A retrospective study on Tuberculous Lymphadenitis; A retrospective finding from multicenters referal hospitals

Background Extra-pulmonary tuberculosis (EPTB) represents about 14% of all cases of tuberculosis (TB) in Malaysia. The aims of the study include evaluation of socio-demographic factors, clinical manifestations, co-morbidities among patients with Tuberculous Lymphadenitis and their treatment outcomes. Methods The retrospective study was conducted from 2006 to 2008. Data on socio-demographic along with histopathological results were collected. Signs and symptoms were also recorded from TB registers, treatment cards and TB medical personal files using standard data collection tool. Among multiple variables significant factors identified by univariate analysis, were included in multivariate logistic regression to estimate the odds ratios (ORs) with the 95% confidence intervals (CIs). The statistically significant p value was considered as < 0.05. Results There were 348 (57%) males and on the other hand 262 (43%) females which shows almost equal incidence rate of Lymphadenitis in both genders. Mean age was found as 34.3 ± 14.6 years were majorly reported with positive diagnosis. 196 (32.1%) Malay was found with Tuberculous lymphadenitis followed by Chinese population of 148 (24.3%). Geographically from 386 (63.3%) urban population were found positive for lymphadenitis and over 224 (36.7%) of rural region. treatment outcome was observed 444 (72.8%) with successful treatment. WHO states the types of treatment failures and accordingly 85 (13.9%) patients were continued with the therapy that can be due to non-compliance or relapse of Tb. Among unsuccessful outcomes 194 patients of age group 26 -35 years, 65 (33.5%) were reported and 38 (29.7%) patients out of 128 between 16 – 25 years. Blood results showed erythrocyte sedimentation rate greater than 10 in 280 (45.9%) patients. Therefore, among 280 there were 115 (41.1%) patients found to have unsuccessful treatment showing strong association with p-value of <0.001.

Conclusion Finding signifies that effect of weight loss on poor treatment outcomes` and active screening measures for patients with comorbidities are therefore recommended in patients with Tb lymphadenitis along with improvements in the diagnosis and early management of co-morbidities complications. As young age group were found to have poor or unsuccessful treatment outcomes and required aggressive strategy together with educating patients can further increase the treatment success rate.

Background
Infectious diseases are one of the major causes of health burden and among that Tuberculosis is a disease caused by mycobacteria belonging to the Mycobacterium tuberculosis complex. A small group of people gets affected by Mycobacterium africanum, Mycobacterium. canetti, Mycobacterium. caprae, Mycobacterium. microti, and Mycobacterium. Pinnipedii [ 1]. Mycobacterium. bovis was previously a major cause of human disease, but its relative importance has considerably declined as for an estimate 1.4% incident TB cases were reported in 2016. [2] Despite of many new updated and advanced diagnostic and treatment techniques are available an estimate of ten (10) million incident TB patients were reported globally in 2017 [3]. The most communal consequence is a subclinical (latent), asymptomatic infection. Whether one can achieve a spontaneous or drug-induced complete eradication of latent infection from the host is unclear, [3] but latent infection is typically kept under control through a cell-mediated immune response, preventing the activation of infection into disease. Histopathological damages of an uncontrolled infection are responsible for clinical signs and symptoms of TB disease. [4] TB typically affects the lungs but, in up to a third of patients, can also affects other sites. [5] It is not practically possible to identify M. tuberculosis strains present in the body in patients latently infected. [3] In Malaysia the early 1940s and 1950s was the era when Tuberculosis was one of the major diseases causing death in the region. Understanding the situation the Malaysian government launched its health controlling body named as National TB Control Program in 1961 [6]. According to the recent extensive research performed in Malaysia, 25,739 reported TB cases were observed during 2016 among those 22,135 (86%) were Pulmonary TB cases and on the other hand 3604 (14%) were extra pulmonary TB [6]. The most common forms of EPTB seen in Malaysia are TB lymphadenitis and bone/joint TB [7]. have the most number of TB cases in Malaysia, Penang and Selangor states were considered for its densely populated multiracial and expatriate population [10].

