|
 
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| THE EXTRAPULMONARY DISEASE - THE BIG DILEMMA |
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| Year : 2017 | Volume
: 4
| Issue : 2 | Page : 80-86 |
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Tuberculosis of the lymph nodes: Many facets, many hues
Avinash Gandhare, Ashok Mahashur
Department of Respiratory Medicine, P D Hinduja National Hospital, Mumbai, Maharashtra, India
| Date of Web Publication | 30-Nov-2017 |
Correspondence Address:
Ashok Mahashur
Department of Respiratory Medicine, P D Hinduja National Hospital, Mumbai, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/astrocyte.astrocyte_65_17
Lymph node tuberculosis (LNTB) is one of the most common extrapulmonary manifestations of tuberculosis. A high index of suspicion is needed for diagnosis of tuberculous lymphadenitis, which is known to mimic numerous pathological conditions. Availability of molecular technology has improved the ease of diagnosis. Molecular techniques are also useful for the early detection of drug resistance. With the advent of endobronchial ultrasound in the last decade, the diagnosis of mediastinal tuberculosis has also improved. Management of LNTB often has difficulties. However, most cases can be managed medically and surgical intervention is rarely required. The treatment is similar to pulmonary tuberculosis. However, paradoxical reaction, which is observed in 10–15% of immunocompetent and about 50% of human immunodeficiency virus positive patients needs a special mention for an appropriate management of LNTB.
Keywords: Endobronchial ultrasound, lymph node, paradoxical reaction, tuberculosis
How to cite this article:
Gandhare A, Mahashur A. Tuberculosis of the lymph nodes: Many facets, many hues. Astrocyte 2017;4:80-6 |
| Introduction | |  |
Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis (TB). Extrapulmonary tuberculosis comprises 10–50% of all TB in human immunodeficiency virus (HIV) negative patients and approximately 35–80% in HIV infected patients. TB lymphadenitis is seen in nearly up to 40% of extrapulmonary TB which constitutes approximately 15–20% of all cases of TB in India.[1],[2],[3] In rural India, the prevalence of tuberculous lymphadenitis in children up to 14 years of age is approximately 4.4 cases per 1000 as per Narang et al., who studied TB lymphadenitis of children in Wardha district.[4] Causes of mycobacterial lymphadenitis includes Mycobacterial tuberculosis, M. bovis, M. africanum, and the atypical Mycobacteria (M. scrofulaceum, M. avium-intracellulare complex, and M. kansaii).
| Pathogenesis | | |
Tuberculous lymphadenitis is considered a local manifestation of the systemic disease, whereas lymphadenitis due to nontuberculous Mycobacteria is truly a localized disease.[5]
TB lymphadenitis may occur due to:
- Reactivation of healed focus involved during primary infection
- Progressive primary tuberculosis i.e. spread from lung into mediastinal lymph node
- Spread from tonsil and
- Hematogenous spread due to miliary TB
The most common mode of development of tuberculous lymphadenitis is reactivation of healed focus and progressive primary tuberculosis. M. tuberculosis usually enters the human body via the respiratory tract and forms primary complex or Ghon's complex in the posterior segment of the upper lobe and undergoes lymphohematogenous dissemination. Because the entry is via respiratory tract, the first lymphoid tissues encountered are presumably hilar and mediastinal lymph nodes, however, these lymph nodes are not often picked up. Tuberculous lymphadenitis most frequently involves the cervical lymph nodes followed in frequency by mediastinal, axillary, mesenteric, hepatic portal, perihepatic, and inguinal lymph nodes.[5],[6],[7]
Jones and Campbell in 1962 described stages of TB lymphadenitis. These are as follows:[8]
- Enlarged, firm, mobile, discrete nodes.
- Large rubbery nodes fixed to surrounding tissue.
- Central softening abscess.
- Collar stud formation.
