Tuberculosis Infection and Comorbidities: A Public Health Issue in Baja California, Mexico

Abstract

According to the World Health Organization (WHO), tuberculosis (TB) remains a significant global health challenge, with approximately 10 million new cases and 1.4 million deaths reported in 2020. TB disproportionately affects low- and middle-income countries, where factors such as migrant population, malnutrition, type 2 diabetes, human immunodeficiency virus (HIV) co-infection, and COVID-19 exacerbate its impact. TB also leads to substantial economic losses due to decreased productivity and high healthcare costs. Despite advances in treatments, TB remains a major public health issue, particularly in poorer regions. In Mexico, TB is considered a moderate-incidence disease, with higher prevalence in border states, mainly due to population displacements. Effective TB control requires collaboration between Mexico and the United States of America given the high cross-border human movement, like in the Baja California State that reported predominantly pulmonary TB cases. Effective management of TB involves rapid diagnosis and identification of antibiotic resistance. Techniques such as PCR, high-resolution computed tomography (HRCT), and/or Xpert MTB/RIF have enhanced diagnostic accuracy. Future perspectives about TB management focus on developing new drugs and vaccines to combat drug-resistant strains, and the comorbidities associated, which must be addressed to reinforce of health public programs.

1. Tuberculosis

1.1. Introduction

The World Health Organization’s (WHO) global tuberculosis (TB) report estimated that there were approximately 10 million new cases of TB worldwide in 2022. TB caused an estimated 1.30 million deaths (deaths from TB among people with HIV included) [1]. TB is particularly prevalent in low- and middle-income countries, where socio-economic conditions, malnutrition, human immunodeficiency virus (HIV) co-infection and other infectious diseases such as COVID-19 are significant risk factors [2]. TB is caused by the bacillus Mycobacterium tuberculosis, which is spread when sick people with TB expel bacteria into the air (e.g., by coughing). TB is estimated to cause billions of dollars in annual economic losses due to decreased productivity of those with the pathology and costs associated with its diagnosis and treatment. Additionally, TB has a global public health impact owing to the emergence of drug-resistant strains that complicates treatment and increases morbidity and mortality associated with the disease. To effectively tackle the impact of TB on global health, it is imperative to strengthen health systems, improve access to diagnosis and treatment of quality, promote preventive interventions such as vaccination [3] and increase investment in research for the development of novel antituberculosis drugs. Although advances have been made in the diagnosis and treatment of the disease, it remains a global public health problem, especially in the poorest regions [4].

Mexico is considered a moderate-incidence country for TB. However, certain states, particularly those along the border with the United States of America (U.S.), have higher TB rates. This increased incidence is mostly attributed to the migration between Mexico and the U.S., contributing to the global spread of the disease [5]. Comorbidities also exacerbate the risk and aggravation of TB infections in Baja California (border state between Mexico and the U.S.). These main factors include (i) deficit nourishment or malnutrition, and also excess nourishment, metabolic syndrome and type 2 Diabetes (T2DM), with trends of T2DM-TB among hospitalized TB patients increasing significantly over recent years, likely due to the rise in T2DM cases [6]; (ii) human immunodeficiency virus (HIV), where a higher prevalence of HIV/acquired immunodeficiency syndrome (AIDS) and addictions or alcohol use are also associated with increased TB incidence [2]; and (iii) migratory phenomena, as migrants are at higher risk of communicable diseases, traumatic events, and inadequate healthcare [5]. Other variables are also discussed further below.

Mexico reports over 19,000 cases and nearly 2000 deaths annually from tuberculosis in all forms, with more than 80% of cases and deaths being pulmonary. Baja California has the highest morbidity and mortality rates from tuberculosis in the country, and the incidence of cases has been increasing each year, indicating that the transmission chain of the disease has not been controlled. In the last five years, the morbidity rate for pulmonary tuberculosis increased from 46.5 in 2017 to 48.9 per 100,000 inhabitants in 2021, with a peak rate of 63.0 in 2019 [7].

