Tuberculosis weight loss: Decreased Plasma Leptin Concentrations in Tuberculosis Patients Are Associated with Wasting and Inflammation | The Journal of Clinical Endocrinology & Metabolism

12.06.197701.11.2021 by alexxlab

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Decreased Plasma Leptin Concentrations in Tuberculosis Patients Are Associated with Wasting and Inflammation | The Journal of Clinical Endocrinology & Metabolism

Tuberculosis patients often suffer from severe weight loss, which is considered to be immunosuppressive and a major determinant of severity and outcome of disease. Because leptin is involved in weight regulation and cellular immunity, its possible role in tuberculosis-associated wasting was investigated. In an urban clinic in Indonesia, plasma leptin concentrations, indicators of adipocyte mass, appetite, C-reactive protein (CRP), tuberculin reactivity, and cytokine response were measured in tuberculosis patients and healthy controls. Plasma leptin concentrations were lower in patients than in controls (615 vs. 2,550 ng/liter; P < 0.001). Multivariate regression analysis showed that body fat mass and inflammation were two independent factors determining plasma leptin concentrations; there was a positive correlation between fat and leptin, whereas, unexpectedly, leptin was inversely associated with CRP and tumor necrosis factor-α production. Concentrations of both CRP and leptin were independently associated with loss of appetite. Our results do not support the concept that weight loss in tuberculosis is caused by enhanced production of leptin. Rather, loss of body fat leads to low plasma leptin concentrations, and prolonged inflammation may further suppress leptin production. Because leptin is important for cell-mediated immunity, low leptin production during active tuberculosis may contribute to increased disease severity, especially in cachectic patients.

WASTING HAS LONG been recognized as a prominent feature of tuberculosis and is probably one of the determinants of the disease severity and outcome (1). However, uncertainty surrounds cause as well as effect of a poor nutritional status in tuberculosis patients. The cause, or pathogenesis of tuberculosis-associated wasting is incompletely understood, although it is likely that inflammatory mediators such as tumor necrosis factor-α (TNFα) do play a role (2). Similarly, a poor nutritional status is known to suppress cellular immunity, which is essential against Mycobacteriumtuberculosis, but the precise mechanism remains uncertain (3, 4).

Leptin, the 16-kDa product of the ob-gene, may be involved in this cross-regulation between nutritional status and the immune response in tuberculosis. Leptin is produced by adipocytes and binds to specific receptors in the hypothalamus, from which it suppresses appetite (5). Concentrations of circulating leptin are proportional to fat mass (6), are reduced in starvation (7, 8), and are increased by inflammatory mediators (9). Administration of leptin to leptin-deficient ob/ob mice reduces food intake and increases energy expenditure (10). Experimental evidence has shown a number of other possible functions of leptin, including immune regulation. Leptin stimulates the proinflammatory response (11) and promotes proliferation, differentiation, and activation of hematopoietic cells (12). In mice, the reduction of leptin concentrations induced by starvation enhances sensitivity to endotoxic shock (13). Falling leptin concentrations also appear to be responsible for reduced T-cell function during starvation (14).

On the basis of the above, plasma leptin concentrations in tuberculosis may be the result of two antagonistic mechanisms. Whereas tuberculosis-associated loss of body fat mass may lead to reduced production of leptin (15), the host inflammatory response may increase leptin production (9). If, as an overall result, plasma leptin concentrations are increased in tuberculosis patients, then this might theoretically suppress appetite and food intake and be one of the mechanisms underlying weight loss. However, if plasma leptin concentrations are decreased in tuberculosis, then this might suppress cellular immunity and aggravate disease outcome. Therefore, the aim of this study was to measure plasma leptin concentrations in tuberculosis patients and to explore determinants of leptin such as nutritional status and the inflammatory response. The study was conducted in Indonesia, where malnutrition is highly prevalent among tuberculosis patients (3).

Subjects and Methods

Subjects

In an outpatient tuberculosis clinic in Jakarta, Indonesia, 60 consecutively selected patients with pulmonary tuberculosis were evaluated before and after 2 months of standard antituberculous treatment with isoniazide, rifampicin, pyrazinamide, and ethambutol. Diagnosis was based on clinical presentation and radiology and confirmed by sputum microscopy and culture for M. tuberculosis. In a subgroup of 20 (untreated) patients, tuberculin reactivity was measured. Thirty healthy individuals resident in the same neighborhood as the patients were selected for comparison. These controls had no history or signs of active pulmonary tuberculosis and had no abnormalities on chest x-ray examination. Informed consent was obtained from all patients and control subjects, and the study was approved by the ethical committee of the Faculty of Medicine, University of Indonesia, Jakarta.

Anthropometric measurements

Patients and control subjects were weighed barefoot with minimum clothing using an electronic weighing scale (SECA-770). Body weight was recorded to the nearest 0.1 kg. Height was measured to the nearest 0.1 cm using a microtoise. Total body fat was estimated from the average of two duplicate measurements of skinfold thickness at four sites (biceps, triceps, subscapular, and suprailiac regions) (16). Food intake was estimated from two 24-h recalls using World Food version 2.0 (University of California, Berkeley, CA).

Laboratory methods

Plasma leptin concentrations were measured by capture ELISA according to guidelines of the manufacturer (Quantikine DLP00, R&D Systems, Minneapolis, MN). Plasma C-reactive protein (CRP) concentrations were measured by standard turbidimetry. In a subgroup of 20 patients, ex vivo production of cytokines was assessed in whole blood as previously described (17). Briefly, whole blood was incubated in closed vacutainer tubes at 37 C without stimulation or with lipopolysaccharide (LPS; final concentration, 10 μg/liter), phytohemoagglutinin (10 mg/liter), or purified protein derivative (PPD; 10 mg/liter). Supernatants were harvested after incubation for 6 h (LPS and phytohemoagglutinin) or 24 h (PPD). Concentrations of TNFα, IL-1β, and IL-1 receptor antagonist (IL-1ra) were measured by specific RIA (18), and concentrations of interferon-γ (IFN-γ) and IL-6 were measured by ELISA (Pelikine, CLB, Amsterdam, The Netherlands). All relevant comparisons were made within single assays. The intra-assay coefficient of variation was 3% for leptin, 6% for IFN-γ, and less than 10% for TNFα, IL-1β, and IL-1ra. Day to day variation of whole blood ex vivo cytokine production in humans is 12% for TNFα, 23% for IL-1β, 5% for IL-1ra, and 47% for IFN-γ (17).

Statistical analyses

Data were analyzed using SPSS version 7.5.2 for Windows (SPSS, Inc., Chicago, IL). Patients and controls were compared regarding their plasma leptin concentrations, body weight, body mass index (BMI) (calculated as weight/height², kg/m²), body fat mass, sex, and age, using t test or Mann-Whitney U test as appropriate. The relationship between plasma leptin concentrations and body fat mass, and between plasma concentrations of leptin and CRP was analyzed by univariate regression. Multivariate regression models were used to assess whether data were consistent with our hypothesis that a tuberculosis-associated change in plasma leptin concentration is mediated through changes in body fat mass and CRP. Hence, log (plasma leptin concentration) was modeled with body fat mass and CRP as main terms. A term for tuberculosis was retained to account for possible mechanisms through which it might influence plasma leptin concentration independently from body fat and CRP. The geometric mean changes in plasma leptin concentration, food intake, and the mean change in body weight, body fat mass, and CRP after 2 months of antituberculous treatment were evaluated by one-sample t tests. Multivariate logistic regression analysis was used to evaluate plasma leptin concentrations and inflammation as determinants of reported appetite (normal or below normal) in tuberculosis patients at baseline. CRP was used as a marker of the inflammatory response, which was considered as a possible confounder in the relation of plasma leptin concentration with appetite.

Results

Plasma leptin concentrations are lower in tuberculosis patients than in controls

The subjects included in this study were mostly young adults and more often male (Table 1). Patients with tuberculosis presented with a 2- to 6-month history of respiratory symptoms (100%), fever (60%), night sweats (68%), fatigue (83%), and weight loss (80%). None of the investigated patients was HIV-positive. Reported weight loss ranged from 0–25 kg (median, 5 kg). Patients with untreated tuberculosis had substantially lower weight, BMI, and body fat mass than controls (Table 1). BMI in patients was reduced by 16% compared with controls, and body fat mass (percentage) by 45%. Patients had a geometric mean [95% confidence interval (CI)] plasma leptin concentration of 617 (range, 469–810) ng/liter, compared with 2,539 (range, 1,548–4,168) ng/liter in healthy control subjects (P < 0.001; Fig. 1A). This difference corresponded with a 76% reduction in patients. Patients were somewhat older than controls, but no association was found between age and plasma leptin concentration among either controls or patients. Women had substantially higher plasma leptin concentrations than men (geometric mean, 1,938 ng/liter compared with 575 ng/liter; ratio, 3. 4; 95% CI, 2.0–5.6), but the sex ratio was similar among patients and controls (Table 1). In both male and female subjects, plasma leptin concentrations were significantly reduced in tuberculosis patients (Fig. 1B).

Figure 1.

Plasma leptin concentrations in tuberculosis patients and healthy controls. A, Log-transformed plasma leptin concentrations of 60 tuberculosis patients (black dots) and 30 healthy controls (white dots). Geometric mean plasma leptin concentrations are significantly lower in patients vs. control subjects (P < 0.001 according to t test). B, Log-transformed plasma leptin concentrations according to sex. Plasma leptin concentrations are significantly higher in females (P < 0.001), but both in males and females, plasma leptin is significantly reduced in tuberculosis patients.

Figure 1.

Table 1.

Nutritional status in patients with untreated tuberculosis and healthy control subjects

.	Patients (n = 60) .	.	Controls (n = 30) .	.	Difference .	P .
Male/female (%)	58/42		53/47
Age (yr)¹	“>30.0	[23.3–40.0]	23.0	[19.0–39.3]	7.0
Weight (kg)²	42.2	(40.4–44.1)	49.6	(47.2–52.0)	7.4	<0.001⁴
BMI (kg·m⁻²)³	16.8	(16.2–17.4)	20.0	(19.0–21.0)	3.2	<0.001⁴
Body fat mass (%)¹	11.8	[7.9–19.1]	21.4	[12.9–26.8]	9.6	0.001⁵
Body fat mass (kg)¹	4.6	[3.3–8.4]	9.0	[6.4–14.7]	4.4	<0.001⁵

.	Patients (n = 60) .	.	Controls (n = 30) .	.	Difference .	P .
Male/female (%)	58/42		53/47
Age (yr)¹	30.0	[23.3–40.0]	23.0	[19.0–39.3]	7.0
Weight (kg)²	42.2	(40.4–44.1)	49.6	(47.2–52.0)	7.4	<0.001⁴
BMI (kg·m⁻²)³	16.8	(16.2–17.4)	20.0	(19.0–21.0)	3.2	<0.001⁴
Body fat mass (%)¹	11.8	[7.9–19.1]	“>21.4	[12.9–26.8]	9.6	0.001⁵
Body fat mass (kg)¹	4.6	[3.3–8.4]	9.0	[6.4–14.7]	4.4	<0.001⁵

Table 1.

Nutritional status in patients with untreated tuberculosis and healthy control subjects

.	Patients (n = 60) .	.	Controls (n = 30) .	.	Difference .	P .
Male/female (%)	58/42		53/47
Age (yr)¹	30.0	[23.3–40.0]	23.0	[19.0–39.3]	7.0	“>
Weight (kg)²	42.2	(40.4–44.1)	49.6	(47.2–52.0)	7.4	<0.001⁴
BMI (kg·m⁻²)³	16.8	(16.2–17.4)	20.0	(19.0–21.0)	3.2	<0.001⁴
Body fat mass (%)¹	11.8	[7.9–19.1]	21.4	[12.9–26.8]	9.6	0.001⁵
Body fat mass (kg)¹	4.6	[3.3–8.4]	9.0	[6.4–14.7]	4.4	<0.001⁵

.	Patients (n = 60) .	.	Controls (n = 30) .	.	Difference .	P .
Male/female (%)	58/42		53/47
Age (yr)¹	30.0	[23.3–40.0]	23.0	[19.0–39.3]	7.0
Weight (kg)²	42.2	(40.4–44.1)	49.6	(47.2–52.0)	7.4	<0.001⁴
BMI (kg·m⁻²)³	16.8	(16.2–17.4)	20.0	(19.0–21.0)	3.2	<0.001⁴
Body fat mass (%)¹	11.8	[7.9–19.1]	21.4	[12.9–26.8]	9.6	0.001⁵
Body fat mass (kg)¹	“>4.6	[3.3–8.4]	9.0	[6.4–14.7]	4.4	<0.001⁵

Body fat mass and inflammation are associated with plasma leptin concentrations

Univariate analysis showed that plasma leptin concentration increased proportionally with body fat mass (Fig. 2A). For every 10 U increment in fat percentage, plasma leptin concentration increased 3.1-fold (95% CI, 2.4–3.9) and 2.6-fold (95% CI, 1.4–4.7) in patients and control subjects, respectively. Median CRP was 52 mg/liter (interquartile range, 19–95 mg/liter) in tuberculosis patients and 2 mg/liter (1–3 mg/liter) in controls (P < 0.001). Among patients, plasma leptin concentrations were reduced by 33% (95% CI, 15–46%) for every 50 mg/liter increment in CRP. In control subjects, there was insufficient variation in CRP to assess its relation with plasma leptin concentration.

Figure 2.

Plasma leptin concentration and body fat mass in tuberculosis patients and healthy controls. A, Log-transformed plasma leptin concentrations and percentage body fat in tuberculosis patients (white circles) and healthy controls (black squares). The lines represent linear regression analysis for patients (r = 0.78; P < 0.001) and controls (r = 0.53; P = 0.002). B, The estimates ([Y] = 10^{2.1078 + 0.0484 [X]} for tuberculosis patients; [Y] = 10^{2.5669 + 0.0414 [X]} for healthy controls) based on a multivariate regression model with terms for tuberculosis, body fat mass, and their product term. They indicate that tuberculosis affects plasma leptin concentrations directly, and through loss of body fat mass. The thin curve ([Y] = 10^{2.3750 + 0.0424 [X]}) is based on univariate regression to model plasma leptin concentration as a function of body fat mass in tuberculosis patients who have completed 2 months of treatment (n = 38). This curve indicates that plasma leptin concentrations show a partial recovery during treatment, which cannot be explained by an increase in fat mass.

Figure 2.

