a systematic review of the literature - International Journal of Infectious ...

International Journal of Infectious Diseases 56 (2017) 54–61

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Review

Tuberculosis and hypertension—a systematic review of the literature Anneline Borchsenius Seegerta,* , Frauke Rudolfb,c,d , Christian Wejseb,c,d, Dinesh Neupanec a

Aarhus University, Aarhus, Denmark Department of Clinical Medicine – Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark c Department of Public Health – Department of Health Services Research, Aarhus University, Aarhus C, Denmark d Bandim Health Project, INDEPTH Network, Apartado 861, Bissau, Guinea-Bissau b

A R T I C L E I N F O

S U M M A R Y

Article history: Received 24 October 2016 Received in revised form 12 December 2016 Accepted 13 December 2016 Corresponding Editor: Eskild Petersen, Aarhus, Denmark

Background: Tuberculosis (TB) remains a major health problem in low- and middle-income countries, and in many of these countries, the burden of non-communicable diseases such as hypertension is rising. Knowledge about how these diseases influence each other is limited. Methods: A systematic review of the literature was performed to evaluate the evidence for an association between hypertension and TB. Results: Three retrospective cohort studies, three case–control studies, eight cross-sectional studies, 12 case series, and 20 case reports exploring the association between hypertension and TB were included in the review. One cohort study found a significantly higher prevalence of hypertension among TB patients compared to controls. Cross-sectional studies reported a prevalence of hypertension in TB patients ranging from 0.7% to 38.3%. No studies were designed to assess whether hypertension is a risk factor for developing active TB. Conclusions: Overall, no evidence was found to support an association between TB and hypertension; however, the results of this review must be interpreted with caution due to the lack of properly designed studies. © 2016 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Keywords: Tuberculosis Hypertension Systematic review

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Search results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypertension in TB patients compared with non-TB controls . . . . . . . . . . . Prevalence of hypertension among TB patients—cross-sectional studies . . . Case series describing hypertension in patients with renal TB . . . . . . . . . . Occurrence of hypertension in TB patients—individual clinical observations Hypertension and the outcome of TB treatment . . . . . . . . . . . . . . . . . . . . . . Hypertension as a risk factor for developing active TB . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renal TB leading to hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Potential indirect mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Confounders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author. E-mail address: [email protected] (A.B. Seegert). http://dx.doi.org/10.1016/j.ijid.2016.12.016 1201-9712/© 2016 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A.B. Seegert et al. / International Journal of Infectious Diseases 56 (2017) 54–61

Introduction The global burden of tuberculosis (TB) is decreasing, yet TB continues to be a major health problem in many low- and middleincome countries (LMICs).1 On the other hand, with improved socioeconomic status, decreased morbidity and mortality related to infectious diseases, rapid urbanization, and changes in lifestyle and dietary habits, LMICs are also facing a rapid increase in noncommunicable diseases (NCDs) such as cardiovascular diseases, cancer, and diabetes.2 Cardiovascular diseases account for one third of deaths worldwide, and more than 75% of cardiovascular deaths occur in LMICs.3 Hypertension is a key risk factor for cardiovascular disease (CVD) and is responsible for a large proportion of deaths due to heart disease, stroke, and kidney disease.3 Lifestyle factors are known to affect the risk of hypertension and CVD, but it is possible that chronic infections, such as TB, also contribute to the development of these diseases in different ways. Furthermore, a reverse association may possibly exist, such that hypertension may lead to an increased risk of developing TB. With regard to TB leading to hypertension, it has been hypothesized that the triggering of immunological responses can cause an impairment of endothelial function and lead to an increased risk of CVD and possibly hypertension.4,5 TB may lead to parenchymal destruction of the lung tissue,6 which may affect the vascular structure and cause vasculitis and endarteritis, subsequently leading to a reduced cross-sectional area of the pulmonary vasculature and thereby pulmonary hypertension. Additionally, hypertension may occur if TB infection in the kidney results in parenchymal destruction of the renal tissue, decreased renal function, and impaired ability of the kidney to regulate blood pressure.7,8 Autopsy studies on patients who have died of TB have found evidence of kidney involvement of TB in 50–65% of the patients.9–11 Regarding the reverse association, hypertension may have subtle effects on the immune system,12 which could increase the risk of TB, or the association could be via HIV, which has also been shown to increase the risk of CVD.13,14 According to the World Health Organization, the risk of developing TB is estimated to be up to 30 times greater in HIV patients than in those without HIV.15 TB may also be associated indirectly with hypertension through

