Epidemiology

The epidemiology of infectious cervical adenitis is that of its infectious agents. Although cervical lymphadenitis can be a manifestation of focal viral infections of the oropharynx or respiratory tract, often it is part of a more generalized reticuloendothelial response to systemic infection. Viruses that commonly present with prominent cervical adenitis are Epstein-Barr virus and cytomegalovirus. In children infected with human immunodeficiency virus (HIV), prominent cervical adenopathy may either herald or be a part of more generalized lymphadenopathy associated with this infection. Although human herpesvirus–6 (HHV-6), the cause of roseola in infants (exanthem subitum), is associated with the development of a mononucleosis syndrome and cervical adenopathy in adults, lymphadenitis is not a prominent feature in children with primary infection. Adenoviral and enteroviral infections are causes of generalized rather than isolated cervical lymphadenopathy. The epidemiology of cervical adenitis varies by age, geographic location, and socioeconomic status. Generally, lower socioeconomic status is associated with a higher incidence of infectious etiology in younger children.

When bacterial in origin, with the exception of group A streptococci and Mycobacterium tuberculosis, the agents isolated from these glands are the normal inhabitants of the nose, mouth, pharynx, and skin— Staphylococcus aureus, anaerobes, nontuberculous mycobacteria, Actinomyces spp.—and person-to-person transmission does not occur. In contrast, group A streptococci and M. tuberculosis infection of cervical lymph nodes results from contact with human infection by way of airborne droplets. Except in neonates, for whom male dominance has been reported in cases caused by group B streptococci, infectious lymphadenitis has no gender or seasonal predilection.

Any age group can be affected by cervical lymphadenitis. In neonates, S. aureus and group B streptococci are the most common pathogens. Suppurative cervical lymphadenitis caused by Staphylococcus epidermidis in an otherwise healthy infant has been reported. Nonetheless despite the high frequency of nasal colonization by S. epidermidis, it remains a rare etiologic agent. There are rare reports of Streptococcus pneumoniae causing suppurative adenitis in older children. Some studies indicate that S. aureus has the leading role in infants, whereas in children, either group A streptococci or S. aureus is equally likely to be pathogenic. Other reports have varied regarding the relationship between age and probable etiologic agent.

Overall, S. aureus and Streptococcus pyogenes accounted for 65% to 89% of consecutive cases in prospectively evaluated series. Recent reviews indicate that S. aureus is more common in infants with cervical lymphadenitis, especially if suppuration occurs. Methicillin-resistant S. aureus (MRSA) must be strongly considered as a possible etiology because of the increased incidence of health care–acquired MRSA and community-associated MRSA (CA-MRSA) infections in the United States and elsewhere and recognition that the highest rates of CA-MRSA colonization and disease are found in children. Many studies have shown that CA-MRSA strains predominantly cause skin and soft tissue infections, but a wide spectrum of illness is reported, and invasive CA-MRSA has been associated with a variety of clinical manifestations, including severe illness and death. Retrospective and prospective case series report an increasing incidence of CA-MRSA infections manifesting as cervical adenitis and deep neck infections. One single-center study found that MRSA was the infectious etiology of no head and neck abscesses from July 1999 through December 2001 but accounted for 34% of cases from January 2002 through June 2004. In other reports of 76 and 185 children with neck abscess, MRSA was the etiologic agent in 33% and 42%, respectively, and was more likely to be found in abscesses located laterally in black patients and in infants and toddlers.

The epidemiology of bacterial lymphadenitis varies by geographic location. Resurgence of infection with Yersinia pestis in the southwestern United States in 2015 means that, in areas where it is endemic, it also must be considered in the differential diagnosis. Epidemic diphtheria, reported in the Russian Federation in 1990, subsequently spread to several newly independent states in the European region, with the number of reported cases (50,425) peaking in 1995. After the implementation of diphtheria control measures, the number of cases declined by more than 95% from 2000 through 2009. However, because circulation continues in some countries in Eastern Europe and with increasing migration between countries, sporadic cases may occur even in countries with high vaccination rates. Diphtheria also must be included as a possible cause of cervical lymphadenitis in those regions of the world.