Plasma leptin concentration and body fat mass in tuberculosis patients and healthy controls. A, Log-transformed plasma leptin concentrations and percentage body fat in tuberculosis patients (white circles) and healthy controls (black squares). The lines represent linear regression analysis for patients (r = 0.78; P < 0.001) and controls (r = 0.53; P = 0.002). B, The estimates ([Y] = 10^{2.1078 + 0.0484 [X]} for tuberculosis patients; [Y] = 10^{2.5669 + 0.0414 [X]} for healthy controls) based on a multivariate regression model with terms for tuberculosis, body fat mass, and their product term. They indicate that tuberculosis affects plasma leptin concentrations directly, and through loss of body fat mass. The thin curve ([Y] = 10^{2.3750 + 0. 0424 [X]}) is based on univariate regression to model plasma leptin concentration as a function of body fat mass in tuberculosis patients who have completed 2 months of treatment (n = 38). This curve indicates that plasma leptin concentrations show a partial recovery during treatment, which cannot be explained by an increase in fat mass.

Figure 2B shows the results of a multivariate regression model to assess the role of body fat mass and possible other mechanisms whereby tuberculosis may affect plasma leptin concentration. This figure shows that patients with untreated tuberculosis have lower plasma leptin concentrations than expected for body fat mass. Table 2 gives a comparison of two regression models to assess the role of body fat mass, CRP, and other possible mechanisms whereby tuberculosis may affect plasma leptin concentrations. Multivariate regression analysis showed no evidence for effect modification or confounding by age and sex in these associations. Univariate regression (model 1) gave a crude assessment of the association between tuberculosis and plasma leptin concentration. Multivariate regression, with addition of CRP and body fat mass (model 2), reduced this association (from 76–35%) and shows that plasma leptin concentration was positively associated with body fat and inversely associated with CRP. The estimated proportion of variability in plasma leptin concentration explained (multiple R²) in model 2 was 0.64. Taken together, these findings are consistent with our hypothesis that tuberculosis-associated reductions in plasma leptin concentrations are mediated independently through a decreased percentage of body fat, inflammation, and possibly other, unidentified mechanisms.

Table 2.

Independent associations of various variables with plasma leptin concentration

Model .	Variable .	Effect estimates¹ .		95% CI_(10β) .	P .
Model .	Variable .	Regression coefficient, β .	Factor (10β) .	95% CI_(10β) .	P .
1	Tuberculosis	−0.628	0.24	0.14–0.39	<0.001
2	Tuberculosis	−0.190	0.65	0.41–1.02	0.06
	10% increase in body fat mass (%)	0.432	2.7	2.1–3.4	<0.001
	100 mg/liter increase in plasma C-reactive protein concentration	−0.287	0.52	0.34–0.79	0.003

Model .	Variable .	Effect estimates¹ .		95% CI_(10β) .	P .
Model .	Variable .	Regression coefficient, β .	Factor (10β) .	95% CI_(10β) .	P .
1	Tuberculosis	−0.628	0.24	0.14–0.39	<0.001
2	Tuberculosis	−0.190	0.65	0.41–1.02	0.06
	10% increase in body fat mass (%)	0.432	2.7	2.1–3.4	<0.001
	100 mg/liter increase in plasma C-reactive protein concentration	−0.287	0.52	0.34–0.79	0.003

Table 2.

Independent associations of various variables with plasma leptin concentration

Model .	Variable .	Effect estimates¹ .		95% CI_(10β) .	P .
Model .	Variable .	Regression coefficient, β .	Factor (10β) .	95% CI_(10β) .	P .
1	Tuberculosis	−0.628	0.24	0.14–0.39	<0.001
2	Tuberculosis	−0.190	0.65	0.41–1.02	0.06
	10% increase in body fat mass (%)	0.432	2.7	2.1–3.4	<0.001
	100 mg/liter increase in plasma C-reactive protein concentration	−0.287	0.52	0.34–0.79	0.003

Model .	Variable .	Effect estimates¹ .		95% CI_(10β) .	P .
Model .	Variable .	Regression coefficient, β .	Factor (10β) .	95% CI_(10β) .	P .
1	Tuberculosis	−0.628	0.24	0.14–0.39	<0.001
2	Tuberculosis	−0.190	0.65	0.41–1.02	0.06
	10% increase in body fat mass (%)	0.432	2.7	2.1–3.4	<0.001
	100 mg/liter increase in plasma C-reactive protein concentration	−0.287	0.52	0.34–0.79	0.003

Plasma leptin concentrations increase during antituberculous treatment

The effect of antituberculous treatment on plasma leptin concentrations, appetite, nutritional status, and acute phase proteins was evaluated in 38 patients for whom blood test results were available after 2 months of treatment. These patients reported a clear improvement of symptoms within 1–3 wk after start of treatment. Plasma leptin concentrations were substantially higher after treatment (geometric mean difference, 409 ng/liter; 95% CI, 219–676 ng/liter; P < 0.001), corresponding to an increase of 64% relative to baseline (Fig. 2B). There was no evidence that selection bias caused by missing data substantially affected the estimated effect of treatment on the change in plasma leptin concentration (data not shown). Loss of appetite was reported by 27 patients (71%) before treatment and by none after treatment. After 2 months of treatment, patients had a higher energy intake (mean difference, 375 kJ), body weight (mean difference, 1.6 kg; 95% CI, 0.9–2.3 kg; P < 0.001), and body fat mass (mean difference, 1.6%, 95% CI, 0.6–2.5%; P = 0.003), and lower CRP (mean difference, 50 mg/liter; 95% CI, 26–74 mg/liter; P = 0.001).

Plasma leptin and cytokine response

The relationship between plasma leptin concentrations and the ex vivo production of proinflammatory cytokines was investigated in 19 tuberculosis patients for whom data were available. Linear regression analysis showed an inverse correlation between spontaneous ex vivo production of TNFα and plasma leptin concentrations before treatment. Plasma leptin concentrations reduced by 42% (95% CI, 12–62%) for every 0.1 ng/ml increment in plasma TNFα concentration. LPS-mediated production of TNFα, as well as the production of IL-1β, IL-1ra, and IL-6, was not significantly associated with plasma leptin concentrations before treatment. After treatment, there was a substantial decrease of plasma concentrations of IL-6 and ex vivo production of IL-1β, IL-6, and TNFα (data not shown). However, we could not directly demonstrate a significant association between changes in leptin concentrations and changes in cytokine production.

To investigate the relationship between plasma leptin concentrations and T-cell immunity, tuberculin skin tests and production of IFN-γ were evaluated in untreated patients. The size of skin reactions to PPD showed a positive but statistically nonsignificant correlation with plasma leptin concentrations (P = 0. 30). A similar result was found for plasma leptin concentrations and PPD-induced ex vivo production of IFN-γ (P = 0.38). Ex vivo production of IFN-γ increased after treatment (mean difference, 188 pg/ml; 95% CI, −7 to 539 ng/liter). However, no significant relationship could be shown between change in plasma leptin concentrations and IFN-γ production (P = 0.39).

Determinants of appetite

Both inflammation and plasma leptin concentration were associated with loss of appetite in tuberculosis patients. Every 50-mg/liter increment in CRP was associated with a 1.4-fold increase (95% CI, 0.8–2.6) in the odds of reporting loss of appetite. When adjusted for CRP, every 1,000-ng/liter increment in plasma leptin concentration was associated with a 1.7-fold increase (95% CI, 0.7–4.3) in the odds of reporting loss of appetite.

Discussion

Tuberculosis often leads to severe weight loss (wasting), probably through the production of inflammatory mediators (2). Wasting, in turn, affects the inflammatory response, suppresses cellular immunity, and aggravates the outcome of tuberculosis (19). In these complex relations between tuberculosis, nutritional status and the host immune response, leptin is a possible mediator. In this study, plasma leptin concentrations were significantly suppressed in tuberculosis patients in Indonesia. Body fat mass was strongly correlated with plasma leptin concentrations, both in patients and controls. Unexpectedly, in tuberculosis patients, plasma CRP and in vitro production of TNFα showed an inverse correlation with plasma leptin concentrations. Results of multivariate regression analysis support the hypothesis that tuberculosis-associated reductions of plasma leptin were mediated independently by weight loss and inflammation. Although previous data have shown that leptin stimulates cell-mediated immunity, we were unable to demonstrate a statistically significant correlation of plasma leptin concentrations with tuberculin reactivity or IFN-γ production.

To our knowledge, there is one previous study on plasma leptin concentrations in tuberculosis patients (21). In that report, leptin concentrations, as determined by RIA, were much higher than in ours. The (Turkish) patients in that report had a much higher BMI, but it seems surprising to us that after treatment they had 3-fold higher leptin concentrations than control subjects. Also, the control subjects had increased plasma TNFα values, an unexpected finding in healthy individuals.

Loss of body fat mass could not entirely explain the observed low plasma leptin concentrations in tuberculosis patients in our study. Body fat mass is the most important determinant of plasma leptin concentrations, but starvation, hormones (including insulin and cortisol), as well as inflammatory mediators are able to modulate leptin production (22). Animal studies have shown that LPS, TNFα, and IL-1β raise leptin concentrations in serum and leptin mRNA in adipose tissue (7). Similarly, in cancer patients, recombinant TNFα (22) and IL-1β (23) increased plasma leptin. In sepsis patients, leptin levels were found to be elevated (23–25). To our surprise, in our study in tuberculosis, CRP and TNFα production were inversely correlated with plasma leptin concentrations. Attenuation of the acute phase response and proinflammatory cytokine production during antituberculous treatment was accompanied by an impressive increase of plasma leptin concentrations. Of course, the acute inflammatory response in the animal and patient studies described above is different from the more chronic response in tuberculosis patients. The pattern of plasma leptin concentrations in weeks or months before diagnosis remains unknown, but one may hypothesize that the prolonged inflammatory response in tuberculosis down-regulates or exhausts leptin production.

In this study, multivariate analysis indicated that plasma leptin concentrations were associated with loss of appetite in tuberculosis. However, plasma leptin concentrations were substantially higher in control subjects (without anorexia), and patients regained appetite during treatment, despite a substantial increase in plasma leptin concentrations. Therefore, anorexia in tuberculosis seems to be determined to a much larger degree by inflammatory mediators (e.g. proinflammatory cytokines) than by leptin. Leptin signals the brain to decrease food intake, but so far no evidence has been found that anorexia in AIDS (26, 27) and other inflammatory disorders is caused by increased leptin levels (28, 29). In fact, it may be the other way around; in both laboratory animals (30) and human subjects (8), fasting induces falling leptin levels that evoke a number of adaptive responses, including suppression of metabolic rate (7). Similarly, in tuberculosis, decreased energy intake may reduce leptin production. We did not measure energy intake, but it is likely to be lower among tuberculosis patients than healthy controls.

Suppressed production of leptin may be detrimental for host defense against infections. In septic shock, mortality was found to be associated with decreased plasma leptin levels (23). In an animal model, the absence (13) or starvation-induced down-regulation of leptin increased susceptibility to endotoxic shock, and leptin partially reversed this effect (13). In addition, leptin reversed starvation-induced T-cell suppression (14). Host defense against tuberculosis depends on cell-mediated immunity, with a crucial role for Th2-type cytokines, primarily IFN-γ (31). Therefore, it may be hypothesized that decreased leptin production during active tuberculosis contributes to T-cell unresponsiveness. Indeed, in our patient group, both plasma leptin and ex vivo IFN-γ production were low and increased upon successful antituberculous treatment. We did not find a significant correlation between these two variables, which might be due either to the limited number of patients analyzed for cytokine production or to substantial intra- and interindividual variation of ex vivo cytokine production (17). We were also unable to show a statistical association between leptin and tuberculin reactivity, but skin testing, which was only done before treatment, is a rather crude measurement.

Based on our data and results from previous studies, we hypothesize that in untreated tuberculosis, loss of body fat, reduced energy intake, and the host immune response reduce leptin production (Fig. 3). Because leptin is important for cell-mediated immunity, suppressed leptin concentrations may contribute to a worse outcome of tuberculosis, especially in cachectic patients. In theory, administration of leptin might benefit tuberculosis patients, but this is not feasible in a country like Indonesia. Supplementation of micronutrients such as vitamin E (32) or zinc, which are known to increase leptin production (33), might be a cost-effective alternative. Of interest, zinc has the additional advantage of stimulating appetite (34).

Figure 3.

Hypothesized role of leptin in human tuberculosis. The inflammatory response in tuberculosis may suppress leptin production directly (A), and through loss of body fat mass (B) and decreased energy intake (C). Suppressed leptin production may contribute to decreased cell-mediated immunity. In addition, wasting (cachexia) may contribute to a worse disease outcome through other, undefined mechanisms.

Figure 3.

We greatly appreciate the help of Wilma de Lenne and Yelilsan Veeraragu and the staff members of the outpatient clinic of the Perkumpulan Pemberantasan Tuberkulosis Indonesia, Jl Baladewa, Jakarta. Dr. Iskandar Zulkarnain, head of the Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, provided staff to conduct this study. We thank Trees Verver, Liesbeth Jacobs, and Johanna van de Ven-Jongekrijg for their help with the cytokine assays.

R.v.C. is financially supported by the Dutch Organization for Scientific Research NWO (SGO Stipendium Infectious Diseases Grant SGO-INF 002). E.K. is financially supported by grants from Gesellschaft für Technische Zusammenarbeit, GmbH (Eschborn, Germany), the Neys-van Hoogstraten Foundation, Directorate General of Communicable Disease Control and Environmental Health, Ministry of Health, Republic of Indonesia, and the Integrated Excellent Research project from the Ministry of Research and Technology, Republic of Indonesia. H.V. is supported by a grant from The Netherlands Foundation for the Advancement of Tropical Research (NWO/WOTRO, Grant WV93-273). Quantikine leptin ELISAs (R&D Systems) were provided free of charge by Amgen, Inc. (Breda, The Netherlands).

Abbreviations:

BMI,

CRP,

IL-1ra,
IL-1 receptor antagonist;

IFN-γ,

LPS,

PPD,
purified protein derivative;

TNFα,
tumor necrosis factor-α.

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Relation of Leptin, Ghrelin and Inflammatory Cytokines with Body Mass Index in Pulmonary Tuberculosis Patients with and without Type 2 Diabetes Mellitus

Abstract

Background

Pulmonary tuberculosis (TB) patients often suffer from anorexia and poor nutrition, causing weight loss. The peptide hormones leptin and its counterpart ghrelin, acting in the regulation of food intake and fat utilization, play an important role in nutritional balance. This study aimed to investigate the association of blood concentrations of leptin, ghrelin and inflammatory cytokines with body mass index (BMI) in TB patients with and without type 2 diabetes mellitus (T2DM).

Methods

BMI, biochemical parameters and plasma levels of leptin, ghrelin and inflammatory cytokines were measured before the start of treatment in 27 incident TB patients with T2DM, 21 TB patients and 23 healthy subjects enrolled in this study.

