|Year : 2020 | Volume
| Issue : 2 | Page : 107-115
An evidence-based clinical pathway for the diagnosis of tuberculous lymphadenitis: A systematic review
Lavanyah Sivaratnam, Azmawati Mohammed Nawi, Mohd Rizal Abdul Manaf
Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
|Date of Web Publication||29-May-2020|
Azmawati Mohammed Nawi
Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur
Source of Support: None, Conflict of Interest: None
To achieve the World Health Organization end TB Strategy, early detection, and prompt treatment of not only pulmonary but also extrapulmonary tuberculosis (EPTB) should be achieved. The most common EPTB is tuberculous lymphadenitis, and the diagnosis is typically time-consuming. This review aimed to identify the best diagnostic pathway for preventing treatment delay and thus further complications. A systematic keyword search was done using four databases and other relevant publications and using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart to search for relevant articles that met the inclusion criteria. The quality of the articles was assessed using Newcastle–Ottawa Scale, and the articles were summarized based on the test for diagnosing tuberculous lymphadenitis. A total of ten articles were included for the synthesis of results, which compared the sensitivity and specificity of each diagnostic test for tuberculous lymphadenitis. The most promising test is the Xpert Mycobacterium tuberculosis/RIF, which has high sensitivity and specificity, but costs much more in comparison to the other tests. An ideal diagnostic method should include the combination of relevant patient history, clinical examination, and laboratory and radiological testing to avoid delays in treatment, misdiagnosis, and further complications.
Keywords: Clinical pathway, diagnostic pathway, extrapulmonary tuberculosis, tuberculous lymphadenitis
|How to cite this article:|
Sivaratnam L, Nawi AM, Abdul Manaf MR. An evidence-based clinical pathway for the diagnosis of tuberculous lymphadenitis: A systematic review. Int J Mycobacteriol 2020;9:107-15
|How to cite this URL:|
Sivaratnam L, Nawi AM, Abdul Manaf MR. An evidence-based clinical pathway for the diagnosis of tuberculous lymphadenitis: A systematic review. Int J Mycobacteriol [serial online] 2020 [cited 2020 Aug 11];9:107-15. Available from: http://www.ijmyco.org/text.asp?2020/9/2/107/285221
| Introduction|| |
Infection caused by Mycobacterium tuberculosis (MTB) complex organisms is one of the top ten causes of death worldwide in recent years. Every year, millions of people develop a new tuberculosis (TB) infection and in 2018 alone, an estimated ten million people developed TB worldwide. TB can be broadly divided into two types: pulmonary TB and extrapulmonary TB (EPTB). Most efforts are expended for managing pulmonary TB, as it is a major public health concern. Nevertheless, the other, silent TB that contributes to the overall prevalence of TB should not be overlooked. EPTB is an infection also caused by MTBcomplex organisms, but to the parts of the body other than the pulmonary system.
EPTB can affect many organs, for example, the lymph nodes, nervous system, joints, genitourinary tract, bones, gastrointestinal system, and others. The infection can present on its own or concomitantly with pulmonary TB infection. In our local setting, the trend of EPTB is on the rise, with an increase of around 70% from 2005 to 2011 for newly diagnosed cases. The most common type of EPTB is tuberculous lymphadenitis. A study in Spain has also shown a slow increase in EPTB cases over time (30.6% to 37.6% over 10 years). In Korea, EPTB comprises about 20% of the diagnosed TB cases. The more alarming feature is that it also shows an increasing trend over time. The most common type of EPTB in Korea is pleural EPTB, followed by that of the lymph nodes and gastrointestinal organs.
Tuberculous lymphadenitis is one of the more common types of EPTB in many countries and is often diagnosed very late, and diagnosis requires a high index of suspicion. Lymphadenitis can be caused by both the nontuberculous mycobacteria (NTM) and the MTB complex organisms. NTM causing lymphadenitis is commonly seen among children and should be ruled out at the soonest as the treatment differs for both. Most of the time, NTM infection would resolve spontaneously without treatment, whereas tuberculous lymphadenitis would require a prolonged duration of treatment. Tuberculous lymphadenitis is typically found in the cervical region, and involves unilateral and painless swelling. Apart from that, the clinician would also have to rule out other differential diagnoses before diagnosing tuberculous lymphadenitis. This could lead to delayed initiation of treatment.