- Sinus tract formation.
| Presentation | | |
The clinical manifestation of TB lymphadenitis largely depends upon the anatomical location of the affected nodes and immune status of the individual.[9],[10],[11],[12]
TB lymphadenitis occurs more frequently in women than in men.[13] Previously considered a disease of the childhood its peak age of onset in developed countries has shifted from childhood to ages of 20 to 40 years.[14] In several contemporary series, the median age in developed countries was determined to be approximately 40 years (range, 1–88 years).[15],[16],[17]
The most common presentation in young adults is isolated chronic nontender lymphadenopathy. Systemic symptoms are not common; fever has been reported in 20–50% of the cases in HIV-uninfected patients and 60–80% in HIV-infected patients.[13] The mass may be present for up to 12 months before diagnosis.[15],[18] Physical examination reveals a firm, discrete mass or matted nodes fixed to surrounding structures; the overlying skin may be indurated. Uncommon findings include fluctuance, draining sinus, or erythema nodosum.[9]
Cervical lymphadenopathy
Cervical lymphadenopathy [Figure 1] is the most common manifestation of tuberculous lymphadenitis; in contemporary series, it represents 63–77% of the cases.[15],[16],[17] | Figure 1: Cervical lymph node seen as enlarged cervical swelling in posterior triangle of neck.
Click here to view |
Most frequently, a unilateral mass appears in the anterior or posterior cervical triangles; submandibular and supraclavicular lymph node involvement also occurs.[12],[18],[19],[20]
Bilateral disease is uncommon (up to 26% of the cases).[12] Although most patients have disease at only one site, multiple nodes may be involved at that site.[11],[18]
Cervical lymphadenopathy may sometimes be associated with a simultaneous involvement of other nodes in the region, which may produce a variety of signs and symptoms depending upon the anatomical location of the affected nodes.
In general, it is common to meet with the following patterns of presentations and complications:
- Tuberculous cervical lymphadenitis is commonly complicated by ulceration, fistula, or abscess formation.
- Mediastinal lymph node involvement [Figure 2] usually occurs as a complication of primary TB. Nodal enlargement can result in compression of the upper airways with bronchial or tracheal stenosis.[21],[22],[23] 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.[24],[25],[26],[27]
- Subcarinal node enlargement can cause external compression of both, the esophagus (producing dysphagia), and bronchus. Esophageal perforation and tracheoesophageal fistula have both been reported.[28],[29],[30]
- 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. Extrinsic compression of renal arteries due to tuberculous abdominal lymphadenopathy can result in renovascular hypertension.[31],[32]
 | Figure 2: Chest radiographs showing hilar and paratracheal lymph adenopathy in a patient with cervical lymph node TB before treatment (a) and after starting of treatment (b). CT chest in mediastinal widow (c and d) showing multiple mediastinal lymph nodes with rim enhancement and central attenuation.
Click here to view |
Other sites of tuberculous lymphadenitis include the axillary, inguinal, and intramammary lymph nodes.
Presentation in HIV patients
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. Patients with mediastinal and hilar node involvement are likely to have active pulmonary TB and may have symptoms including dyspnea and tachypnea.[10],[19]
| Differential Diagnosis | | |
The differential diagnosis of isolated peripheral lymphadenopathy is extensive and includes malignancy (e.g., Hodgkin lymphoma and non-Hodgkin lymphoma), infections (e.g., nontuberculous Mycobacteria (M. scrofulaceum, M. avium complex, M. kansasii), reactive hyperplasia, cat scratch disease, fungal infection, toxoplasma lymphadenitis, sarcoidosis, berylliosis, bacterial adenitis, and Kikuchi disease (idiopathic histiocytic necrotizing lymphadenitis).[33],[34]
It is difficult to differentiate tuberculosis from other causes of lymphadenitis on clinical grounds. One study found no distinguishing clinical features between patients with lymphadenitis due to tuberculous or nontuberculous Mycobacteria.[35] Another report noted the same results regardless of HIV status.[19]
| Diagnosis | | |
History of exposure to a person suffering from pulmonary TB is highly suggestive of lymphatic TB in a given clinical setting.
Diagnosis of tuberculous lymphadenitis is established by histopathology examination along with acid-fast bacilli (AFB) smear and AFB culture of lymph node material.