Results

The levels of leptin were significantly higher in TB patients (35.2±19.1 ng/ml) than TB+T2DM (12.6±6.1 ng/ml) and control (16.1±11.1 ng/ml) groups. The level of ghrelin was significantly lower in TB (119.9±46.1 pg/ml) and non-significantly lower in TB+T2DM (127.7±38.6 pg/ml) groups than control (191.6±86.5 pg/ml) group. The levels of TNF-α were higher, while IFN-γ and IL-6 levels were lower in patients than in the control group. Leptin showed a negative correlation with BMI in TB (r=-0.622, p<0.05) and TB+T2DM (r= -0.654, p<0.05) groups, but a positive correlation with BMI in the control group (r=0.521, p<0.05). Contrary ghrelin showed a positive correlation with BMI in TB (r=0.695, p<0.05) and TB+T2DM (r= 0.199, p>0.05) groups, but negative correlation with BMI in the control (r=-0.693, p<0.05) group. Inflammatory cytokines were poorly correlated with BMI in this study. Only IFN-γ showed a significant negative correlation with BMI in the control group (r=-0.545, p<0.05).

Conclusions

This study may suggest that possible abnormalities in ghrelin and leptin regulation (high levels of leptin and low levels of ghrelin) may be associated with low BMI and may account for the poor nutrition associated with TB and TB+T2DM.

Citation: Zheng Y, Ma A, Wang Q, Han X, Cai J, Schouten EG, et al. (2013) Relation of Leptin, Ghrelin and Inflammatory Cytokines with Body Mass Index in Pulmonary Tuberculosis Patients with and without Type 2 Diabetes Mellitus. PLoS ONE 8(11):
e80122.

https://doi.org/10.1371/journal.pone.0080122

Editor: Salomon Amar, Boston University, United States of America

Received: June 6, 2013; Accepted: September 29, 2013; Published: November 8, 2013

Copyright: © 2013 Zheng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors thank The National Natural Science Funds (81172662/h3603)(http://159.226.244.22/portal/Proj_List.asp) and Specialized Research Fund for the Doctoral Program of Higher Education (20123706110004)(http://www.cutech.edu.cn/cn/kyjj/gdxxbsdkyjj/2013/02/13541734880805
63.htm) for the grants supporting the study. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Pulmonary tuberculosis (TB) is a major cause of mortality around the world, nearly one-third of the world’s population is infected, and 8~12 million people become newly infected each year [1]. TB incidence is influenced by several social and economic factors, such as poverty or poor nutrition [2], as well as by other diseases, such as diabetes mellitus (DM). Many studies now show that DM may be associated with an increased risk (almost triple) of developing active TB [3-5], and TB patients who also have diabetes may have higher rates of treatment failure and death [6,7]. China has the second highest rate of TB morbidity in the world and DM rates are reaching epidemic proportions [8]. This harmful synergy of TB and DM has led public health systems in China to attempt to tackle the two diseases concurrently. A study was initiated in which active TB patients in poverty zones are screened for DM and the effect of a diet and lifestyle intervention is evaluated [9].

Poor nutrition represented by wasting and anorexia, is a prominent feature of both TB and DM, being a hypercatabolic state, characterised by accelerated protein degradation and muscle wasting, resulting in weight loss, and deteriorating clinical functions with resultant poor prognosis [4]. The appetite-related hormones, leptin and ghrelin, may be new candidate causes of TB-associated malnutrition [10-13]. Leptin is a protein hormone of 167 amino acids. Its main effect relates to energy exhaustion and control of food intake, implicated as an anorexigenic factor that reduces appetite [14].The connection of leptin to adipose tissue emphasizes the endocrine function of that compartment. Conversely, ghrelin is a 28-amino-acid peptide, which is produced by the stomach and has recently attracted interest as a novel anti-catabolic and orexigenic factor, that is increased in anorexic conditions and stimulates appetite [15]. Many studies have also revealed that both leptin and ghrelin are immune system regulators in addition to their effect on food intake [15,16]. Plasma levels of leptin and ghrelin can be altered in disease states associated with anorexia [10-13]. However, previous data regarding leptin levels in TB patients are conflicting. One study has shown that pretreatment plasma leptin levels were lower in TB patients than in healthy controls and there was a strong positive correlation between leptin concentration and body mass index (BMI) in both the control and patient group [11]. Serum leptin level was found to be higher in TB patients than controls in other studies [13,17] in which leptin levels were positively related to BMI only in the control group. Ghrelin has not been widely studied in patients with TB [18-20], let alone patients with TB+DM. There may be increased activation of the inflammatory system and alterations of the immune system in TB and TB+T2DM [21-23]. Leptin and ghrelin secretion and their circulating levels are effected by diet, adiposity, energy balance, and hormonal factors together with many intrinsic adiposity factors and cytokines [24]. Tumor necrosis factor-alpha (TNF-α) shows antimycobacterial activity and promotes granuloma formation in TB patients [25]. The increase of TNF-α· may cause anorexia and consequent weight loss in TB patients [26]. Interferon-gamma (IFN-γ), a Th2-type cytokine, is known to be a key cytokine in the host immune response to tuberculosis infection. If IFN-γ cannot be produced or cannot exert its effects, TB infection is more severe and often fatal [25].Some studies showed there were negative correlations between inflammatory mediators like CRP, IL-1 and TNF-α with BMI in patients with active lung tuberculosis [11,17,27]. However, evidence for a link between the inflammatory response and malnutrition is still equivocal and Incomplete [22,28]. Whether weight loss in tuberculosis is probably due to over release of cytokines remains unknown.

This study was undertaken to investigate whether the plasma levels of leptin, ghrelin and inflammatory cytokines are associated with BMI (reflecting nutritional status) in TB patients with and without type 2 diabetes (T2DM).

Materials and Methods

Ethics Statement

Permission from the ethics committee of the affiliated hospital of Medical School of Qingdao University was obtained before the study. And study was conducted according to the principles outlined in the Declaration of Helsinki. Study subjects were informed, each submitted written informed consent before the study.

Subjects

27 patients with TB +T2DM from the Chest Hospital of Qingdao were enrolled prospectively in this cross sectional study. TB+T2DM patients had positive sputum culture of mycobacterium tuberculosis and positive chest X ray, also had a fasting plasma glucose ≥7.0 mmol/l (mM) or a random blood sugar >11.1 mM 21 TB patients (also from chest hospital of Qingdao) and 23 healthy subjects from medical center of the affiliated hospital of Qingdao medical college both with similar age and gender distribution were enrolled. Patients with type 1 diabetes, miliary TB, non-tuberculous mycobacteria (NTM), or human immunodeficiency virus co-infection were excluded. Patients and control subjects who had any other serious concomitant diseases or had been previously treated with anti-TB drugs were also excluded. Informed consent was obtained from all subjects.

Measurements

A blood sample was collected before any treatment had been given via a venous catheter into a Heparin Sodium tube and non- anticoagulation tube (5ml respectively), between 7 and 8 AM after overnight fasting. After centrifugation of the heparin sodium tube, plasma was stored at -80°C. Samples with non-anticoagulation tubes, were water bathed for 20~30min at 37°C, and then centrifuged at 1580g for 5 min. All biochemical analyses (including fasting plasma glucose, hemoglobin, lipids, hepatic function parameter) in non-anticoagulation tubes were performed on 7600-210 automatic biochemistry analyzer (HITACHI, Inc, Japan), using Synchron reagents provided by leadmanbio, Beijing. Blood samples collected in the Heparin Sodium tubes for the following assesments: plasma levels of leptin (eBioscience; BMS2039INST, USA), total ghrelin (Millipore, EZGRA-88K, USA), TNF-α (Peprotech; 900-M25, USA), interleukin-6 (IL-6) (Peprotech; 900-M16, USA) and IFN-γ (Peprotech; 900-M27, USA) were determined using enzyme-linked immuno sorbent assay. Subjects were weighed barefoot with minimum clothing using an electronic weighing scale, body weight was recorded to the nearest 0.1 kg. Height was measured to the nearest 0.1 cm using stadiometer, the BMI was calculated as Weight (kg)/ height² (m).

Statistical analysis

The sample size was estimated with a two-sided alpha of 5% and a power of 80%. Data were tested for normal distribution using the Kolmogorov–Smirnov test. If the distribution appeared nonnormal, the continuous variables were transformed by calculating the log₁₀ prior to using parametric test statistics. Results are expressed as mean±SD for normally distributed data and geometric means for log₁₀ transformed data. Statistical testing for transformed variables were carried out by ANOVA if the data were normally distributed, and by non-parametric tests if the data were non-normally distributed. Correlations between transformed variables were estimated using pearson correlation coefﬁcient. Multivariate linear regression analysis was carried out to evaluate the relationship between the parameters. SPSS 11.5 software was used for all statistical analyses and a p-value <0.05 was deemed statistically significant.

Results

The anthropometric and biochemical characteristics of the 3 groups are shown in Table 1. TB (23.0±4.3 kg/m²) and particularly TB+T2DM (22.2±3.5 kg/m²) groups had lower levels of BMI than the control group (24.8±3.6 kg/m²). TB+T2DM showed a higher level of serum glucose than TB and control groups (10.6±4.4 versus 5.1±0.5 mM, 10.6±4.4 versus 5.2±0.5 mM, respectively, p<0.05). The control group had higher level of HDL-cholesterol, proteins and uric acid than patients groups (p<0.05).

	TB	TB+ T2DM	Control
N(male/female)	21(17/4)	27(23/4)	23(20/3)
Age(years)	50.2±10.9	52.9±10.3	49.4±15.6
BMI(kg/m²)	23.0±4.3	22.2±3.5 ^c	24.8±3.6
Glucose(mM)	5.1±0.5	10.6±4.4 ^{^a, c}	5.2±0.5
Cholesterol(mM)	5.9±7.6	4.4±1.3	4.7±0.8
Triglycerides(mM)	1.1±0.2	1.12±0.5	1.1±0.3
VLDL-cholesterol(mM)	2.6±0.7	2.3±0.7	2.2±0.3
HDL-cholesterol(mM)	1.1±0.3 ^b	1.2±0.3 ^c	1.3±0.3
Total protein(mM)	62.6±7.5 ^b	63.9±7.6 ^c	75.9±4.1
Albumin(mM)	39.1±7.0 ^b	37.9±5.4 ^c	43.8±2.4

Table 1. Characteristics of the study subjects (N= 71).

The levels of peptide hormones and inflammatory cytokines are shown in Table 2. The level of leptin was significantly higher in TB patients than in TB+T2DM and control groups (35.2±19.1 versus 12.6±6.1 ng/ml, 35.2±19.1 versus16.1±11.1 ng/ml respectively, p<0.05), while the level of ghrelin was lower in TB (119.9±46.1 pg/ml) and TB+T2DM (127.7±38.6 pg/ml) groups compared with control group (191.6±86.5 pg/ml). Levels of TNF-α were higher in TB and TB+T2DM compared with control group (486.9±30.4 versus 340.9±23.6 pg/ml, p>0.05; 616.0±24.9 versus 340.9±23.6 pg/ml, p<0.05). Levels of IL-6 were higher in control group but the differences were not significant. Levels of IFN-γ were lower in TB and TB+T2DM compared with control group (2278.7±929.2 versus 4020.7±838.5 pg/ml, p<0.05; 3501.2±488.3 versus 4020.7±838.5 pg/ml, p>0.05).

	TB	TB+ T2DM	Control
N	21	27	23
Leptin(ng/ml)	35.2±19.1 ^{a ,b}	12.6±6.1	16.1±11.1
Ghrelin(pg/ml)	119.9±46.1 ^b	127.7±38.6	191.6±86.5
TNF-α(pg/ml)	486.9±30.4	616.0±24.9 ^c	340.9±23.6
LogIL-6(pg/ml)	24.2(19.6-28.8)	26.8(22.8-30.8)	29.9(25.0-30.8)
IFN-γ(pg/ml)	2278.7±929.2 ^b	3501.2±488.3	4020.7±838.5

Table 2. Circulating levels of appetite-related hormones and inflammatory cytokines in patients and healthy subjects (N= 71).

Table 3 shows the correlation of appetite-related hormones and inflammatory cytokines with BMI among the 3 groups. Leptin showed a negative correlation with BMI in TB (r=-0.622, p<0.05) and TB+T2DM (r= -0.654, p<0.05) groups, but positive correlation with BMI in control group (r=0.521, p<0.05). Ghrelin showed positive correlation with BMI in the TB (r=0.695, p<0.05) and TB+T2DM (r= 0.199, p>0.05) groups, but negative correlation with BMI in control group (r=-0.693, p<0.05). There were positive nonsignificant correlations for all 3 cytokines in the TB group, negative nonsignificant correlations for TNF-α and IFN-γ and a positive nonsignificant correlation for IL-6 in the TB+T2DM group. In the control group, all correlations were negative and nonsignificant, except for IFN-γ (r=-0.545, p<0.05).

	TB	TB+ T2DM	Control
N	21	27	23
Leptin	-0.622*	-0.654*	0.521*
Ghrelin	0.695*	0.199	-0.693*
TNF-α	0.163	-0.085	-0.350
Log10IL-6	0.293	0.364	-0.313
IFN-γ	0.205	-0.211	-0.545*

Table 3. Correlation of characteristics with BMI among different groups.

Multivariate linear regression of BMI as dependent variable with age, sex, appetite-related hormones and inflammatory cytokines in the three groups are showen in Table 4. Leptin was significantly inversely associated with BMI in the TB (p=0.009) and TB+T2DM (p=0.012) groups, but positively in the control group (p=0.436). Ghrelin had a significant positive association with BMI in the TB (p=0.026) and TB+T2DM (p=0.049) groups, but an inverse association in the control group (p=0.233). There were no important associations between BMI and age, sex, inflammatory cytokines in 3 groups respectively. Leptin was the major factor affecting BMI in the TB group, while ghrelin was the major factor in the TB+T2DM group.

	TB		TB+ T2DM		Control
	B Coefficients	P	B Coefficients	P	B Coefficients	P
Age(year)	-0.025	0.731	-0.006	0.916	-0.007	0.913
Sex	2.234	0.218	0.236	0.913	0.018	0.990
Leptin(ng/ml)	-3.873	0.009	-0.164	0.012	0.037	0.436
Ghrelinpg/ml)	1.341	0.026	0.531	0.049	-0.330	0.233
TNF-α(pg/ml)	0.00	0.874	0.001	0.791	0.001	0.891
Log10IL-6(pg/ml)	0.082	0.299	0.109	0.086	-0.065	0.278
IFN-γ(pg/ml)	0.113	0.156	0.002	0.976	-0.110	0.174

Table 4. Multivariate linear regression of BMI with age, sex, appetite-related hormones and inflammatory cytokines in different groups.

