Background
Anemia, defined as low blood hemoglobin (Hb) concentration (less than 11.0 g/dl for 6–59-month children, 11.5 g/dl for 5–11-year-old children, 12.0 g/dl for 12–14-year-old children and non-pregnant women (for age 15 years and above), 11.0 g/dl for pregnant women, and 13.0 g/dl for adult men (for age 15 years and above). It is a global public health problem affecting both developing and developed countries. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children [
1,
2]. Globally, it affects 24.8% of the population [
3] with the highest prevalence occurred in preschool-age children (43%) [
1]. It is the result of a wide variety of causes in which 50% of the cases are due to iron deficiency. Acute and chronic infections, including malaria, cancer, and HIV are also the cause of anemia [
1,
3].
Anemia is classified into three categories based on the severity; mild, moderate, and severe anemia. Mild anemia is defined as Hb concentration of 10.0–10.9 g/dl for pregnant women and 6–59-month children, 11.0–11.4 g/dl for 5–11-year-old children, 11.0–11.9 g/dl for non-pregnant women, 12–14-year-old children, and 11.0–12.9 g/dl for adult men. On the other hand, moderate anemia defined as the Hb value of 7.0–9.9 g/dl for pregnant women and 6–59-month children and 8.0–10.9 g/dl for 5–11-year-old children; 12–14-year-old children, non-pregnant women, and adult men while severe anemia is defined as the Hb value less than 7.0 g/dl for pregnant women and 6–59 months of children; and less than 8.0 g/dl for 5–11-year-old children, 12–14-year-old children, non-pregnant women, and adult men [
2].
Anemia reduces health-related quality of life, increases morbidity and mortality in patients with chronic disease. It also predisposes an individual to some infectious diseases including tuberculosis (TB) [
4]. It is a common hematological finding among TB patients with the prevalence of 44–89.1% [
5‐
9]. On the other hand, the proportion of TB among anemic patients is higher than non-anemic patients (the highest burden in severe anemic patients) [
10,
11]. In anemic patients, cell-mediated immune response and bactericidal capacity of leucocytes are significantly suppressed [
12,
13].
Tuberculosis is an airborne chronic infectious disease caused by
Mycobacterium tuberculosis and predominantly occurred in low socio-economical segments of population. It is the second most common cause of death among infectious diseases. A total of 8.7 million new active TB cases and 1.4 million TB-related deaths were estimated globally [
14‐
16].
The assessment of potentially modifiable risk factors is a vital for the development of TB control policies [
17]. Accordingly, some TB risk factors have been known for decades, including systemic diseases such as diabetes mellitus and chronic kidney disease as well as tobacco smoking, alcohol use, body mass index, silicosis, human immunodeficiency virus (HIV) infection, splenectomy, and gastrectomy [
17,
18]. Under-nutrition, refugee, homeless, and direct contact with active TB are also risk factors for TB [
18]. People exposed to these factors are called the risk groups for TB in which the prevalence or incidence of TB is significantly higher than in the general population. The World Health Organization (WHO) recommended and established guidelines for these risk groups to be prioritized for screening of active TB than the general population [
19].
However, even the diagnosis of anemia with Hb measurement is a low cost, and more widely available in clinical settings to know the anemic status of the individual [
20], there is no any established guideline or policies to consider anemic patients as the risk group for TB and to be prioritized them for screening for active TB. But, studies have investigated the link between anemia and TB prevalence (the relationship between anemia and the risk of contracting TB). Accordingly, some studies showed that anemia is risk for TB [
21‐
23]. In contrast, others showed that anemia is not the risk of development of TB [
20,
24]. These contradict findings and the absence of systemic review and meta-analysis conducted about the risk of contracting TB among anemic patients; motivate the authors to conduct this systemic review and meta-analysis. Thus, the main objective of the current systematic review and meta-analysis was to determine the pooled risk effect of anemia on the development TB.
Discussion
To the best of our information, this is the first systematic review and meta-analysis conducted to determine the pooled risk factor of anemia for TB. Anemia defined by low Hb or red blood cell (RBC) concentration is a major hematological finding in chronic diseases [
39,
40]. It is also a known risk factor for some chronic diseases [
41]. In the current systematic review and meta-analysis, majority of the included studies showed that anemia was a higher predicator of TB [
10,
11,
17,
22,
27‐
29,
30,
31]. However, some studies showed that anemia was not the risk of TB [
20,
24,
33]. The reason for discrepancy might be different in sample size, study design, diagnostic method, and geographical location.
But, according to the current systematic review and meta-analysis pooled effect size estimate, anemia was the risk factor of TB. The pooled effect of cross-sectional and case-control studies showed that the odds of TB among anemic patients were 3.56 times higher than non-anemic patients. Indeed, this may not show the cause and effect association due to the limitation of study design (is anemia the cause of TB infection? or is TB disease the cause of anemia?).