55

diabetes, which is strongly associated with an increased risk of CVD and hypertension.16 Epidemiological evidence suggests an association between diabetes and TB infection, possibly because of immune impairment leading to increased susceptibility to active TB infection.17,18 Several systematic reviews have assessed the evidence for the association between diabetes and TB, but not much research has been conducted to explore the association between TB and hypertension; to the authors’ knowledge, there have been no previous systematic reviews on this topic. Interestingly, there is great geographical overlap between countries where the prevalence of hypertension is high and countries with a high incidence of TB (Figure 1). This co-existence of TB and NCDs constitutes a major global public health issue, and how these disease units influence each other and possibly potentiate the effects of the other is not yet fully understood. The aim of this review was to systematically assess the current literature investigating the association between arterial hypertension and TB. Methods This systematic review was conducted according to the guidelines set forth by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group for the reporting of systematic reviews of observational studies. The main research focus was hypertension in TB disease, and therefore only data concerning hypertension/blood pressure measurements were extracted from articles that included a variety of baseline characteristics or outcome measures. Data were extracted through a three-stage selection process. In the first stage, a search of the MEDLINE database was performed with a combination of the following search terms: (“hypertension”[MeSH Terms] OR “hypertension”[All Fields] OR (“arterial”[All Fields] AND “hypertension”[All Fields]) OR “arterial hypertension”[All Fields]) AND (“tuberculosis”[MeSH Terms] OR “tuberculosis”[All Fields]). The search limits were as follows: language (“English”) and species (“Humans”). A manual search for references of published articles was also performed. In the second stage, the titles and abstracts were reviewed against predefined screening criteria. If the required information was not available in

Figure 1. Distribution of the prevalence of hypertension (HT) and incidence of tuberculosis (TB). Data sourced from the World Health Organization.

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the abstract, the full-text article was further reviewed to gather the information. In the third stage, an exclusion criterion was used for further filtering of the articles: only studies that contained data on arterial hypertension among TB patients were included, and studies on TB and portal and pulmonary hypertension were excluded. The heterogeneity in terms of study design, aim, and outcome measures of the studies included prohibited a meta-analysis. Instead, the studies were reviewed systematically and the details recorded under different subcategories according to the type of study. The evidence of an association between TB and hypertension is summarized and discussed. The potential biological mechanisms underlying a possible association between hypertension/CVD and TB are presented. Results Search results The literature search yielded 802 articles, which were screened by title and abstract. Of these, 735 were excluded because they did

not contain data on hypertension among TB patients. Sixty-seven full-text articles were assessed for eligibility, and of these, 21 did not meet the inclusion criteria and were excluded. Forty-six articles were included in this review, all published in English (Figure 2). Of the studies included, three were retrospective cohort studies, three were case–control studies, eight were crosssectional studies, 12 were case series, and 20 were case reports. Hypertension in TB patients compared with non-TB controls Seven studies that contained data on hypertension in both TB patients and non-TB controls were identified.7,19–24 Table 1 shows the distribution of hypertension reported by the different studies. Three were retrospective cohort studies, two were case–control studies, and two were cross-sectional studies; these studies were conducted between 2001 and 2016. The sample size of the TB group varied from 73 to 10 168 patients. Four studies were conducted in Taiwan, one in the UK, one in India, and one in France. All studies included both sexes. The studies were very heterogeneous in terms of aim and outcome measures. None of the studies aimed specifically to study

Figure 2. PRISMA flow diagram of the article selection process.


