Cervical lymphadenitis in children: Etiology and clinical manifestations

INTRODUCTION — Cervical lymphadenitis is common in childhood. The incidence is difficult to ascertain because it is usually caused by a viral upper respiratory infection and is self-limited.

The etiology, pathophysiology, and clinical manifestations of cervical lymphadenitis in children will be reviewed here. The evaluation and treatment of cervical lymphadenitis in children is discussed separately, as is peripheral lymphadenopathy. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management" and "Peripheral lymphadenopathy in children: Etiology" and "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach".)

DEFINITIONS

●Cervical lymphadenopathy – Enlarged lymph node(s) of the neck, including preauricular, parotid, jugulodigastric, submental, submandibular, posterior cervical, superficial cervical, deep cervical, occipital, and posterior auricular (mastoid) (figure 1); lymphadenopathy encompasses both inflamed and noninflamed lymph nodes

●Cervical lymphadenitis – Enlarged, inflamed, and tender lymph node(s) of the neck; although strictly speaking, "lymphadenitis" refers to inflamed lymph nodes, the terms "lymphadenitis" and "lymphadenopathy" often are used interchangeably

●Acute lymphadenitis – Develops over a few days (but may persist for weeks to months)

●Subacute/chronic lymphadenitis – Develops over weeks to months

●Generalized lymphadenopathy – Enlargement of two or more noncontiguous lymph node regions (eg, cervical and axillary) and is the result of systemic disease (see "Peripheral lymphadenopathy in children: Etiology", section on 'Generalized lymphadenopathy')

ANATOMY — Lymph nodes frequently associated with cervicofacial lymphadenitis of childhood and the anatomic areas they drain are listed in the table (figure 1 and table 1). More than 80 percent of childhood cervical lymphadenitis involves the submandibular or deep cervical nodes because they filter much of the lymphatic fluid from the head and neck. The jugulodigastric node, part of the superior deep cervical nodes and located below the mandible at the angle of the jaw, is commonly involved in cervical lymphadenitis.

PATHOPHYSIOLOGY — The pathophysiology of cervical lymphadenitis has not been fully elucidated, but it is suspected that infection of cervical lymph nodes results from contact with potential pathogens by airborne droplet transmission or when microorganisms penetrate the mucosa or skin of the head and neck, infiltrate the surrounding tissue, and are transported by afferent lymph vessels to lymph nodes. Although obvious infection of the anatomically drained area may be present, the infiltration of organisms often is asymptomatic, with no clinical evidence of an inoculation site. If the lymph nodes filter infectious and antigenic materials from the lymphatic fluid, lymphocytes proliferate, causing subsequent nodal enlargement.

Involvement of pyogenic organisms, such as Staphylococcus aureus and Streptococcus pyogenes (group A Streptococcus), usually results in acute reactions within the lymph node, manifested by a sudden onset of swelling, erythema, warmth, and tenderness. Recruitment of neutrophils to the lymph node may result in abscess formation. Mycobacterial, fungal, and Bartonella henselae infections generate a more chronic granulomatous inflammatory response with typically less dramatic clinical features, although suppuration can occur.

INFECTIOUS CAUSES — Infectious causes of cervical lymphadenitis frequently are considered in four broad categories: acute bilateral, acute unilateral, subacute/chronic bilateral, and subacute/chronic unilateral (table 2).

The clinical manifestations of the most common infectious causes of cervical lymphadenitis in children are described below. The diagnostic approach to children with cervical lymphadenitis is presented separately. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management".)

Acute bilateral — Acute bilateral cervical lymphadenitis is the most common clinical presentation. The evaluation and initial management of acute bilateral cervical lymphadenitis are discussed separately. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Subacute/chronic'.)

Viral upper respiratory infection — Acute bilateral cervical lymphadenitis is most often caused by a benign, self-limited viral upper respiratory infection (eg, enterovirus, adenovirus, influenza virus) (table 3). Patients often have a history of an ill contact and current or recent symptoms that may include sore throat, rhinorrhea, nasal congestion, and/or cough. (See "The common cold in children: Clinical features and diagnosis", section on 'Clinical features'.)