Discussion

In our study, we found TB patients with or without T2DM had a worse nutritional status (lower BMI and plasma protein levels) than controls. Our results demonstrate that plasma leptin levels were significantly higher in the TB group compared to the TB+T2DM and control groups, whereas levels of plasma ghrelin were lower in patients than in the control group. The association with BMI was negative for leptin and positive for ghrelin in the patients whereas these associations were opposite in control group. Levels of TNF-α were higher and IFN-γ were lower in the patients compared with the controls. However, in mulivariate analysis, the association of leptin and ghrelin with BMI was not explained by the cytokines.

Our study examined not only TB and healthy subjects, but TB+T2DM patients as well, a group which has rarely received attention until now. This relates to the special situation in China where TB and DM constitute a double-burden. Patients in our study were not yet treated by anti-tuberculosis drugs. Limitations were the relatively small sample size, and the small number females within group, so the sex effect on related hormones and inflammatory cytokines could not be investigated. We have measured total ghrelin levels in the plasma, which contains both “active” and “inactive” forms. However, it has been reported that total ghrelin levels can reflect the level of the active form in the plasma [29,30]. In this study, we chose BMI as a correlate of body fat. The hospital in our area could not afford equipment to measure the percent body fat. Otherwise, body fat estimated from skinfold thickness is dependent on accurate measurements at the right sites (biceps, triceps, subscapular, and suprailiac regions), this requires skillful staff to carry out the work. However, patients in our study were mainly from counties and villages in poor rural areas, and although skinfold thickness was measured, it was difficult to train local staffs to perform standardized measurements for percent body fat measurement. According to many reports, BMI could effectively predict the percentage of body fat. Suchanek P et al [31] aimed to compare estimates of body fat content, like BMI, body adiposity index (BAI), waist-hip ratio (WHR), with respect to their ability to predict the percentage of body fat. They found BMI index was the better universally valid index to predict the percentage of body fat than BAI index and WHR index. Also others reported a good correlation of BMI and percentage of body fat especially in Asian. The correlation coefficient (R) could go up to 0.90 [32]. Researchers in China also made many investigations to evaluate the possibilities to use BMI as predictor of body fat status and diseases caused by obesity [33–35]. With respect to difference according to race, Asian people have less muscle and skeleton tissue than westerns with the same BMI, and the percentage of body fat is higher. So given the quality of the skinfold thickness measurements in our study and based on the reports of correlation between BMI and body fat in Asians, we prefer to use BMI as a correlate of body fat applicable to individuals in China.

TNF-α induces fever and weight loss, which are prominent symptoms of TB. It has been shown to be associated with both protection and pathogenesis in mycobacterial infections [36]. Raised concentrations of TNF-α may underly much of the metabolic clustering due to diabetes mellitus [37]. In our study, the level of TNF-α was higher in TB patients, especially those with T2DM. This finding may suggest that mycobacterium tuberculosis (MTB), mainly multiplying in macrophages，stimulates TNF-α release, especially in the presence of high glucose concentrations. IFN-γ as one of the typical Th2 cytokines is a key cytokine in the host immune response to tuberculosis infection. We found that TB patients with or without T2DM had lower levels of IFN-γ than controls like others reported [38], which may indicate that they have a weaker defense against tuberculosis infection.

Leptin is mainly synthesized by adipose tissue. But under inflammatory conditions, one study suggested a ‘‘cytokine–leptin hypothesis’’ implying that higher multiple cytokine levels are correlated with increased leptin levels [39]. In the TB patient group, we found higher levels of TNF-α and leptin compared to the control group. However, the TB+T2DM group had higher levels of TNF-α in combination with lower leptin levels compared to the control group in our study. Experimental studies showed that the leptin levels in patients with type 2 diabetes are diverse and seem to be related to the duration of the disease. In subjects with poorly controlled type 2 diabetes who lost weight rapidly, with lower levels of BMI and leptin, levels of TNF-α were reported to be higher than in controls [40,41]. So possibly in patients with type 2 diabetes, leptin and TNF-α status can not be explained by the ‘‘cytokine–leptin hypothesis’’. Therefore in TB patients with T2DM, the pathogenesis of wasting may be different. To our knowledge there have been no reports in the literature on this. Maybe there is a more complicated mechanism at work when TB and T2DM are combined. Leptin may be an important factor involved in the mechanism behind wasting, because both in TB patients with and without T2DM, leptin showed a negative correlation with BMI. Two articles [18,20] found that ghrelin in TB patients is elevated compared to controls, and correlates negatively with BMI [20]. But Kim et al [19] found that plasma ghrelin levels were significantly lower in malnourished patients than in well nourished patients with TB before treatment. In correlation analysis, ghrelin levels were negatively correlated to the malnutrition score. Our results were similar showing a positive correlation of ghrelin with BMI in TB and TB+T2DM groups as Kim et al [19].

Interestingly, the correlation of leptin and ghrelin with BMI in the patient groups is contrary to what is observed in the healthy control group where it is correlated with the amount of fat tissue.as reported in the literature [13,17]. In TB patients high leptin levels may be a cause of the low BMI instead of being a consequence of the amount of fat tissue. Inflammatory cytokines were poorly correlated with BMI in our patients, although there was a negative association of leptin and TNF-α with BMI. Cakir B et al [17] have found increased and correlated levels of TNF-α and leptin in tuberculosis patients, and his interpretation was that the elevated leptin level leads to weight loss, and through that may contribute to the inflammatory process. However, Kim JH et al [19] found higher levels of TNF-α in the TB group, that were poorly correlated with weight loss, whereas leptin levels were positively correlated with TNF-α, although not statistically significant. Combined with our findings, higher levels of leptin and TNF-α may indicate that although TNF-α may correlate with leptin, it is not directly responsible for the lower BMI. Although some reports have shown that plasma TNF-α levels are associated with weight loss in TB, we were unable to demonstrate this. Although high inflammatory status maybe primarily responsible for low BMI in patients with TB, low BMI in TB cannot be explained by the investigated inflammatory cytokines only [21,42]. This may suggest that externalization of leptin and ghrelin in these patients is not determined by nutritional status (amount of fat tissue), but in fact is a causal factor in the development of low BMI. The effect of leptin and ghrelin on BMI seems to be largely independent of the investigated cytokines. Further studies are needed to investigate the complex mechanisms.

Conclusions

This study provides novel evidence of status and relationship between appetite-related hormones, inflammatory cytokines and BMI in TB patients with or without T2DM. We conclude that possible abnormalities in leptin and ghrelin regulation may be associated with the development of poor nutrition (low BMI) during the inflammatory response in TB patients with or without T2DM. TB patients with T2DM may have more complex and different pathogenesis compared to TB patients only. Given the complexity of the interaction of appetite-related hormones and cytokines, further studies are needed to clarify this issue and underlying mechanisms.

Acknowledgments

We would like to thank our study volunteers, the staffs in hospitals, and the laboratory staffs for their assistance in performing the studies.

Author Contributions

Conceived and designed the experiments: AM QW. Performed the experiments: YZ YL. Analyzed the data: XH JC. Contributed reagents/materials/analysis tools: EGS FJK. Wrote the manuscript: YZ EGS.

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Fact Sheets | General | Latent TB Infection vs. TB Disease | TB

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The Difference Between Latent TB Infection and TB Disease

What is TB?

Tuberculosis (TB) is a disease caused by a germ called Mycobacterium tuberculosis that is spread from person to person through the air. TB usually affects the lungs, but it can also affect other parts of the body, such as the brain, the kidneys, or the spine. When a person with infectious TB coughs or sneezes, droplet nuclei containing M. tuberculosis are expelled into the air. If another person inhales air containing these droplet nuclei, he or she may become infected. However, not everyone infected with TB bacteria becomes sick. As a result, two TB-related conditions exist: latent TB infection and TB disease.

What is Latent TB Infection?

Persons with latent TB infection do not feel sick and do not have any symptoms. They are infected with M. tuberculosis, but do not have TB disease. The only sign of TB infection is a positive reaction to the tuberculin skin test or TB blood test. Persons with latent TB infection are not infectious and cannot spread TB infection to others.

Overall, without treatment, about 5 to 10% of infected persons will develop TB disease at some time in their lives. About half of those people who develop TB will do so within the first two years of infection. For persons whose immune systems are weak, especially those with HIV infection, the risk of developing TB disease is considerably higher than for persons with normal immune systems.

Of special concern are persons infected by someone with extensively drug-resistant TB (XDR TB) who later develop TB disease; these persons will have XDR TB, not regular TB disease.

A person with latent TB infection

Usually has a skin test or blood test result indicating TB infection
Has a normal chest x-ray and a negative sputum test
Has TB bacteria in his/her body that are alive, but inactive
Does not feel sick,
Cannot spread TB bacteria to others
Needs treatment for latent TB infection to prevent TB disease; however, if exposed and infected by a person with multidrug-resistant TB (MDR TB) or extensively drug-resistant TB (XDR TB), preventive treatment may not be an option

What is TB Disease?

In some people, TB bacteria overcome the defenses of the immune system and begin to multiply, resulting in the progression from latent TB infection to TB disease. Some people develop TB disease soon after infection, while others develop TB disease later when their immune system becomes weak.

The general symptoms of TB disease include

Unexplained weight loss
Loss of appetite
Night sweats
Fever
Fatigue
Chills

The symptoms of TB of the lungs include

Coughing for 3 weeks or longer
Hemoptysis (coughing up blood)
Chest pain

Other symptoms depend on the part of the body that is
affected.

Persons with TB disease are considered infectious and may spread TB bacteria to others. If TB disease is suspected, persons should be referred for a complete medical evaluation. If it is determined that a person has TB disease, therapy is given to treat it. TB disease is a serious condition and can lead to death if not treated.

A person with TB disease

Usually has a skin test or blood test result indicating TB infection
May have an abnormal chest x-ray, or positive sputum smear or culture
Has active TB bacteria in his/her body
Usually feels sick and may have symptoms such as coughing, fever, and weight loss
May spread TB bacteria to others
Needs treatment to treat TB disease

Additional Information

Tuberculosis

Tuberculosis (TB) is caused by bacteria (Mycobacterium tuberculosis) that most often affect the lungs. Tuberculosis is curable and preventable.

TB is spread from person to person through the air. When people with lung TB cough, sneeze or spit, they propel the TB germs into the air. A person needs to inhale only a few of these germs to become infected.

About one-quarter of the world’s population has a TB infection, which means people have been infected by TB bacteria but are not (yet) ill with the disease and cannot transmit it.

People infected with TB bacteria have a 5–10% lifetime risk of falling ill with TB. Those with compromised immune systems, such as people living with HIV, malnutrition or diabetes, or people who use tobacco, have a higher risk of falling ill.

When a person develops active TB disease, the symptoms (such as cough, fever, night sweats, or weight loss) may be mild for many months. This can lead to delays in seeking care, and results in transmission of the bacteria to others. People with active TB can infect 5–15 other people through close contact over the course of a year. Without proper treatment, 45% of HIV-negative people with TB on average and nearly all HIV-positive people with TB will die.

Who is most at risk?

Tuberculosis mostly affects adults in their most productive years. However, all age groups are at risk. Over 95% of cases and deaths are in developing countries.

People who are infected with HIV are 18 times more likely to develop active TB (see TB and HIV section below). The risk of active TB is also greater in persons suffering from other conditions that impair the immune system. People with undernutrition are 3 times more at risk. Globally in 2020, there were 1.9 million new TB cases that were attributable to undernutrition.

Alcohol use disorder and tobacco smoking increase the risk of TB disease by a factor of 3.3 and 1.6, respectively. In 2020, 0.74 million new TB cases worldwide were attributable to alcohol use disorder and 0.73 million were attributable to smoking.

Global impact of TB

TB occurs in every part of the world. In 2020, the largest number of new TB cases occurred in the WHO South-East Asian Region, with 43% of new cases, followed by the WHO African Region, with 25% of new cases and the WHO Western Pacific with 18%.

In 2020, 86% of new TB cases occurred in the 30 high TB burden countries. Eight countries accounted for two thirds of the new TB cases: India, China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh and South Africa.

Symptoms and diagnosis

Common symptoms of active lung TB are cough with sputum and blood at times, chest pains, weakness, weight loss, fever and night sweats. WHO recommends the use of rapid molecular diagnostic tests as the initial diagnostic test in all persons with signs and symptoms of TB as they have high diagnostic accuracy and will lead to major improvements in the early detection of TB and drug-resistant TB. Rapid tests recommended by WHO are the Xpert MTB/RIF Ultra and Truenat assays.

Diagnosing multidrug-resistant and other resistant forms of TB (see Multidrug-resistant TB section below) as well as HIV-associated TB can be complex and expensive.

Tuberculosis is particularly difficult to diagnose in children.

Treatment

TB is a treatable and curable disease. Active, drug-susceptible TB disease is treated with a standard 6-month course of 4 antimicrobial drugs that are provided with information and support to the patient by a health worker or trained volunteer. Without such support, treatment adherence is more difficult.

Since 2000, an estimated 66 million lives were saved through TB diagnosis and treatment.

TB and HIV

People living with HIV are 18 (Uncertainty interval: 15-21) times more likely to develop active TB disease than people without HIV.

HIV and TB form a lethal combination, each speeding the other’s progress. In 2020, about 215 000 people died of HIV-associated TB. The percentage of notified TB patients who had a documented HIV test result in 2020 was only 73%, up from 70% in 2019. In the WHO African Region, where the burden of HIV-associated TB is highest, 85% of TB patients had a documented HIV test result. Overall in 2020, 88% of TB patients known to be living with HIV were on ART.

WHO recommends a 12-component approach of collaborative TB-HIV activities, including actions for prevention and treatment of infection and disease, to reduce deaths.

Multidrug-resistant TB

Anti-TB medicines have been used for decades and strains that are resistant to one or more of the medicines have been documented in every country surveyed. Drug resistance emerges when anti-TB medicines are used inappropriately, through incorrect prescription by health care providers, poor quality drugs, and patients stopping treatment prematurely.

Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to isoniazid and rifampicin, the 2 most effective first-line anti-TB drugs. MDR-TB is treatable and curable by using second-line drugs. However, second-line treatment options are limited and require extensive chemotherapy (up to 2 years of treatment) with medicines that are expensive and toxic.

In some cases, more severe drug resistance can develop. TB caused by bacteria that do not respond to the most effective second-line anti-TB drugs can leave patients without any further treatment options.

