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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorDenis Spelman, MBBS, FRACP,FRCPA, MPH

Section EditorC Fordham von Reyn, MD

Deputy EditorElinor L Baron, MD, DTMH

Tuberculous lymphadenitis

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Feb 23, 2015.

INTRODUCTION — Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis (TB). Tuberculous lymphadenitis

in the cervical region is known as scrofula [1]. This syndrome can also be caused by nontuberculous mycobacteria.

TB is responsible for up to 43 percent of peripheral lymphadenopathy in the developing world [2]. In rural India, the prevalence of tuberculous lymphadenitis

in children up to 14 years of age is approximately 4.4 cases per 1000 [3]. In the United States, about 20 percent of patients with TB have extrapulmonary

disease, and lymphadenitis is a presenting symptom in about 30 to 40 percent of cases [4-6]. (See "Evaluation of peripheral lymphadenopathy in adults".)

The human immunodeficiency virus (HIV) epidemic has been associated with an increase in the total incidence of TB and an increased proportion of

miliary, disseminated, and extrapulmonary TB cases including lymphadenitis [7]. (See "Epidemiology of tuberculosis" and "Epidemiology and pathology of

extrapulmonary and miliary tuberculosis".)

Issues related to tuberculous lymphadenitis will be reviewed here. Other issues related to tuberculosis are discussed separately. (See related topics.)

PATHOGENESIS — Isolated peripheral tuberculous lymphadenopathy is usually due to reactivation of disease at a site seeded hematogenously during

primary tuberculosis (TB) infection, perhaps years earlier [8].

It has been postulated that cervical tuberculous lymphadenitis occurs as a result of TB infection involving the tonsils, adenoids, and Waldeyer's ring,

leading to cervical lymphadenopathy [2]. Abdominal tuberculous lymphadenopathy may occur via ingestion of sputum or milk infected with Mycobacterium

tuberculosis or M. bovis [9]. (See "Natural history, microbiology, and pathogenesis of tuberculosis" and "Mycobacterium bovis".)

Though most cases of tuberculous lymphadenitis occur in the setting of reactivation of latent infection, miliary dissemination with prominent lymph node

involvement in the setting of primary infection can also occur [7,10,11].

EPIDEMIOLOGY — The epidemiology of tuberculous lymphadenitis varies between developed and developing countries.

In developed countries, most cases of tuberculous lymphadenitis occur among adult immigrants from tuberculosis (TB)-endemic countries [12-14]. This

was illustrated by case series of tuberculous lymphadenitis in France and Germany in which about 70 percent of cases occurred in immigrants; in the

German study, two-thirds of patients had immigrated >3 years prior to diagnosis [12,13]. In the United States, the rate of tuberculous lymphadenitis is

higher among Asian Pacific Islanders and in females [2,5,15]. Rarely, tuberculous lymphadenitis can also occur in travelers to endemic areas [16,17].

Tuberculous lymphadenitis occurs more frequently in women than in men [1].

®

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Previously, tuberculous lymphadenitis was considered a disease of childhood; however, the peak age of onset in developed countries has shifted from

childhood to ages 20 to 40 years [18]. In contemporary series, the median age has been approximately 40 years in developed countries (range 1 to 88

years) [12,14,19].

In developing countries where TB is endemic, extrapulmonary TB occurs in up to 60 percent of HIV-infected patients with TB and is frequently

accompanied by signs of pulmonary involvement [20-22]. Most extrapulmonary TB cases (including tuberculous lymphadenitis) occur among patients with

HIV at CD4 counts <300 cells/microL (usually below 100 cells/microL) [7,23].

CLINICAL MANIFESTATIONS — Clinical manifestations depend on the site of the lymphadenopathy and the immune status of the patient [8,10,15,16].

The most common presentation is isolated chronic nontender lymphadenopathy in a young adult without systemic symptoms. The mass may be present

for up to 12 months before diagnosis [16,24]. Physical examination reveals a firm, discrete mass or matted nodes fixed to surrounding structures; the

overlying skin may be indurated [8]. Uncommon findings include fluctuance, draining sinus, or erythema nodosum.

Cervical lymphadenopathy — Cervical lymphadenopathy is the most common manifestation of tuberculous lymphadenitis; in contemporary series, it

represents 63 to 77 percent of cases [12,19].