The distinctive epidemiologic features of mycobacterial infection are summarized in Table 12.1 . Scrofula caused by M. tuberculosis is a rare disease. When it does occur, it usually affects adults and older children. In contrast, children with nontuberculous mycobacterial infection almost always are 1 to 6 years of age, live in suburban or rural communities, and have no history of contact with M. tuberculosis . Although M. tuberculosis is an infection acquired primarily by inhalation, the gastrointestinal tract or respiratory tract may be the primary portal of entry for nontuberculous mycobacteria. There seems to be an ethnic predilection for nontuberculous mycobacterial infection to occur in whites and for tuberculous infections to occur in blacks, Hispanics, Asians, and the Australian Aboriginal population. A recent study of 139 children with confirmed M. tuberculosis cervical lym­phadenitis in Taiwan demonstrated an association of a polymorphism in the mannose-binding lectin gene with this etiology, suggesting the potential role for innate immunity in the pathogenesis.

The advent of the HIV pandemic had a major impact on the nature and frequency of mycobacterial infections. The availability of highly active antiretroviral therapy (HAART) resulted in significant decreases in the incidence of opportunistic infections, including tuberculous and nontuberculous mycobacterial infections, in HIV-infected children. However, cases of tuberculous and nontuberculous infection as part of an immune reconstitution syndrome in individuals started on HAART have been reported.

The presence of tuberculosis infection in the community means that all children are at risk for exposure to an infectious adult. The annual tuberculosis rate in the United States decreased steadily during the years 1993 through 2014, but the annual decline has decelerated. Drug-resistant tuberculosis also is increasingly detected in industrialized and developing countries, both multidrug-resistant (e.g., resistant to isoniazid and rifampin, first-line drugs in the treatment of tuberculosis) and extensively drug-resistant (resistant to isoniazid, rifampin, and three of the six classes of second-line antituberculosis drugs).

The incidence of nontuberculous mycobacterial infections has increased since the 1980s, although some of this apparent increase most likely has resulted from improvements in diagnostic methods. Nontuberculous mycobacteria are ubiquitous and are found in food, water, animals, and soil. An association between nontuberculous cervical adenitis and cold weather is prompted by observations that 68% of cases occur in the winter and spring months. A 10-year Canadian retrospective study reported that 70% of cases occurred in girls; however, most reports suggest no gender difference.

Until the 1970s, Mycobacterium scrofulaceum was the usual etiologic agent in children with nontuberculous adenitis, followed by Mycobacterium avium-intracellulare . This trend has reversed, with M. avium-intracellulare now accounting for 50% to 98% of culture-proven cases. Previously uncommon species, such as Mycobacterium kansasii, Mycobacterium malmoense (found primarily in Europe) , Mycobacterium fortuitum , Mycobacterium haemophilum, and Mycobacterium bohemicum, also are being detected more frequently. Some of these uncommon species probably are responsible for many cases of culture-negative lymphadenitis because of their fastidious growth requirements. New diagnostic methods have led to increasing reports of cervical adenitis secondary to slow-growing species, such as Mycobacterium lentiflavum and Mycobacterium interjectum . Cervical lymphadenitis caused by Mycobacterium chelonae is rare, usually involves the submandibular glands, and typically occurs in patients with an antecedent history of dental pathology.

Cervical lymphadenopathy may be the direct result of infection with HIV per se. However, the development of acute, tender adenitis in an HIV-infected child should provoke a search for another etiology. Although the typical childhood pathogens remain the most common pathogens in this setting, as in other immunocompromised children, opportunists also should be sought. Patients with HIV infection beginning therapy with potent antiretroviral agents can develop new-onset mycobacterial lymphadenitis (tuberculous and nontuberculous mycobacteria). When this lymphadenitis occurs, it is more localized, is associated with more sinus formation, and is more often caused by nontuberculous mycobacteria ( M. avium-intracellulare ) than by M. tuberculosis .