This work examines the status of TB, highlighting the comorbidities and the challenges faced by public health programs in this region of Mexico.

1.2. General Mechanisms and Immune Evasion of Tuberculosis (TB)

Tuberculosis (TB) is transmitted from person to person through the air when an infected individual coughs, sneezes, or talks, releasing TB bacteria in the form of tiny droplets known as aerosols. It is not, however, transmitted through casual contact, such as shaking hands or sharing food. However, individuals with a weakened immune system, or inflammatory low-grade chronic diseases such as obesity and other metabolic pathologies with prolonged and close exposure to someone with active TB are at higher risk of contracting the disease [8]. Nowadays, several genetic polymorphisms related to the host susceptibility for contracting the infection are described in human leukocyte antigens, Toll-like receptors, and even other micronutrient status-related factors such as vitamin D receptors [9,10].

Overcrowded conditions, such as those found in prisons or shelters, can increase the risk of disease transmission and infection. This latter implies a mechanistic path that begins when a disruption of the innate axis leads to the arrival of the inhaled bacteria to the lungs and the epithelial cells perceive their presence through pattern recognition receptors for consequently unclenching antimicrobial changes in the surface liquid or even by releasing inflammatory cytokines such as IFN-γ or TNF-α [11]. If the ratio of other cells as macrophages is enough to fight the bacterial challenge, macrophages can start the immune intervention. However, some bacteria can slowly replicate inside macrophages instead of being eliminated. In fact, following the life cycle of the bacteria, they rest inside the phagosome during the latent infection, leading to the formation of granulomas, inflammatory structures containing bacteria that function by limiting their spread [12,13].

Bacteria can remain latent in granulomas for years until the immune system weakens and the disease becomes active. The symptoms of this condition can vary depending on the form of the disease. In cases of pulmonary TB, the most common symptoms include persistent cough for more than two weeks, chest pain, weakness, weight loss, fever, night sweats, and fatigue. However, it is important to note that some patients may have a latent form of the disease, meaning that they do not exhibit visible symptoms but may develop active disease in the future. In addition to clinical symptoms, laboratory tests such as the tuberculin skin test and imaging diagnostic tests can help to confirm the diagnosis of TB. In fact, many factors can induce compromised immune systems, such as those with HIV/AIDS or receiving immunosuppressive treatments, to be at a higher risk of developing the disease. These include nutrient depletion, smoking history, antioxidant changes and several other epigenetic or genetic individual factors [14]. Moreover, unfavorable socio-economic conditions, such as poverty, overcrowding, and malnutrition, also increase TB susceptibility.

Furthermore, M. tuberculosis expresses several factors that block the macrophage efforts in suppressing the pathogen. Among these, strategies such as the inhibition of intracellular trafficking and autophagy, the acquisition of cytosol access, induction of eukaryotic cell death or even the neutralization of components such as reactive species can be further analyzed [13,15].

