Immunological Interactions of Tuberculosis with Drugs and Substance Use: A Systematic Review and Update

Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis affecting the lungs and sometimes disseminates to other body parts [1]. TB is a major global health concern and parallels Human Immunodeficiency Virus (HIV) and diabetes as a leading cause of mortality worldwide [2]. Recent reports estimate a global TB prevalence of 9.0 million with over 1.5 million deaths annually [2]. Likewise, drug and substance use is an emerging health, social and economic problem worldwide. An approximated 5.2% of the global population aged between 15 and 64 years were reported to be using illicit drugs, with over 183,000 deaths occurring in 2012 [3]. The global burden is estimated at 2 billion alcohol users, 1.3 billion smokers and 185 million drug users mainly dependent on cocaine and heroin [3].


Background
Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis affecting the lungs and sometimes disseminates to other body parts [1]. TB is a major global health concern and parallels Human Immunodeficiency Virus (HIV) and diabetes as a leading cause of mortality worldwide [2]. Recent reports estimate a global TB prevalence of 9.0 million with over 1.5 million deaths annually [2]. Likewise, drug and substance use is an emerging health, social and economic problem worldwide. An approximated 5.2% of the global population aged between 15 and 64 years were reported to be using illicit drugs, with over 183,000 deaths occurring in 2012 [3]. The global burden is estimated at 2 billion alcohol users, 1.3 billion smokers and 185 million drug users mainly dependent on cocaine and heroin [3].
Underlying disease conditions and substance abuse accelerates host inflammatory responses. As such, TB positive illicit drug and substance users suffer heightened systemic inflammation and immune activation as a result of alterations in cytokines expression [4]. Cytokines play a crucial role in the pathogenesis of TB, the outcome of which is mediated by interaction of macrophages, T cells and the interplay of the signals they produce [5]. For instance, pro-inflammatory cytokines including interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) are involved in granuloma formation that controls mycobacterial replication [6]. In addition, animal model experiments have shown that, mice deficient of IFN-γ or IL-12 are highly susceptible to M. tuberculosis [7,8].

Abstract
Background: Illicit drug and substance use exacerbates tuberculosis (TB) pandemic and complicates management of the disease. Cytokines play a crucial role in TB infection, and recreational drugs of abuse present a confounder in the understanding of immunology of TB. Therefore, this review presents an updated summary describing the immunological link between illicit drug use and TB.
Methods: Information was obtained from previous research findings via Medline search (1990-2015) using the headings tuberculosis, drug interactions, cytokine alterations, prevalence of TB and illicit drug use. In addition, Google scholarly articles and PubMed citations were included in our search.
Discussion: Recreational drug induced immunosuppression hastens TB progression among habitual substance users. Additionally, substance consumption in the context of TB infection alters cytokine production and the ensuing immune responses. In this regard, understanding these interactions forms an integral component in improving clinical outcomes among this cohort.
Conclusions: Drug and substance abuse aggravates TB pandemic and remains a hindrance to effective TB diagnostic and therapeutic strategies. As such, poor adherence to TB treatment and interactions with drugs of abuse remain a hallmark for drug resistance that poses a unique setback in the fight against the world epidemic. In addition, substance consumption promotes derangement in inflammatory responses implicated in TB immunopathogenesis. This review necessitates clear identification on contribution of each substance towards TB predisposition and cytokine dysregulation while adjusting for confounders.
On the other hand, anti-inflammatory IL-10 and IL-4 can inhibit immune response to MTB infection and may hence escalate disease progression [9,10]. Although IL-6 is considered a Th-2 cytokine, it has been associated with protective immunity against Mycobacterium tuberculosis [11]. CD4+ T cell count may be employed as a surrogate marker in assessing the functionality and integrity of the cellular immunity component among TB infected population. In light of this, studies have documented that CD4+ T cell counts influence both the frequency and severity of active TB disease [12]. Clinical reports indicate that during various microbial infections including Mycobacterium tuberculosis, plasma CD4+ T cells mount crucial adaptive immune responses against these microbial pathogens [13]. However, the exact mechanisms behind this activity are not well understood.
In this review, we compile data on the complexity of the immune response to TB as well as drug and substance use with a view to improve the understanding of the immunological interaction between illicit substance consumption and TB pathogenesis. We begin by giving an overview on TB immunopathogenesis followed by immunologic derangements caused by various drugs and substance, and finally link these alterations with TB severity. We conclude with a summary of the relationship between TB and substance use, then give directions for future investigations.