Cat-scratch disease is a common cause of lymphadenitis in children and young adults. In 1988, English and associates first isolated a pleomorphic gram-negative bacillus, later identified as Afipia felis, from lymph nodes of patients with cat-scratch disease. Bartonella henselae , a morphologically similar but genetically distinct pleomorphic gram-negative bacillus, now is recognized as the cause of cat-scratch disease.

The cervical nodes are the second most common site of cat-scratch disease involvement. Although unusual and severe manifestations of this infection have been described, it remains mostly a mild, self-limited infection in children and adolescents, with no ethnic predilection. Seasonal variation with an increased incidence in fall, winter, and early spring does occur in temperate zones. A history of animal contact with cats usually can be elicited. The importance of bites and scratches by kittens in transmitting this disease has been well defined. However, the absence of a history of traumatic contact with cats in a substantial number of cases supports the hypothesis of an alternative mode of transmission. The detection of Bartonella DNA by polymerase chain reaction (PCR) assay in collections of fleas from cats owned by two infected patients suggests that fleas or other arthropods may serve as vectors, but their role in human transmission is not well established.

Pathophysiology

Although cervical lymphadenitis is a common entity in pediatric clinical practice, little information exists regarding its pathogenesis. Viral cervical adenitis may be part of either a local response to viruses invading the oropharynx or respiratory tract (e.g., adenoviruses or coxsackieviruses) or a more generalized reticuloendothelial response to systemic viral infection (e.g., Epstein-Barr virus, cytomegalovirus, HHV-6, or HIV). Infection attributed to group A streptococci and S. aureus is presumed to enter the cervical lymphatics from the oropharynx (group A streptococci) or anterior nares ( S. aureus ). In a patient with group A streptococcal pharyngitis or tonsillitis, whether infection remains localized at the pharyngotonsillar tissues or spreads to cervical lymph nodes and results in suppuration primarily is a function of host response and probably strain virulence. Although peak attack rates for group A streptococcal pharyngitis are observed among school-age children, suppurative cervical adenitis is an uncommon occurrence. In contrast, infants and children younger than 3 years of age rarely have group A streptococci isolated from throat cultures, but this age group is more likely to develop suppurative cervical lymphadenitis.

In infections attributed to S. aureus, colonization of the anterior nares is thought to be a prerequisite for cervical lymphadenitis. Brook and Winter arrived at this conclusion because organisms of identical phage types were isolated from the anterior nares and the cervical abscesses of their patients. An investigation of children in St. Louis found no such correlation between isolates from nasal and cervical node cultures. The role of S. aureus as a primary pathogen has been the subject of some debate. In most series, 30% of aspirates yield mixed cultures of S. aureus and group A streptococci, and frequently significant elevations of antistreptolysin O titer are found in the sera of patients whose lymph nodes yielded a pure culture of S. aureus .

In a California study, 65% of patients had lymph node aspirates yielding a pure culture of S. aureus, and 41% exhibited an immune response to one or more of the extracellular antigens of group A streptococci. Similarly, the finding that many children improve with penicillin or ampicillin treatment, despite the high prevalence of penicillin resistance among S. aureus, suggests that, although streptococci and staphylococci may coexist in these nodes, staphylococci may sometimes play a subsidiary role as secondary invaders. However, most children with isolates of S. aureus from suppurative lymph nodes show no evidence of coexistent streptococcal infection or viral upper respiratory tract infection. In addition, the resurgence of S. aureus (often MRSA) as a single pathogen in more recent case series argues that this organism has a strong capacity to be the primary invader.

Recovery of anaerobic bacteria from cervical nodes suggests invasion of the lymphatics by mouth flora, often as a result of local tissue destruction by periodontal disease. The delineation of the pathophysiology of cervical lymphadenitis of diverse bacterial etiology requires an understanding of the interaction between a given microorganism (e.g., inoculum size, elaboration of extracellular enzymes, and ability to adhere to epithelium) and the host (e.g., humoral and surface immune capacity and degree of trauma).

