ABSTRACT
Background:
Globally, tuberculosis (TB) poses a severe threat to human health. Prior to the COVID-19 pandemic, TB was the commonest infectious cause of mortality, surpassing HIV/AIDS. A strong index of suspicion is required for the diagnosis of extrapulmonary tuberculosis (EPTB) because of the paucibacillary nature of biological specimens. Primary care physicians, as the first point of contact for patients, are in an ideal position to detect TB early due to its multisystemic nature and varied presentation. This study aims to determine microbiological, demographic, clinical, and changing trends of EPTB in our region.
Aim:
To study the clinico-microbiological and drug susceptibility profile of patients with confirmed EPTB.
Methodology:
This was a prospective observational study in which all presumptive EPTB cases were screened, and confirmed EPTB cases were studied using various demographic criteria and clinical aspects.
Results:
A total of 1425 extrapulmonary samples were obtained from suspected TB cases between 2023–24. Of these, 194 samples with various diagnostic modalities and 68 patients were selected for the study based on inclusion and exclusion criteria. The prevalence of EPTB cases was found to be more prevalent in males, with majority of cases belonging to the 21–30 years age group. The maximum positivity was reported in pleural samples, followed by lymph node aspirates. Cartridge-based nucleic acid amplification test (CBNAAT) was found to be having highest sensitivity followed by solid culture. Rifampicin resistance was 4.4% cases.
Conclusions:
Since most of the tests rely on the presence of mycobacteria in the specimen, none of them have a 100% sensitivity; thus, suboptimal performance of all assays in the diagnosis of EPTB cases underlines the continuing relevance of systematic clinical investigations for making the diagnosis of EPTB and also calls for the need for novel tests.
Keywords: Extrapulmonary tuberculosis, North India, paucibacillary, rifampicin resistance
Introduction
Tuberculosis (TB) remains a significant public health challenge with global implications. It is one of the ancient yet dreadful infections affecting immunocompetent as well as immunocompromised individuals.[1] Primary care physicians are considered the very first point of contact for patients presenting with nonspecific symptoms. Given the high prevalence of TB and the important role played by the private sector in primary care, it is imperative that TB care be integrated into primary healthcare in India. This will entail enhancing diagnostic, therapeutic, and support services as well as involving all healthcare providers both public and private.[2] It accounts for significant morbidity and mortality across the globe and is primarily caused by Mycobacterium tuberculosis, which transmits via airborne particles expelled through coughing or spitting.[1] TB has been referred to as a “medical chameleon” as it can manifest in a plethora of ways, infecting any organ or tissues of the human body; except enamel, hair, and nails, with pulmonary TB (PTB) being the most common type.[3,4] However, TB can also affect other sites, and this medical condition is called as extrapulmonary tuberculosis (EPTB). Of all the TB cases, ~72% and 28% are attributed to pulmonary and EPTB, respectively. With a large number of people with TB being managed by the private sector, there are concerns about the suboptimal quality of care; lack of systems for ensuring treatment adherence, patient support, and contact investigations; and high loss to follow-up rate, eventually raising the risk of drug resistance to TB.[5]
EPTB can occur primary or postprimary (reactivation or reinfection) TB.[3] Based on the organ it affects, EPTB presents with different clinical and radiological characteristics that frequently resemble those of other illnesses.[6] EPTB constitutes 16% of the globally reported 7.5 million TB cases and 19% of the reported TB cases in South-East Asia.[7]
The World Health Organization (WHO) does not provide treatment outcomes for EPTB or stratify the incidence of the disease according to factors including age, sex, HIV status, or subtype.[4,8] Therefore, diagnosing EPTB is difficult due to its similarity to other illnesses, and it often requires invasive procedures for specimen collection.[9] Diagnosis of EPTB mainly relies on the clinical profile, microscopy, culture, and radiography, though the diagnosis is difficult, as lesions are usually paucibacillary in nature.[10]
The gap in the diagnosis of EPTB has been narrowed to some extent by the advent of cartridge-based nucleic acid amplification test, Xpert Mycobacterium tuberculosis/rifampicin (MTB/Rif) (GeneXpert). Xpert MTB/Rif, which is WHO recommended automated nucleic acid amplification assay widely used for the diagnosis of MTC and resistance to rifampicin concurrently.[11]
EPTB has also been associated with HIV infection in over 50% of individuals.[12] In individuals with late-stage HIV, the ratio of EPTB to PTB rises to 50:50 from 20:80.[13] Despite the escalating problem of Multidrug resistant (MDR) EPTB, the data from India remains scarce. Moreover, there is a dearth of data pertaining to the epidemiological and clinical profile of EPTB patients from India, where the burden is quite high. There is a need to define the risk factors and determine the commonly afflicted sites, along with management and resistance profile in patients presenting with EPTB. Thereby, the present study was conducted to determine microbiological, demographic, clinical, and changing trends of EPTB in our region.