The diagnostic modalities can be divided into (1) primary diagnostic studies and (2) ancillary diagnostic studies.[13]
Primary diagnostic studies
Fine needle aspiration
Caseating granuloma with AFB positivity is fairly sensitive and specific for the diagnosis of TB. Necrosis which can mimic “caseation” along with granuloma can be seen in many diseases such as lymphoma and sarcoidosis. Overall, the diagnostic accuracy of lymph node FNAC ranges from 71.3% to 97%.[28],[29],[30],[31],[32] Histologic features, such as nonspecific lymphoid infiltrates, noncaseating granulomas, or Langerhans giant cells in areas of extensive caseous necrosis, support a diagnosis of probable tuberculosis.[13]
Lymph node biopsy
In studies from developed countries, M. tuberculosis is typically cultured from excisional biopsies in 70–90% of cases. Excisional biopsy is preferred over incisional biopsy; the latter may be associated with sinus tract formation. For mediastinal lymph node biopsy, CT-guided biopsy or endobronchial ultrasound (EBUS)-guided biopsy and rarely mediastinoscopy may be required.[13]
Culture
Isolation of Mycobacteria by culture still represents the cornerstone on which the definitive diagnosis is based. Although culture can be performed with aspirated specimen, the positive rates are at times significantly lower in aspirated specimen as compared to biopsy specimen (17% vs 80%, respectively, in a study from Hong Kong.[36] Although culture establishes the diagnosis most definitively, the time consumed to grow Mycobacteria makes it unsuitable for routine use. Hence, a few modern rapid methods have been developed. These include microcolony detection on solid media, septic check AFB method, microscopic observation of broth culture, the BACTEC 460 radiometric system, BACTEC MGIT 960 system, MB/BacT system, and ESP II culture system.[37] Of these, currently MGIT culture is the gold standard.
Molecular tests
Molecular diagnosis or nucleic acid amplification (NAA) are used to detect mycobacterial DNA instead of detection of Mycobacteria. They have higher sensitivity, are quicker and allow identification of the species and drug resistance earlier compared to conventional methods.[37]
(1) Amplified molecular tests for detecting M. tuberculosis: These are PCR-based fast and useful techniques for the demonstration of mycobacterial DNA fragments in patients with clinically suspected mycobacterial lymphadenitis. The most common target used in PCR is IS6110.[1] A systematic review of NAA using PCR technique in tuberculous lymphadenitis revealed highly variable and inconsistent results (sensitivity, 2–100%; specificity, 28–100%), with more favorable performance from commercial assays and with sample sizes of more than 0.20 uL.[38] Due to these highly inconsistent results, these PCR-based tests are not recommended and TB Gene Xpert (mentioned below) is preferred.
(2) Test for detecting drug resistance to M. tuberculosis: They can be performed on cultured TB isolates or directly on pretreated primary specimens. Some assays (Cepheid Xpert and INNOLIPA) have been designed to detect TB and resistance to rifampicin only, whereas others (GenoType MTBDR plus) are able to detect both isoniazid and rifampicin-resistance in primary specimens and cultures. The Cepheid GeneXpert®, INNO-LiPA Rif. TB and GenoType MTBDRplus system have all been approved for TB detection in sputum by regulatory agencies. Though all have not been approved for use in extrapulmonary TB, in 2013 the World Health Organization (WHO) endorsed the use of Cepheid GeneXpert® for diagnosis of extrapulmonary TB. A meta-analysis of FNAC samples for Cepheid GeneXpert has shown a sensitivity of 50–100% with pooled sensitivity of 83.1% and pooled specificity of 93.6%. The pooled sensitivity for INNOLIPA for extrapulmonary sample is somewhat lower at 63–68%.[38],[39],[40]
As per our RNTCP guidelines, TB Gene Xpert is recommended to be used on every FNAC or biopsy sample of lymph node for its high sensitivity and specificity in diagnosing TB and rifampicin resistance.