2. The Current Situation Regarding Tuberculosis Infections and Their Related Comorbidities in Baja California

2.1. Migration

The migration phenomenon at the Mexican border with the U.S. is another reason why this population is vulnerable to infections like TB. The fact that the states of California on the U.S. side and of Baja California on the Mexican side have the highest incidence rates, coincides with high concentrations of migrants, located in both states. The disease cannot be controlled successfully by either one or the other countries. Considering that there are approximately 400 million human crossings by land registered along this border each year. It is noteworthy that certain states located on the border between Mexico and the U.S. have an increased TB rate. In terms of number of infections rate, in 2023, Veracruz, Baja California, Guerrero, Tamaulipas, and Sonora ranked highest TB cases. In 2023, 2668 TB cases were diagnosed in Baja California, of which 2078 were pulmonary presentations (77.88%). Most cases occurred in the population aged between 25 and 49 years, with a ratio of 2 to 1 for men and women. 98% of diagnosed patients-initiated treatment, which is free and available at health facilities [16]. By 2024, the states of Baja California (9.5%, 681 cases), Chiapas (7.4%, 536 cases), Nuevo León (8.4%, 605 cases), and Veracruz (9.9%, 712 cases) lead in the highest accumulated cases of respiratory TB, contributing to a total of 7,203 cases in Mexico [17]. Despite this, only 14.8% of TB deaths were among the uninsured, and bacteriological or histological methods failed to confirm TB deaths in 61.5% of registered cases. Delayed diagnosis and treatment of TB can increase mortality risk. Some states mentioned above belong to southern Mexico; however, the strains reported in these places could spread to the border regions due to the phenomenon of migration. For example, The Haarlem and LAM lineages of M. tuberculosis were the most common in southern Mexican population [18], and were the most frequently detected in Baja California, whereas, only a subset of isolates (12%) seemed to be autochthonous of BC [19], this without considering the possible dissemination of another M. tuberculosis strains from Central and South America, where incident rates of tuberculosis increased [20,21]. In the specific case of Mexico, migration to the U.S. has faced unique challenges. Over the past decade, 394,482 individuals have undergone medical examinations as part of their legal migration process to the U.S. Out of those, 8775 (2.2%) were suspected of having TB, and 157 (1.8%) were confirmed to have TB. TB symptoms and/or evident recent close contact with TB-infected individuals, or in subjects whose chest X-ray shows suggestive TB images. In other words, the pathology is diagnosed through positive cultures or via clinical-epidemiological elements supporting it. The relative risk among migrants (with a 2.9 average for the period) reflected that this group has nearly three times the likelihood of acquiring TB compared to the population without this condition. This also indicates that healthcare personnel in contact with this population group have the same risk of contracting this condition [22]. Financial barriers make it difficult for uninsured individuals to access healthcare services, such as diagnostic tests, medications, and hospitalization. If health insurance is not available, medical care may be delayed, leading to more severe disease progression and poorer outcomes [8]. Consequently, it is imperative to cover and enhance diagnostic methods and treatments.

2.2. Human Immunodeficiency Virus (HIV)

Human immunodeficiency virus (HIV) is an agent that has caused a serious public health problem since it was identified in 1981. With a fast and aggressive replication starting in the first stages of the pathology, it causes the destruction of the immune system and becomes acquired immunodeficiency syndrome (AIDS) in the most advanced stage of the disease [23]. As HIV targets the different leukocyte populations, it weakens the immunological system, increasing the probability of presenting normally harmless community acquired infections and other diseases like TB and several kinds of cancer [23,24]. Furthermore, these changes in the immunological system can also be increased by risk factors such as a higher body mass index, high levels of HbA1c, insulin resistance, hypertension or high serum lipidic levels [25], which imply a chronic systemic low-grade inflammatory status with or without obesity [26].

It is also remarkable that for pharmaceutical control of HIV, antiretroviral therapy (ART), a combination of molecules that can decrease the viral multiplication, must be used, reducing the viral load and thus the viral activity in the host and the possibility of its transmission. Nevertheless, these substances have also been related with adverse metabolic effects (especially when used in a long-term administration) that include immune activation, chronic inflammation, adipose tissue dysfunction, modifications in insulin–glucose homoeostasis, and even lipidic and cardiovascular changes [27,28].

By 2021, it was reported that nearly 38.4 million people lived with HIV around the world, with 2.1 million in Latin America, 340,000 in Mexico, and over 40,000 in Mexico City [29,30]. In Mexico, the states of Veracruz (13%), Mexico City (9.5%), Jalisco (8%), the State of Mexico (6.9%), and Baja California (6.8%) have the highest rates of HIV-related deaths [31]. This highlights the importance of the control of this pathology when analyzing TB implications in this vulnerable population.