MDR-TB remains a public health crisis and a health security threat. Only about one in three people with drug resistant TB accessed treatment in 2020.

Worldwide in 2018, the treatment success rate of MDR/RR TB patients was 59%. In 2020, WHO recommended a new shorter (9-11 months) and fully-oral regimen for patients with MDB-TB. This research has shown that patients find it easier to complete the regimen, compared with the longer regimens that last up to 20 months. Resistance to fluoroquinolones should be excluded prior to the initiation of treatment with this regimen.

In accordance with WHO guidelines, detection of MDR/RR-TB requires bacteriological confirmation of TB and testing for drug resistance using rapid molecular tests, culture methods or sequencing technologies. Treatment requires a course of second-line drugs for at least 9 months and up to 20 months, supported by counselling and monitoring for adverse events. WHO recommends expanded access to all-oral regimens.

By the end of 2020, 65 countries started using shorter MDR-TB treatment regimens and 109 had started using bedaquiline, in an effort to improve the effectiveness of MDR-TB treatment.

Catastrophic cost

WHO’s End TB Strategy target of “No TB patients and their households facing catastrophic costs as a result of TB disease”, monitored by countries and WHO since WHA67.1 End TB Strategy was adopted in 2015, shows that the world did not reach the milestone of 0% by 2020.

According to the results of 23 national surveys on costs faced by TB patients and their families, the percentage facing catastrophic costs* ranged from 13% to 92% and the pooled average, weighted for each country’s number of notified cases, was 47% (95% CI: 33–61%).

*total costs > 20% annual household income

Investments in TB prevention, diagnosis and treatment and research

US$ 13 billion are needed annually for TB prevention, diagnosis, treatment and care to achieve global targets agreed on UN high level-TB meeting.

Investments in TB prevention, diagnosis and care for tuberculosis in low- and middle-income countries (LMICs) accounting for 98% of reported TB cases, fall far short of what is needed. Less than half (41%) of the global TB funding target is available, leaving a US$ 7.7 funding gap in 2020 to achieve global targets.
TB funding is back to the level of 2016 with an 8.7% drop in TB spending between 2019 and 2020 (from US$ 5.8 billion to US$ 5.3 billion)
Of the US$5.3 billion funding for tuberculosis available in 2020, 81% was from domestic sources, with the BRICS countries (Brazil, Russian Federation, India, China and South Africa) accounting for US$2.8 billion (65% of total domestic funding).
Over the past decade, US$ 0.9 billion were invested annually in tuberculosis by international donors, 76% of which accounted by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund), the largest contribution.
The United States (US) Government is the largest contributor of funding to the Global Fund and also the largest bilateral donor; overall, it contributes close to 50% of international donor funding for TB.
Provisional data for TB funding in 2021 suggests that allocations for 2021 will remain inadequate. Increases in both domestic and international funding for TB are urgently required
For research and development, according to the Treatment Action Group, only US$ 0.9 billion were available in 2019 of the US$2 billion required per year to accelerate the development of new tools. At least an extra US$ 1.1 billion per year is needed to accelerate the development of new tools.

Global commitments and the WHO response

On 26 September 2018, the United Nations (UN) held its first- ever high-level meeting on TB, elevating discussion about the status of the TB epidemic and how to end it to the level of heads of state and government. It followed the first global ministerial conference on TB hosted by WHO and the Russian government in November 2017. The outcome was a political declaration agreed by all UN Member States, in which existing commitments to the SDGs and WHO’s End TB Strategy were reaffirmed, and new ones added.

SDG Target 3.3 includes ending the TB epidemic by 2030. The End TB Strategy defines milestones (for 2020 and 2025) and targets (for 2030 and 2035) for reductions in TB cases and deaths. The targets for 2030 are a 90% reduction in the number of TB deaths and an 80% reduction in the TB incidence rate (new cases per 100 000 population per year) compared with levels in 2015. The milestones for 2020 are a 35% reduction in the number of TB deaths and a 20% reduction in the TB incidence rate. The strategy also includes a 2020 milestone that no TB patients and their households face catastrophic costs as a result of TB disease.

The political declaration of the UN high-level meeting included four new global targets:

treat 40 million people for TB disease in the 5-year period 2018–2022;
reach at least 30 million people with TB preventive treatment for a latent TB infection in the 5-year period 2018–2022;
mobilize at least US$ 13 billion annually for universal access to TB diagnosis, treatment and care by 2022;
mobilize at least US$ 2 billion annually for TB research.

As requested in the political declaration:

WHO finalized and published a Multisectoral Accountability Framework for TB (MAF-TB) in 2019. WHO is supporting countries to adapt and use the framework to translate commitments into actions and to monitor, report, and review progress, with the engagement of high-level leadership, all relevant sectors, civil society and other stakeholders.
In 2020, a progress report of the UN Secretary-General to the General Assembly was developed and released with the support of WHO.
Examples of high-level leadership on multisectoral accountability include Presidential or Head of State End TB initiatives and formalized mechanisms for the engagement and accountability of stakeholders in India, Indonesia, Pakistan, Philippines and Viet Nam as well as national campaigns to drive progress such as the Race to End TB.

WHO is working closely with countries, partners and civil society in scaling up the TB response. Six core functions are being pursued by WHO to contribute to achieving the targets of the UN high-level meeting political declaration, SDGs, End TB Strategy and WHO strategic priorities:

Providing global leadership to end TB through strategy development, political and multisectoral engagement, strengthening review and accountability, advocacy, and partnerships, including with civil society;
Shaping the TB research and innovation agenda and stimulating the generation, translation and dissemination of knowledge;
Setting norms and standards on TB prevention and care and promoting and facilitating their implementation;
Developing and promoting ethical and evidence-based policy options for TB prevention and care;
Ensuring the provision of specialized technical support to Member States and partners jointly with WHO regional and country offices, catalyzing change, and building sustainable capacity;
Monitoring and reporting on the status of the TB epidemic and progress in financing and implementation of the response at global, regional and country levels.

Weight loss: “My TB got worse because of my weight!”

Getting a bad health diagnosis can be scary for anyone but when you are overweight, even simple health issues can take a turn for the worse. When Adhiraj, a 27-year-old professional was recovering from TB, he underwent a similar situation and thought he would never get healthy. In his recovery, he decided to make a change and switch to a healthier lifestyle. To know some of his secrets, read about his transformation:

Name: Adhiraj

Age: 27 years old

Highest weight recorded: 98 Kilos

Weight lost: 10 Kilos

Duration it took me to lose weight: 5 months

The turning point: In 2017, I was diagnosed with Pleural TB and spent a lot of time in the hospital recovering. Along with the heavy medications, my weight also made it difficult for me to recover faster. This incident was very scary and made me realise that I am very unhealthy. There were days when I thought I would never get okay and might even die like this. This pushed me to change.

Then, there were also days when it was difficult to fit into clothes. I work in a fashion retail company and need to look presentable before customers. The real shock of my life came when I couldn’t find my size and had to start wearing XL size clothes. Everybody started suggesting weight loss tips and that got to my head. I hated how I looked in the mirror on days.

My breakfast: I have a bowl of oatmeal with 2 egg whites. I also munch on some almonds, cashews during the day.

My lunch: I have a serving of daal, 250 gm chicken and 2 chapatis. I also have a couple of eggs if I want to eat proteins for the day.

My Dinner: Before losing weight, I used to eat at odd hours and have a lot of carbs. Now I do not consume anything without knowing its nutritional value. I eat some boiled chicken and salad for dinner every day. I make sure to have a glass of milk before going to bed every day.

My workout: I prefer working out in the mornings. My workout regime is something like this:

1 hour of cardio

30 min of strength training

30 min of weight training.

I am also training to take part in marathons now.

Low-calorie recipes I swear by: Egg whites, lemon juice and oatmeal topped off with some peanut butter are absolutely yummy and healthy!

Fitness secrets I unveiled: The motivation to workout comes from inside. When I wake up every day, I remind myself that I need to be fit and prove all those people who mocked me wrong! I follow the principle of three D’s- Discipline, Dedication and Dare to try new things. These three are my personal fitness secrets!

How do I stay motivated? I come from an army family. My dad is the biggest motivator who encourages me to do my best every day. Even after getting retired, he woke up at 4 a.m. every day. So, from him, I got the motivation and made the big decision to workout on my body and get fitter for better. It seems tough at times but I know, gradually, it will help me stay fit in the long run.

If you too have a weight loss story to share, send it to us at [email protected]

Frontiers | Dietary Practice and Nutritional Status of Tuberculosis Patients in Pokhara: A Cross Sectional Study

Introduction

Tuberculosis (TB) is caused by Mycobacterium tuberculosis which often affect the lungs, although it can spread to other organs in the body (1). TB is the second deadliest disease worldwide caused by a single infectious agent (1). Globally, in 2014, 9.6 million people were estimated to have fallen ill with TB; among them, 3.2 million were women, 5.4 million were men, and 1.0 million were children. Of the 9.6 million TB cases, in 2014, 12% of them were HIV positive. Now, TB ranks along with HIV as a leading cause of death worldwide (2). However, TB is completely curable through a short course of chemotherapy (DOTS), which has been recognized as a highly cost-efficient and effective strategy (3).

TB spreads from person to person through the air (4). There are two kinds of TB infections: latent and active. In latent TB, the bacteria remain inactive and do not show any typical signs and symptoms of TB. While they are not contagious, they can become active at any time. In active TB, the bacteria show signs and symptoms of TB and are contagious to others (1). Symptoms of active pulmonary TB are coughing, chest pain, fever, night sweats, weight loss, fatigue, and sometimes, the coughing up of blood (5). Active TB, like other infectious diseases, requires high energy consumption i.e., 20–30% extra energy of recommended daily allowance (RDA). Undernutrition increases the risk of progression from TB infection to an active TB disease. Food insecurity and poor nutritional status in the population are important contributors to the global burden of the TB disease (6).

Both malnutrition and TB are of considerable magnitude in most of the underdeveloped regions of the world. Nutritional status is significantly lower in patients having active TB than others (7). Therefore, the present study focused on the dietary intake and nutritional status of TB patients in Pokhara, Nepal.

Methods

This was a cross-sectional descriptive study conducted among TB patients taking anti-tubercular drug in Pokhara, Nepal, from 4th October to 7th November, 2016. The total number of TB patients in Pokhara were 203 in FY 2072/73. The sample size was determined by assuming the prevalence of malnutrition in TB patients to be 51% (8), 95% confidence limit, and 5% marginal error, and the sample size was 133.

List of total 12 Directly Observed Treatment Short Course (DOTS) centers in Pokhara was obtained from District Public Health Office (DPHO), Kaski, and arranged from numbers one to twelve. A sequential sampling technique was used. Of them, the required sample size was met at the 11th DOTS center. Patients who visited the DOTS center during the data collection period were included in the study.

The structured questionnaire was developed referencing STEP wise approach to Surveillance (STEPS) survey, Nepal (9, 10), and was translated into the Nepali language. The questionnaire was pre-tested on 10% of the total sample in Tanahun, Nepal. Primary data collection was performed through face-to-face interviews. Tools for the data collection were a structured questionnaire, checklist (patient treatment card), bathroom scale weighing machine for weight measurement, stature meter for height measurement, and locally available cups, plates, and glasses for measuring the amount of food consumed.

Data were entered into EpiData software and analyzed by using SPSS 20 version software. Univariate and bivariate analyses were performed for data analysis. The size of dishes used to measure the amount of food was of 250 ml, which was equivalent to a standard cup size. Through this reference, the amount of food was converted into a standard serving size, and the daily energy intake was calculated by Nutrition facts 0.9.5.0 version and Food tables (11).

The study protocol was reviewed and approved by the Ethical Review Committee of Pokhara University Research Centre and permission was taken from DPHO Kaski. Informed verbal consent was obtained from all the participants prior to data collection, and data confidentiality was maintained.

Results

Out of 133 participants, the majority (33.1%) of them were between 20 and 30 years of age, with the mean age being 35.23 years (SD ± 15.05). More than half (60.9%) of them were males. Most were predominantly upper caste by ethnicity and Hindu by religion (Table 1).

Table 1. Socio-demographic characteristics of TB patients (n = 133).

Information related to diseases and health service utilization among TB patients is given in Table 2. More than half of the patients have Pulmonary TB. 57.9% TB patients started medication in less than 1 month after diagnosis.

Table 2. Disease and health services utilization related information.

Information related to food and its consumption is given in Table 3. The majority (78.2%) of the participants consumed a sufficient amount of calories, whereas 21.8% did not. The mean was 3239.39 (SD ± 1352.47).

Table 3. Food related information.

The nutritional status among TB patients is given in Table 4. Mean weight and height were 51.98 kg and 1.57 m, respectively. Relatively, a higher percent were underweight (21.8%) than overweight (17.3%).

Table 4. Nutritional Status of TB patients.

Factors which are associated with calorie intake are shown in Table 5. Working conditions and food intake frequency were significantly associated with calorie intake. Socio-demographic factors and disease-related factors were not found to be associated with calorie intake.

Table 5. Factors associated with calorie intake.

Factors that are associated with recent nutritional status of TB patients are given in Table 6. Food frequency, TB types, calorie intake, and nutritional status at the time of registration were significantly associated with the recent nutritional status of the participants.

Table 6. Factors associated with recent nutritional status.

Statistical differences between mean BMI at registration and recent BMI (MD −1.04; 95% CI −1.05 to −1.39; p < 0.001) and mean weight at registration and recent weight (MD −1.52; 95% CI −1.004 to −1.003; p < 0.001) are shown in Table 7.

Table 7. Mean difference between BMI and Weight at registration and recent BMI and Weight.

Discussion

This study revealed that about one-fifth of TB patients did not consume sufficient amounts of calories as per the RDA. The study found that 36.1% were underweight and 11.35% were overweight during the time of registration. In contrast, studies conducted in other countries found that 51% in Ghana (8), more than 85% in India (12), 70.6% in Brazil (13), 57% in Malawi (14), and more than 58% in Tanzania (15) were underweight during the time of registration. It might be due to the difference in sampling size and study setting. This study found that male patients were more underweight than females. In contrast, a study conducted in India found that females were more underweight than males during the time of registration (12). However, nutritional status improved by 15.3% in patients who had completed two months of medication. Other studies showed that nutritional status was improved by 11% (8) and 13.5% (12) at the end of the treatment.

The prevalence of co-morbidity was 21.85%, where diabetes was the most prevalent (31%) followed by hypotension and arthritis. A study done in Tanzania showed that prevalence of diabetes among PTB was 6.7% (16). In India, annual cases of TB increased to 46% among people with diabetes (17).