Tuberculous cervical lymphadenopathy occurs within months of the initial exposure, through pulmonary infection and involvement of the regional and then more distant lymph nodes. It is a rapid process; chest radiographic evidence of active pulmonary disease often is seen. Nontuberculous mycobacteria are ubiquitous in the environment, and oropharyngeal acquisition with local infection leads to lymph node involvement. Most children with nontuberculous mycobacterial cervical lymphadenitis are immunocompetent. However, some studies suggest that children who develop necrotic nodes may have deficient production of interferon (IFN)-γ, and disseminated infections are almost always associated with impaired T-cell function. Despite M. avium skin test positivity being linked with pet birds, no clear relationship with lymphadenitis has been shown. Discontinuation of childhood bacille Calmette-Guérin vaccination has been associated with an increase in atypical mycobacterial infection in many countries, suggesting that this vaccine may have a protective effect. Progressive cervical adenitis developing after bacille Calmette-Guérin vaccination also has been reported.

Clinical Presentation

The clinical manifestations of cervical lymphadenitis vary considerably but are consistent with the diverse etiologies associated with cervical node enlargement in infants and children. Categorizing the mode of presentation as acute, subacute, or chronic is useful because, although the boundaries are ill defined and much overlap exists, common etiologies tend to fall consistently within one of the categories. Cervical lymphadenitis of acute onset may be categorized further as bilateral or unilateral. In most situations, acute, bilateral cervical adenitis is either part of a generalized reticuloendothelial response to a systemic infection or a localized reaction to acute pharyngitis. The presence or absence of associated features (e.g., pharyngitis, enanthems or exanthems, generalized adenopathy, and hepatosplenomegaly) aids in making the differentiation.

Acute unilateral cervical lymphadenitis is caused by streptococcal or staphylococcal infection in 53% to 89% of cases. In newborns, S. aureus is the most common cause, and clinical features are similar to those seen in older children. Group B streptococci have been described as causative in a “cellulitis-adenitis” syndrome in infancy. These infants differ from infants with staphylococcal adenitis in that they are younger, are more often male, and have a greater incidence of systemic symptoms, irritability, and anorexia; 94% have associated bacteremia. The typical patient has fever, facial or submandibular cellulitis, and ipsilateral otitis media. Isolated cervical adenitis caused by group B streptococci also has been described.

Patients with disease attributed to S. aureus or group A streptococci can become ill at any age but typically are 1 to 4 years old (70–80% of cases), and the male-to-female ratio is equal. Clinically, little differentiates streptococcal from staphylococcal infections. Cervical adenitis can occur as part of the “streptococcosis” syndrome of infancy, with an onset heralded by coryza, an irregular low-grade fever, nasal discharge with excoriation and crusting around the nares, vomiting, and loss of appetite. Lymph node enlargement occurs within a few days of onset and resolves, as do other symptoms, without treatment within 6 to 8 weeks. Suppuration of cervical glands can occur at any time during this interval but seldom does so if effective antimicrobial therapy is given early in the illness. Group A streptococci also should be suspected as a cause of cervical adenitis in a patient with typical vesiculopustular or crusted lesions of impetigo involving the face or scalp.

Systemic symptoms in children with staphylococcal or streptococcal cervical adenitis usually are minimal or absent unless associated with cellulitis, metastatic foci of infection, or bacteremia. The primary site of lymph node involvement by frequency is submandibular (50–60%), upper cervical (25–30%), submental (5–8%), occipital (3–5%), and lower cervical (2–5%). Involved nodes generally vary in size from 2 to 6 cm in diameter, and one-fourth to one-third suppurate. Patients with lymphadenitis caused by S. aureus are more likely to develop suppuration and a longer duration of symptoms and signs before diagnosis than are patients with disease caused by other bacterial agents ( Fig. 12.2 ). Among patients who develop suppurative adenitis, the majority do so within 2 weeks of onset.