The issue with most EPTB cases is late presentation and late diagnosis, which often leads to many complications. Physicians with a poor index of suspicion, coupled with the long duration of culture, add to the delay in treatment., Even though EPTB patients without concomitant lung infection are rarely contagious and a source of TB infection, we still need an efficient and systematic clinical care for these patients. From the natural progression of the disease, EPTB can either be a complication of PTB or the EPTB can progress and be disseminated to the lungs. As both ways can become as an infectious disease, urgent care is needed in treating these patients. The patient factor is difficult to control, but awareness can be improved. Regarding the health-care delay, the time from when the patient first seeks treatment to the actual diagnosis and treatment can be reduced by educating staff and having a proper reference guideline or pathway to minimize misdiagnosis and avoid subjecting patients to unnecessary investigation and treatment.
The clinical pathway is currently used to help clinicians standardize case management; it involves an evidence-based pathway that has been well structured to help provide optimum treatment quality while keeping the cost to a minimum. The clinical pathway is typically a comprehensive process developed by a multidisciplinary team that is usually required in for managing that case. The aim of the present article is to review all evidence of the diagnostic pathway used and to identify the best pathway for diagnosing tuberculous lymphadenitis to prevent delayed treatment and further complications.
| Methods|| |
A systematic review of the literature was done to identify studies that reported on any clinical pathway in the management of tuberculous lymphadenitis. Here, we describe computerized methods for searching relevant information on the best means of diagnosing and treating tuberculous lymphadenitis. Four databases (PubMed, SCOPUS, MEDLINE and Ovid, and the Cochrane Library), with a guideline (the Malaysian clinical practice guidelines on EPTB), and a program were used for assessing the quality of the information. Further relevant articles were searched using the snowballing method. The search comprised a set of keywords that included terms related to tuberculous lymphadenitis and the clinical pathway together with their MeSH terms from 2014 until 2019. We used the following keywords:“tuberculosis” OR “tuberculous” AND “lymphadenitis” OR “lymphadenopathy” OR “lymph node enlargement” AND “clinical pathway” OR “care pathway.”
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used as the guideline to search for eligible articles. [Table 1]shows the search summary according to each database; the PRISMA checklist is shown in [Figure 1]. The articles were screened by their title, followed by the abstract and full text. Only relevant articles were considered for analysis.
|Figure 1: Preferred Reporting Items for Systematic Reviews and meta-analyses flow chart|
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The inclusion criteria were: (a) reported on any clinical pathway/flow for treating tuberculous lymphadenitis, (b) published in 2014–2019, and (c) full article. The exclusion criteria were: (a) qualitative studies and commentary articles, (b) study in languages other than English, and (c) animal studies. In view of the rapid advancement of diagnosing techniques, where older methods may be obsolete, only articles from the last 5 years were selected.
Data synthesis and quality assessment
From the search summary using the PRISMA flowchart, an initial 3280 studies were retrieved using the keyword search; after much filtering, we identified an eventual ten articles for the final results synthesis. The findings from the ten selected articles were used in the pathway process and development. The quality of evidence of the observational studies was assessed using the Newcastle–Ottawa scale [Table 2] and [Table 3]. Studies that met at least five of the nine criteria were deemed of high quality.
| Results|| |
For result analysis, we selected ten articles that described the testing requirements and comparison of testing to aid the diagnosis of tuberculous lymphadenitis. Two articles were case–control studies, four were cohort studies, three were report articles, and one was a clinical practice guideline. Most of the studies were from the UK (40%),,, and India (30%).,, The other studies were from Malaysia, Korea, and Turkey. All of the studies described similar investigation methods for diagnosing a suspected tuberculous lymphadenitis case. We compared the methods used for identification based on the time until results were obtained, and compared the sensitivity and specificity of each test used. The frequencies of the content of the articles are detailed in [Table 4]; the detailed findings of each article are summarized in [Table 5] and the proposed diagnostic pathway for tuberculous lymphadenitis is detailed in [Figure 2].