Study data analysis
Complete data was assigned a unique identification serial number to ensure the traceability of each data collection form. Data was coded into the computer for analysis and result interpretation and generation and analysis was performed by using statistical package for SPSS for Windows version 24.0.0 (SPSS, Inc., Chicago, IL, USA). To analyze the predictors of extra pulmonary TB specifically Lymphadenitis treatment outcomes univariate analysis was used to identify the importance of risk factors through Chi square test for categorical variables and independent sample t-test/ Mann Whitney U Test for continuous data. Significant factors identified by univariate analysis, were included in multivariate logistic regression to estimate the odds ratios (ORs) of unsuccessful treatment outcome of the Lymphadenitis TB with the 95% confidence intervals (CIs). The statistically significant p value was considered as < 0.05.

Socio-demographic characteristics:
Among the four states of Malaysia during the study, data of 610 patients was collected which showed Tuberculous lymphadenitis. As shown in Table 1. There were 348 (57%) males and on the other hand 262 (43%) females which shows almost equal incidence rate of Lymphadenitis in both genders. The age group was observed from 2-83 years old.
Therefore, the age groups between 26-35 years showed 194 (31.8%) patients diagnosed with lymphadenitis and followed by 16-25 years (21%). Mean age was found as 34.3 ± 14.6 years were majorly reported with positive diagnosis. Malaysia being a multi-racial country and consisting of numerous expatriates working or residing, 196 (32.1%) Malay population was found with Tuberculous lymphadenitis followed by Chinese population of 148 (24.3%). The other prominent races were Pilipino, Indonesians and other expatriates.
As mentioned in Table 1. Geographically patients were from both urban and rural background but 386 (63.3%) urban population were found positive for lymphadenitis over 224 (36.7%) population of rural region. Lymphadenitis and co-morbidities/ risk factors with major symptoms:

Discussion
There are multiple studies performed on Pulmonary and extra pulmonary Tuberculosis but with numerous important limitations with either gives up biased data or lack of adequate sample size to conclude. Therefore, to best of our know knowledge there is the pioneer study in Malaysia explaining the epidemiological characteristics along with the clinical outcomes either successful or unsuccessful according to the WHO guidelines with the diagnostic approach chosen for the specific Tubercular lymphadenitis patients.
Among multiple races and expatriates available in different states of Malaysia, Malays were found to have higher risk of lymphadenitis TB. Similar results were published in previous studies performed in Malaysia, as the population of Malays is higher than others and rate of relapse of diseases is also considered higher in Malay race.
A similar study performed on the extra-pulmonary TB shows that Patients at the risk of EPTB were more likely to be females [11], Contrary to that current study shows that Males were more in number 348 (57%) .The higher number of males can be due to the age factor as mostly males were belonging to the mean age group of 34.3 which has proved to have a higher risk of Lymphadenitis. Since the study shows the patients bet ween the age of 18 to 35 years were found to have most diagnosed with lymphadenitis compared to other age groups despite of gender. Similar results were reported by an Egyptian study performed prospectively on extra-pulmonary Tb patients, which states 34.8 ± 12.5 years as the mean age diagnosed with Tuberculosis [12]. Another recent study was performed in Penang General Hospital on Tuberculous Lymphadenitis patients also states that average mean age is 36.4 ± 12.87 among the active Tuberculosis patients [13] There was strong association found in the research as those who were using other intravenous drugs for addiction or abuse were found to have unsuccessful treatment outcomes. Most of the unsuccessful treatment outcome was reported among the IV drug users which lead to weight loss as well among the tuberculous lymphadenitis patients. A similar study performed in Kota Bahru Malaysia also reported the similar reasons for unsuccessful treatments leading to TB load in Malaysian population in 2011 [14]. Similarly another similar study performed prospectively on the TB lymphadenitis patients concluded the weight loss as a factor for loss of appetite leading to unsuccessful treatments which can be due to other confounding factors such as non-compliance or Intra venous drug abuse [15] There are multiple risk factors associated with Tuberculosis but current research showed contradictory results in relation to extra pulmonary TB lymphadenitis. Diabetes, Human Immuno deficiency virus and Hepatitis were studied and it shows no statistically significant result to any of the risk factors. Recently study performed in North-East Peninsular Malaysia on the mortality among the Tb and HIV co-morbid patients reported strong relationship on the unsuccessful treatment outcomes of TB and a major risk factor for extra-pulmonary Tb [16]. Present study findings shows only few patients were found to have diabetes which is less than 15 percent of the total diagnosed population with Tb lymphadenitis. Therefore there is no direct risk association found in the study which is contradictory to some of the other researches performed to evaluate the treatment outcomes in relation to risk factors such as Diabetes etc. A review was performed on DM and TB risk analysis shows that 41 TB drug trials 12 were reported DM as comorbidity among the study participants and there was reports of DM to be found higher in drugresistant-TB [17]. Similarly a cross sectional study performed in Manjung district of Malaysia reported that the commonest comorbidity was diabetes mellitus (DM) with majority of cases of the PTB patients having diagnosed or undiagnosed DM prior to PTB diagnosis, followed by Human Immunodeficiency Virus (HIV) and Hepatitis C infection which accounted for the study populations [18] This study has revealed some strong association between the risk factors and treatment outcomes. One of few reasons is weight loss or lower BMI which showed unsuccessful treatment outcome in the present study. Recently another study was performed in Yemen on multi drug resistant Tuberculosis and their analysis revealed that a baseline body weight of ≤ 40 kg was found to have lower successful treatment rate [19]. Another study performed in Pakistan shows that patient with baseline body weight of < 40 kg were at significantly greater risk of developing death and treatment failure [20]. Similar positive association between low body weight and unfavorable treatment outcomes have been reported by studies conducted elsewhere [21,22,23]. Poor absorption from GI tract is one of the main reasons of sub-therapeutic serum concentration of anti-TB drugs. Lower body weight or BMI is believed to be a contributing factor for lower serum drug levels in TB patients [24]. It not only reduces the gastrointestinal absorption of drugs but also increase the renal clearance of free drugs, subsequently resulting in sub-therapeutic drug levels and poor treatment outcomes. Moreover, inadequate dosing of drugs in underweight patients could be another cause of sub-therapeutic serum drug concentration and high incidence of death and treatment failure in these patients [24]. Age is another important factor which defines the physical condition as well as metabolic level of an individual. This study reported that younger age group between 16-35 years were found to have unsuccessful treatment outcomes which may be due to no follow up or any confounding factors. In Yemen a study was performed among general population and it shows homelessness, male gender and age ≥ 25 years were the risk factors reported for poor treatment outcomes [25]. Furthermore, in Netherlands recently a study showed predictors for mortality were aged 74-84 years (OR, 5.58; 95% CI 3.10-10.03) or ≥ 85 years which is contradictory to current study results as these were not specific to lymphadenitis Tuberculosis [26]. Another study performed in Malaysia states that the mean age of unsuccessful treatments was 34.6 ± 10.55 years and among them 68.9% were females [27]. Moreover, Factors associated with death were older age, HIV positivity and not receiving directly observed therapy (DOTS) as it is important for health care professionals to be aware of these increased risks and for authorities to implement protective measures [27]. Current study shows younger age group are more associated with unfavorable treatment outcomes which shows that for Tb lymphadenitis younger age should be considered for followed up and intensive therapy to prevent mortality and have higher rate of successful treatment in Malaysia.

Limitations
This study has some limitations for its retrospective nature. We could not assess whether patients who completed treatment increased their weight. Beside this, documentation of diabetes, hepatitis and HIV was likely to be incomplete.

Conclusions
With continuous growing trend, Tb Lymphadenitis is a grave concern to public health in Malaysia for mainly affecting nationals. High prevalence of EPTB-DM, EPTB-HIV and EPTB-HEP is found in Malaysia. In the present study signifies the fact that these patients are at high risk of developing lymphadenitis. Effect of weight loss on poor treatment outcomesà nd active screening measures for patients with comorbidities are therefore recommended in patients with Tb lymphadenitis along with improvements in the diagnosis and early management of co-morbidities complications. As young age group were found to have poor or unsuccessful treatment outcomes and required aggressive strategy together with educating patients can further increase the treatment success rate. Age as a risk factor in young group should be considered for intensive therapy and early diagnosis.