The lymph nodes typically are small, rubbery, mobile, and discrete (so called "shotty" lymph nodes); minimally tender; and without erythema or warmth; they are often referred to as "reactive" lymphadenopathy. Although the clinical course is self-limited, the lymphadenopathy may last for weeks.

Group A streptococcus — Group A streptococcal (GAS) pharyngitis is a common cause of bilateral cervical lymphadenitis, which is often tender. GAS pharyngitis is discussed separately. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Clinical features'.)

Other causes — Other viral and bacterial causes of acute bilateral cervical lymphadenitis include (table 3):

●Primary herpes simplex gingivostomatitis. (See "Herpetic gingivostomatitis in young children", section on 'Clinical features'.)

●Epstein-Barr virus usually causes generalized lymphadenopathy but may present as acute bilateral cervical lymphadenitis. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

●Cytomegalovirus usually causes generalized lymphadenopathy but may present as acute bilateral cervical lymphadenitis. (See "Overview of cytomegalovirus infections in children" and "Overview of cytomegalovirus infections in children", section on 'Clinical manifestations'.)

●Mycoplasma pneumoniae pharyngitis. (See "Mycoplasma pneumoniae infection in children", section on 'Clinical manifestations'.)

●Arcanobacterium haemolyticum pharyngitis occurs predominantly in adolescents [1-3]. Clinical features overlap with those of GAS. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Other bacterial infections'.)

Acute unilateral — Acute unilateral cervical lymphadenitis occurs less frequently than acute bilateral cervical lymphadenitis. Acute unilateral cervical lymphadenitis is usually caused by bacteria (S. aureus, group A Streptococcus [GAS], and, in young infants, Streptococcus agalactiae [group B Streptococcus, or GBS]) (table 4). The evaluation and initial management of acute unilateral cervical lymphadenitis are discussed separately. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Acute unilateral'.)

S. aureus and GAS — Between 53 and 89 percent of cases of acute unilateral cervical lymphadenitis are caused by S. aureus (including methicillin-resistant S. aureus) (picture 1) or GAS [4]. Clinical features are usually not helpful in differentiating between staphylococcal and streptococcal lymphadenitis. Most of these infections occur in children younger than five years of age (70 to 80 percent of cases). Patients may have a history of a recent upper respiratory infection or impetigo. (See "Impetigo".)

Although systemic symptoms of fever, tachycardia, and malaise may be present, the patient usually does not appear toxic. Submandibular nodes are affected in more than 50 percent of cases. The lymph node usually is 3 to 6 cm in diameter, tender, warm, erythematous, nondiscrete, and poorly mobile. One-fourth to one-third of infected nodes suppurate and become fluctuant, generally within two weeks of the onset of illness. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Clinical features'.)

Group B Streptococcus — GBS cellulitis-adenitis usually is a manifestation of late-onset GBS infection (which has onset between 7 and 89 days of age or corrected gestational age for preterm infants), but it is a rare manifestation of this disease. Affected infants usually are between three and seven weeks of age, male, more often premature, febrile, and irritable, and have poor feeding [5-7]. Examination reveals tender, erythematous facial or submandibular swelling with ill-defined margins. The majority (94 percent) also have bacteremia, and meningitis may also occur [4,8]. However, isolated cervical adenitis has also been described. (See "Group B streptococcal infection in neonates and young infants", section on 'Other focal infection'.)

Anaerobic bacteria — Acute unilateral cervical lymphadenitis in older children with history of periodontal disease usually is caused by an infection with anaerobic bacteria. In one study, anaerobic bacteria were isolated from 38 percent of lymph node aspirates, collected primarily from children with dental disease [9]. Identification of periodontal disease during examination of the oral cavity may suggest anaerobic infection. However, lymph node examination cannot distinguish anaerobic infection from lymphadenitis resulting from S. aureus or GAS. Laboratory studies are necessary to determine the underlying etiology. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Acute unilateral'.)