|Figure 2: Diagnostic pathway for tuberculous lymphadenitis. NAAT: Nucleic acid amplification test, 2HRZE/4HR: 2 months isoniazid, rifampicin, pyrazinamide, ethambutol/4 months isoniazid, rifampicin|
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| Discussion|| |
EPTB is an increasing problem worldwide today. As evidenced by a recent World Health Organization (WHO) report, as much as 15% of all TB cases are due to EPTB. Due to the limitation of late presentation, clinicians typically wind up treating a more complicated case, and thus morbidity increases. One method for reducing the time to treatment is to ensure that clinicians have a high index of suspicion and order the appropriate treatment and start treatment promptly. With the diagnostic pathway, not only can the time to start treatment be shortened, but also as evidenced by using a clinical pathway, management among clinicians can be synchronized, and at the same time, costs can be minimized by avoiding unnecessary procedures.
As EPTB is not a main concern when dealing with TB, less effort has been expended on managing the disease. This is also the reason for the limited number of research articles specifically on EPTB as compared to pulmonary TB. Based on the available references, the first step in creating a clinical pathway can be achieved. Gathering all recent evidence that supports the pathway is valuable to the aim of reducing the delay in providing early treatment.
The evidence is then broken down to a few focused reviews in creating the diagnostic flow. First, once a patient is suspected to have tuberculous lymphadenitis, identifying the sample to be taken must be considered. Depending on the site of lymph node enlargement, there are many methods for obtaining the sample: from a needle biopsy, excision, or a more invasive endoscopic or laparoscopic sampling. If the lymph node enlargement is visible, the best sampling technique is fine-needle aspiration (FNA), as it has been proven to be minimally invasive.,,, While it is claimed to be more sensitive, excision biopsy is a more invasive procedure, therefore it should be reserved if the FNA is inconclusive or if the patient has persistent lymph node enlargement despite completing treatment. FNA has been widely studied, and a 9-year study concluded that FNA is simple, is cost-effective, and can be done as an outpatient procedure, which is particularly useful in a resource-poor setting. There is good agreement for this evidence, and it is accepted by all countries, as advocated by the WHO.
Once clinical samples have been obtained, the best test for diagnosing tuberculous lymphadenitis is dependent on what is available in the current setting, what can be used, laboratory capacity, and operator expertise. The most basic test for diagnosing pulmonary TB is sputum microscopy for detecting the acid-fast bacilli, as both tuberculous and NTM are acid-fast. This test is fast and has high specificity and sensitivity. However, this is not true for EPTB infection, as the main issue in this case is the paucibacillary nature. Most EPTB patients are not smear positive; therefore, microscopy for detecting acid-fast bacilli is neither highly specific nor highly sensitive, but it is a rapid method. A Canadian guideline mentioned that the sensitivity for sputum in a tuberculous lymphadenitis patient was only 5%–14%. This could be due to the portion of patients having co-infection of pulmonary TB and EPTB.
The next step typically involves cytology studies using the FNA specimen, or histopathology using an excision biopsy specimen, together with culture. Typically, both have very high sensitivity but low specificity for EPTB. This method is typically done for all new cases. The mode of detection is the identification of granulomas. This becomes problematic becomes it cannot specifically detect TB granulomas from other diseases that also feature the presence of granulomas in the tissue, such as nontuberculous mycobacterium infection and leprosy, and occasionally syphilis, fungal infection, and brucellosis., On the other hand, culture specimens are usually highly specific but have low sensitivity, and the time for obtaining results is usually about 3–8 weeks., This greatly delays treatment for EPTB, thus increasing the complications of the disease.