Most frequently, a unilateral mass appears in the anterior or posterior cervical triangles; submandibular and supraclavicular lymph node involvement also

occurs [16,20,24,25]. Bilateral disease is uncommon (up to 26 percent of cases) [16,26]. Although most patients have disease at only one site, multiple

nodes may be involved at that site [15,24].

Other involved nodes — Local complications of tuberculous lymphadenitis are dependent on local anatomical structures:

Other sites of tuberculous lymphadenitis include the axillary, inguinal, and intramammary lymph nodes [8,10,41].

HIV coinfection — Among patients with tuberculous lymphadenitis in the setting of HIV infection, there may be a significant mycobacterial load with

concomitant systemic findings including fever, sweats, and weight loss [20]. Abnormal chest radiography is frequently observed, and such patients are

more likely to have disseminated TB with lymphadenitis at more than one site [10,20]. Patients with mediastinal and hilar node involvement are likely to

Tuberculous cervical lymphadenitis can be complicated by ulceration, fistula, or abscess formation.●

Mediastinal lymph node involvement usually occurs as a complication of primary tuberculosis (TB). Nodal enlargement can result in compression of

the upper airways with bronchial or tracheal stenosis [27-29]. These complications may be more common in children, who have softer cartilage in

their airway, and also more common in patients with HIV [27]. Tuberculous mediastinal lymphadenopathy can present with dysphagia, esophageal

perforation, vocal cord paralysis due to recurrent laryngeal nerve involvement, or pulmonary artery occlusion mimicking pulmonary embolism [30-33].

●

Subcarinal node enlargement can cause external compression of both the esophagus (producing dysphagia) [34] and bronchus [35]. Esophageal

perforation and tracheoesophageal fistula have both been reported [36].

●

Tuberculous peritoneal lymphadenopathy most commonly involves lymph nodes in the periportal region, followed by peripancreatic and mesenteric

lymph nodes [10]. Hepatic lymph node involvement can lead to jaundice, portal vein thrombosis, and portal hypertension [37]. Extrinsic compression

of renal arteries due to tuberculous abdominal lymphadenopathy can result in renovascular hypertension [38]. Enlargement of tuberculous

intraabdominal lymph nodes has resulted in external compression of segments of the gastrointestinal tract, such as the duodenum [39,40].

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have active pulmonary TB and may have symptoms including dyspnea and tachypnea [42].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of isolated peripheral lymphadenopathy is extensive and includes malignancy (eg, Hodgkin

lymphoma and non-Hodgkin lymphoma) and other infections (eg, nontuberculous mycobacteria [M. scrofulaceum, M. avium complex, M. kansasii], cat

scratch disease, fungal infection, sarcoidosis, and bacterial adenitis). Kikuchi's disease can cause a necrotizing lymphadenitis and mimic tuberculous

cervical lymphadenopathy; indistinct margins of necrotic foci demonstrated on computed tomography (CT) scan may be an independent predictor of

Kikuchi’s disease [43,44]. The most likely alternative diagnoses depend on the clinical setting including the patient's age, ethnic background, immune

status, and presenting clinical features.

It is difficult to differentiate tuberculosis (TB) from other causes of lymphadenitis on clinical grounds. One study found no distinguishing clinical features

between patients with lymphadenitis due to TB or nontuberculous mycobacteria [45]. Another report noted the same results regardless of HIV status [20].

DIAGNOSIS — Diagnosis of tuberculous lymphadenitis is established by histopathology examination along with acid-fast bacilli (AFB) smear and culture

of lymph node material. Chest imaging should also be obtained.

Histopathology — Material for histopathology evaluation may be obtained by fine needle aspiration or excisional lymph node biopsy.

Fine needle aspiration — Fine needle aspiration (FNA) is appropriate for initial evaluation of cervical lymphadenopathy to evaluate for tuberculous

lymphadenitis. The yield of FNA appears to be highest in the setting of HIV infection and in regions where the prevalence of tuberculosis (TB) is high

[16,20,46-48]. In these circumstances, the burden of organisms is likely to be high. In a series of 1193 patients evaluated for tuberculous lymphadenitis in

Hong Kong, for example, FNA had good sensitivity and specificity (77 and 93 percent, respectively) [49].

FNA is a relatively safe and inexpensive procedure, with few complications when a 21 to 23 gauge needle is used [16]. Specimens should be submitted for

microscopy, culture, cytology, and polymerase chain reaction testing (where available).