Tularemia — Tularemia is a febrile illness caused by an infection with Francisella tularensis that usually occurs following contact with infected animals (eg, rabbits, pet hamsters, other rodents) or the bite of blood-sucking arthropods (tick and deer flies). The most common clinical presentation is the ulceroglandular syndrome, characterized by a papular lesion in the drainage field of the inflamed lymph node (picture 2); however, regional lymphadenopathy without an ulcer is also common. Most cases in the United States occur in the south-central region. (See "Tularemia: Microbiology, epidemiology, and pathogenesis" and "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention".)

Subacute/chronic bilateral — Subacute/chronic bilateral lymphadenitis is most commonly seen in Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infections (table 5). It also may be caused by tuberculosis (TB), human immunodeficiency virus (HIV), toxoplasmosis, and syphilis. The evaluation and initial management of subacute/chronic bilateral cervical lymphadenitis are discussed separately. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Subacute/chronic'.)

Epstein-Barr virus and cytomegalovirus — Subacute/chronic bilateral cervical lymphadenitis is most often caused by EBV or CMV infection. EBV causes infectious mononucleosis that may manifest as fever, exudative pharyngitis, lymphadenopathy, and hepatosplenomegaly. CMV also can cause a mononucleosis-like illness. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Overview of cytomegalovirus infections in children".)

Other causes — TB is an uncommon cause of chronic cervical lymphadenitis that affects older children and adults more frequently than younger children. It is usually unilateral but occasionally can be bilateral. (See "Tuberculous lymphadenitis".)

Other uncommon causes of chronic bilateral cervical lymphadenitis include HIV infection, toxoplasmosis, and syphilis, all of which are usually associated with generalized lymphadenopathy. (See "Toxoplasmosis: Acute systemic disease" and "Pediatric HIV infection: Classification, clinical manifestations, and outcome", section on 'Clinical manifestations' and "Syphilis: Epidemiology, pathophysiology, and clinical manifestations in patients without HIV", section on 'Clinical manifestations'.)

Subacute/chronic unilateral — Subacute/chronic unilateral cervical lymphadenitis is usually caused by nontuberculous mycobacteria (NTM) infections or B. henselae, the agent of cat scratch disease (CSD). However, it also may be caused by tuberculosis (TB) or toxoplasmosis (table 6). The evaluation and initial management of subacute/chronic unilateral cervical lymphadenitis are discussed separately. (See "Cervical lymphadenitis in children: Diagnostic approach and initial management", section on 'Subacute/chronic'.)

Nontuberculous mycobacteria infection — Most NTM infections occur predominantly in immunocompetent children younger than five years of age. The organisms are ubiquitous and can be found in soil, dust, and water. The child may have a history of pica. The Mycobacterium avium complex (MAC) is responsible for the majority of NTM cervical lymphadenitis, but previously uncommon species are being detected more frequently and may be responsible for some cases of culture-negative NTM lymphadenitis because they are fastidious. (See "Nontuberculous mycobacterial lymphadenitis in children", section on 'Epidemiology'.)

NTM lymphadenitis generally presents as a unilateral firm, nontender node that slowly enlarges over several weeks. The submandibular, jugulodigastric, and parotid nodes are most commonly infected and usually are less than 4 cm in size. The overlying skin gradually changes from a pink color to a violaceous hue and thins to a parchment-like appearance (picture 3). Despite the discoloration, skin temperature is normal. Fever, pain, and tenderness are unusual, and this lack of pain is often referred to as "cold" nodes. Suppuration and formation of a draining sinus tract that can persist for months frequently occurs in untreated lymph nodes. (See "Nontuberculous mycobacterial lymphadenitis in children", section on 'Clinical features'.)