2.3. Diabetes

In Baja California, Mexico, the prevalence of type 2 diabetes mellitus (T2DM) in the population aged 20 years and over is 10% according to data from the National Health and Nutrition Survey (ENSANUT) 2018. Furthermore, 86.9% of adults with a previous medical diagnosis of diabetes in the country use some form of pharmacological treatment, with oral hypoglycemic agents being the most common (67.1%) [32]. Although TB susceptibility is typically associated with underweight individuals, low-grade chronic inflammation due to obesity and related metabolic comorbidities [33], particularly T2DM, has been shown to triple the risk of infection and exacerbate its severity [34]. More importantly, the metabolic pathology increases the treatment failure rate and the susceptibility of infection with a resistant strain [35]. Worse immunological markers have been associated with this stage, with dysregulated cytokine responses and relations between 1 and 2 profile cytokines, impaired pathogen recognition, decreased phagocytosis, and cellular activation [36]. Other epigenetic modulators in these patients and other pathogenic strategies including the dormancy adaption via two-component systems, redox-potentiated proteins, and other strategies to dampen the oxidative damage may also increase immune evasion bacterial mechanisms and can further impact the establishment of the infection. Lifestyle is thus a determining factor for control and normal immunological outcomes, which include granuloma formation and the non-infective cycle of M. tuberculosis.

A low body mass index is an established risk factor for active TB. Recent evidence suggests that TB is linked to an acute or chronic decrease in body weight [33]. In fact, being underweight increases vulnerability to TB through mechanisms related to compromised immune and thymic function. Low plasma leptin levels are associated with this condition, which is the opposite to the high leptin concentration that occurs in obesity because of the increment in fat mass. Leptin promotes proliferation and activation of T lymphocytes upon mitogen stimulation, thus, despite the proinflammatory role of this molecule, it can serve as a protective factor against infections [33]. Nutritional factors and the related obesity and adiposity can influence the activity of the immune system to combat TB and other infections. The role of cytokine-mediated innate immunity in host protection against TB infection has been demonstrated in numerous experimental models of infection and established critical roles for interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukins (IL) in controlling infection [33]. In obesity, there is an over-expression of TNF-α, which attracts M1-polarized macrophages, thereby increasing the levels of inflammatory mediators such as C-reactive protein, IL-1β, IL-6, IL-8, IL-12, and IFN-γ.

In the case of obesity associated with diabetes, no mediated effect on TB has been observed. The protective effect of a high body mass index (BMI) seems to be stronger than the increased risk due to diabetes itself [37]. In this sense, T2DM also results in an increase in neutrophils and monocyte-secreted cytokines, including TNF-α, IL-6, and IL-8. In addition, there is an impairment in infection by the induction of cytokine production and a reduction in phagocytic and antibacterial activity. T2DM decreases the level of regulatory T cells (Tregs) while increasing Th17 populations, promoting an exaggerated inflammatory response [38]. Thus, T2DM could be considered as a risk factor for developing TB, which has to be considered in the search for new prophylactic strategies [38]. Additionally, T2DM is associated with the development of drug-resistant TB, which contributes to maintaining the TB condition as a serious health concern [39]. T2DM increases the risk of developing TB by 3.1-fold, and the association with TB has been recognized as a risk factor for unfavorable treatment outcomes, increasing the probability of failure, relapse, or death. Comorbidities have a 4.7-fold greater risk of becoming single-drug resistant, and a 2.8- to 3.5-fold increased risk of becoming multidrug resistant (DR-TB), promoting the elongation of the infection and proliferation of the microorganism, which has been partially explained by the decreased plasma concentrations of anti-TB drugs, interference by drugs used for glycemic control, and immunological alterations. Chronic hyperglycemia due to poorly controlled diabetes may promote the accumulation of advanced glycation products (AGEs) and receptors for AGEs (RAGEs), mainly expressed in the lungs, the primary site of TB infection. Activation of RAGEs leads to increased inflammation due to the production of reactive oxygen species and proinflammatory cytokines, such as IL-1β and IL17, resulting in defective phagocytosis, coupled with an increase in oxidative stress and changes in the distribution of anti-TB drugs, which are factors that could modify the mutation rates of the increasing risk of developing drug- and multidrug-resistant TB. Particularly, katG S325T mutation has been associated with isoniazid resistance at an early stage of the infection [39].