Excisional biopsy — Excisional lymph node biopsy for histopathologic and microbiological evaluations has the highest diagnostic yield and should be

pursued in cases where fine needle aspiration is not diagnostic [25,49]. In a series of 47 patients evaluated for tuberculous lymphadenitis, for example, the

diagnosis of TB was established by excisional biopsy in all cases; FNA was definitive in only 62 percent [25].

An excisional biopsy is preferred; incisional biopsy may result in sinus tract formation. For mediastinal lymph node biopsy, mediastinoscopy may be

required.

Specimens should be submitted for histology, culture, and nucleic acid testing.

The finding of caseating granulomas on histopathology is highly suggestive of TB although is not diagnostic since other diseases can also have similar

histology [25].

Culture and nucleic acid testing — Nucleic acid testing can facilitate the diagnosis of TB in lymph node tissues (including aspirates) for which histology

findings are not specific and acid-fast organisms are not seen [50-52]. In a systemic review and meta-analysis including 18 studies, the sensitivity and

specificity for the Xpert MTB/RIF assay (compared with culture) in lymph nodes were 83 and 94 percent, respectively [52].

Culture permits susceptibility testing and therefore provides important therapeutic information even in the setting of positive nucleic acid test results.

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Imaging

Chest imaging — Many patients (90 to 100 percent) with tuberculous lymphadenitis have no evidence of active pulmonary TB on chest radiograph

[12,17]. Pleural thickening and apical fibrosis suggestive of previous TB may be observed [8,20]. Chest radiograph abnormalities have been described more

frequently among patients with HIV infection in some series. One report of 10 HIV-infected patients described abnormal radiography on presentation with

tuberculous lymphadenitis in 90 percent of cases [20].

Chest imaging suggestive of active pulmonary TB should prompt further evaluation, as outlined separately. (See "Diagnosis of pulmonary tuberculosis in

HIV-uninfected patients" and "Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients".)

Neck imaging — Neck imaging modalities include ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI).

Other diagnostic tools — Diagnosis of tuberculous lymphadenitis is established by histopathology examination and AFB smear and culture of lymph

node material as discussed above. Additional diagnostic tools that may be useful in the setting of suspected tuberculous lymphadenitis are outlined below.

Further discussion of issues related to diagnosis of TB is presented separately. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected patients" and

"Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients".)

Ultrasonography – In a study comparing lymph node metastases with tuberculous lymphadenitis, the latter was associated with a higher incidence of

abnormal surrounding soft tissue, cystic necrosis, matting, posterior enhancement (when structures posterior to the node were more echogenic than

neighboring structures), and a heterogeneous rather than a homogenous pattern [53].

●

Computed tomography – CT can be a useful tool to distinguish between tuberculous lymphadenitis and lymphoma. In one Chinese series including

26 patients with tuberculous lymphadenitis and 43 patients with lymphoma, lower paraaortic node involvement was more common in lymphoma; TB

more often involved upper paraaortic, lesser omental, mesenteric, and anterior pararenal lymph nodes [9]. Peripheral enhancement (often with a

multilocular appearance) was also a feature of tuberculous lymphadenopathy; homogeneous attenuation was more common in the setting of

lymphomatous adenopathy.

●

Magnetic resonance imaging – In a report of MRI evaluation among nine Chinese patients with tuberculous lymphadenitis, three patterns of disease

were noted: discrete nodes, matted nodes, and confluent masses [54]. Necrotic foci, when present, were more frequently peripheral rather than

central.

●

Sputum smear and culture – Positive sputum cultures are uncommon (0 to 14 percent) in the setting of tuberculous lymphadenitis [12,16,55]. Chest

radiography findings consistent with active pulmonary TB should prompt sputum cultures; if positive, evaluation for miliary TB should be pursued.

(See "Clinical manifestations, diagnosis, and treatment of extrapulmonary and miliary tuberculosis".)

●

Bronchoscopy – In the setting of isolated intrathoracic lymphadenopathy, bronchoscopy may be useful to establish a diagnosis of TB if sputum

studies are negative [56,57].

●

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) – This modality may be useful in the setting of isolated intrathoracic

lymphadenopathy [58,59]. In one report of 24 patients with isolated intrathoracic lymphadenopathy and a high clinical suspicion for tuberculosis,

material obtained by EBUS-TBNA confirmed the diagnosis in 79 percent of cases (sensitivity and specificity 95 and 100 percent, respectively) [58].