Methods
Relevant literature was systematically reviewed for the immunological interaction of tuberculosis and substance use through a Medline database search (1990-2015) with restriction to English only articles. The search terms applied included; substance use and Tuberculosis, illicit drugs and TB interactions, immune alterations during TB and substance use, prevalence of TB and substance use. The common names of frequently used recreational drugs and substances such as cocaine, heroin, opium, bhang, khat and alcohol were also searched. Additionally, relevant Google scholarly articles (Google search), Hinary and PubMed citations matching our search criteria were also critically reviewed for potential significance. Available abstracts of International and National conferences were also included in our review study. Finally standard text books and grey literature material were also examined for essential information before being considered for inclusion in our review.

Results
Multiple studies were assessed governed by our inclusion and exclusion criteria. This review focused on articles defining cytokine profiles as immunological correlates among Tuberculosis monoinfected drug and substance using population. Hence, articles defining TB in the context of co-morbidities including HIV and Hepatitis failed to meet the threshold for inclusion into the study. Majority of studies identified, employed cross-sectional design; however, case control and prospective cohort studies also featured ( Table 1 and Figure 1).

Discussion
Recreational drug use contributes significantly towards TB transmission and progression. In addition, drug and substance use modifies cytokine expression and release during TB infection [14]. However, there is insufficiency of information regarding how these harmful substances modulate TB immune responses. Therefore, data in this review provide an insight into mechanisms through which drug and substance use influences TB pathogenesis (Table 2).

Opiates
Opioid use has been linked to TB acquisition, a fact evidenced by studies describing greater than 100-folds TB incidences among opiate users compared to general population [15]. Experimental studies show that opiates modulate diverse functions of immune cells including phagocytosis, chemotaxis and cytokine expression [4,16], which are crucial for TB elimination. Opiates suppress production of IFN-γ and TNF-α which are involved in monocytes and granulocytes recruitment during active TB infection [17]. In addition, opioids down-regulate IL-8 production that is necessary in attracting neutrophils and T cells besides monocytes recruitment [18,19]. They exert their effects through specific µ-opioid receptors on immune cells or through regulatory actions on the cells of central nervous system (CNS) [20]. Morphine activates CNS µ-opioid receptors causing suppression of Natural Killer (NK) cell activity in experimental model rats [20], which in turn inhibits IFN-γ production in TB [21]. It is noteworthy that variations in expression pattern of these cytokines and chemokines may also be differentially impacted by the type of opioid used.

Cocaine
Hard drugs, for instance cocaine, may be taken intravenously or through other routes such as inhalation which do not necessarily involve use of injection [22]. On the other hand, respiratory damage arising from habitual use of cocaine makes illicit drug users more vulnerable to infection with pulmonary tuberculosis [23,24]. This may be feasibly attributable to the fact that cocaine consumption has been shown to impair alveolar macrophage and immunoregulatory cytokine production which are of vital importance in conferring resistance against tuberculosis disease [25,26]. Studies conducted by Roth et al. describe cocaine to cause significant reduction in inducible nitric oxide synthase (iNOS) activity, which results in poor alveolar macrophage antibacterial action [27]. Additionally, cocaine decreases monocyte proinflammatory responses including IFN-γ, monocyte chemoatttractant protein-1 (mcp-1), TNF-α and granulocyte/macrophage-colony stimulating factor (GM-CSF) which are required in anti M. tuberculosis immunity [26,28]. Overall, cocaine use attenuates the capacity of monocytes and alveolar macrophages protective mechanisms resulting in failure of response to a mycobacterial challenge with ultimate consequence of failure to arrest TB disease.

Heroin
Heroin, a morphine derivative is categorized among the routinely used recreational drugs [29]. Its consumption has been associated with heightened risk of TB acquisition and transmission due to immunosuppressive effects and mode of use [30]. Moreover, studies have documented that heroin uptake modulates cell mediated host inflammatory responses [4], which are key determinants of TB outcome. However, few studies have established combined effects of heroin and cytokine dysregulation in a classical TB setup. Studies conducted in both human and animal model experiments show suppressed IFN-γ and TNF-α production following exposure to heroin [31][32][33], suggesting that heroin down-regulates pro-inflammatory responses which are necessary for host mycobacterial control.