Aim of the study: To study the clinico-microbiological and drug susceptibility profile of patients with confirmed EPTB.
Material and Methods
This prospective observational study was conducted at government medical college and hospital, Chandigarh. Extrapulmonary specimens like pus, fluids, CSF, lymph node aspirates etc. were collected from presumptive EPTB patients presented to various OPDs during the study period from January 2023 to May 2024. Inclusion criteria: Patients with a clinical suspicion of EPTB, referred by specialists, and meeting the WHO definition of EPTB, which involves TB outside the lungs (e.g. pleura, lymph nodes (LNs), abdomen, genitourinary tract, skin, meninges, joints, and bones).
Patients who refuse consent, lack an appropriate or sufficient sample, or have concomitant PTB were excluded. The samples were subjected to various microbiological procedures like ZN staining, fluorescent staining, solid culture, and CBNAAT using standard protocol. Informed consent was taken from all the participants of the study. The CBNAAT test was conducted according to the guidelines provided by Cepheid. Thorough history and radiographic images were obtained from the participants of the study. Since the yield of AFB culture in EPTB is low, CRS was taken as the surrogate gold standard. The CRS comprised bacteriological confirmation of TB by Xpert and/ or culture and/or AFB microscopy.
Statistical analysis
The presentation of the categorical variables was done in the form of numbers and percentages (%). On the other hand, the quantitative data were presented as the means ± SD and as median with 25th and 75th percentiles (interquartile range). Sensitivity, positive predictive value, and negative predictive value were calculated of CBNAAT, Ziehl–Neelsen (Zn) staining, fluorescent, and culture for predicting positive findings after taking composite reference standard (CRS) as the gold standard. The data entry was done in the Microsoft EXCEL spreadsheet, and the final analysis was done with the use of Statistical Package for Social Sciences software, IBM manufacturer, Chicago, USA, ver 25.0.
Inclusion criteria: Patients with a clinical suspicion of EPTB, referred by specialists, and meeting the WHO definition of EPTB, which involves TB outside the lungs (e.g. pleura, lymph nodes (LNs), abdomen, genitourinary tract, skin, meninges, joints, and bones).
Exclusion criteria: Patients who refuse consent, lack an appropriate or sufficient sample, or have concomitant PTB.
The following definition was included for PRESUMPTIVE EPTB, which refers to the presence of organ-specific symptoms and signs like swelling of LNs, pain and swelling in joints, neck stiffness, disorientation, etc., and/or constitutional symptoms like significant weight loss, persistent fever ≥2 weeks, night sweats.
Sample collection and Processing: Samples like pus, sterile body fluids, LNs aspirates were received from 1425 presumptive cases of EPTB and subjected to various microbiological procedures like ZN staining, fluorescent staining, solid culture, and CBNAAT using standard protocol. Informed consent was taken from all the participants of the study. The CBNAAT test was conducted according to the guidelines provided by Cepheid. Thorough history and radiographic images were obtained from the participants of the study.
Since the yield of AFB culture in EPTB is low, CRS, as mentioned earlier, was taken as the surrogate gold standard. The CRS comprised bacteriological confirmation of TB by Xpert and/or culture and/or AFB microscopy.
Results
A total of 68 bacteriologically confirmed cases have been included in our study. Out of these, 58.8% males and 41.2% females were recruited for the study with a sex ratio 1.43:1. The highest incidence of EPTB cases was identified within the age bracket of 21–30 years. In the study, it was observed that the lowest incidence of EPTB cases occurred within the 51–60 age group, with no cases recorded among females. In our study, 19.12% (n = 13) of the patients were in the paediatric age category (less than or equal to 18 years). In the paediatric age group, 53.85% (n = 7) were females and 46.15% (n = 6) were males.
Overcrowding, as per the WHO, occurs when there is an excess of individuals residing in a specific area beyond its intended capacity, resulting in compromised living conditions and increased health risks. Rural communities can vary in population size, ranging from fewer than 100 residents to over 10,000 residents [Table 1].
Table 1.