However, pooled analysis of cohort studies, which show the cause and effect association, also revealed that anemia was a risk for TB. According to the pooled effect estimate of 10 cohort studies analyzed by HR, the hazard of TB among anemic patients was 2.01 times higher than non-anemic patients. This might be due to that anemic patients might be nutritionally imbalanced and immuno-compromised. Anemia was used as indirect assessment of nutritional and immune status of the individuals. Most of the included studies did not report the type of anemia. However, the WHO reported that 50% of the cases of anemia are due to iron deficiency [
42] which might be true for the included studies. Successful transmission of TB is influenced by a variety of conditions, including proximity and duration of contact with an individual with active TB disease, and the immune-competency of the individual infected with tuberculosis [
43]. Individuals with a weak immune response (immune compromise individuals) are at risk of TB [
44].
Iron was confirmed to be a vital element not only for erythropoiesis, but also for immune system development and play an important role in the integrity of the immune system; and its deficiency can cause impairment of immunity. Ekiz et al. suggests that the important immunogenic mechanisms like humoral, cell-mediated, and nonspecific immunity and the activity of cytokines are influenced by iron deficiency anemia. Especially, the percentage of monocytes with oxidative burst activity and the ratio of monocytes with phagocytic activity were highly reduced in iron deficiency anemia [
13]. Macrophage phagocytic activities are important immunological response in controlling of TB infection by forming granulomas which is an aggregate of immune cells and walls of the mycobacterium which limiting further replication and spread of the tubercle bacilli [
44,
45]. Aly et al. and Das et al. also showed that iron deficiency anemia impaired cell-mediated immune response specifically T cell-mediated immunity [
46,
47]. A review by Stephen stated that even all studies did not show a consistence result, there were an impairment of polymorph neutrophil function and intracellular bacteriocidal activity of immunological cells in iron deficient individuals [
1]. Iron status may also modulate the type of immune response mounted through its influence on the body’s cytokine profile. Experimental evidence has shown that iron deficiency changes the balance between Th1 and Th2 cytokines, promoting a dominant Th2 response that has been associated with clinical TB disease [
48]. Generally, morbidity from infectious disease is increased in iron-deficient populations, because of the adverse effect of iron deficiency on the immune system [
49,
50]. Therefore, the anemic patients probably might have impaired or modulated immune system that favors the replication of TB.
The other cause of anemia are the presence of other micronutrient deficiencies, including vitamins A and B12, folate, riboflavin, and copper [
42]. These micronutrient deficiencies can also cause immunological impairment [
51]. According to Erkurt et al, vitamin B12 has important immunomodulatory effects on cellular immunity, and abnormalities in the immune system in pernicious anemia are restored by vitamin B12 replacement therapy [
12].
The other possible explanation might be the direct involvement of RBCs in maintaining of the innate and adaptive immune system. Evidence shows that RBCs are modulators of T cell proliferation. In particular, RBCs are able to enhance T cell expansion and survival by inhibiting activation-induced T cell death, an effect possibly associated with a decrease of oxidative stress within activated T cells. Optimal T cell proliferation and survival were only observed with intact RBCs and when RBCs were in close contact or proximity with activated T cells [
52].
In the current systematic and meta-analysis, the burden of TB was increased with anemia severity. According to the pooled effect estimate of case-control and cross-sectional studies, the odds of TB among mild anemic patients is 2.33 times higher than non-anemic patients, while in moderately and severely anemic patients, it was 3.65 and 6.91 times higher than non-anemic patients, respectively. The included cohort studies also revealed that the hazard of TB was increased from 1.37 times (statistically insignificance) to 2.08 times and 2.66 times among mild, moderately, and severely anemic patients compared to non-anemic patients, respectively. One in vitro experimental study conducted by Bishlawy and IM EL showed that Hb is strongly bacteriostatic. According to this experiment, a drop of washed RBCs is put in a Petri dish containing nutrient agar inoculated with staphylococci and incubated for 24–48 h at 37 °C. The RBCs used were undiluted or 50% diluted with saline. The result showed undiluted washed RBCs blocked bacterial growth, but impaired by dilution [
53]. This justifies the finding, the higher incidence of TB among anemic patients than non-anemic patients, and why it was increased in moderate and severe anemic patients compared to mild anemic patients. In anemic patients, there are low RBCs (low concentration of Hb), especially in moderate and severe anemic patients. Therefore, anemic patients might have disturbed immune system and low bacteriocidal activity due to low Hb concentration, which enhances the growth of TB.
Generally, anemia is a risk factor for TB; this is because anemic patients might be immuno-suppressed and susceptible to TB, and it is known that TB is common in immuno-compromised population patients [
54].
Strength and limitation of the study
One of the strengths of this review was being the first systematic review and meta-analysis to determine the pooled risk estimate of anemia for TB. Moreover, the review was conducted according to the preferred reporting items for systematic review and meta-analysis (PRISMA-P statement) protocol. However, this review had limitations. The extent of heterogeneity between included studies was high. We were unable to get adjusted risk ratio from some of the included studies. Therefore, we used crude risk measures from these articles. The other limitation of this systematic review and meta-analysis was, only articles published in English were used for our literature search. Most of the included studies were conducted in Africa which might cause geographical bias.
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