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Table 1 Distribution of hypertension among TB cases and non-TB controls. First author Chung19 Tocque

23

24

Marak Shen7

Sheu22 20

Giral

Lin21

Country and year of study

Study design

Number of TB cases (% male)

HT in cases

Number of controls (% male)

HT in controls

Significance Comments

Taiwan 1997–2010 England 1989–1996 India 2013–2014 Taiwan 1998–2002 Taiwan 2000–2003 France 2005

Retrospective cohort Case–control

10 168 (68.2)

38.7%

40 672 (68.2)

37.5%

p < 0.05

112 (55.4)

10.7%

198 (54.5)

19.4%

p < 0.05

Hypertension based on ICD9 diagnosis Hypertension based on self-report

Crosssectional Retrospective cohort Retrospective cohort Case–control

110 (63.6)

24.5%

110 (63.6)

17.3%

p = 0.41

–

8735 (59.4)

25.1%

34 940 (59.4)

24.6%

p = 0.30

2283 (63.9)

13.4%

6849 (57.1)

12.9%

p = 0.53

147 (51.7)

24%

147 (51.7)

31%

p = 0.19

Taiwan 2015

Crosssectional

Newly diagnosed: 12 (83.3) Total: 73 (76.7)

50%

3075 (47.9)

64.2%

p = 0.31

43.8%

3014 (47.3)

64.7%

p < 0.001

Hypertension based on ICD9 diagnosis Hypertension based on ICD9 diagnosis All participants were hypercholesterolemic Cases were past TB patients All patients were older than 65 years and had diabetes –

TB, tuberculosis; HT, hypertension; ICD-9, International Classification of Diseases, ninth revision.

the association between TB and hypertension, but all included hypertension as a potential confounder (for example for the association between TB and the risk of acute coronary syndrome or chronic kidney disease). There were inconsistencies in the methods of determining hypertension, but in the majority of studies the diagnosis of hypertension was based on International Classification of Diseases, ninth revision (ICD-9) diagnoses from the medical records. A positive association was found by four studies, but only one showed statistical significance. In a large retrospective cohort study, Chung et al. reported a small but significantly higher prevalence of hypertension in the TB cohort at the time of diagnosis (38.7% in the TB cohort vs. 37.5% in the non-TB cohort, p = 0.03).19 Five studies reported no significant difference between the groups,7,20–22,24 and one reported hypertension to be less frequent among TB patients than the control group.23 This latter study was, however, limited by high rates of non-responders, untraceable persons, and deaths, and the lower rate of hypertension found in the TB group could possibly have been related to a survival bias if the TB subjects who died were the ones with the highest rates of hypertension.

Prevalence of hypertension among TB patients—cross-sectional studies The literature search returned six cross-sectional studies that contained data on the prevalence of hypertension among TB patients.25–30 The majority aimed to study the burden and clinical profile of diabetes in TB patients, and the number of TB patients included varied from 75 to 38 881. The studies were conducted in Nigeria, Taiwan, Brazil, and South Africa between 2009 and 2016, and all included both sexes. The reported prevalence rates for hypertension are shown in Table 2, as well as the definition of hypertension, which varied greatly across the studies and was not specified by some. Reis-Santos et al. reported a prevalence of hypertension of only 0.7% among 38 881 TB patients, but data on co-morbidities in this study were based on optional entry in the database, leading to a high risk that the prevalence was underestimated.29 In the study by Oni et al., hypertension was based on prescriptions of the antihypertensive drugs hydrochlorothiazide, enalapril, or amlodipine, which are not specific for hypertension. 28 In general, the studies were heterogeneous and lacked a detailed description of how the hypertension data were obtained.