Frequency of overcrowding and residence setting of the study population
| Socioeconomic factor | Frequency | Percentage |
|---|---|---|
| Overcrowding | ||
| Yes | 44 | 64.71 |
| No | 24 | 35.28 |
| Residence | ||
| Urban | 48 | 70.59 |
| Rural | 20 | 29.41 |
A significant portion of the participants, i.e. 85.3% (n = 58) in the study had attained presecondary and secondary education levels. There were no defaulters among the patients who acquired postsecondary education (n = 10), and only one patient passed away.
The largest group of patients in whom MTB was identified comprised those with pleural TB, accounting for 41.18%, followed by LN TB in 20.59% of EPTB cases. The contributions by other types of EPTB are as follows: bone and joint TB (14.71%), CNS TB and soft tissue TB (7.35%), disseminated TB (2.94%), abdominal TB, pericardial TB, breast TB, and genitourinary TB (1.47%).
The two patients diagnosed with disseminated TB exhibited multiple foci of infection throughout their bodies. Out of 13 paediatric cases, one had pleural TB (7.69%), four had LN TB, and four had soft tissue TB (30.77% each), while two had disseminated TB and two had bone/joint TB (15.38% each). While in adult age group, pleural TB is the most common type of EPTB (49.09%, n = 27), LN TB (18.18%, n = 10), bone and joint TB (14.55%, n = 8), and TB meningitis (7.35%, n = 5).
Duration of illness in months is around 3.21 ± 5.48 with a range 0.25–36 months. Fever was the most common presenting complaint which was present in 77.9% patients, followed by weight loss in 72% patients. Anorexia and night sweats were seen in 44.1% patients. Seven patients presented with complaints of swelling and four of them were having chest wall swelling.
Among the 17 patients presented with regional lymphadenopathy, 70.59% (12/17) had cervical Lymphadenopathy (LNAP) followed by axillary LNAP in four patients. Among them, two were having EPTB, one was diagnosed with MDR PTB in the past.
Microbiological diagnostic methods
In our study, all pleural fluid samples (100%, n = 24%) tested were positive using CBNAAT. LN aspirate samples showed a higher rate of positive culture results (50%, n = 7) as compared to other sample types. None of the five Cerebrospinal fluid (CSF) samples tested positive for bacilli using staining methods. Pericardial fluid and endometrial tissue (100%, n = 1) were detected with the presence of TB bacilli only with the aid of CBNAAT [Table 2].
Table 2.
Distribution of positive samples by different diagnostic methods
| Sample | Total samples | ZN staining | Fluorescent microscopy | Culture | CBNAAT |
|---|---|---|---|---|---|
| Pleural fluid | 24 | 5 | 8 | 9 | 24 |
| Lymph node aspirate | 14 | 3 | 4 | 7 | 13 |
| CSF | 5 | 0 | 0 | 1 | 5 |
| Endometrial tissue | 1 | 0 | 0 | 0 | 1 |
| Pus | 19 | 6 | 6 | 11 | 18 |
| Pericardial fluid | 1 | 0 | 0 | 0 | 1 |
| Peritoneal fluid | 1 | 1 | 1 | 0 | 1 |
| Synovial fluid | 3 | 2 | 2 | 1 | 3 |
ZN=Ziehl–Neelsen
Culture yielded positive results in 42.65% (n = 29) of the samples. Contamination occurred in eight samples on the LJ medium. According to our study findings, two samples exhibited bacterial growth in culture, yet CBNAAT failed to detect the presence of bacteria in those samples. Out of the 68 samples tested for CBNAAT, 66 samples detected the presence of TB bacilli. The sensitivity of ZN staining, fluorescent staining, LJ media culture, and CBNAAT are 25%, 30.88%, 42.655%, and 97.06%, respectively, as shown in Table 3 after taking CRS. The bacterial load was measured based on the cycle threshold (Ct) values. The bacterial load is categorized as high if the Ct value is less than 16, medium if it falls between 16 and 22, low if it ranges from 22 to 28, and very low if it exceeds 28. Out of the 66 CBNAAT-positive samples, none of the samples had high bacterial load in our study. Medium bacillary load found in pleural fluid, pleural pus, peritoneal fluid, and pus samples. A significant number of samples are falling into the low load and very load category, which emphasizes the paucibacillary nature of EPTB.
Table 3.