This study found that the amount of calorie, food frequency per day, types of TB, and nutritional status during registration was found to be associated with recent nutritional status. However, socio-demographic factors were not associated with nutritional status, whereas a study in Tanzania found that sex was significantly associated with nutritional status (18). In this study, the majority (86.5%) of patients belonged to the Hindu religion. A study conducted in immigrant Asians from South London revealed Hindu Asians were found to have a significantly increased risk for TB compared with Muslims (19).

Conclusions

This study revealed that about one-fifth of TB patients did not consume the sufficient amount of calories as per the RDA. The Mean calorie intake was 3239.39 (SD ± 1352.47). More than one-third of the patients were underweight at the time of registration, but this is reduced to 21.6% in the present situation. The mean BMI was 20.99 kg/m² (SD ± 5.81): 20.56 kg/m² in males and 21.67 kg/m² in females. Similarly, mean BMI among PTB was 19.82 and 22.52 kg/m² in Extra PTB. The prevalence of co-morbidity was 21.85%, where diabetes was the most prevalent (31%). Working conditions and food intake frequency were significantly associated with calorie intake. This study found that the amount of calories, food frequency per day, types of TB, and nutritional status during registration were found to be associated with the recent nutritional status. There was statistical differences between mean BMI at registration and after treatment and mean weight at registration and after treatment. It was increased after treatment. The nutritional status has improved comparatively from the time of registration to the present situation. Proper nutritional counseling along with nutritional support should be given to severely malnourished TB patients, and nutritional assessment of TB patients should be done periodically.

Ethics Statement

Ethical clearance was obtained from the institutional review committee of Pokhara University at the beginning of the study. Detailed information was available in Nepali to all participants. Confidentiality was maintained and the information was used for research purposes only. Each participants participated voluntarily in this study. Written consent was taken from all the participants before the data collection. Participants were informed about their BMI status. In case of an abnormal range, educational counseling was given regarding a balanced diet and they were referred to a nutritionist for the further services.

Author Contributions

LG was the principle investigator for the study. She compiled all contributor tasks, generated the topic and reviewed the related literature. LG and LB facilitated data collection. DY designed the study methodology and overall analysis and helped write the results section. LG, LB, and IK drafted the manuscript. DY reviewed the manuscript.

Funding

DY received a Faculty Research Grant from the University Grant Commission of Nepal and the research was titled Prevalence of Diabetes Mellitus among TB Patients and their Quality of Life in Western Region of Nepal in 2016 (Nepalese fiscal year 2072-2073). DY was required to supervise the dissertation of students researching in a similar area.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Chest pain, loss of appetite, unintentional weight loss symptoms of TB —Expert

Elvis Igbinovia, a specialist general practitioner, tells ALEXANDER OKERE about tuberculosis, the risk of infection and how the diseases can be treated

What is tuberculosis?

Tuberculosis is a serious but treatable and curable infectious disease that predominantly affects the lungs but which can affect other parts of the body.

What is the cause and how does infection occur?

Tuberculosis is caused by a germ called mycobacterium tuberculosis. It is an airborne disease transmitted from person to person. Infection occurs after inhaling germ-laden droplets that have been released into the air from coughing, sneezing and even singing. The germs are drawn into the lungs where they settle. From the lungs, they sometimes migrate via the bloodstream to other parts of the body.

Are there environmental factors that increase the risk of infection?

Certainly. Some that readily come to mind are overcrowding, poor ventilation, air pollution, including pollution from vehicular and factory effluents, fumes from burning biofuels like firewood and cigarette smoke. Whilst some of these environmental factors facilitate the spread of the infection, others affect how well the body can mount a reasonable response against the germ to rid the body of it.

Are there different types of TB?

Yes. Tuberculosis can be divided into two broad groups: Latent tuberculosis and active tuberculosis. The vast majority of people with tuberculosis have latent tuberculosis or LTB. In terms of the site of disease, tuberculosis can either be pulmonary (in the lungs) or extra-pulmonary (outside the lungs).

When should people with chronic cough go for a TB test?

Cough is defined as chronic when it has lingered for more than eight weeks in adults or four weeks in children. It is usually investigated further then and testing for tuberculosis at that point would be reasonable.

What are the other signs and symptoms of TB?

Bear in mind that tuberculosis can be in the lungs (majority) or outside the lungs. The common symptoms of pulmonary tuberculosis are cough, which can sometimes involve coughing blood up, chest pain, difficulty with breathing, loss of appetite, unintentional loss of weight, drenching night sweats, fever and fatigue. When it affects other parts of the body, it can cause headache, back pain (when the backbone is affected), bloody urine (when the kidneys are affected).

Are there other medical conditions that could be mistaken for TB?

Yes. Other conditions which can cause a lingering cough, as well as the other symptoms, are atypical pneumonia, lung abscess, whooping cough, lung cancer, etc.

Can cultural beliefs, like witchcraft, affect early treatment and cure for TB?

Yes, belief in witchcraft, perhaps as the instigator of their illness, can cause people to seek alternative therapies they perceive as more potent antidotes. The result is that the condition progresses while the wrong solutions are being sought, the delays sometimes costing lives.

A healthy immune system is said to be a strong defence against TB. Are there medical conditions that could make this impossible?

A healthy immune system is a formidable defence but there are medical conditions that could compromise this line of defence. One that readily comes to mind is HIV. Others are diabetes mellitus, severe kidney disease, some cancers, malnutrition, alcoholism and medications that suppress the immune system, like those used to treat cancers, rheumatoid arthritis and other autoimmune diseases.

What are the complications that tuberculosis can cause in an infected individual?

Some of the complications that can develop in untreated tuberculosis include impaired lung function, meningitis, liver disease, kidney disease, heart disease, spinal pain, spinal stiffness and joint damage.

In what ways can tuberculosis be tested?

There are many different tests for tuberculosis. There is the tuberculin skin test or Mantoux test which checks the size of a skin reaction to introduced tuberculin extract or purified protein derivative. The degree of reaction is usually read off after 48 to 72 hours of injection of the PPD. Blood tests are also used to check for tuberculosis. The Interferon Gamma Release Assay test measures the body’s immune response to tuberculosis. A polymerase chain reaction test can detect tuberculosis antigens. Using special staining techniques and microscopy, the organism can be visualised on a smear. The germ can also be cultured in the lab from a sputum sample or tissue biopsy sample. Chest x-rays are useful for excluding pulmonary TB when screening tests have returned positive results in a person with or without obvious respiratory symptoms.

Which among the methods of testing for TB is the most effective?

Culture of sputum or biopsy specimen is the most effective means of diagnosing tuberculosis. Further tests can also be done using the sputum. For example, checking for drug-resistant strains of the germ and directing treatment, ensuring it is targeted.

How can TB be treated?

The type and duration of treatment deployed depends on the type of tuberculosis being treated: active versus latent. The medications selected are also influenced by whether or not drug resistance is anticipated following testing. Broadly, a number of medications can be used either singly or in combination, usually over a variable number of months. Since people with latent tuberculosis are without symptoms and do not spread the infection, latent tuberculosis is treated in a less aggressive manner using a single agent like isoniazid, rifampicin or a combination of isoniazid and rifapentine over a few months, according to a number of different schedules.

As for active tuberculosis, treatment is more aggressive, starting with four different agents: isoniazid, rifampicin, ethambutol and pyrazinamide for the first two months, then continuing with rifampicin and isoniazid for another four months, in varying dosing regimens depending on the schedule. In multi-drug resistant tuberculosis, treatment can last up to 20 months using carefully selected targeted medications. The treatment is usually facilitated by a support system known as directly observed therapy which has been found to improve adherence to treatment and help people manage the challenges resulting from the long duration of treatment and medication side effects.

What are the common side effects to expect from the consumption of drugs used for the treatment of the infection?

The common side effects of treatment are suppression of appetite, nausea or vomiting, yellowness of skin or jaundice, tingling sensation on the skin, dark coloured urine, fever, visual changes. It is important to see your doctor if you experience any of these side effects.

Why does it take a long time before a person can be cured of TB?

It takes a long time to treat because the germ is an expert at evading the host’s immune system’s defences. It can hide successfully within the cells which should ordinarily attack and kill it. Its waxy cell wall also proves a hard nut for antibiotics to crack!

In what ways can transmission be prevented?

Prevention of tuberculosis is multi-pronged. The Bacille Calmette Guerin vaccine offers protection against some forms of tuberculosis. Majority of people with tuberculosis have the non-contagious latent tuberculosis. However, there is always a chance that anyone with latent TB could develop active disease. Hence, people with latent TB are akin to reservoirs of the germ albeit in an inactive state. Treating everyone with latent tuberculosis becomes a logical part of our prevention arsenal. But how would we treat if we don’t identify these ones? And can we identify without mass screening?

The biggest spreaders are those with active TB. Hence, every effort should be made to promptly isolate and initiate treatment of active TB cases and their close contacts. Part of this effort should be directed towards improving notification rates so accurate data is available to the public health authorities to facilitate their containment efforts. HIV came and awakened the monster called TB and they have become a tag team. Prevention and proper management of HIV would also help with reducing the burden of tuberculosis. The government can put policies in place that curb smoking, alcoholism and air pollution. All of us can endeavour to catch our droplets in face towels and wash our hands regularly.

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90,000 Pulmonary and extrapulmonary tuberculosis – Ravijuhend

This patient guide is based on the 2017 Estonian treatment guide “Management of patients with pulmonary and extrapulmonary tuberculosis” and the topics presented therein together with recommendations. In this manual, you will find the recommendations that are most important from the patient’s point of view. The guide provides an overview of the main problems associated with the disease.

The manual is intended for people with tuberculosis, as well as for their loved ones and health care workers.This guide will help patients and their loved ones cope better with their illness, provide answers to the most frequently asked questions about treatment and daily problems, and can support patients and their loved ones during the treatment process. The Patient Guide provides an overview of tuberculosis as a disease, the tests used for diagnosis, treatment, and the organization of a daily regimen during a controlled treatment process.

The guidelines were compiled by experts in the field, along with former patients who have previously experienced and recovered from tuberculosis.The importance of the topics described in the manual and the clarity of the text have been appreciated by TB patients and their families. Patient feedback and feedback has been instrumental in the development of this manual and has helped to improve it.

You can learn more about the topics covered in this patient guide by following the links at the end of the guide.

During tuberculosis treatment, strictly adhere to the treatment regimen prescribed by your doctor. Take medication regularly, in the prescribed amount and at the correct time .
Do not change the dose of medication you are taking or the frequency of taking it yourself. Always check with your doctor.
If you feel unwell or if you experience any side effects, immediately inform your doctor or other healthcare professional who monitors your treatment.
If you feel better during TB treatment, do not interrupt treatment anyway.It is very important that you take your medication for the entire period of treatment prescribed by your doctor.
During tuberculosis treatment, you need to eat well and maintain a healthy lifestyle.
When planning a pregnancy, check with your doctor first. You should be aware that TB medicines can weaken the effects of contraception.
Avoid alcohol as much as possible.Drinking alcohol during treatment increases the risk of side effects (including liver damage). If you drink alcohol, do so in moderation.
Give up all types of tobacco products (including hookahs and electronic cigarettes). Smoking interferes with the protective functions of the lungs and therefore slows down recovery.
Avoid excessively hot steam when using the sauna.
Avoid sunbathing and tanning beds.Due to the side effects of TB drugs, there is a high risk of pigmentation and sunburn.
Inform your loved ones about the illness and ask them to go for a medical examination.
If you have recovered from tuberculosis, but you still have symptoms suggestive of tuberculosis, contact your family doctor right away or make an appointment with a pulmonologist.

Tuberculosis is an infectious disease caused by a bacteria called Mycobacterium tuberculosis .The causative agents of tuberculosis are spread by airborne droplets. When a tuberculosis patient coughs, sneezes, singing or talking, together with droplets of saliva, tuberculosis pathogens are thrown into the air, which can be inhaled by other people nearby. As a result, a person can become infected with tuberculosis. One untreated TB patient can infect up to 10-15 people a year.

Not all people who have come into contact with an infectious (ie contagious) TB patient can develop TB.The more tuberculosis pathogens are thrown into the air by the carrier of the disease and the denser and longer contact with him, the more the likelihood of the spread of tuberculosis increases. Of all those who have close contact with an infectious TB patient (family members, friends and colleagues who are with the patient every day), approximately one third will become infected. It is impossible to get sick with TB, for example, by shaking hands, using the same dishes or the same toilet room.

Tuberculosis can damage all organs of a person, but most often the lungs are the focus of the disease.Of other organs, the disease can most often affect the pleura of the lungs, bones and joints, as well as the kidneys. This form of tuberculosis, in which the lungs themselves are not damaged, is called extrapulmonary tuberculosis, and patients with this disease are usually not contagious. At the same time, in the case of patients with extrapulmonary tuberculosis, it is very important to adhere to the prescribed course of treatment and bring treatment to the end.

All people can become infected with TB, regardless of their financial income or social status.Thus, the assumption that TB only affects people with a low standard of living is incorrect.

In 2016, 190 patients were diagnosed with TB in Estonia, of which 166 contracted TB for the first time. In 31 patients, tuberculosis was found not only in the lungs, but also in other organs. Extrapulmonary tuberculosis alone was diagnosed in 15 patients in 2016. Children rarely get sick in Estonia; up to 10 cases of the disease are diagnosed a year.

Tuberculosis is an airborne infectious disease caused by a bacterium Mycobacterium tuberculosis .
Tuberculosis most commonly affects the lungs, but it can also affect other organs in the body.

In case of infection (infection) with tuberculosis, viable but inactive tuberculosis bacteria enter the human body. In most cases, the body’s protective immune system is able to prevent the spread of bacteria in the body. People who become infected with tuberculosis feel healthy, have no symptoms of the disease, and do not spread tuberculosis to others.Infection with tuberculosis can be diagnosed with a blood test (determination of the level of interferon gamma of the causative agent of tuberculosis M. tuberculosis in the blood) or with a tuberculin test (tuberculin test).

The risk of contracting tuberculosis after infection is approximately 5–15%. The risk of getting sick is highest precisely within two years after infection, but you can get sick many years later if, for any reason, the person’s immune system weakened and can no longer keep the multiplication of tuberculosis bacteria.Therefore, it is very important that people who become infected with tuberculosis know how to track their symptoms, which are characteristic of tuberculosis, and if they are found, they immediately go to a doctor.

In some cases, a person who has become infected with tuberculosis is prescribed preventive treatment in order to prevent the further process of becoming ill with tuberculosis. Preventive treatment most often involves one anti-TB drug and treatment lasts six to nine months.