A 2-year-old boy with fever and unilateral inflammation of the cervical lymph nodes of 2 days’ duration. Needle aspirate culture of this nonfluctuant node grew Staphylococcus aureus . Antistaphylococcal therapy resulted in complete resolution of adenitis without surgical drainage.

Approximately one-third of patients in one study had concomitant lymphadenopathy at other anatomic sites. A history of recent upper respiratory tract symptoms, including sore throat (40%), earache or coryza (16%), and impetigo (32%), is a frequent finding, as are signs of pharyngitis, tonsillitis, or otitis media. These factors do not help delineate the etiology, however. Hepatomegaly or splenomegaly is a rare occurrence and, if present, should suggest bacteremia or generalized disease processes (e.g., Epstein-Barr infection, reticuloendotheliosis, tuberculosis, or HIV infection).

Kawasaki disease may manifest as a febrile illness associated with bilateral or unilateral cervical lymphadenopathy and may be confused with more common acute pyogenic infections. Other features (e.g., conjunctivitis, oral manifestations, changes in the peripheral extremities, and polymorphic erythematous rash) are required criteria for the diagnosis. Although originally termed mucocutaneous lymph node syndrome, unilateral lymph node enlargement of at least 1.5 cm is the most inconsistent feature. Lymphadenopathy usually subsides when the fever subsides, although in some cases it may follow a more chronic course.

The rapid development of painful lymphadenitis, quickly succeeding the sudden onset of fever, chills, weakness, and headache, is a classic presentation of infection caused by Y. pestis (bubonic plague). The groin is the site most often involved. Other locations, including the cervical area, may be affected, however. Establishing the diagnosis and providing treatment quickly are crucial because infection can be fulminant.

In cases of diphtheria, cervical adenopathy develops secondary to infection of the posterior structures of the mouth and proximal pharynx. A whitish gray membrane covers the mucosal surfaces. In severe cases, the cervical adenopathy, which typically is bilateral, can result in a “bull neck” appearance.

Careful physical examination of the head and neck, particularly areas drained by affected lymph nodes, may yield important clues about etiology. The presence of periodontal disease is associated with a higher incidence of anaerobic organisms causing adenitis, the history or presence of tick bites suggests the possibility of tularemia, and the presence of papular or pustular lesions suggesting an inoculation site raises the possibility of other causes of infection, including Nocardia and Bartonella spp. , actinomycosis, sporotrichosis, plague, and cutaneous diphtheria.

Mycobacterial and Bartonella spp. infections and toxoplasmosis are more common entities presenting as subacute or chronic lymphadenitis. The epidemiologic and clinical features that aid in the differentiation of tuberculous and nontuberculous mycobacterial infections are summarized in Table 12.1 . The clinical manifestations virtually are identical ( Fig. 12.3 ). Typically a child presents with a history of painless (so-called cold) cervical node swelling. The submandibular cervical nodes usually are involved in nontuberculous mycobacterial infection, whereas other cervical nodes are involved more frequently with M. tuberculosis . As the infection progresses, the skin overlying the node may develop a pinkish or violaceous discoloration caused by increased vascularity, although the skin temperature usually is not increased. This finding may be followed by adherence of the skin to the underlying mass. If left untreated, fluctuance and spontaneously draining sinus tracts may develop.

A 4-year-old boy who had bilateral nontender enlargement of lymph nodes of 6 weeks’ duration, without other symptoms. Placement of a tuberculin skin test resulted in 18-mm induration, excisional biopsy acid-fast stain was positive, and cultures grew Mycobacterium tuberculosis .

