According to the ‘Global tuberculosis report 2022’ of the World Health Organization (WHO), the worldwide incidence of tuberculosis (TB) has steadily declined since the 2000s (Fig. 1) ⁽¹⁾. However, due to the coronavirus disease 19 pandemic, disruptions in TB management programs, and a reduction in dedicated TB healthcare workers have led to an increase in TB mortality rates for the first time in the last 20 years. This has resulted in serious issues with many individuals potentially transitioning from latent to active TB ^(1,2).

Fig. 1. The World Health Organization (WHO) global tuberculosis programme. Data from the article of WHO (Global tuberculosis report 2022. WHO; 2022. p. 31) ⁽¹⁾.

In the Republic of Korea, 23,821 new TB cases were reported in 2019, with a notification rate of 46.4 per 100,000 individuals. Although the number of cases has decreased by 9.9% compared to 2018 ⁽³⁾, the Republic of Korea still has the highest incidence and mortality rates of TB among the OECD countries ⁽⁴⁾. Notably, TB is caused by Mycobacterium tuberculosis (MTB), which is an acid-fast bacillus ⁽⁵⁾.

This infectious disease is transmitted through the inhalation of respiratory droplets released via coughing or sneezing by a person infected with MTB ⁽⁶⁾. Owing to the various mechanisms of immune evasion and immune response manipulation by MTB, it can lead to a state known as latent TB infection (LTBI), which does not cause active TB or clinical symptoms ^(7,8).

The major risk factors for TB infection include human immunodeficiency virus infection, diabetes, smoking, alcohol abuse, malnutrition, and drug abuse. Notably, alcohol misuse and alcohol use disorders (AUDs) account for 8%–15% of global TB mortality ^(9-11). This study indicated that consumption of >40 g of ethanol per day or being diagnosed with AUD increased the risk of TB by almost three times ⁽¹²⁾.

Individuals with alcohol addiction or AUDs are classified as having a high risk of immune system impairment. Therefore, they have a higher incidence of infectious diseases than abstainers ^(13-16).

The WHO classifies alcohol as a psychoactive drug that possesses addictive qualities ⁽¹⁷⁾. The criteria for alcohol dependence according to Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) of the American Psychiatric Association and the International classification of diseases, 11th revision (ICD-11) of the WHO ^(18,19).

In DSM-5, alcohol dependence is classified as AUD, whereas ICD-11 uses the term Alcohol Dependence and provides criteria for diagnosis. Over the past few decades, alcohol consumption has increased exponentially, and approximately 1.4% of the global population is reported to have AUDs ⁽²⁰⁾.

Since the 19th century, studies have consistently emphasized the correlation between alcohol consumption and increased rates of TB and other infections such as pneumonia ⁽²¹⁾. Typically, individuals with MTB infection who have a well-functioning immune system do not develop the clinical disease ⁽²²⁾. However, patients with an impaired immune system are more likely to develop active TB ⁽²³⁾. According to current research, excessive alcohol use is a risk factor for immune system impairment and increases vulnerability to active TB and the reactivation of the LTBI (Fig. 2) ⁽²⁴⁾. In cases of alcohol dependence, individuals are particularly exposed to pulmonary infections such as TB and pneumonia. Due to the higher incidence and severity of infectious diseases compared to abstainers, individuals who are alcohol dependent are considered to be in a state of “immunodeficiency.” ^(25-28)

Fig. 2. Summary schema of the epidemiologic data of AUD and TB. Individuals with AUD are at a higher risk for TB, more infectious, have more severe disease, and are more likely to experience poor outcomes. See main text for further details. AUD, alcohol use disorder; TB, tuberculosis; MDR-TB, multidrug-resistant tuberculosis; AFB, acid-fast bacillus; Mtb, mycobacterium tuberculosis. Data from the article of Wigger et al. Front Immunol. 2022;13:864817 ⁽²⁴⁾.