Table 2 Hypertension among TB patients: cross-sectional studies. First author

Country and year Number of TB of study cases (% male)

ReisBrazil Santos29 2011 28 South Africa Oni 2012–2013 Ogbera Nigeria 201426 2010–2012 Ogbera Nigeria 201527 2011–2012 Taiwan Ko25 2000–2010 30 Taiwan Weng 2003–2008

Prevalence of hypertension

Hypertension definition/BP data

Comments

38 881 (67.8)

0.7%

Optional entry in database

–

387 (28.7)

30%

Prescription of antihypertensives from database

Prescription of medicine that was not specific for hypertension Extrapulmonary TB patients were excluded All patients had been treated for TB

a

b

3376 (57)

1.5% to 7.4%

Not specified

4000 (60)

2.7%a to 8.7%b

9831 (67.1)

36.8%a to 71.3%b

BP measurement with mercury sphygmomanometer; BP threshold not specified ICD-9

75 (58.7)

a

38.3% to 66.7% 44% (overall)

b

Not specified

TB, tuberculosis; BP, blood pressure; ICD-9, International Classification of Diseases, ninth revision. a Prevalence of hypertension among non-diabetic TB patients. b Prevalence of hypertension among diabetic TB patients.

– –

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Table 3 Hypertension among TB patients: case series. First author

Country and year of study

Number of TB cases

Hypertension in TB cases

Hypertension definition/BP data

Comments

Schwartz37

USA 1932–1964 Canada 1958–1961 India 1965–1970 China 1950–1962 England 1952–1970 England 1970–1977 USA 1961–1972 USA 1963–1972 Switzerland 1971–1981

540

2%

–

50

20%

BP >150/95 mmHg from clinical record + cardiac hypertrophy Not specified

150

8%

761

5.9%

BP >150/95 mmHg, repeat measurements BP measurement >150/100 mmHg

227

11.8%

BP measurement 150/90 mmHg

87

16%

BP measurement >180/100 mmHg

30 patients were treated with nephrectomy BP was lowered in 23 patients In 4 out of 39 patients BP improved after anti-TB treatment; in 10 out of 52 patients BP improved after nephrectomy –

102

3%

Not specified

–

44

0%

–

39

30%

Diastolic BP >90 mmHg from clinical record Diastolic BP measurement >95 mmHg

36

Mercer

31

Chowdhury Hsiung35

Gow 197133 Gow 1979

34

Christensen32 Teklu38 Studer

8

Half of the hypertensive cases underwent nephrectomy, which resolved HT 11 patients completed anti-TB treatment and became normotensive

All patients had finished treatment for TB; 7 out of 12 patients became normotensive after nephrectomy

TB, tuberculosis; BP, blood pressure; HT, hypertension.

Case series describing hypertension in patients with renal TB The literature search yielded nine case series describing hypertension in patients with renal TB, published between 1962 and 1984.8,31–38 Table 3 shows the frequency of hypertension among the TB cases reported by the studies. The blood pressure value that defined hypertension varied across the studies, the majority using a cut-off value of 150/90 to 150/100 mmHg.

Occurrence of hypertension in TB patients—individual clinical observations Several case reports have described the occurrence of hypertension among TB patients. Fourteen case reports published between 1948 and 2012, involving 19 cases in total, have described hypertension as a presenting feature of renal TB. Nephrectomy has previously been a common way to treat renal hypertension, and some authors have reported cure of hypertension by removal of a tuberculous kidney. In 11 of the 19 cases, hypertension was resolved or improved after surgical removal of the affected kidney, 39–45 while in two cases, hypertension was not cured by this procedure.45,46 In five cases, hypertension improved after treatment with both an anti-TB drug regimen and nephrectomy,47–49 or anti-TB drugs alone.50,51 In one case, hypertension due to bilateral renal TB leading to end-stage renal disease occurred 2 years after pharmacological treatment for pulmonary TB and was not cured by further treatment.52 These case reports were published over a time course of 50 years, and they therefore differ in terms of diagnostic criteria and methods (e.g., blood pressure measurements and method of obtaining the TB diagnosis), surgical interventions, preand postoperative treatment, and methods of data acquisition. The period of follow-up varied between 3 months and 6 years. Lavender reviewed 10 case reports on renal TB and hypertension involving 23 cases from 1938 to 1956.46 All patients underwent nephrectomy, and 15 patients had a subsequent fall in blood pressure, whereas treatment had no effect or a doubtful effect in the remainder. A case series by Ocón et al. published in 1984 reported a significant average blood pressure fall (from 176.8/ 117.7 mmHg to 138/88 mmHg) in 11 hypertensive TB patients treated with nephrectomy for renal TB.53 Vaish et al. reported one patient with renal TB among 60 young hypertensive patients.54