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TREATMENT — Treatment of tuberculous lymphadenitis consists of antimycobacterial therapy. In some circumstances, excisional biopsy in theory may

be sufficient for treatment of immunocompetent patients with localized disease, though in general all patients should also receive antimycobacterial

therapy.

Choice of therapy — The American Thoracic Society (ATS), Centers for Disease Control (CDC), and the Infectious Diseases Society of America (IDSA)

have published recommendations for the treatment of tuberculosis (TB) [62]. In general, treatment for adults with tuberculous lymphadenitis consists of two

months of rifampicin, isoniazid, ethambutol, and pyrazinamide (given daily) followed by four months of rifampicin and isoniazid (given either daily or three

times weekly) [63]. Dosing, monitoring, and further details related to antimycobacterial regimens for TB are presented separately as are issues related to

patients with HIV infection. (See "Treatment of pulmonary tuberculosis in HIV-uninfected patients" and "Treatment of pulmonary tuberculosis in the HIV-

infected patient".)

The recommended duration of therapy for HIV-seronegative adults is six months [62,64,65]. In a randomized trial comparing a six-month regimen (four

drugs for four months followed by two drugs for two months) with a nine-month regimen (four drugs for four months followed by two drugs for five months),

there was no difference in treatment failure or remission at five years between the two regimens [64].

Alternative regimens for drug-susceptible M. tuberculosis have also been evaluated, including [63]:

Although these regimens were comparable to each other in a trial of 277 patients with tuberculous lymphadenitis in India (90 percent of patients had fully

susceptible M. tuberculosis), the two-drug regimen is not generally recommended.

The optimal duration of therapy in children is uncertain [66]. The relapse rate in children after six months of therapy is not well established; nine months of

therapy may be appropriate pending further study.

Longer duration of therapy also may be appropriate for patients with HIV infection with evidence of suboptimal response, who cannot tolerate first-line

medications, or who have infection due to resistant organisms [62]. In such situations, selection and duration of therapy should be individualized in

consultation with infectious disease expertise. Treatment of drug-resistant tuberculosis is discussed elsewhere. (See "Diagnosis, treatment, and

prevention of drug-resistant tuberculosis".)

Blood culture – Blood cultures for M. tuberculosis are rarely positive but may be positive in disseminated TB, especially in patients with HIV and

other forms of immunosuppression [60].

●

Tuberculin skin test – The tuberculin skin test (TST) is positive in the majority (74 to 100 percent) of patients with tuberculous lymphadenitis (in the

absence of HIV infection), although positive TST is not sufficient to establish the diagnosis [8,12,14,16,17,20]. A negative TST is not helpful in

excluding the diagnosis, especially in immunosuppressed individuals [20].

●

Interferon-gamma release assays (IGRAs) — In a report including 44 patients with suspected tuberculous cervical lymphadenitis, the diagnosis was

confirmed in 21 patients; IGRA demonstrated a sensitivity and specificity of 86 and 87 percent, respectively [61].

●

HIV testing – Patients with suspected or proven TB should undergo HIV testing [42]. (See "Screening and diagnostic testing for HIV infection".)●

Two months of rifampicin, isoniazid, and pyrazinamide (two times weekly) followed by four months of rifampicin and isoniazid (two times weekly)●

Six-month regimen of daily rifampicin and isoniazid●

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Response to therapy — Tuberculous lymphadenitis tends to respond slowly to effective treatment. This may include enlargement of nodes while on

treatment or after cessation of treatment.

Paradoxical reaction — Antimycobacterial therapy may prompt a paradoxical reaction or increase in lymph node size and/or enlargement of

additional lymph nodes during or after cessation of treatment [12,55]. This is attributable to an immune response to dying M. tuberculosis organisms [67].

Clinical manifestations may include lymph node enlargement (12 percent), fluctuance (11 percent), overlying erythema, and/or spontaneous discharge (7

percent) [55,68]. Constitutional symptoms are uncommon [55]. (See "Immune reconstitution inflammatory syndrome".)

In HIV-negative patients, such paradoxical reactions occur in up to 23 percent of cases [12,55,67,69]. Predictors include male gender and presence of

local erythema at the time of diagnosis [67].

In HIV-positive patients, paradoxical reactions are more common in some but not all reports [70,71]. It may be more temporally associated with the

initiation of antiretroviral therapy (ART) than antituberculosis therapy [70]. There appears to be no association between baseline CD4 counts or CD4

response to ART [72].

The differential diagnosis includes treatment failure due to resistance or noncompliance, another infection, or an alternative diagnosis [72].