New modalities have been researched for overcoming the issue of long waiting time for results, and molecular techniques have been developed. Using a nucleic acid amplification test such as the polymerase chain reaction can greatly increase sensitivity and dramatically reduce the turnaround time to about 6–8 h.,, As it is an amplification method, it can detect as few as ten mycobacteria, and this increases the sensitivity of the test. The newer modality is the Xpert® MTB/RIF assay, which is an automated cartridge-based method that enables more rapid diagnosis,, and provides high sensitivity for detecting tuberculous lymphadenitis.,, This appears to be a promising method for the rapid detection of EPTB as compared to other methods; the only setback is that it is relatively costlier.,,
Others have compared these techniques, and one such review of 18 studies noted a pooled sensitivity of 83.1% for Xpert MTB/RIF as compared to culture specimens. The sensitivity and specificity of each test also increased when the tests are combined.,
[Table 6] shows the positive and negative traits of each test. Clearly, each test has its pros and cons, and using only one specific test for diagnosing tuberculous lymphadenitis is insufficient. Therefore, the ideal diagnostic test should be a combination of laboratory testing, together with relevant patient history and clinical examination.,,
Apart from the standard laboratory tests, additional radiological intervention can be used to support the diagnosis. Chest X-ray (CXR) is usually performed to rule out pulmonary involvement, as it is possible for a pulmonary TB patient to also have EPTB infection simultaneously. It can also be used to rule out any pleural, vertebral, or joint involvement. Even if the CXR is nonspecific for TB, the presence of cavitation, lymph nodes, and infiltrates is highly suggestive of TB infection. Computed tomography scan and magnetic resonance imaging can be used to aid in the diagnosis of EPTB.,
Once a diagnosis is made, the recommended treatment for tuberculous lymphadenitis is 6-month first-line antitubercular treatment.,,, The treatment includes 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) and 4 months of isoniazid and rifampicin (2HRZE/4HR) in cases where no resistance were detected. The required duration of treatment for tuberculous lymphadenitis was studied by comparing a 6- and 9-month regimen, which showed that both regimens were not greatly different. Both regimens had almost equal relapse and cure rates, but the authors noted that patients would prefer a shorter treatment duration and would be likely to follow the treatment and would have lower risk for adverse effects.
One limitation of this study is the limited articles on EPTB infection and more specifically on tuberculous lymphadenitis. Most articles only compared one or two types of test, and not all tests were available for comparison of the best method. Apart from that, the studies were all different in terms of sample size, aim, and outcome.
| Conclusion|| |
Diagnosing tuberculous lymphadenitis would first require a high index of suspicion by the treating physician. With that, and the proper algorithm to follow, there would be no delays and clinicians would be able to ensure that all patients are treated as soon as possible and avoid complications brought on by delayed treatment, misdiagnosis and incorrect treatment, and complication of the progressing disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
World Health Organization. Global Tuberculosis Report 2019. World Health Organization; 2019.
World Health Organization. Tuberculosis Fact Sheets. World Health Organization; 2019.
Ministry of Health Malaysia. Clinical Practice Guidelines, Management of Tuberculosis. Ministry of Health Malaysia; 2012.
Swarna Nantha Y. A review of tuberculosis research in Malaysia. Med J Malaysia 2014;69 Suppl A: 88-102.
García-Rodríguez JF, Álvarez-Díaz H, Lorenzo-García MV, Mariño-Callejo A, Fernández-Rial Á, Sesma-Sánchez P. Extrapulmonary tuberculosis: Epidemiology and risk factors. Enferm Infecc Microbiol Clin 2011;29:502-9.
Lee JY. Diagnosis and treatment of extrapulmonary tuberculosis. Tuberc Respir Dis (Seoul) 2015;78:47-55.
Fontanilla JM, Barnes A, von Reyn CF. Current diagnosis and management of peripheral tuberculous lymphadenitis. Clin Infect Dis 2011;53:555-62.
Mathiasen VD, Hansen AK, Eiset AH, Lillebaek T, Wejse C. Delays in the diagnosis and treatment of tuberculous lymphadenitis in low-incidence countries: A systematic review. Respiration 2019;97:576-84.
Jørstad MD, Aßmus J, Marijani M, Sviland L, Mustafa T. Diagnostic delay in extrapulmonary tuberculosis and impact on patient morbidity: A study from Zanzibar. PLoS One 2018;13:e0203593.
Ismail A. Clinical pathways: Development and implementation at a tertiary hospital in Malaysia. Int J Public Health Res 2012;2:153-60.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-5.
Asimacopoulos EP, Berry M, Garfield B, Roesner M, Jepson A, McCarthy J, et al
. The diagnostic efficacy of fine-needle aspiration using cytology and culture in tuberculous lymphadenitis. Int J Tuberc Lung Dis 2010;14:93-8.