Alcohol abuse is associated with nutritional deficiencies, liver disease, and smoking, which make the determination of the exact mechanism by which alcohol exerts its immunosuppressive effects difficult. Furthermore, alcohol consumption disrupts the function of cytokines such as TNF-α, inhibits the expression of growth factors such as granulocyte-conlony stimulating factor in the lungs, and interferes with the phagocytic activity and intracellular killing of MTB by macrophages ^(29-31). Notably, >90% of the aspirated MTB is eliminated by alveolar macrophages. However, if alveolar macrophages fail to kill the bacteria, they proliferate within the macrophages, leading to pulmonary TB. Alcohol impairs anti-TB defense by inhibiting recruitment, adhesion, phagocytosis, and superoxide production of alveolar macrophages ^(32-35).

Additionally, it suppresses the antigen-presenting ability of macrophages, thereby reducing the activation of antigen-specific T cells (Fig. 3) ⁽²⁷⁾.

Fig. 3. Monocyte/macrophage-derived substances potentially affected by alcohol. Monocytes and macrophages produce numerous substances that initiate and regulate inflammatory reactions; attract other immune cells (i.e., chemokines); stimulate T cells; help in the elimination of pathogens, such as bacteria; and perform other functions throughout the body. Alcohol may interfere with the production and secretion of all these substances, thereby impairing the body’s immune response. IL, interleukin; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha. Data from the article of Szabo. Alcohol Health Res World. 1997;21:30-41 ⁽²⁷⁾.

Furthermore, alcohol reduces macrophage responses to IL-6, IL-1β, TNF-α, and IL-8, and suppresses cytokine production. This disturbs the balance of Th1 and Th2 immune responses, impairs immune defense, and increases the probability of MTB infection ^(36-38).

According to a 2007 study, consuming >40 g of alcohol per day or being diagnosed with AUD increases the risk of MTB infection by almost three times ⁽³⁹⁾. A study conducted in the United States of America reported that excessive alcohol use among all adult TB cases (aged >14 years) reported between 1994 and 2006 was associated with a higher probability of pulmonary TB than other cases. It affects 3% of the African population. Additionally, a study conducted in a hospital in Ottawa, Kenya to establish the association between alcohol abuse and prevalence of TB found that 20% of patients with TB were alcohol-dependent ⁽⁴⁰⁾.

In Russia, 44% of all patients who discontinued treatment for active TB were alcohol abusers, and patients with TB who abused alcohol were seven times more likely to not complete treatment ⁽⁴¹⁾. In the Republic of Korea, the diagnosis of alcohol-induced mental disorders increased by an average of 4.3% per year from 2007 to 2011 ⁽⁴²⁾. The prevalence of AUDs, including alcohol abuse and dependence, was 4.3% with 1.8 million alcoholics ⁽⁴³⁾. The social cost was estimated to be 20 trillion won ⁽⁴⁴⁾.

However, the immunosuppressive effects of alcohol abuse may be compounded by smoking status. Smoking can play a direct role in lungs affected by pulmonary TB by causing changes in the mucociliary apparatus and disrupting both innate and adaptive cellular immunity ⁽⁴⁴⁾. Smoking and drinking are interconnected, and smoking is reportedly associated with an increase in the incidence of pulmonary TB and related diseases ^(45-47).

A study conducted in Portugal from 2013 to 2015 among adults aged ≥18 years reported that smokers who consumed >38 g of alcohol per day were more likely to develop TB. Additionally, a report from India on the treatment of patients with TB that combined smoking status (never smoked, past smokers, and current smokers) with alcohol use status found that the combined effect of alcohol abuse and smoking on adverse treatment outcomes was significantly higher in past and current smokers ⁽⁴⁸⁾. Considering the association between alcohol and TB, both smoking and alcohol abuse present potential risks for active and latent MTB infections.

Notably, TB often lacks distinctive clinical symptoms in the early stages of infection, which can lead to misdiagnosis and result in delayed diagnosis ^(49,50).