A patient with M. tuberculosis is more likely than one with atypical mycobacterial disease to be older than 4 years of age and to have generalized lymphadenopathy (10–20% of cases), bilateral node enlargement (10% of cases), a history of exposure to tuberculosis (93% of cases), and an urban residence. No differences have been noted, however, with regard to duration of adenopathy, fever, and presence or absence of constitutional symptoms. An abnormal chest radiograph has been noted in 28% to 71% of cases caused by M. tuberculosis, contrasting with the 98% to 100% of normal chest radiographs found in patients with nontuberculous mycobacterial adenitis.

In a summary of 447 reported childhood cases of nontuberculous mycobacterial infections from 15 countries, Lincoln and Gilbert detected only six cases of bilateral cervical node involvement, four with abnormal chest radiographs, and none with nodal enlargement other than cervical. Similar findings have been reported by other investigators. Intradermal tuberculin skin testing with purified protein derivative uncommonly produces more than 15 mm of induration at 48 hours in a child with nontuberculous mycobacterial infection, but reactions between 5 and 15 mm are common. Reactions of 10 to 20 mm can occur with Mycobacterium marinum and M. fortuitum infection. Tuberculin skin test positivity may persist, even when children are retested many years after infection. Unlike the findings with tuberculosis, IFN-γ release assays generally are negative with nontuberculous mycobacterial infections unless the infecting organism is M. kansasii, Mycobacterium szulgai, M. marinum, or Mycobacterium flavescens, which share some antigens that react in the assay and may cross react.

Bartonella infection may manifest days to weeks after the initial inoculation. Characteristically a history of contact with a cat or kitten or a scratch is present. Later, when the primary small papular lesion may have healed, tender regional adenopathy appears. Although axillary nodes most frequently are affected, 25% of children have isolated cervical node involvement. Middle cervical and parotid nodes are involved more often than submandibular nodes. Constitutional symptoms, present early in the course of the illness, usually are mild and may have resolved by the time the adenitis appears. Fever is observed in one-fourth of patients and, if present, has a mean duration of 5 to 7 days. Fever prolonged beyond this time should prompt evaluation for characteristic hepatosplenic granulomatous lesions defined by high-resolution ultrasonography with disseminated cat-scratch disease. Nodes suppurate in one-tenth to one-third of patients. Rare manifestations include Parinaud oculoglandular syndrome, encephalopathy, exanthems (usually of the erythema nodosum type), and osteolytic lesions.

Acquired toxoplasmosis may manifest as regional lymphadenopathy, frequently with posterior cervical node involvement. Most children exhibit few, if any, constitutional symptoms. If present, fatigue and generalized myalgia are prominent. The characteristic location combined with a history of exposure to cats or of eating undercooked meats should raise this diagnostic possibility, and the diagnosis can be confirmed by serologic testing. It is an uncommon etiology for cervical adenopathy in children living in the United States.

Chronic, recurrent cervical adenitis forms part of the periodic fever, aphthous ulcers, pharyngitis, cervical adenitis (PFAPA) syndrome, a chronic syndrome first described in 1987. It is characterized by periodic episodes of high fever, greater than 39°C (102.2°F), lasting 3 to 6 days and recurring every 3 to 8 weeks in association with aphthous ulcers, pharyngitis, and cervical adenitis. Symptoms such as abdominal pain, nausea, diarrhea, and headache also are described in 20% to 73% of children, but if any of these are the dominant features, other hereditary fever syndromes should be excluded. In most children with PFAPA, the onset of disease occurs before they reach 5 years of age, the syndrome is self-limited, and recovery without long-term sequelae is the rule. Although there appears to be a familial predisposition for PFAPA, to date no single gene trait has been found, suggesting that this condition may have a heterogeneous, polygenic, or complex inheritance. Oral corticosteroids are effective in aborting an attack.

Kikuchi-Fujimoto disease, also called subacute necrotizing lymphadenitis, is an uncommon disorder of uncertain etiology that also may manifest as cervical adenopathy, with or without fever. This disorder was described first in 1972 and seems to have a predilection for Asian women 25 to 30 years of age, who generally have a benign course with spontaneous resolution over 3 to 4 months. Kikuchi-Fujimoto disease also has been reported in children, typically adolescents, although cases in children as young as 2 years old are documented.