Ancillary Diagnostic Tests
Tuberculin skin test
The tuberculin skin test (TST) is positive in the majority (74–100 percent) of patients with tuberculous lymphadenitis (in the absence of HIV infection), although positive TST is not sufficient to establish the diagnosis. A negative TST is not helpful in excluding the diagnosis, especially in immunosuppressed individuals.[15],[41] Tuberculin anergy is useful in distinguishing sarcoidosis and lymphoma from TB.[3],[42]
Interferon-gamma release assays
The interferon-gamma release assays (IGRAs) have a high sensitivity and specificity for diagnosis of TB lymphadenitis, but positive test results are not sufficient to establish a diagnosis. The Indian government banned serological antibody tests in 2012, and both Standards for TB Care in India (STCI) and International Standards for TB Care (ISTC) discourage the use of IGRAs for the diagnosis of active TB.[43]
Sputum smear and culture
Positive sputum cultures are uncommon (0–14%) in the setting of tuberculous lymphadenitis. Chest radiography findings consistent with active pulmonary TB should prompt sputum cultures; if positive, evaluation for miliary TB should be pursued.[15],[12],[44]
Bronchoscopy
In the setting of isolated intrathoracic lymphadenopathy, bronchoscopy may be useful to establish a diagnosis of TB if sputum studies are negative and transbronchial needle aspiration of the involved lymph nodes through bronchoscopy can also be done.[26],[45]
Endobronchial ultrasound-guided transbronchial needle aspiration and biopsy
This modality may be useful in the setting of isolated intrathoracic lymphadenopathy.[45],[46] Lymph node stations 2, 4, 7, 10, and 11 can be sampled by EBUS. In tuberculosis, EBUS-TBNA has been shown to have a sensitivity of 85%. Gahlot et al. concluded that EBUS-TBNA is highly accurate (diagnostic yield, 92%) and safe procedure for diagnosing mediastinal lymphadenopathy and granulomatous lymphadenitis was most common with TB as the main etiology.[47]
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.[48]
| Treatment | | |
Treatment of tuberculous lymphadenitis consists of multidrug antimycobacterial therapy. In some circumstances, excisional biopsy in theory may be sufficient for the treatment of immunocompetent patients with localized disease, though in general all patients should also receive antimycobacterial therapy.[38]
Medical therapy
The recent RNTCP and WHO updates recommend a fixed dose weight based daily regimen with isoniazide (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) for 2 months followed by isoniazide (H), rifampicin (R), ethambutol (E) for 4 months for drug susceptible TB (WHO/RNTCP2017). The 6-month recommendation is supported by studies that showed no difference between 6 and 9 months of treatment in cure rates (89–94%) or relapse rates (3%).[49]
In patients with drug-resistant TB, the treatment must rely upon the recent WHO guidelines which are primarily based on drug sensitivity pattern.
Response to therapy
Tuberculous lymphadenitis is characteristically slow to respond to effective treatment, and nodes may enlarge during 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 in up to 20% of patients during or after cessation of treatment. Most paradoxical reactions occur between 3 weeks and 4 months after initiation of treatment. Cultures are usually negative and such reactions do not usually indicate treatment failure.[13],[15],[44]
Paradoxical reactions have been attributed to an immune response to dying M. tuberculosis organisms. Clinical manifestations may include lymph node enlargement (12%), fluctuance (11%), overlying erythema, and/or spontaneous discharge (7%). Constitutional symptoms are uncommon.[44],[50],[51]
In HIV-uninfected patients, such paradoxical reactions occur in up to 23% of the cases. Predictors include male gender and presence of local erythema at the time of diagnosis.[15],[44],[52]
In HIV-infected patients, paradoxical reactions are more common in some but not all reports. It may be more temporally associated with the initiation of antiretroviral therapy (ART) than anti-TB therapy. There appears to be no association between baseline CD4 counts or CD4 response to ART.[53],[54]
The differential diagnosis of paradoxical reaction includes treatment failure due to resistance or noncompliance, another infection, or an alternative diagnosis.[54]
There are no consensus guidelines for management of paradoxical reaction, and the approach should be based on whether the patient is experiencing significant discomfort. Options include observation, aspiration, surgical excision, or a trial of nonsteroidal anti-inflammatory agents or corticosteroids. Infliximab has also been used in this setting.[55]
FNA for AFB microscopy and culture may be pursued to distinguish between a paradoxical reaction and treatment failure.