Alcohol
Alcohol consumption has been related with alterations in innate immune responses. As a result, circulating levels of IFN-γ, TNF-α, IL-12, IL-13, IL-6, monocytes chemo-attractant protein1 (MCP-1) and IL-1 are observed to be elevated across the time course of alcohol uptake, and the levels have been correlated with serum concentrations of IgG [34,35]. Similarly, interactions between cytokines levels among alcoholics and infectious agents such as TB have been reported [36], whereby repeated alcohol use suppresses TNF-α production which is identified as a mononuclear phagocyte-derived cytokine that has anti-TB protective effects [37,38]. In retrospect, from the above discussion, it is increasingly clear that circulating levels of inflammatory cytokines produced by monocytes and macrophages is distorted. Thus, these findings imply that, chronic alcohol use causes a dysregulation in cytokine and chemokines expression. Furthermore, alveolar macrophages are recognized as the predominant cells that respond to infectious agents within the lungs [39]. Phagocytic monocytes and macrophage cell function is affected by frequent alcohol use. As such, individuals with alcoholic cirrhosis have shown defects in monocyte phagocytic function [40,41], which plays a critical activity in host immune response against Mycobacterium tuberculosis.

Cannabis sativa (Marijuana)
The plant Cannabis sativa (Marijuana) contains active constituents termed as Cannabinoids. These active ingredients possess immunomodulatory effects including anti-inflammatory and immunosuppressive characteristics [42,43]. Animal model studies using mice demonstrate that cannabidiol (CBD), a non-psychoactive  cannabinoid, causes a significant reduction in plasma levels of proinflammatory cytokines such as IFN-γ and TNF-α while augmenting secretion of IL-10 and IL-4 levels [44], which play a pivotal role in host immunity against TB disease. Similarly, frequent marijuana use has been shown to impair production of TNF-α, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-6 from alveolar macrophages [25,27]. Taken together, these observations indicate that habitual use of marijuana significantly alters normal lung immune responses. However, exact mechanisms describing interactions between cannabinoids and TB immunopathology have not been clearly elucidated [45,46].

Cigarette
Epidemiological studies have identified cigarette smoking as among the major cofactors increasing susceptibility to respiratory diseases [47,48]. However, exact mechanisms through which cigarette smoke predisposes individuals to these infections remains unclear. Cigarette contains nicotine as the addictive component, a stimulant that has been implicated in inhibition of host immune responses [49]. Nicotine impairs IL-10 and TNF-α production through alpha-7 (α 7 ) nicotinic receptor or nicotinic acetylcholine receptors (nAChRs) which are located on the cells of central nervous system (CNS) as well as immune cells [50,51]. In addition, cigarette smoke reduces both PBMCs and alveolar compartment macrophage IFN-γ production [52], which are utilized by the host adaptive mechanism to clear mycobacterial infection [53,54]. Experimental animal models using murine mice have shown nicotine to inhibit IL-6, IL-12 and TNF-α production by alveolar macrophages through nAChRs [55]. In conclusion, there is substantial proof that nicotine and other cigarette derivatives attenuate cytokine responses which are essential for conferring protective immunity against pulmonary infections such as Mycobacterium tuberculosis.
Articles excluded after reviewing title or abstract (n = 869)

Drugs Substances
Opioids Alcohol

Cocaine Cigarettes
Heroin

Cannabis sativa (Marijuana)
Catha edulis (Khat) Middle East regions [56]. Leaves of khat are known to comprise of two alkaloids namely, cathinone and cathine which possess amphetaminelike features that cause psycho-stimulation manifesting as euphoria and excitement [57,58]. Habitual khat chewing has been linked with increased risk of oral diseases. As a result, various studies show that prolonged use of khat promotes pathological alterations in human buccal mucosa which triggers an abnormal differentiation of the buccal epithelium [59]. Consequently, additional studies suggest that this abnormal buccal epithelial cell differentiation is associated with high incidence of oral cancer [60,61]. However, there is limited information on the effects of khat on immune cells. Khat-treated PBMCs have shown reduced expression of inflammatory cytokines including TNF-α and IL-6 while production of IFN-γ, IL-2 and IL-10 is significantly increased [62]. This suggests that khat interferes with kinetics of cytokine expression from immune effector cells, which impacts negatively on the host immune surveillance system. On the other hand, regular khat use escalates the risk of acquiring Mycobacterium tuberculosis infection through immune modulation of lung resident macrophages [63] that offer first line defense against pulmonary TB [64].

Conclusions and Future Directions
Immune factors and their influence on TB disease among drug and substance users remains poorly defined. However, there is adequate evidence linking drug and harmful substance use to modification of inflammatory responses, which are crucial in TB immunopathology. Therefore, this review highlights the need for clinicians and other healthcare providers to assess the impact of recreational drug and substance use among TB patients for effective therapeutic strategies.