In contrast to the 4 : 1 female predominance documented in adult series, pediatric Kikuchi-Fujimoto disease occurs more commonly in boys (male-to-female ratio ranges from 1.2 : 1 to 1.9 : 1). The most common presentation is unilateral or bilateral lymphadenopathy of multiple nodes. In most cases, posterior cervical chain nodes are involved, and affected nodes can be painful and tender. Fever is an inconsistent symptom. Extranodal manifestations include malaise, night sweats, weight loss, maculopapular skin rashes, gastrointestinal symptoms, hepatosplenomegaly, arthritis, and aseptic meningitis. Associated laboratory findings include leukopenia (33% to 100% of cases with prolonged fever), elevated erythrocyte sedimentation rate, mild anemia, elevated C-reactive protein, and elevated liver enzymes.

Diagnosis is established by biopsy of the lymph nodes (not by fine-needle aspiration cytology) which shows lymphadenitis with focal proliferation of reticular cells accompanied by histiocytes and extensive nuclear debris. Lymph node biopsy also has been associated with prompt resolution of fever. Treatment generally is supportive, although steroids are reported to provide more rapid resolution of symptoms. The prognosis is favorable; most cases of Kikuchi-Fujimoto disease resolve within 6 months, although a recurrence rate of 3% to 4% is recorded. Some children subsequently develop autoimmune disorders, most commonly systemic lupus erythematosus; thus clinical follow-up looking for signs of evolving autoimmune disorder is recommended. Whether Kikuchi-Fujimoto disease is infectious or genetic, perhaps the result of infection with a single novel agent or a nonspecific host response to any of a variety of agents, remains to be determined.

Another rare but important cause of cervical lymphadenitis in association with generalized lymphadenopathy or hepatosplenomegaly is hemophagocytic lymphohistiocytosis, also known as hemophagocytic syndrome. This diagnosis should be considered if the aforementioned features occur with prolonged fever, cytopenia in at least two cell lines, low fibrinogen, and high ferritin and triglyceride serum levels. Other features include rash, respiratory distress, hypotension, and coagulopathy. The diagnosis is confirmed by the presence of hemophagocytosis in bone marrow or lymph node biopsy specimens. Finally, when presented with a history of subacute or chronic lymphadenitis, careful physical examination should be undertaken to exclude obvious local causes (e.g., seborrhea, head lice, tinea capitis, and chronic otitis media) before an extensive diagnostic evaluation is initiated.

Differential Diagnosis

Cervical swellings are encountered frequently in pediatric practice, and most of them represent lymph nodes. When considering the diagnostic possibilities in patients with cervical lymphadenitis, whether the pathologic process involves a lymph node first must be ascertained, then whether its cause is infectious, and, if infectious, the likely etiologic agent. The duration of the cervical swelling aids in the differential diagnosis because most tumors or developmental anomalies have been noted for weeks. Rapid enlargement may occur in the latter entities but usually as a result of secondary infection. Location is a helpful clue because midline masses rarely represent lymph nodes, and the most common neck masses of congenital origin (thyroglossal duct cyst, branchial cleft cyst, and cystic hygromas) have characteristic anatomic locations.

Of the midline masses, thyroglossal duct cysts are the most common. These cysts occur from the foramen cecum to the thyroid, are midline, and move on protrusion of the tongue. They may have an associated sinus tract, midline or just lateral to it, from which cloudy mucus sometimes can be expressed. They can become infected secondarily, but in the noninfected state these cysts are nontender, smooth, and round, with well-defined margins. Thyroglossal duct cysts must be differentiated from other midline masses, including epidermoid cysts, lipomas, thyroid tumors, and the rare midline lymph node.