Diagnostic accuracy of various tests using the composite reference standard (CRS) as the gold standard
| Composite reference standard | Zn staining | Fluorescent | Culture | CBNAAT |
|---|---|---|---|---|
| Sensitivity (95% CI) | 25.00% (15.29–36.98%) | 30.88% (20.24–43.26%) | 42.65% (30.72–55.23%) | 97.06% (89.78–99.64%) |
| Positive Predictive Value (95% CI) | 100.00% (80.49–100.00%) | 100.00% (83.89–100.00%) | 100.00% (88.06–100.00%) | 100.00% (94.72–100.00%) |
| Negative Predictive Value (95% CI) | 0.00% (0.00–6.98%) | 0.00% (0.00–7.55%) | 0.00% (0.00–9.03%) | 0.00% (0.00–84.19%) |
| Diagnostic accuracy | 25.00% | 30.88% | 42.65% | 97.06% |
CI=Confidence interval, ZN=Ziehl–Neelsen
Rifampicin resistance was detected in two pleural samples and one peritoneal fluid sample. Among the 11 patients who got tested for Adenosine deaminase enzyme (ADA) levels in body fluids, it was observed that ADA is within the normal range for all the CSF samples (n = 5) tested. However, 14 out of 16 pleural fluid samples tested showed elevated ADA levels.
TB meningitis had the highest mortality rate, accounting for 5 out of the total 15 deaths. Treatment is currently in progress for 16 cases, with the majority being pleural and LN EPTB. Treatment failure was rare, occurring in only two cases, both of which were in the pleural EPTB category.
Discussion
EPTB poses a significant challenge in combating TB in developing countries like India. Primary care centres can play a crucial role in containing EPTB infections by addressing delays in diagnosis and treatment, especially in rural areas, through regular sensitization of physicians on standardized guidelines and enhancing their ability to recognize its complex clinical manifestations.[14]
During the study period, 1425 presumptive EPTB patients were screened for the presence of MTB complex infection. Among these, 194 (13.6%) patients were found to have EPTB and 68 confirmed EPTB patients were selected based on inclusion and exclusion criteria. Of these, 55 were adults and 13 were in the paediatric age group (<18 years).
The average age of the participants in the study was 30 ± 18.1 years, spanning from 0.33 to 90 years old. The highest occurrence of EPTB cases occurred among individuals aged 21–30 years, accounting for 36.76% of the total cases. This age group comprises of young, individuals, thus emphasizing the socioeconomic burden of EPTB.[15] These findings were consistent with the study done by Yadhav K et al.[16]
The sex ratio for the distribution of EPTB was found to be 1.4:1 with a male predominance of 58.82%, which has been noticed in a study by Yadav K and Veena M. We postulate that higher prevalence among males could be due to a higher number of social contacts, working in high-risk occupations, and indulging in risky habits like smoking.[17]
Among the 19.13% of paediatric patients, 53.85% were females (seven individuals), while 46.15% were males (six individuals). In a study by Chander V et al., the paediatric patients constituted a good (11.6%) portion of all EPTB cases.[18]
The distribution of EPTB types, among the adult patients (n = 55), were as follows: TB pleural effusion and empyema thoracis represented the most common type, comprising 49.09% (n = 27) of cases. In both males and females, pleural effusion was the most frequent EPTB. LN TB (18.18%, n = 10) was the second prevalent form, while bone and joint TB accounted for 14.54% (n = 8) cases. TB meningitis constituted 9.09% (n = 5) of cases. Soft tissue TB, abdominal TB, genitourinary TB, pericardial TB, and breast TB each represent 1.82% (n = 1) of cases. In the study done by Desai M. et al.,[19] similar findings had been observed.
The majority of researchers have reported LN TB as the most common type of EPTB.[15,20] According to the study done by Nishal N. et al.,[20] it was observed that the most prevalent EPTB was LN TB (48.1%), followed by CNS TB (4.8%), abdominal TB (14.4%), TB pleural effusion (15.4%), and bone and joint TB (13.5%). The site of TB infection varies depending on the population due to several factors. Though it has not been thoroughly investigated, genetic variation in the NRAMP1 gene may make the pleura more susceptible to TB (13). In our study, spinal TB was observed in 11.8% (n = 8) of EPTB patients with psoas abscess, accounting for 10.3% (n = 7) of total EPTB cases, out of which six had thoracic vertebrae affected and lumbar vertebrae were involved in two patients.
In the 13 paediatric patients, the distribution of EPTB sites revealed a distinct pattern. LN TB and soft tissue TB each constituted 30.77% (n = 4) cases. Disseminated and bone/joint TB had been observed in 15.38% (n = 2) cases each. Pleural TB (n = 17.69%) was found to be the lowest prevalent form. Two female patients, aged 15 and 17, were diagnosed with disseminated TB, one with bilateral abdominal and spinal TB, and the other with Potts spine and scrofuloderma.