People infected with tuberculosis:
• are not sick and have no symptoms of the disease
• do not spread tuberculosis to other people
• may develop tuberculosis in the future if their immune system weakens

Tuberculosis can be contracted both immediately after infection and several years later.In a disease, the general condition of the human body plays an important role – malnutrition, mental stress, alcoholism, drug addiction, chronic diseases, and immune deficiency (including HIV infection) contribute to the disease. If the immune system of a person infected with tuberculosis is significantly weakened (for example, due to infection with HIV or another disease), then viable tuberculosis bacteria in the body will begin to multiply and become the cause of tuberculosis. In the case of tuberculosis, the person develops characteristic symptoms and the person can spread the tuberculosis bacteria to others.

The risk of contracting tuberculosis after infection is higher in the following cases:

in HIV-infected people
for people with a transplanted organ or people who are waiting for a transplant
in people with chronic renal failure who are receiving dialysis treatment
in people with silicosis (a rare lung disease that occurs when silica is inhaled)
for diabetics
in people taking certain types of biological medications
in persons in close contact with infectious TB patients

People with tuberculosis:
• are sick and may have symptoms of the disease
• can spread tuberculosis to other people

In case of tuberculosis, the type of symptoms depends on which organ was affected by the tuberculosis bacterium.

If the lungs are affected, the following symptoms may appear:

• cough lasting more than two weeks
• expectoration with purulent sputum or blood
• chest pain

The following symptoms can often occur:

• weakness, feeling of exhaustion
• decrease in appetite and body weight
• temperature rise
• increased sweating at night, chills

Photo: Scanpix

Sometimes TB can be asymptomatic.

In case of symptoms characteristic of tuberculosis, you should immediately contact your family doctor or pulmonologist. If you suspect tuberculosis, you can go directly to the pulmonologist dealing with tuberculosis without asking for a referral from your family doctor. Tuberculosis screening tests are also free of charge for those without health insurance.

If tuberculosis is suspected in a child, then for the next examinations you need to consult a doctor dealing with infectious diseases of children.

In pulmonary tuberculosis, the most common symptom is a cough that lasts more than two weeks, to which general symptoms can join.
In case of symptoms typical of tuberculosis, you should immediately contact your family doctor or pulmonologist.

If there is a suspicion of pulmonary tuberculosis, the doctor should ask the person about the symptoms of the disease and check if there have been any previous contacts with tuberculosis patients.Most often, X-rays are taken afterwards and at least two sputum samples are taken at different times. These sputum samples are sent for examination to detect the appearance of tuberculosis bacteria. In the event that a person cannot give a sputum test himself, expectoration can be caused (provoked) and for this inhalation with saline is done. Another option is to refer the person for a bronchoscopy or for a bronchial tract viewing procedure. Since young children do not know how to take a sputum test, instead of sputum, the fluid obtained after rinsing the stomach is examined.

Photo: Scanpix

A sputum test is primarily examined under a microscope. If during examination under a microscope (so-called microscopy) tuberculosis bacteria are found in the sputum, this means that there is an extensive secretion of bacteria and such a patient can be considered infectious. The attending physician can receive the results of microscopy the very next day after the tests. The sputum is then examined using the culture method, and it can take up to eight weeks to obtain the results of such an examination.The inoculation method can be used to finally confirm the presence of tuberculosis bacteria if the excretion of bacteria was small. A patient in whom tuberculosis bacteria are found in sputum only using the culture method can also be infectious and infect others with tuberculosis bacteria.

In general, such patients are considered less infectious than those patients who find tuberculosis bacteria in their sputum immediately, upon the first examination under a microscope.Searching for tuberculosis bacteria in sputum using the culture method will help to finally confirm the diagnosis of tuberculosis. The inoculation method also determines the drug resistance of tuberculosis bacteria, and this will be the basis for drawing up a treatment regimen.

When diagnosing tuberculosis, rapid tests are also used, the results of which are clarified within a few days. Since it is impossible to determine the sensitivity of the tuberculosis pathogen to all drugs used in treatment with the help of express tests, a parallel examination is carried out using a microscope and a seeding method.

In case of suspicion of tuberculosis, blood tests are also checked, sometimes computed tomography is done to assess more accurately the damage to the lungs or other organs, and its volume.

In Estonia, in case of suspected tuberculosis, all examinations are free of charge, regardless of the availability of health insurance.

For the diagnosis of pulmonary tuberculosis, the following are carried out:

Chest X-ray
sputum analysis

In Estonia, tuberculosis screening tests are free of charge for a patient, regardless of whether they have health insurance.

If the tuberculosis bacterium is susceptible to the main drug against tuberculosis (that is, the drug destroys the bacterium), then the course of treatment lasts from six to nine months and treatment is started simultaneously with four to five different drugs. Most often, drugs are used in the form of tablets, but at the beginning of treatment, an injectable drug may also be present in the scheme. With proper medication, your doctor may reduce your daily medication after two or three months.

In case of drug sensitivity, the main drugs are:

• isoniazid
• rifampicin
• ethambutol
• pyrazinamide
• streptomycin

Photo: Scanpix

Tuberculosis is almost always curable, but full recovery requires strict adherence to the course of treatment prescribed by your doctor. The well-being of a patient with a drug-sensitive tuberculosis pathogen usually improves after a few weeks after starting treatment.Often during this period, a person is no longer infectious. Still, it is very important to remember that the multiplying pathogens of tuberculosis persist for some time in the body, even when the patient no longer has any problems and does not feel sick anymore. Therefore, for complete recovery, strict adherence to the tuberculosis treatment regimen is necessary throughout the entire period of treatment.

Untreated tuberculosis is still dangerous for people around, and especially for children and those with weakened immunity.

Tuberculosis is curable in most cases.
The duration of the course of treatment depends on the sensitivity of the pathogen of tuberculosis, in the case of susceptible tuberculosis to essential drugs, it lasts 6-9 months.
Tuberculosis screening tests are free of charge for a patient in Estonia, regardless of whether they have health insurance.

If the causative agent of tuberculosis cannot be destroyed with a specific drug, then this means that the bacterium is not sensitive to the drug, i.e.that is, it is resistant. If the causative agent of tuberculosis is resistant to the main two drugs for tuberculosis, isoniazid and rifampicin, then this form of the disease is called multidrug-resistant tuberculosis. Treatment for MDR-TB is more difficult and takes significantly longer than for drug-sensitive TB (one and a half to two years).

A person can become ill with drug-resistant tuberculosis in two ways:

already initially infected with drug-resistant bacteria
Drug resistance can develop during treatment when the patient does not take the prescribed drugs in the correct amount, with the necessary frequency and for a long time.

Five to seven drugs are used at the same time to treat MDR TB, and these drugs can cause more side effects.

In 2016, MDR TB was diagnosed in 24 patients in Estonia, of whom 17 contracted TB for the first time.

If the patient is not properly adhered to the course of treatment, then he may develop resistance to the causative agent of the disease (tuberculosis bacteria).
In this case, the duration of the course of treatment is lengthened and there should be more drugs in the treatment regimen.

In the process of treating tuberculosis, the so-called Directly Observed Treatment (DOT) is used. DOT means that the patient must take the medication every day in the presence of the nurse, who directly checks if the medication has been taken.Usually tuberculosis treatment begins in the hospital, but after the infectious period passes, treatment can be continued on an outpatient basis, i.e. at home.

Photo: Scanpix

DOT are trying to make it as convenient and accessible for the patient as possible. For example, a patient can be compensated for by public transportation to a hospital to receive medication. If the patient is allowed home treatment, but he cannot come to the nurse who monitors the treatment of tuberculosis, then the medicine is brought to the patient’s home.In the last months of the course of treatment, when the patient feels well and is no longer infectious, he can return to work or school and lead a normal life.

During treatment, the pulmonologist constantly monitors the patient’s course of treatment and the recovery process. To do this, new examinations of the composition of sputum are carried out every month, X-rays are repeated and, if necessary, blood tests are done.

Tuberculosis is a particularly dangerous infectious disease, which is dangerous both for the patient himself and for those around him.Based on this, those who refuse tuberculosis treatment or interrupt the course of treatment in Estonia can be sent for compulsory treatment for up to six months (182 days) to the Jamejala Tuberculosis Treatment Unit in Viljandi hospitals.

Tuberculosis treatment begins in the hospital, but most of the treatment is carried out on an outpatient basis using directly observed treatment (DOT). In this method of treatment, the patient takes medication on a daily basis in the presence of a healthcare professional or in a medical facility or at home.
During treatment, the necessary tests and examinations are carried out every month.
Doctors have the right to refer patients who refuse treatment for tuberculosis or who interrupt treatment for compulsory treatment.

Tuberculosis medications can cause side effects. It is important that the patient monitors the occurrence of side effects during treatment and immediately informs the attending physician about them.Medicines for the treatment of side effects are provided by the attending physician to patients free of charge. Certain vitamins are given along with TB medicines to reduce the risk of side effects.

Safe side effects of drugs	Dangerous side effects of drugs
Nausea, lack of appetite, mild abdominal pain	Itchy skin, rash
General fatigue, impotence	Yellowing of the skin / eyeballs
Disorders of the digestive tract (diarrhea, bloating)	Recurrent nausea and severe abdominal pain
Metal taste in mouth	Hearing or vision impairment
Orange color of urine and other body fluids (saliva, tears)	Dizziness, imbalance
Mild joint pain	Attack of muscle spasms in the limbs
Skin redness when exposed to the sun	Hallucinations

Lifestyle during TB treatment

If the patient has been transferred to outpatient treatment, then he can lead a normal life, leave the house and communicate with friends and acquaintances.It is important to adhere to the prescribed treatment regimen and the principles of a healthy diet. For a better course of the treatment process, it is advisable to give up unhealthy habits, such as drinking alcohol and cigarettes.

If the patient is no longer infectious, has no symptoms of the disease and the drugs do not cause side effects, then he can return to work or school and during treatment for tuberculosis. It is important to remember that it is imperative that the patient continue to receive DOT visits when returning to work or school.Therefore, during treatment of tuberculosis, in general, the patient cannot leave for a long time from the place of treatment.

If the patient is not able to work during the treatment, then a certificate of incapacity for work is issued for him for this period. Compensation for a certificate of incapacity for work can be obtained up to 240 calendar days and, if necessary, at the end of this period, you can apply for the appointment of a status of incapacity for work. To do this, you need to submit an application for an assessment of the work ability to the unemployment fund.A patient attending a high school can apply for a sabbatical leave for the duration of the treatment.

Photo: Scanpix

During TB treatment:

Smoking interferes with the protective functions of the lungs and therefore slows down recovery
Alcohol consumption during treatment can cause serious side effects
after the period of infectious danger has passed, it is possible to restore sexual life
pregnancy during this period is not desirable, and you should take into account that anti-tuberculosis drugs can weaken the effect of contraception.
Sunbathing and tanning should be avoided, as the side effects of medications can cause age spots and increase the risk of sunburn
Saunas are not prohibited, but very hot steam is contraindicated.
You can eat all foods, good nutrition helps the healing process

During treatment, you must adhere to the treatment regimen prescribed by your doctor, eat well and avoid alcohol.
After a period of infection and no side effects, it is possible to return to work or school, but the obligation to attend DOT treatment visits remains.
If necessary, a certificate of incapacity for work is issued for the duration of tuberculosis treatment, and you can also apply for a work ability allowance.

Case management after tuberculosis treatment

A patient who has suffered tuberculosis caused by a tuberculosis agent sensitive to treatment, has completed the full cycle of treatment prescribed by the attending physician, and recovered, does not need regular medical supervision after recovery.And yet it is very important that this patient is able to monitor his own state of health himself and in case of symptoms of tuberculosis, he must turn to a pulmonologist or family doctor.

A patient who has had multidrug-resistant tuberculosis, who has HIV and does not adhere to the exact prescribed medication regimen, after recovery should be followed up for two years with a frequency of every six months. For observation, the patient must visit a pulmonologist and during each visit he will be asked questions about possible symptoms, take X-rays and check the sputum for the content of tuberculosis bacteria.

Photo: Scanpix

After recovering from tuberculosis, you no longer need to see a doctor regularly.
If a patient has suffered multidrug-resistant tuberculosis, or is infected with HIV, or does not fully adhere to the drug regimen, then after recovery, he should be followed up for two years with a frequency of every six months.

A patient with tuberculosis can protect their loved ones from the danger of infection if he:

Takes tuberculosis medication strictly as prescribed by a doctor
when coughing, turns his head away and covers his mouth with his hand or paper towel
will ask all persons in contact with him to see a doctor for a health check

In the case of each patient, the circle of close contacts with him is found out, for whom the risk of infection is very high.To do this, the nurse observing a patient with tuberculosis asks him about those contacts who may be infected and who have a high risk of also contracting tuberculosis. Finding out the contact persons allows you to call people at risk for a medical examination and detect new cases of tuberculosis as early as possible.

If the patient himself does not want to inform his contacts about his illness, then this can be done by a medical officer. Informing contacts and inviting them for examination should be delicate, and the name of the sick patient should not be mentioned.Both for the patient himself and for all persons in contact, all examinations related to tuberculosis are carried out free of charge, regardless of whether the person has health insurance. You do not need a referral from your family doctor for the examination.

For most people in contact, X-rays are taken and a blood test (determined by the level of interferon gamma M. tuberculosis) or a test for tuberculin. Sometimes a sputum composition is examined.

In some cases, prophylactic treatment is prescribed for persons who have come into contact with a patient with a drug-sensitive pathogen of tuberculosis, who have been found to be infected with tuberculosis.The goal of preventive treatment is to prevent tuberculosis. During preventive treatment, you need to take one essential TB drug almost every day for six to nine months. Before prophylactic treatment is prescribed, tests are always carried out to prevent tuberculosis.

Preventive treatment is prescribed, if necessary, after infection with tuberculosis:

mothers of children under 5 years old
for HIV-infected people in contact

90,016 people taking certain type of biological medications

90 016 people whose immune system is weakened due to any disease or its treatment

90,016 people with a transplanted organ or people who are in the waiting list for a transplant

Those who have come into contact with a patient with multidrug-resistant tuberculosis and who are infected as a result are not prescribed preventive treatment, since effective treatment regimens have not yet been developed for this case.To observe them, X-rays are taken every two years. Also, all persons who have been in contact with a patient with multidrug-resistant tuberculosis are trained to monitor their symptoms of tuberculosis.

Informing contacts and inviting them for examination should be delicate, and the name of the sick patient should not be mentioned.
For all persons in contact, all examinations related to tuberculosis are carried out free of charge, regardless of whether the person has health insurance.
In some cases, preventive treatment is prescribed, the purpose of which is to prevent tuberculosis. The duration of preventive treatment is six to nine months.