Self-reported measures of alcohol use are generally prone to underreporting which may fail to explain the higher prevalence of pulmonary disease and positivity of smear and culture tests in TB cases caused by excessive alcohol use ^(51,52). Additionally, both AUD and TB are classified as “diseases of poverty.” Patients suspected of having TB frequently have delays in receiving a prompt diagnosis, and their living and financial conditions, resulting in pauses to their treatment. Many countries routinely report low medication adherence among patients with AUD and an increase in primary TB treatment failures ^(53-55).

A recent report on the management of patients with active pulmonary TB in the Republic of Korea highlighted delays in care and the associated risk factors. They found that delays of ≥17 days in seeking care were associated with neuropsychiatric disorders and excessive alcohol consumption ^(56,57).

Accurate diagnosis and appropriate treatment are essential to reduce MTB infections and TB-related mortality ⁽⁵⁸⁾. Molecular biomarkers of excessive alcohol use and alcohol-related liver damage include γ-Glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, mean corpuscular volume, and carbohydrate-deficient transferrin ⁽⁵⁹⁾. However, the diagnostic accuracy of these biomarkers for AUDs is low. To discover various biomarkers for TB, ongoing research is being conducted to analyze samples such as sputum, blood, tissue, and urine from patients with active TB ⁽⁶⁰⁾. These studies have focused on small RNA, MTB-derived proteins, cytokines, and exosomes. Additionally, studies are underway to identify biomarkers through gene expression pattern analysis of the blood and peripheral blood mononuclear cells. In particular, individuals with AUD who are at high risk for TB often experience diminished treatment efficacy due to a combination of factors such as immunosuppression, social deprivation, and treatment interruptions (Fig. 4) ⁽⁶¹⁾.

Fig. 4. Dysregulated gene expression could lead to improper cellular function, circuit function, and eventually contribute to abnormal behavior observed in alcohol use disorder (AUD). Data from the article of Ferguson et al. Front Mol Neurosci. 2022;15:1032362 ⁽⁶¹⁾.

Therefore, to address the management of TB caused by excessive alcohol consumption, targeted preventive interventions are necessary to resolve the issues associated with infection prevention and treatment. In addition to the current diagnostic approaches, additional diagnostic tests are needed to identify biomarkers specific to these individuals.

The resurgence of TB can be attributed to multiple factors including reduced funding for TB management programs, high unemployment rates, decreased personal income, nutritional issues, dismantling social support systems, and high rates of alcohol addiction. These factors can affect individuals differently depending on sex, age, education, environment, lifestyle, mental health, financial status, and place of residence, leading to diverse treatment outcomes.

Alcohol abuse is a major global public health issue that not only causes various health problems but is also strongly associated with the incidence of TB. Excessive alcohol use is a risk factor that impairs the immune system and increases susceptibility to pulmonary infections and related complications, which in turn increases vulnerability to active TB and reactivation of LTBI.

Despite the longstanding recognition of the association between alcohol use and TB, research on the potential biological mechanisms underlying this relationship is lacking. While the connection between alcohol use and TB has been mentioned before, the etiology of TB is fully understood, and epidemiological evidence for a causal relationship remains inconclusive due to the possibility of other contributing factors.

Accurate detection and appropriate treatment of TB are essential to reduce new infections and TB-related mortality. Identifying biomarkers that reveal the link between alcohol use and TB could be a key strategy for the early detection and proactive intervention of TB infections, and would be valuable for monitoring responses to anti-TB treatments.

None.

No potential conflict of interest relevant to this article was reported.

This study was supported by the Brain Busan 21 Plus project.

Conceptualization: Sunghyun K, JEC. Data curation: YJO, MJ. Formal analysis: HJW. Investigation: Sohyeong K, YP. Supervision: Sunghyun K, JEC. Writing – original draft: YJO. Writing – review and editing: Sunghyun K.