Cat scratch disease — CSD is a relatively common infection caused by inoculation of B. henselae into the skin following a cat bite or scratch [10-12]. From 7 to 60 days following the scratch, the lymph node draining the site of inoculation becomes warm, tender, and slightly erythematous (picture 4). There is usually (but not always) a history of contact with a cat, often a kitten, although patients and caregivers frequently do not recall a bite or scratch. Careful physical examination may reveal a papule at the primary site of inoculation (picture 5). Axillary lymph nodes are most commonly affected, but approximately one in four children have isolated cervical nodes. Middle cervical and parotid nodes are affected more often than submandibular nodes [4]. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

Fever and mild systemic symptoms occur in 30 percent of patients and can last for four to six weeks. Nodes suppurate in up to one-third of affected children. Occasionally, infection may manifest as Parinaud oculoglandular syndrome, with conjunctivitis and ipsilateral preauricular or submandibular lymphadenitis following conjunctival inoculation. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Parinaud oculoglandular syndrome'.)

Tuberculosis — Pediatric TB is uncommon in the United States but remains a significant cause of cervical lymphadenitis in other parts of the world (figure 2) [13]. Infection of the cervical nodes is usually caused by extension from the paratracheal nodes to the jugulodigastric and submandibular nodes [14]. It also can occur by direct spread from the apical pleura to the supraclavicular nodes. Clinical symptoms compatible with TB, an abnormal chest radiograph, a history of contact with persons who have symptoms of TB, or a history of travel to an endemic area for TB should prompt an evaluation for Mycobacterium tuberculosis disease [15]. (See "Epidemiology of tuberculosis" and "Tuberculous lymphadenitis".)

Toxoplasmosis — Acquired Toxoplasma gondii infection is symptomatic in only 10 percent of patients, in whom lymphadenopathy and fatigue without fever are common manifestations, although a mononucleosis-like illness with rash and hepatosplenomegaly is also described [16]. The majority of cases are benign and self-limited. Adenopathy usually affects posterior cervical nodes, is discrete, nonsuppurative, sometimes tender, and may persist for months. Oocysts are excreted from the stool of cats, the definitive host for T. gondii. Human infection occurs by ingesting poorly cooked meat that contains cysts or by inadvertently ingesting mature oocysts from soil, litter boxes, or contaminated food. (See "Toxoplasmosis: Acute systemic disease".)

NONINFECTIOUS CAUSES — Noninfectious causes of cervical lymphadenopathy in children are less common but always should be considered in the differential diagnosis (table 7). The clinical manifestations of the most common noninfectious causes of cervical lymphadenitis in children are described below.

Connective tissue disorders — Prolonged fever, rash, and arthralgias suggest a possible connective tissue disorder (eg, juvenile idiopathic arthritis, systemic lupus erythematosus). (See "Classification of juvenile idiopathic arthritis" and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Neoplasm — Leukemia or lymphoma should be suspected in patients with persistent or progressive nontender cervical or generalized lymphadenopathy; no evidence of HIV, Epstein-Barr virus, or cytomegalovirus infection; and constitutional symptoms (eg, weight loss, fever, fatigue). (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Presentation' and "Overview of Hodgkin lymphoma in children and adolescents", section on 'Clinical presentation'.)

Kawasaki disease — Kawasaki disease should be considered in young children with acute cervical adenitis associated with fever for ≥5 days, rash, nonexudative conjunctivitis, mucositis, and swelling of the hands and feet (table 8), although incomplete presentations are increasingly recognized. The constellation of symptoms sometimes can be confused with a toxin-mediated S. aureus or group A streptococcal infection. (See "Kawasaki disease: Clinical features and diagnosis".)

MIS-C (postinfectious) — Multisystem inflammatory syndrome in children (MIS-C) is an uncommon postinfectious complication of children with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its presentation may be similar to incomplete Kawasaki disease or toxic shock syndrome, although the full spectrum of clinical features is evolving. The clinical features (table 9) and diagnosis of MIS-C are discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

PFAPA syndrome — Preschool-aged children with a history of recurrent fevers lasting four or five days, aphthous stomatitis, pharyngitis, and cervical adenitis have a benign periodic fever syndrome referred to by its abbreviation, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis). (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

Kikuchi disease — Kikuchi disease, or subacute necrotizing lymphadenitis, is a rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy (although lymphadenopathy may be more generalized) with or without fever [17]. It is discussed in detail separately. (See "Kikuchi disease".)