Ai J-W, Ruan Q-L, Liu Q-H, Zhang W-H. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerg Microbes Infect. 2016 Feb; 5 (2): e10.
Landry J, Menzies D.Preventive chemotherapy. Where has it got us? Where to go next? Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis. 2008 Dec; 12 (12): 1352–64.
Malaysia Health Technology Assessment Section Ministry of Health Malaysia. Management of Tuberculosis (3rd Edition). 2012.
Ministry of Science and Innovation, Spain. Clinical Practice Guideline on the Diagnosis, Treatment and Prevention of Tuberculosis. 2010.
National Institute for Health and Care Excellence.Tuberculosis. 2016.
Public Health Agency of Canada. Canadian Tuberculosis Standards 7th Edition. 2014.
TB CARE I. International Standards for Tuberculosis Care, Edition 3. The Hague: TB CARE I; 2014.
Viiklepp, P. Tuberkuloosihaigestumus Eestis 2012-2013. Tallinn: Tervise Arengu Instituut; 2014
World Health Organization. Global Tuberculosis Report 2016. Geneva: World Health Organization.
World Health Organization.Systematic screening for active tuberculosis: principles and recommendations. 2013.

On Health Information Portal
On the website of the Finnish Lung Health Society
On the medical portal inimene.ee
On the medical portal kliinik.ee
On the portal of the Institute for Health Development hiv.ee
Information brochures on tuberculosis published by the Institute for Health Development

Nutritional recommendations can be found on the website of the Institute for Health Development www.toitumine.ee.

Medical institutions that can be contacted in case of suspicion of tuberculosis

You do not need to ask a family doctor for a referral to receive an examination, and all examinations related to the detection of tuberculosis are free for those patients who do not have health insurance.

Tallinn
Polyclinic for Tuberculosis Treatment of the Pulmonary Center of the North Estonia Regional Hospital
Hiiu 39, Tallinn
Reception of adults and children – patients from Tallinn, Harju County and Raplamaa.
Reception phone 617 2929
Children’s office – phone 617 2951

Tartu
Admission to adults – patients from Tartu, Tartu County, Jõgeva County, Valgamaa, Põlvamaa
Polyclinic for Lung Diseases of the University of Tartu Clinic, Riia 167, Tartu
Pulmonologist’s office – phone 731 8949
Reception of children – patients from Tartu, Tartu County, Võrumaa, Jõgevamaa, Valgamaa, Põlvamaa
Children’s Clinic of the University of Tartu Clinic, Lunini 6, Tartu
Children’s office in Tartu – phone 731 9531

Jõgeva
Jõgeva Hospital, Piiri 2, Jõgeva
Reception phone 776 6220

Kohtla-Jarve
Polyclinic Ida-Viru Central Hospital, Ravi 10d, Kohtla-Järve
Reception phone number 339 5057, 331 1133

Narva
Narva Hospital Infectious Diseases Department, Haigla 5, Narva
Reception phone 357 2778
Pulmonologist’s office – phone 354 7900

Haapsalu
Läänema Hospital, Vaba 6, Haapsalu
Reception phone number 72 5800,
Pulmonologist’s office – phone – 472 5855

Kuressaare
Kuressaare Hospital, Aia 25, Kuressaare
Reception phone number 452 0115

Paide
Järvama Hospital, Tiigi 8, Paide
Registry phone 384 8132
Pulmonologist’s office – phone 384 8117

Pylva
Põlva Hospital, Uus 2, Põlva
Registry phone 799 9199

Pärnu
Pärnu Hospital, Ristiku 1, Pärnu
Reception phone 447 3300
Pulmonologist’s office – phone 447 3382

Rakvere
Rakvere Hospital, Lõuna Põik 1, Rakvere
Reception phone 322 9780
Pulmonologist’s office – phone 327 0188

Viljandi
Viljandi Hospital, Pärsti Rural Municipality, Viljandi County
Reception phone 434 3001
Pulmonologist’s office – phone 435 2053

Voru
South Estonian Hospital, Meegomäe village, Võru parish
Reception phone 786 8569
Pulmonologist’s office – phone 786 8591

90,000 Pulmonary and extrapulmonary tuberculosis – Ravijuhend

This patient guide is based on the 2017 Estonian treatment guide “Management of patients with pulmonary and extrapulmonary tuberculosis” and the topics presented therein together with recommendations.In this manual, you will find the recommendations that are most important from the patient’s point of view. The guide provides an overview of the main problems associated with the disease.

The manual is intended for people with tuberculosis, as well as for their loved ones and health care workers. This guide will help patients and their loved ones cope better with their illness, provide answers to the most frequently asked questions about treatment and daily problems, and can support patients and their loved ones during the treatment process.The Patient Guide provides an overview of tuberculosis as a disease, the tests used for diagnosis, treatment, and the organization of a daily regimen during a controlled treatment process.

The guidelines were compiled by experts in the field, along with former patients who have previously experienced and recovered from tuberculosis. The importance of the topics described in the manual and the clarity of the text have been appreciated by TB patients and their families. Patient feedback and feedback has been instrumental in the development of this manual and has helped to improve it.

You can learn more about the topics covered in this patient guide by following the links at the end of the guide.

During tuberculosis treatment, strictly adhere to the treatment regimen prescribed by your doctor. Take medication regularly, in the prescribed amount and at the correct time .
Do not change the dose of medication you are taking or the frequency of taking it yourself.Always check with your doctor.
If you feel unwell or if you experience any side effects, immediately inform your doctor or other healthcare professional who monitors your treatment.
If you feel better during TB treatment, do not interrupt treatment anyway. It is very important that you take your medication for the entire period of treatment prescribed by your doctor.
During tuberculosis treatment, you need to eat well and maintain a healthy lifestyle.
When planning a pregnancy, check with your doctor first. You should be aware that TB medicines can weaken the effects of contraception.
Avoid alcohol as much as possible. Drinking alcohol during treatment increases the risk of side effects (including liver damage).If you drink alcohol, do so in moderation.
Give up all types of tobacco products (including hookahs and electronic cigarettes). Smoking interferes with the protective functions of the lungs and therefore slows down recovery.
Avoid excessively hot steam when using the sauna.
Avoid sunbathing and tanning beds. Due to the side effects of TB drugs, there is a high risk of pigmentation and sunburn.
Inform your loved ones about the illness and ask them to go for a medical examination.
If you have recovered from tuberculosis, but you still have symptoms suggestive of tuberculosis, contact your family doctor right away or make an appointment with a pulmonologist.

Tuberculosis is an infectious disease caused by a bacteria called Mycobacterium tuberculosis .The causative agents of tuberculosis are spread by airborne droplets. When a tuberculosis patient coughs, sneezes, singing or talking, together with droplets of saliva, tuberculosis pathogens are thrown into the air, which can be inhaled by other people nearby. As a result, a person can become infected with tuberculosis. One untreated TB patient can infect up to 10-15 people a year.

All people can become infected with TB, regardless of their financial income or social status.Thus, the assumption that TB only affects people with a low standard of living is incorrect.

Tuberculosis is an airborne infectious disease caused by a bacterium Mycobacterium tuberculosis .
Tuberculosis most commonly affects the lungs, but it can also affect other organs in the body.

The risk of contracting tuberculosis after infection is higher in the following cases:

in HIV-infected people
for people with a transplanted organ or people who are waiting for a transplant
in people with chronic renal failure who are receiving dialysis treatment
in people with silicosis (a rare lung disease that occurs when silica is inhaled)
for diabetics
in people taking certain types of biological medications
in persons in close contact with infectious TB patients

People with tuberculosis:
• are sick and may have symptoms of the disease
• can spread tuberculosis to other people

In case of tuberculosis, the type of symptoms depends on which organ was affected by the tuberculosis bacterium.

If the lungs are affected, the following symptoms may appear:

• cough lasting more than two weeks
• expectoration with purulent sputum or blood
• chest pain

The following symptoms can often occur:

• weakness, feeling of exhaustion
• decrease in appetite and body weight
• temperature rise
• increased sweating at night, chills

Photo: Scanpix

Sometimes TB can be asymptomatic.

If tuberculosis is suspected in a child, then for the next examinations you need to consult a doctor dealing with infectious diseases of children.

In pulmonary tuberculosis, the most common symptom is a cough that lasts more than two weeks, to which general symptoms can join.
In case of symptoms typical of tuberculosis, you should immediately contact your family doctor or pulmonologist.

Photo: Scanpix

In case of suspicion of tuberculosis, blood tests are also checked, sometimes computed tomography is done to assess more accurately the damage to the lungs or other organs, and its volume.

In Estonia, in case of suspected tuberculosis, all examinations are free of charge, regardless of the availability of health insurance.

For the diagnosis of pulmonary tuberculosis, the following are carried out:

Chest X-ray
sputum analysis

In Estonia, tuberculosis screening tests are free of charge for a patient, regardless of whether they have health insurance.

In case of drug sensitivity, the main drugs are:

• isoniazid
• rifampicin
• ethambutol
• pyrazinamide
• streptomycin

Photo: Scanpix

Untreated tuberculosis is still dangerous for people around, and especially for children and those with weakened immunity.

Tuberculosis is curable in most cases.
The duration of the course of treatment depends on the sensitivity of the pathogen of tuberculosis, in the case of susceptible tuberculosis to essential drugs, it lasts 6-9 months.
Tuberculosis screening tests are free of charge for a patient in Estonia, regardless of whether they have health insurance.

A person can become ill with drug-resistant tuberculosis in two ways:

already initially infected with drug-resistant bacteria
Drug resistance can develop during treatment when the patient does not take the prescribed drugs in the correct amount, with the necessary frequency and for a long time.

Five to seven drugs are used at the same time to treat MDR TB, and these drugs can cause more side effects.

In 2016, MDR TB was diagnosed in 24 patients in Estonia, of whom 17 contracted TB for the first time.

If the patient is not properly adhered to the course of treatment, then he may develop resistance to the causative agent of the disease (tuberculosis bacteria).
In this case, the duration of the course of treatment is lengthened and there should be more drugs in the treatment regimen.

Photo: Scanpix

Tuberculosis treatment begins in the hospital, but most of the treatment is carried out on an outpatient basis using directly observed treatment (DOT). In this method of treatment, the patient takes medication on a daily basis in the presence of a healthcare professional or in a medical facility or at home.
During treatment, the necessary tests and examinations are carried out every month.
Doctors have the right to refer patients who refuse treatment for tuberculosis or who interrupt treatment for compulsory treatment.

Safe side effects of drugs	Dangerous side effects of drugs
Nausea, lack of appetite, mild abdominal pain	Itchy skin, rash
General fatigue, impotence	Yellowing of the skin / eyeballs
Disorders of the digestive tract (diarrhea, bloating)	Recurrent nausea and severe abdominal pain
Metal taste in mouth	Hearing or vision impairment
Orange color of urine and other body fluids (saliva, tears)	Dizziness, imbalance
Mild joint pain	Attack of muscle spasms in the limbs
Skin redness when exposed to the sun	Hallucinations

Lifestyle during TB treatment

Photo: Scanpix

During TB treatment:

Smoking interferes with the protective functions of the lungs and therefore slows down recovery
Alcohol consumption during treatment can cause serious side effects
after the period of infectious danger has passed, it is possible to restore sexual life
pregnancy during this period is not desirable, and you should take into account that anti-tuberculosis drugs can weaken the effect of contraception.
Sunbathing and tanning should be avoided, as the side effects of medications can cause age spots and increase the risk of sunburn
Saunas are not prohibited, but very hot steam is contraindicated.
You can eat all foods, good nutrition helps the healing process

During treatment, you must adhere to the treatment regimen prescribed by your doctor, eat well and avoid alcohol.
After a period of infection and no side effects, it is possible to return to work or school, but the obligation to attend DOT treatment visits remains.
If necessary, a certificate of incapacity for work is issued for the duration of tuberculosis treatment, and you can also apply for a work ability allowance.

Case management after tuberculosis treatment

Photo: Scanpix

After recovering from tuberculosis, you no longer need to see a doctor regularly.
If a patient has suffered multidrug-resistant tuberculosis, or is infected with HIV, or does not fully adhere to the drug regimen, then after recovery, he should be followed up for two years with a frequency of every six months.

A patient with tuberculosis can protect their loved ones from the danger of infection if he:

Takes tuberculosis medication strictly as prescribed by a doctor
when coughing, turns his head away and covers his mouth with his hand or paper towel
will ask all persons in contact with him to see a doctor for a health check

For most people in contact, X-rays are taken and a blood test (determined by the level of interferon gamma M. tuberculosis) or a test for tuberculin. Sometimes a sputum composition is examined.

Preventive treatment is prescribed, if necessary, after infection with tuberculosis:

mothers of children under 5 years old
for HIV-infected people in contact

90,016 people taking certain type of biological medications

90 016 people whose immune system is weakened due to any disease or its treatment

90,016 people with a transplanted organ or people who are in the waiting list for a transplant

Informing contacts and inviting them for examination should be delicate, and the name of the sick patient should not be mentioned.
For all persons in contact, all examinations related to tuberculosis are carried out free of charge, regardless of whether the person has health insurance.
In some cases, preventive treatment is prescribed, the purpose of which is to prevent tuberculosis. The duration of preventive treatment is six to nine months.

Ai J-W, Ruan Q-L, Liu Q-H, Zhang W-H. Updates on the risk factors for latent tuberculosis reactivation and their managements. Emerg Microbes Infect. 2016 Feb; 5 (2): e10.
Landry J, Menzies D.Preventive chemotherapy. Where has it got us? Where to go next? Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis. 2008 Dec; 12 (12): 1352–64.
Malaysia Health Technology Assessment Section Ministry of Health Malaysia. Management of Tuberculosis (3rd Edition). 2012.
Ministry of Science and Innovation, Spain. Clinical Practice Guideline on the Diagnosis, Treatment and Prevention of Tuberculosis. 2010.
National Institute for Health and Care Excellence.Tuberculosis. 2016.
Public Health Agency of Canada. Canadian Tuberculosis Standards 7th Edition. 2014.
TB CARE I. International Standards for Tuberculosis Care, Edition 3. The Hague: TB CARE I; 2014.
Viiklepp, P. Tuberkuloosihaigestumus Eestis 2012-2013. Tallinn: Tervise Arengu Instituut; 2014
World Health Organization. Global Tuberculosis Report 2016. Geneva: World Health Organization.
World Health Organization.Systematic screening for active tuberculosis: principles and recommendations. 2013.

On Health Information Portal
On the website of the Finnish Lung Health Society
On the medical portal inimene.ee
On the medical portal kliinik.ee
On the portal of the Institute for Health Development hiv.ee
Information brochures on tuberculosis published by the Institute for Health Development