There are no consensus guidelines for management. Options include observation, aspiration, surgical excision, or a trial of nonsteroidal antiinflammatory

agents or corticosteroids. Infliximab has also been used in this setting [73].

Fine needle aspiration (FNA) for acid-fast bacillus microscopy and culture may be pursued to distinguish between a paradoxical reaction and treatment

failure. Repeated FNA has been used in an attempt to prevent fistula formation and as an alternative to steroid therapy or to prevent the need for surgical

excision [69].

In one study of 235 HIV-seronegative patients, spontaneous resolution of paradoxical lymph node enlargement occurred in 56 percent of cases [67]. In a

second study including both HIV-infected and noninfected patients, spontaneous resolution occurred in all patients in mean period of 2.5 months; some

patients underwent aspiration or excision [55].

Relapse rates — Relapse rates of up to 3.5 percent have been reported in patients treated for tuberculous lymphadenitis [65]. A minority (7 to 11

percent) of patients have residual lymph nodes present at the end of the treatment course [65,68,74].

SUMMARY AND RECOMMENDATIONS

Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis (TB). Tuberculous lymphadenitis in the cervical

region is known as scrofula. (See 'Introduction' above.)

●

Isolated peripheral tuberculous lymphadenopathy is usually due to reactivation of disease at a site seeded hematogenously during primary TB

infection, perhaps years earlier. Miliary dissemination with prominent lymph node involvement in the setting of primary infection can also occur. (See

'Pathogenesis' above.)

●

Previously, tuberculous lymphadenitis was considered a disease of childhood; however, in reports from developed countries, the peak age of onset

has shifted from childhood to ages 20 to 40 years. In developed countries, most cases of tuberculous lymphadenitis occur among immigrants from

TB-endemic countries. In regions where TB is endemic, extrapulmonary TB occurs in approximately 60 percent of HIV-infected patients with TB and

●

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is frequently accompanied by signs of pulmonary involvement. (See 'Epidemiology' above.)

Clinical manifestations depend on the site of the lymphadenopathy and the immune status of the patient. The most common presentation is isolated

chronic nontender lymphadenopathy in a young adult without systemic symptoms, most commonly in the cervical region. Physical examination

reveals a firm, discrete mass or matted nodes fixed to surrounding structures; the overlying skin may be indurated. (See 'Clinical manifestations'

above.)

●

Among patients with tuberculous lymphadenitis in the setting of HIV infection, there may be a significant mycobacterial load with concomitant

systemic findings including fever, sweats, and weight loss. Abnormal chest radiography is frequently observed, and such patients are more likely to

have disseminated TB with lymphadenitis at more than one site. (See 'HIV coinfection' above.)

●

Diagnosis of tuberculous lymphadenitis is established by histopathology examination along with acid-fast bacilli (AFB) smear and culture of lymph

node material. Fine needle aspiration (FNA) is appropriate for initial evaluation of cervical lymphadenopathy to evaluate for tuberculous lymphadenitis.

The yield of FNA appears to be highest in the setting of HIV infection and in regions where the prevalence of TB is high. Specimens should be

submitted for microscopy, culture, cytology, and nucleic acid testing (where available). Excisional lymph node biopsy for histopathologic and

microbiological evaluation has the highest diagnostic yield and should be pursued in cases where fine needle aspiration is not diagnostic or for

persistent disease despite appropriate therapy. (See 'Histopathology' above.)

●

Chest imaging should be pursued in the setting of suspected tuberculous lymphadenitis. Many patients with tuberculous lymphadenitis have no

evidence of active pulmonary TB on chest radiograph; abnormalities have been described more frequently among patients with HIV infection in some

series. (See 'Imaging' above.)

●

For treatment for HIV-seronegative adults with tuberculous lymphadenitis, we suggest the following regimen: two months of rifampicin, isoniazid,

ethambutol, and pyrazinamide (given daily) followed by four months of rifampicin and isoniazid (given either daily or three times weekly) (Grade 2B).

The preferred duration of therapy for adults is six months. The optimal duration of therapy in children is uncertain, as the relapse rate after six months

of therapy is not well established; nine months of therapy may be appropriate pending further study. (See 'Treatment' above.)

●

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Disclosures: Denis Spelman, MBBS, FRACP, FRCPA, MPH Nothing to disclose. C Fordham von Reyn, MD Nothing to disclose. Elinor LBaron, MD, DTMH Nothing to disclose.

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