TB leading to obstruction of the renal arteries has been reported as a rare cause of hypertension. In two case reports, tuberculous lymphadenopathy compressed the renal arteries, which resulted in hypertension.55,56 A tuberculous aneurysm of the abdominal aorta, compressing the renal arteries and thereby leading to hypertension, has also been reported.57 In another case, tuberculous granulomas in the vascular wall of the renal artery led to renal ischemia and hypertension.58In one case, hypertension was a presenting feature of pulmonary TB in a patient whose kidneys had been removed at a young age.59 Finally, hypertension due to obstruction of the ureters by tuberculous infection, causing hydronephrosis, has also been reported.60 Hypertension and the outcome of TB treatment A nested case–control study from Taiwan that included 302 TB patients, showed that hypertension was associated with a negative outcome of TB treatment.61 However, multivariate regression did not identify hypertension as an independent risk factor for this outcome. Hypertension as a risk factor for developing active TB The literature search did not reveal any studies designed to assess whether hypertension is a risk factor for the development of active TB infection. Discussion Hypertension as a feature of TB has been described in several case reports, but among controlled studies, few have found a significant difference in the prevalence of hypertension between TB patients and non-TB controls. The reported prevalence of hypertension in TB patients varies from 0% to 50%. Few of the studies were designed specifically to assess the association between TB and hypertension, and the studies included in this review are inconsistent regarding methods. Different definitions of hypertension were used across the studies, e.g. ICD diagnosis, prescription of antihypertensives from a prescription database, or single or repeated blood pressure measurements with different cut-off values for hypertension. This constitutes a risk of misclassification at the outcome level, e.g. if hypertension was


underestimated due to a high cut-off value, or if hypertension was not diagnosed and the medical records therefore did not have a diagnosis code. Traditional risk factors for hypertension, such as dietary habits, being overweight, physical inactivity, etc., can be potential confounders, and were not adjusted for in any of the studies. The studies included in this review focused on different types of TB active, chronic, and treated TB, as well as disseminated disease and only pulmonary TB. The detection of TB can be difficult, and the method for establishing the diagnosis also varied across the studies. Some of the patient groups were under treatment for TB or had previously been treated, and any possible effects that the TB medication may have had on blood pressure could have interfered with the results, e.g. if the TB treatment affected TBinduced hypertension, or if the TB medicine itself influenced blood pressure in other ways. For instance, permanent kidney damage has been reported as a rare side effect during TB treatment, most commonly caused by rifampicin.7 Renal TB leading to hypertension Renal TB is a common form of extrapulmonary TB, and because of its non-specific clinical presentation, the diagnosis is easily missed.7 Many of the case reports mentioned in this review described the regression of hypertension after either removal of a tuberculous kidney or pharmacological treatment of renal TB, suggesting that renal TB could be causing renal hypertension in these patients. In general, the cause of renal hypertension can be divided into two groups: stenosis of the renal arteries and parenchymatous lesions (e.g., chronic pyelonephritis).35 Both causes lead to ischemia in the kidney, which results in increased renin production and hypertension. Studer and Weidmann8 and Stockigt et al.42 reported that renin secretion was increased in the tuberculous kidney of patients with renal TB and hypertension, suggesting that renal ischemia was the cause of hypertension in these patients. According to Shen et al., renal TB leads to calcification, atrophy, or caseous necrosis of the renal parenchyma, and the gross anatomy of the kidney is disturbed to such an extent that renal function can decline irreversibly.7 Hsiung et al. suggested that if the destruction of the renal tissue by TB becomes severe enough, the tissue loses its ability to secrete renin, and therefore hypertension does not develop.35 In the study by Hsiung et al., the examination of renal biopsies from hypertensive patients showed pathological changes in the glomeruli and small arteries and arterioles in many of the patients. However, these findings were also present in some of the normotensive TB patients in the study. Based on this, the authors hypothesized that the severity of the renal lesions determines whether hypertension arises. Apart from the rare cases mentioned above, in which swollen lymph nodes or tuberculous aneurysms directly compressed the renal arteries leading to renal ischemia and hypertension, it is still controversial whether renal TB in itself can cause hypertension.