Burrill J, Williams CJ, Bain G, Conder G, Hine AL, Misra RR. Tuberculosis: A radiologic review. Radiographics 2007;27:1255-73.
McAllister KA, MacGregor FB. Diagnosis of tuberculosis in the head and neck. J Laryngol Otol 2011;125:603-7.
Meghji S, Giddings CE. What is the optimal diagnostic pathway in tuberculous lymphadenitis in the face of increasing resistance: Cytology or histology? Am J Otolaryngol 2015;36:781-5.
Gautam H, Agrawal SK, Verma SK, Singh UB. Cervical tuberculous lymphadenitis: Clinical profile and diagnostic modalities. Int J Mycobacteriol 2018;7:212-6.
] [Full text]
Mittal P, Handa U, Mohan H, Gupta V. Comparative evaluation of fine needle aspiration cytology, culture, and PCR in diagnosis of tuberculous lymphadenitis. Diagn Cytopathol 2011;39:822-6.
Suzana S, Ninan MM, Gowri M, Venkatesh K, Rupali P, Michael JS. Xpert MTB/Rif for the diagnosis of extrapulmonary tuberculosis – An experience from a tertiary care centre in South India. Trop Med Int Health 2016;21:385-92.
Engin G, Acunaş B, Acunaş G, Tunaci M. Imaging of extrapulmonary tuberculosis. Radiographics 2000;20:471-88.
World Health Organization. Pathways to Better Diagnostics for Tuberculosis: A Blueprint for the Development of TB Diagnostics by the New Diagnostics Working Group of the Stop TB Partnership. World Health Organization; 2009.
Samaila MO, Oluwole OP. Extrapulmonary tuberculosis: Fine needle aspiration cytology diagnosis. Niger J Clin Pract 2011;14:297-9.
] [Full text]
Peoples M. Canadian Tuberculosis Standards. Public Health Agency of Canada, Winnipeg, Canada; 2014.
Purohit M, Mustafa T. Laboratory diagnosis of extra-pulmonary tuberculosis (EPTB) in resource-constrained setting: State of the art, challenges and the need. J Clin Diagn Res 2015;9:EE01-6.
Zumla A, James DG. Granulomatous infections: Etiology and classification. Clin Infect Dis 1996;23:146-58.
Noussair L, Bert F, Leflon-Guibout V, Gayet N, Nicolas-Chanoine MH. Early diagnosis of extrapulmonary tuberculosis by a new procedure combining broth culture and PCR. J Clin Microbiol 2009;47:1452-7.
Lee HS, Kee SJ, Shin JH, Kwon YS, Chun S, Lee JH, et al
. Xpert MTB/RIF Assay as a Substitute for Smear Microscopy in an Intermediate-Burden Setting. Am J Respir Crit Care Med 2019;199:784-94.
Vadwai V, Boehme C, Nabeta P, Shetty A, Alland D, Rodrigues C. Xpert MTB/RIF: A new pillar in diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 2011;49:2540-5.
World Health Organization. Automated Real-time Nucleic Acid Amplification Technology For Rapid and Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert Mtb. World Health Organization; 2013.
Manjunath N, Shankar P, Rajan L, Bhargava A, Saluja S, Shriniwas. Evaluation of a polymerase chain reaction for the diagnosis of tuberculosis. Tubercle 1991;72:21-7.
Kim YW, Kwak N, Seong MW, Kim EC, Yoo CG, Kim YW, et al
. Accuracy of the Xpert® MTB/RIF assay for the diagnosis of extra-pulmonary tuberculosis in South Korea. Int J Tuberc Lung Dis 2015;19:81-6.
Denkinger CM, Schumacher SG, Boehme CC, Dendukuri N, Pai M, Steingart KR. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: A systematic review and meta-analysis. Eur Respir J 2014;44:435-46.
Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD, Mohan A, et al
. Index-TB guidelines: Guidelines on extrapulmonary tuberculosis for India. Indian J Med Res 2017;145:448-63.
] [Full text]
CoordinationTD. National Tuberculosis Management Guidelines 2014. Republic of South Africa; 2014.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]