Other authors like Lin, Wu, Wang, Fu, Lönnroth, Chang and Huang [37] have reported that individuals who were simultaneously obese/overweight and diabetic had a similar or even lower risk of TB than non-diabetic individuals with normal weight. In addition, metabolic syndrome intensifies with an increase in adiposity, thereby raising the level of immune protection against TB, which at the same time is counterbalanced by the deleterious effects of dysglycemia [38]. Arias, Goig, Cardona, Torres-Puente, Díaz, Rosales, Garcia, Tapia, Comas, Vilaplana and Cardona [38] showed that a high-fat diet can trigger a pro-inflammatory response, resulting in a faster progression toward active TB and an impaired protective effect of Bacillus Calmette-Guérin vaccination, which is not the case for natural immunity. The authors suggested that there is a dysbiosis in gut microbiota either in obesity or TB. As T2DM is a risk factor for developing TB, these findings may prove useful in the search for new prophylactic strategies for this population subset. Curiously, a recent study in a human cohort has shown an increase in gut microbiota diversity in TB patients. This is an interesting finding given that the BMI of TB patients was significantly lower than for healthy controls [40].

The analysis of the disease and variables is indeed very important. In

Table 1. Integration of the factors linked to the typical tuberculosis (TB) pattern.

Factor	Shared Aspects and Importance	Regional Impact in Baja California	Reference
COVID-19	Immunological imbalance. Co-infection may increase the risk of both diseases’ progression. COVID-19 infection may activate latent tuberculosis.	The seroprevalence of COVID-19 infection until February 2021 (in the highest point of the pandemic) was similar to other states in Mexico. There seems to be no association with the fact that it is a border area with higher infection rates, but other factors such as vulnerability, poverty, hygiene, and nutritional changes may induce worst infection scenarios.	[41]
HIV	Close relationship and worst scenarios of the disease. The immunological impairment, and poor treatment response are frequent.	The PreveTB study in Tijuana, Baja California, measured the relationship between TB and HIV in marginalized populations, with the latter having a prevalence of 4.2% in people living with tuberculosis, compared with 0.8% and 0.9% in the country general population.	[42]
		Some other studies have explored the phenomena of aggravation between tuberculosis in people living with HIV. A retrospective review of the medical records of all children with perinatally acquired HIV infection evaluated at Tijuana General Hospital in Baja California noticing cumulative hospital admissions from pneumonia, cough, anorexia, high morbidity, and mortality.	[43]
Diabetes	Close association between diabetes and tuberculosis, especially in populations with low socio-economic status.	This comorbidity has been explored in Baja California analyzing the prevalence of SLCO1A1 and SLCO1B1 polymorphisms to elucidate the relationship with rifampicin resistance and pharmacokinetics although the high diversity in the Mexican population requires more studies.	[44]
		This association was also evaluated in Texas patients hospitalized in the 15 counties along the Mexican border. People living with diabetes were almost twice as likely to have tuberculosis after adjusting by sex, age, and race/ethnicity having these variables a strong association.	[45]
Pollution	Directly linked to tuberculosis. The association with immunological changes has been assessed from levels such as PM2.5.	Although no data from Baja California have yet linked these variables, a 2021 review and meta-analysis showed that long-term exposure to particulate matter PM10, SO2 and NO2 was significantly associated with TB incidence.	[46]
		A nested case–control study within a cohort of Kaiser Permanente of Northern California showed through conditional logistic regression models that single pollutants with the highest odd ratios for tuberculosis were CO and NO2.	[47]
Tobacco smoking	Directly linked to lung impaired immunological responses and worst responses to tuberculosis treatment.	Although no studies have been performed in Baja California, a nested case–control study among members of Kaiser Permanente Northern California (KPNC) explored this relation in the north California population, showing increased pulmonary TB risk among ever-smokers, current and past smokers.	[48]
Low socio-economic status	Directly linked to immunosuppression, parasitism, malnutrition, and hygiene changes.	The area-based socio-economic status measures have been linked with tuberculosis incidence from data of the California TB registry on persons with active TB disease during 2012–2016 showing that persons living in census tracts with low status had higher TB incidence rates than those living in high status census tracts, assessed by education level, poverty, crowding or and the California Healthy Places Index.	[49]
Deficit malnutrition	Directly linked to immunosuppression and parasitism.	Not yet analyzed as single relationships but as cumulative risk factors for disease.
Obesity or a high body mass index (BMI)	Directly linked to low-grade chronic inflammation.	Not yet analyzed as single relationships but as cumulative risk factors for disease.
Drug resistance	Linked to the presence of the other risk factors by neglecting the immune system and global health.	In 2013, an analysis showed that antituberculosis treatment was associated with multidrug-resistant TB in Mexico-born TB patients in California and other patients born elsewhere, noticing that they had greater odds of MDR-TB compared with U.S.-born patients.	[50]
		Although more specific information is still missing in Baja California, in another northern state of Mexico, the linked prevalence of drug-resistant strains was analyzed in HIV and T2DM patients, noticing how important it is to control the other comorbidities to protect high-risk populations.	[51]
Migration	Linked to the presence of the other risk factors by neglecting the immune system and global health.	New studies have clustered most Baja California clinical isolates into three distinctive groups—San Diego and South America strains and other parts from other Mexican regions. Yet, at least 12% of the analyzed strains are autochthonous of Baja California.	[19]