In one study of 235 HIV-uninfected patients, spontaneous resolution of paradoxical lymph node enlargement occurred in 56% of the cases.[56] In a second study including both HIV-infected and uninfected patients, spontaneous resolution occurred in all patients in mean period of 2.5 months; some patients underwent aspiration or excision.[44]
| Surgical Management | | |
The indications for surgical management of TB lymphadenitis are:[13]
- Treatment failure: Surgical treatment is beneficial to establish the diagnosis and management of drug-resistant organisms
- Adjuvant treatment for drug sensitive cases: For patients who have discomfort from tense, fluctuant lymph nodes surgical treatment is beneficial
- Paradoxical reaction: In a retrospective review, aspiration, incision, and drainage or excision were associated with a trend toward a shorter duration of paradoxical reactions
- Nontuberculous mycobacteria: In children with NTM lymph node removal has been associated with better outcomes
| Hurdles in Management | | |
The treatment of TB lymphadenitis may be ridden with following hurdles:[41]
- Appearance of freshly involved nodes
- Enlargement of the existing nodes
- Development of fluctuation
- Appearance of sinus tracts
- Residual lymphadenopathy after completion of treatment
- Relapses.
The possible explanation for this suboptimal response of therapy may include:
- Causative agent being atypical Mycobacteria (rare in India)
- Unidentified drug resistance
- Poor drug penetration into the lymph node
- Unfavorable local milieu
- Enhanced delayed hypersensitivity reaction in response to mycobacterial antigens released during medical treatment of the disease
| Overcoming Difficulties in Management | | |
Proper diagnosis, evaluation, and close monitoring of a patient during treatment are the keys to success in the management of lymph node TB.[41]
The suggested management plan is as under:
- Record all the possible sites of involvement, nature, and size of the involved lymph nodes at the inception of treatment.
- Identify any coexisting disease and treat it simultaneously.
- Performe TB Gene Xpert or line probe assay on initial lymph node sample, so that if lymph nodes enlarge during therapy, it becomes clear whether this is due to a paradoxical reaction or drug resistance.
- Most nodes that enlarge during therapy or appear afresh ultimately respond to treatment. Only a close follow up is required for these patients.
- Appearance of fluctuation in one or more lymph nodes calls for aspiration under all aseptic precautions.
- Any secondary bacterial infection should be dealt with appropriately that may include incision and drainage.
- Any worsening after 8 weeks of therapy calls for en-bloc resection of the involved lymph node chain to avoid appearance of ugly sinus tracts.
- Nonhealing sinus tracts need resective surgery.
- On completion of treatment, if any residual lymph nodes exist, they should be observed closely. Any increase in the size or appearance of symptoms calls for excisional biopsy for histopathology, culture, and TB Gene Xpert. Most patients respond to retreatment with the same regimen.
- Relapse: Relapse rates of up to 3.5% have been reported in patients treated for TB lymphadenitis. This should be treated with the same drugs but culture or molecular diagnostic test must be performed to rule out resistance or NTM disease.[54]
- Drug resistance: Though it is at times difficult to confirm drug-resistance in LNTB, it is essential to demonstrate drug resistance prior to starting multidrug-resistant regime. Similarly, single agent (fluoroquinolones or others) should never be introduced even if response to treatment is not appropriate. Each case should be reasonably investigated with culture or molecular diagnostic tools. Further, appropriate measures should be taken to prevent the use of second-line drugs in unproven cases.[38]
- Systemic steroids have been shown to reduce inflammation during the early phase of therapy for lymph node tuberculosis and may be considered if a node is compressing a vitalStructure, i.e. bronchus or in diseases involving cosmetically sensitive areas. Prednisolone 40 mg per day followed by gradual tapering over the next 6 weeks, along with appropriate chemotherapy is adequate. However, the safety and utility of this approach remains largely unproven except in intrathoracic disease where it was found to relieve the pressure on the compressed bronchus.
| Conclusions | | |
LN TB, which is the most common forms of extrapulmonary TB, is different from pulmonary TB in terms of diagnosis and management. The most usual sign and symptom is the appearance of a chronic, painless mass in the neck, which is persistent and usually grows with time. Because of no other remarkable symptom, its diagnosis and distinction needs a high index of suspicion, and application of a variety of diagnostic modalities. With the availability of molecular diagnosis and EBUS, the diagnostic scenario has changed in the last decade, though treatment has not changed much since the last decade. Paradoxical reactions occur in 10–15% of immune-competent and approximately 50% of human immunodeficiency virus positive patients and need appropriate management. Every effort should be made to know the drug sensitivity of the organism at the onset of treatment by using molecular tests and TB MGIT cultures, so that paradoxical reactions can be confidently differentiated from drug resistance and can be treated appropriately.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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