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suggested mechanism is molecular mimicry, a phenomenon that occurs when antibodies created during an infection cross-react with self-antigen.4 The antigens thought to be involved in this process are heat-shock proteins (HSP), a family of proteins expressed by cells in response to stressful conditions, such as inflammation, heat, ultraviolet light, or other causes of cell damage.62 The genes coding for HSP have been strongly conserved throughout evolution, and many identical epitopes exist in different species. An example is HSP65 in Mycobacterium spp, which shares 40–50% identical residues with human HSP60.4 It has been shown that antibodies produced against mycobacterial HSP are able to cross-react with HSP expressed on host endothelial cells during an infection, resulting in an autoimmune response targeted against cells of the vessel wall.63 Furthermore, studies have found that human HSP60 is expressed on the surface of endothelial cells, macrophages, and vascular smooth muscle cells in an atherosclerotic plaque, and that the anti-HSP60 antibody titre correlates with the presence and extent of CVD.62 It is possible that the same mechanism could play a role in the development of hypertension in TB patients. Rodríguez-Iturbe et al. summarized the evidence supporting the overexpression of HSPs, and HSP-induced autoimmunity, leading to the accumulation of macrophages and T-lymphocytes in the kidney,5 which has been found to be associated with hypertension in experimental animal models. In humans, increased anti-HSP70 and anti-HSP65 antibody levels have also been found in patients with essential hypertension, independent of age, smoking habits, blood lipids, or evidence of atherosclerosis.5 Chronic inflammation and HSP autoimmunity constitutes a possible mechanistic link between TB and hypertension, although no primary research has been conducted to support this hypothesis. None of the studies included in this review focused on hypertension as a risk factor for developing active TB infection, and the potential mechanisms for an association in that direction remain purely speculative.

Confounders Diabetes is well known to be associated with a higher risk of developing active TB infection,17,18 and the link between diabetes and hypertension is well-established.16 Diabetes is therefore a potential confounder for the association between TB and hypertension, and an increased prevalence of hypertension in TB patients could be due to more diabetes in this group. HIV has also been associated with an increased risk of hypertension,64 and at least one third of HIV-infected people are co-infected with TB,65 which makes HIV a potential confounder for the association between TB and hypertension. Other confounders include socioeconomic status and lifestyle factors that increase the risk of hypertension as well as the risk of contracting infectious diseases such as TB.