The second most common benign congenital neck mass is the branchial cleft cyst. It usually arises from the second branchial cleft and lies at the anterior border of the sternocleidomastoid muscle. Although such cysts usually manifest as skin dimples, they may become infected secondarily and manifest as inflammatory swellings or draining sinus tracts. A careful examination should detect a sinus tract. Branchial cleft cysts can manifest in individuals of any age but usually occur in school-aged children.

Cystic hygromas, considerably less common than thyroglossal duct or branchial cleft cysts, are the third most frequent cause of congenital neck masses. These arise from lymphatics derived from the jugular vein or the mesenchymal tissue. They can occur elsewhere but usually are found posterior to the sternocleidomastoid muscle in the supraclavicular fossa. Most cystic hygromas appear in the first 2 years of life, many being noted at birth or soon thereafter. They are soft, compressible tumors that transilluminate well, and, although benign in themselves, they may cause symptoms through pressure exerted on surrounding structures. Confusion may arise when cystic hygromas increase in size in association with an upper respiratory tract infection. The latter process causes increased lymph flow so that the hygroma persists while other lymph nodes decrease in size after resolution of the infection. In most circumstances, palpation and transillumination readily distinguish these congenital malformations.

These four cervical masses—thyroglossal duct cysts, thyroid tumors, branchial cleft cysts, and cystic hygromas—accounted for 63.7% of lesions in children with persistent cervical masses reported by Moussatos and Baffes. Other lesions included neurogenic tumors, parotid tumors, and miscellaneous benign tumors (12.3%). The remainder of masses represented lymph nodes. As a rule, masses located completely anterior to the sternocleidomastoid muscle are benign. The exception is the thyroid tumor. Malignancies that mimic cervical lymph nodes usually are located in the posterior triangle or are multiple masses extending across the anterior and the posterior triangles. In contrast, approximately 50% of masses in the posterior triangle represent malignancies, most of which are of lymphoid origin. Although most cysts and tumors manifest as solitary, unilateral, nontender masses, lymph nodes of noninfectious etiology frequently are multiple and bilateral and may be mildly tender.

Noninfectious chronic inflammatory involvement of cervical lymph nodes may represent a variety of uncommon, usually benign, but sometimes malignant entities ( Table 12.2 ). Fifty percent of malignant neck masses in children are caused by Hodgkin and non-Hodgkin lymphomas. Neuroblastoma is the second most common malignancy, accounting for 15%. The likelihood of a given diagnosis is age dependent, with neuroblastoma being more common than Hodgkin disease in younger age groups. Thyroid tumors are the third most frequent neck malignancies. Other entities to be included in the differential diagnosis include leukemia, metastatic carcinoma, phenytoin-induced pseudolymphoma, serum sickness, storage disorders (Gaucher disease and Niemann-Pick disease), collagen vascular disease, sarcoidosis, sinus histiocytosis with massive lymphadenopathy, and reticuloendotheliosis or histiocytosis X. Except for malignancies, these disease entities almost always are associated with lymphadenopathy that is not limited to the cervical region and have a variety of clinical and laboratory findings that allow the correct diagnosis to be made.

Numerous infectious agents have been reported in association with cervical adenitis in infants and children ( Table 12.3 ). Among patients evaluated prospectively with needle aspirate cultures or cultures from incision and drainage specimens of affected lymph nodes, S. aureus or group A streptococci are the organisms most frequently isolated. No significant difference has been reported that distinguishes between patients with adenitis caused by streptococci or staphylococci with respect to sex, dental problems, symptoms, presence of fever, or site or size of lymph nodes. In patients from whom S. aureus is isolated, a longer duration of disease before diagnosis is established, and a larger percentage of fluctuant lymph nodes and tendency toward slower resolution often are found. Two recent studies reported that S. aureus was more common in infants younger than 12 and younger than 16 months of age, respectively, than in older children with neck abscesses and also noted a predominance of CA-MRSA among black children. Most patients with bacterial cervical lymphadenitis, including patients with mycobacterial infection, are 1 to 6 years of age. Older children are more likely to have negative lymph node aspirate cultures.

TABLE 12.3

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