The common symptoms observed in patients with EPTB were fever (78%), weight loss (72%), anorexia (44%), and night sweats (44%). Contact with TB patients was reported in 26.5% (n = 18) cases in our study. This is much higher than reported by other studies like Luna-Hernández et al.,[21] which reported that only 4% of EPTB patients had a contact history.
In this study, 22% of individuals had a past history of TB and 26.5% of participants had contact with patients who had TB. The comorbidities associated with EPTB patients include diabetes mellitus (22%), smoking (17.6%), HIV infection, and alcohol.
In the 14 LN aspirate samples analysed by fine needle aspiration cytology, several significant findings were observed. Histologically, caseous necrosis, chronic inflammation, and granulomatous inflammation were the most frequent, each occurring in 28.6% of cases.
We used CRS as gold standard to define confirmed TB cases and to compare the sensitivity and specificity of the other microbiological tests. A total of 68 bacteriologically confirmed cases have been included in our study. It has been observed that while CBNAAT provides the highest positivity rates across all sample types, particularly in CSF samples. When considering all samples, the sensitivity rates for ZN staining, fluorescent staining, LJ media culture, and CBNAAT were 25%, 30.88%, 42.65%, and 97.06%, respectively.
Strengths and Limitations A key strength of this study is its prospective design and the use of a composite reference standard (CRS), which enables a pragmatic assessment of diagnostic performance of EPTB. The limitation of the study is the single centre design and modest sample size.
In the study conducted by Uddin MKM et al.,[9] the sensitivity for culture, AFB microscopy, and Xpert MTB/RIF (CBNAAT) assay were found to be 72.72%, 25.3%, and 85.6%, respectively, when compared to the CRS as the gold standard.
Only in two cases, there was bacterial growth on LJ medium which were confirmed as MTB by the MPT-64 test. However, both these had negative CBNAAT. The cause which could have led to culture-positive samples being negative on CBNAAT is due to its limit of detection. The 2 out of 29 culture-positive samples having very low bacillary load may have been missed by GeneXpert. One of the patients was a 16-year-old male having lateral abdominal wall swelling and another one was 39-year-old male presenting with cervical LN enlargement. These findings underscore the importance of utilizing multiple diagnostic modalities to enhance the detection of EPTB, especially in samples with inherently lower bacterial burden like LN aspirates and pus.
The lower sensitivity of solid culture can be attributed to the higher contamination of the egg-containing medium on prolonged incubation. The fluorescent staining is more sensitive than Zn staining for detection in paucibacillary samples. In the study by Gupta S. et al.,[22] fluorescent staining detected TB in 66.7% of cases, compared to 60% with ZN staining.
Rifampicin resistance was identified in approx. 4.5% (n = 3) of the 66 samples that tested positive via CBNAAT. Among these, two were pleural samples and one was peritoneal fluid samples. The rifampicin resistance was detected in 4.2% of positive CBNAAT samples in the study by Jose B.P. et al.[23] The treatment outcomes for various types of EPTB were examined across different categories. Cure or treatment completion was achieved in 44.11% (n = 30) of cases overall, with pleural EPTB having the highest success rate at 36.67% (n = 10). However, mortality was notable, constituting 53.33% (n = 8) of all fatality cases (n = 15), with TB meningitis having the highest fatality rate.
These results emphasize the need for continued research in well-defined populations so as to better understand the role of Xpert/RIF in routine care. To estimate the diagnostic performance of these tests in different forms of TB and varied types of specimens, it is important to enrol sufficient numbers of patients which can be facilitated by organizing multicentric studies.
EPTB is paucibacillary. Since most of the tests rely on the presence of mycobacteria in the specimen, none of them have a 100% sensitivity. Suboptimal performance of all assays in the diagnosis of EPTB cases underlines the continuing relevance of systematic clinical investigations for making the diagnosis of EPTB and also calls for the need for novel tests.
Conclusion
EPTB presents considerable diagnostic and treatment challenges due to its varied clinical manifestations and paucibacillary nature. The prevalence of EPTB was found to be 13.61% in the present study, mostly affecting young and early adulthood, with the highest proportion formed by the TB of the pleural cavity. A multifaceted approach involving comprehensive microbiological testing and close monitoring of comorbid conditions is essential for accurate diagnosis and effective management of EPTB.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
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