Potential indirect mechanisms

Limitations

Apart from the potential direct link between renal TB and kidney damage leading to hypertension, there are also suggestions of a more indirect, immunological link between TB and CVD, which could potentially also apply for the association between TB and hypertension. Huaman et al. reviewed the research on possible mechanisms underlying the association between TB and CVD and suggested that TB disease is associated with chronic inflammation, which through the triggering of a complex cascade of immunological responses may lead to the formation of an atherosclerotic plaque.4 A

The main limitations of this review are as follows: none of the studies included was designed specifically to address the relationship between TB and hypertension; definitions of hypertension were heterogeneous and there was a lack of information on the severity and duration of hypertension; there were differences in the type of TB in the studies included. Another main limitation is that potential confounders in the relationship between TB and hypertension were not adjusted for, such as diabetes, HIV, and lifestyle factors/socioeconomic factors that may increase the susceptibility to infection. The lack of a confirmed

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biologicalmechanism in the association between TB and hypertension in either direction is another limitation. Furthermore, the literature search for this study was limited to studies in English; studies published in other languages were not assessed for eligibility. However, it has been suggested that including Englishonly articles in systematic reviews for chronic diseases does not bias primary findings.66 Finally, only the MEDLINE database was used for the literature search, which may not cover all studies on this topic. Another limitation of this review is the risk of publication bias. Conclusions The available literature is focused on the occurrence of hypertension among TB patients. None of the studies reviewed was designed to address the question of hypertension as a risk factor for developing active TB. No evidence was found to support an association between hypertension and TB in either direction. However, the results should be interpreted with caution because of the lack of properly designed studies. Further studies are needed to systematically assess whether an association between TB and hypertension exists, both in terms of an increased risk of hypertension among TB patients and if hypertension increases the risk of developing active TB infection or affects treatment outcomes for TB. Awareness and understanding of such an association would be of relevance to health care providers, particularly in LMICs, in order to prevent and reduce the risk of hypertension-related outcomes in TB patients. Funding This work was supported through by grant from Novo Nordisk Foundation (NNF15OC0018034) to Christian Wejse. Conflict of interest The authors declare no conflicts of interest. References 1. World Health Organization. Global tuberculosis report 2015. Geneva: WHO; 2015 Available at: http://www.who.int/tb/publications/global_report/en/ (accessed June 1st 2016). 2. World Health Organization. Background paper: Non-communicable diseases in low- and middle-income countries. Geneva: WHO; 2010 Available at: http:// www.who.int/nmh/events/2010/Tehran_Background_Paper.pdf (accessed June 1st 2016). 3. World Health Organization. A global brief on hypertension. Geneva: WHO; 2013 Available at: http://www.who.int/cardiovascular_diseases/publications/global_brief_hypertension/en/ (accessed June 1st 2016). 4. Huaman MA, Henson D, Ticona E, Sterling TR, Garvy BA. Tuberculosis and Cardiovascular Disease: Linking the Epidemics. Trop Dis Travel Med Vaccines 20151. doi:http://dx.doi.org/10.1186/s40794-015-0014-5. 5. Rodríguez-Iturbe B, Pons H, Quiroz Y, Lanaspa MA, Johnson RJ. Autoimmunity in the pathogenesis of hypertension. Nat Rev Nephrol 2014;10:56–62. 6. Marjani M, Baghaei P, Malekmohammad M, Tabarsi P, Sharif-Kashani B, Behzadnia N, et al. Effect of pulmonary hypertension on outcome of pulmonary tuberculosis. Braz J Infect Dis 2014;18:487–90. 7. Shen TC, Huang KY, Chao CH, Wang YC, Muo CH, Wei CC, et al. The risk of chronic kidney disease in tuberculosis: a population-based cohort study. QJM 2014;108:397–403. 8. Studer UE, Weidmann P. Pathogenesis and treatment of hypertension in renal tuberculosis. Eur Urol 1984;10:164–9. 9. Lanjewar DN, Ansari MA, Shetty CR, Maheshwari MB, Jain P. Renal lesions associated with AIDS—an autopsy study. Indian J Pathol Microbiol 1999;42:63– 8. 10. Martinson NA, Karstaedt A, Venter WD, Omar T, King P, Mbengo T, et al. Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. AIDS 2007;21:2043–50. 11. Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N’Gbichi JM, et al. The mortality and pathology of HIV infection in a West African city. AIDS 1993;7:1569–79.

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