin – Localized lesions (e.g. cat scratch)
 Lymph nodes

18. Location
- Localized lymphadenopathy (present in only one region) generally suggests local causes.
- Some systemic diseases can present with local adenopathy. E.g. Unilateral localized
lymphadenopathy occurs in Hodgkin lymphoma or Rosai-Dorfman disease, whereas bilateral
localized lymphadenopathy occurs in non-Hodgkin lymphoma and autoimmune
lymphoproliferative disease.
- Multiple pea-sized occipital nodes are often found in children with acute lymphoblastic
leukemia. Cervical and inguinal nodes are more common in children ≥2 years than in those <6
months of age. Epitrochlear and supraclavicular adenopathy are uncommon at any age, unless
there are skin infections or injuries distal to the node.
- Generalized adenopathy (present in two or more noncontiguous regions) usually is a
manifestation of systemic disease. Palpation of inguinal, cervical, and axillary nodes, in addition
to the liver and spleen, can determine whether lymphadenopathy is localized or generalized.

20. Size - The size of a LN that is considered to be normal varies depending upon the LN region
and age of the child. In neonates (<1 month of age)  <1 cm in diameter. In children ≥1 month
 in most regions generally less than 1 cm in their longest diameter; normal LNs in the
epitrochlear region usually are less than 0.5 cm in diameter, and normal LN in the inguinal
region usually are less than 1.5 cm in diameter. Normal lymph nodes tend to be larger in
childhood (ages 2 to 10 years) than later in life.
 The risk of malignancy is increased in lymph nodes >2 cm in diameter.
Consistency – The consistency of the node may suggest an etiologic category:
 Fluctuance usually indicates infection within the node. E.g. rapidly developing fluctuance
and drainage suggests a bacterial infection, usually S. aureus or GAS
 Hard (fibrotic) nodes generally are due to cancer or previous inflammation.
 Firm, rubbery nodes may indicate lymphoma or chronic leukemia; nodes in acute leukemia
tend to be softer.
Fixation – Normal lymph nodes are freely movable in the subcutaneous space. Abnormal
nodes can become fixed to adjacent tissues by invading cancers or inflammation in tissue
surrounding the nodes. They also can become fixed to each other ("matted") by the same
processes.
Tenderness – Suggests that recent, rapid enlargement has caused tension in the pain
receptors in the capsule. Tenderness typically occurs with inflammatory processes, but it also
can occur because of hemorrhage into a node, immunologic stimulation, and malignancy.
Thus, tenderness is not particularly helpful in discriminating between infectious and
noninfectious causes of lymphadenopathy.

21. CBC
 Cytopenias in more than one cell line – Leukemia, lymphoma, bone marrow metastatic disease
(eg, neuroblastoma), systemic lupus erythematosus (SLE), autoimmune lymphoproliferative
syndrome
 Isolated leukopenia or neutropenia – Viral infection, leukemia
 Leukocytosis with left shift – Bacterial infection
 Atypical lymphocytes – Epstein-Barr virus, cytomegalovirus, human herpesvirus 6
 Eosinophilia – Parasitic infection
 Anemia – SLE, M. tuberculosis
 Thrombocytosis – Kawasaki disease
ESR and CRP - In the evaluation of children with peripheral lymphadenopathy of uncertain
etiology, elevation of ESR and/or CRP raises the level of concern. Persistent or increasing elevation
despite a trial of antimicrobial therapy may warrant biopsy.

22. Cultures and serology
 Throat culture for group A Streptococcus (GAS) – Children with cervical lymphadenopathy and
acute exudative tonsillopharyngitis without associated viral features (eg, rhinorrhea).
 Blood cultures – Children who appear systemically ill and in whom bacterial infection is
suspected.
 Bacterial cultures of the drainage from skin lesions – Children with draining skin lesions.
 Fungal cultures of skin lesions or fungal serology (eg, coccidiomycosis, histoplasmosis,
blastomycosis) – Children with a history suggestive of fungal infection or evidence of infection and
no response to antibacterial therapy.
 Lymph node cultures – Ill-appearing children with localized lymphadenopathy that is fluctuant;
material for culture may be obtained via excisional biopsy (if tuberculous or nontuberculous
mycobacterial infection is strongly suspected), needle aspiration, or incision and drainage.
 Serologic testing – To confirm diagnoses suspected after the initial evaluation or as part of the
subsequent evaluation in children in whom the diagnosis remains uncertain after the initial
evaluation.
Tuberculin skin test

23. Chest radiograph (usual indications):
●Generalized or supraclavicular lymphadenopathy at the time of presentation
●Cervical or inguinal adenopathy ≥2 cm in diameter who do not have signs or symptoms of infection
or who have signs of infection but did not respond to a trial of antimicrobial therapy.
In children with lymphadenopathy, CXRs are obtained primarily to look for mediastinal masses or
hilar adenopathy.
 Mediastinal mass may indicate lymphoma or other malignancy
 Hilar adenopathy may indicate sarcoidosis, tuberculosis, or Hodgkin lymphoma
 Other CXR findings also may be helpful in determining the cause of lymphadenopathy (eg,
pulmonary infiltrates in children with coccidiomycosis or histoplasmosis).
Ultrasonography — Of the lymph node may be helpful in defining the presence and extent of an
abscess if lymph node fluctuance is not obvious by manual examination. May also help to
differentiate metastatic from infectious cervical lymph nodes based upon the more circular shape,
eccentric nodal borders, and hilar distribution of perfusion in metastatic lymph nodes. However,
these features do not provide definitive information, so biopsy is often necessary regardless of the
results of the ultrasound.
 Abdominal ultrasonography may be warranted in children with unexplained inguinal adenopathy
who do not have symptoms of infection, looking for abdominal masses and/or abdominal
lymphadenopathy, which may be associated with malignancy (eg, neuroblastoma, lymphoma).

24. A trial of antibiotic therapy is both a diagnostic and therapeutic intervention in children
with localized adenopathy, uncertain diagnosis, and no worrisome features.
Initial regimen – Generally provide initial empiric coverage for GAS and S. aureus.
 High community associated MRSA prevalence – Clindamycin
 Low MRSA prevalence – First-generation cephalosporin (eg, cephalexin) or amoxicillin-
clavulanate.
 For patients with exposure to cats or kittens - include coverage for B. henselae (eg,
Azithromycin) in the initial regimen.
Broadened coverage – If the patient's systemic symptoms (eg, fever) do not improve
within 72 hours or the lymph node increases in size (at any point during treatment),
include coverage for pathogens that were not included initially. E.g:
•For patients initially treated with a first-generation cephalosporin or amoxi-clav, we
switch to clindamycin to provide coverage for CA-MRSA.

25.  Early excisional lymph node biopsy (ie, when initially seen at a referral center)
may be indicated in patients with worrisome features (slide 13)).
 Excisional biopsy is also recommended for patients in whom tuberculous or NTM
infection is suspected because simple aspiration may result in the development of
a fistulous tract.
 Approximately 20 percent of lymph node biopsies demonstrate a treatable disease
(eg, leukemia, lymphoma, tuberculosis).

26. Thank you 