, some additional comments of the regional situation in Baja California considering other factors linked with tuberculosis are made.

3. Detecting and Implementing Analytical Tools Early Are Crucial for Managing Tuberculosis in the Migratory Region

3.1. New Analytical Tools

The introduction of polymerase chain reaction (PCR) molecular tests has been a significant advancement in TB diagnosis. These tests have high sensitivity and specificity for detecting bacterial DNA in clinical samples. Additionally, rapid diagnostic tests, such as the tuberculin skin test and tests for the detection of specific M. tuberculosis antigens, provide results quickly, allowing for accurate and timely diagnosis and early treatment initiation. In the field of treatment, advances include the development of standard treatment regimens that combine effective and well-tolerated antitubercular drugs. These regimens have cure rates exceeding 90% in cases of drug-sensitive TB [52].

However, drug resistance, especially to rifampicin, has raised concerns. To address this, new treatment regimens have been developed that include second-line medications such as bedaquiline and delamanid, which have been effective against drug-resistant strains of M. tuberculosis. In recent years, there has been concern about the increasing drug resistance, especially resistance to rifampicin. To address this challenge, new treatment regimens for drug-resistant TB have been developed and recommended. These regimens include the administration of second-line medications, such as bedaquiline and delamanid, which have been shown to be effective against drug-resistant strains of M. tuberculosis. According to a study by Piubello et al. [53], the use of these medications in combination with other drugs has led to cure rates exceeding 50% in cases of multidrug-resistant TB.

TB diagnosis by PCR allows for the detection of the bacterial DNA in clinical samples, such as sputum or blood, with high sensitivity and specificity. A recent study conducted by Xu et al. [54] demonstrated that PCR has a sensitivity of 95% and a specificity of 98% compared to traditional diagnostic methods. According to a study, the antigen detection test has a sensitivity of 92% and a specificity of 98%. Advanced imaging techniques, such as high-resolution computed tomography (HRCT), have been developed to aid in the diagnosis of pulmonary TB. HRCT allows the visualization of characteristic TB lesions, such as nodules, cavities, and lymphadenopathy, with greater clarity and precision. Other molecular diagnostic techniques based on the detection and analysis of the genetic material of the microorganism to specifically identify it, are genotypic. These include NAAT (nucleic acid amplification tests), which amplify specific sequences of the genetic material of M. tuberculosis by PCR in clinical samples such as sputum, pleural or ganglia fluid [55]. As they are highly sensitive and specific, they can quickly and precisely help to diagnose TB. Other genotypic tests are fast and can even detect some antibiotic-resistant strains. In this group, INNO-LiPA MYCOBACTERIA and GenoType MTBC are included based on their ability to test for specific DNA sequences such as IS6110, 16S, mce-3, RD, and mtp-40 [56,57,58].