OTHER CAUSES OF NECK SWELLING — Causes of swelling in the neck must be distinguished from cervical lymphadenitis. Midline location is one feature that helps to distinguish thyroglossal duct cysts, epidermoid cysts, and lipomas from cervical adenitis since midline lymph nodes are rare [4]. (See "Thyroglossal duct cyst, thyroglossal duct cyst cancer, and ectopic thyroid" and "The pediatric physical examination: HEENT", section on 'Neck'.)

Other causes of neck swelling include [4,18]:

●Branchial cleft cyst – Branchial cleft cysts are palpable in the upper portion of the neck, anterior to the sternocleidomastoid muscle. These may occur at any age but are most common in school-aged children. (See "The pediatric physical examination: HEENT", section on 'Neck'.)

●Cystic hygroma – Cystic hygroma typically presents as a painless soft mass superior to the clavicle and posterior to the sternocleidomastoid muscle [4]. Cystic hygromas may increase in size during upper respiratory tract infection. Transillumination and compressibility help to distinguish cystic hygroma from lymphadenitis. Most present in children younger than two years.

●Thyroid tumors – Thyroid tumors in children usually present as asymptomatic solitary nodules. (See "Thyroid nodules and cancer in children".)

Causes of neck swelling that appear or are exacerbated during crying or straining include [19,20]:

●Superior mediastinal tumor or cyst – Superior mediastinal tumors or cysts are associated with widening of the mediastinum on plain radiographs.

●Laryngocele – Laryngoceles are outpouchings of the saccular mucosa in the area of the laryngeal ventricle that intermittently fill with air and cause episodic symptoms. They may present as neck masses if they extend through the thyrohyoid membrane. Laryngoceles are visualized as fluid- and air-containing cystic masses on plain radiography, ultrasonography, or computed tomography. (See "Congenital anomalies of the larynx", section on 'Laryngoceles and saccular cysts'.)

●Phlebectasia of the jugular vein – Phlebectasia of the jugular vein is a fusiform or saccular dilation without tortuosity; the diagnosis can be confirmed with color Doppler ultrasonography [21-23].

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●Basics topic (see "Patient education: Swollen neck nodes in children (The Basics)")

SUMMARY

●Infectious causes of cervical lymphadenitis – Cervical lymphadenitis in children is usually caused by an infectious process (table 2). Infectious causes of cervical lymphadenitis frequently are considered in four broad categories.

•Acute bilateral cervical lymphadenitis is usually caused by viral upper respiratory infection (table 3). (See 'Acute bilateral' above.)

•Acute unilateral cervical lymphadenitis is usually caused by bacteria. Staphylococcus aureus and Streptococcus pyogenes (group A Streptococcus) are the most common causes (table 4). (See 'Acute unilateral' above.)

•Subacute/chronic bilateral lymphadenitis is usually caused by Epstein-Barr virus or cytomegalovirus (table 5). (See 'Subacute/chronic bilateral' above.)

•Subacute/chronic unilateral lymphadenitis is usually caused by nontuberculous mycobacteria infections or Bartonella henselae, the agent of cat scratch disease (table 6). (See 'Subacute/chronic unilateral' above.)

●Noninfectious causes of cervical lymphadenopathy – Important noninfectious causes of cervical lymphadenopathy include (table 7) (see 'Noninfectious causes' above):

•Connective tissue disorders

•Neoplasm (eg, leukemia; lymphoma)

•Kawasaki disease (table 8) (see "Kawasaki disease: Clinical features and diagnosis")

•Multisystem inflammatory syndrome in children (MIS-C) (table 9) (see "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis")

•Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) (see "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)")

•Kikuchi disease (see "Kikuchi disease")

●Other causes of neck swelling – Cervical lymphadenitis should be distinguished from other causes of neck swelling, including (see 'Other causes of neck swelling' above):

•Thyroglossal duct cyst

•Epidermoid cyst

•Lipoma

•Branchial cleft cyst

•Cystic hygroma

•Thyroid tumor

•Superior mediastinal tumor or cyst

•Laryngocele

•Phlebectasia of the jugular vein