Several new techniques to determine the presence of the bacteria have also been developed for the diagnosis of the pathology, such as new biomarkers including urinary lipoarabinomannan [59], novel biosensors such as the peptide nuclide acid electrochemical biosensor based on reduced graphene oxide (NH₂-rGO)/2,2,6,6-tetramethylpiperidin-1-yl) oxyl nanocrystalline cellulose (TEMPO-NCC) [60], an electrochemical genosensor assembled to detect Mtb in lyophilized powder [61], an optical biosensor based on the FRET method, also known as a universal fluorescent biosensor for the bacterial detection of the insertion sequence IS6110 gene fragment [62], a green graphene nanofiber laser biosensor (LSG-NF) with oil palm lignin-based synthetic silver nanoparticles [63] and even a MR-biosensor [64] with high potential for TB diagnosis. All future research and applications on the procedures for the extraction, isolation and assessment of clinical samples will allow the use and adaptation of new technologies in a real clinical problem.

In Mexico, TB diagnosis is validated by the National Tuberculosis Program from the Special System of the Epidemiological Vigilance of Tuberculosis and the National Network of public health laboratories for the TB vigilance (RNLSP-tb). Bacilloscopy is established as the most important technique in TB research; and in special cases, other confirmatory methods can also be included. The challenge remains the diagnosis and identification of the antibiotic resistances as soon as possible. For this purpose, phenotypic, genotypic and whole-genome sequencing methods have been developed. The first ones include Bacilloscopy, a fast diagnosis method in which the observation of the sputum under microscope can detect the presence of the acid–alcohol-resistant bacillus, characteristics of M. tuberculosis. Other less specific ways of assessment include optical microscopy, which can be improved by using fluorescent and LED microscopy to increase the visibility of the presence of the bacillus, thus increasing the sensitivity of the diagnosis. Löwenstein–Jensen, Stonebrink & Middlebrook 7H10 and 7H11 and the liquid medium BACTEC are methods used in liquid and solid cultures to promote the growth of M. tuberculosis from clinical samples, confirming its presence in patients. Matrix-Assisted Laser Desorption Ionization-Time-Of-Flight (MALDI-TOF) is also used for the rapid and precise identification of the microorganisms, implying the ionization of their molecules and the measurement of its molecular mass to compare with a database for the identification of the bacteria [65]. The three main selected techniques, PCR, traditional Bacilloscopy and cultures, as long as genotypic tests, are the most practical and widely applied diagnostic tools in Baja California due to their proven effectiveness and availability. PCR is valued for its high sensitivity and specificity, allowing precise and rapid detection of bacterial DNA (

Table 2. Analytical tools for tuberculosis (TB) diagnosis and treatment in Baja California.

Tool/Technique	Description	Current Application in Baja California	Comments and Suggested Improvements
PCR (Polymerase Chain Reaction)	Molecular test with high sensitivity and specificity for detecting bacterial DNA in clinical samples.	Widely applied	Highly effective; improve access to equipment and training.
Traditional Bacilloscopy and Cultures	Bacilloscopy for detecting acid-alcohol-resistant bacilli; cultures (e.g., Löwenstein–Jensen, BACTEC) for growing M. tuberculosis.	Common diagnostic method	Enhance sensitivity and reduce diagnosis time.
Genotypic Tests	Includes NAATs and other tests for detecting genetic material of M. tuberculosis and antibiotic-resistant strains.	Used in advanced diagnostic settings	Increase availability and reduce costs.
Other Tools and Techniques
Tool/Technique	Description	Current Application	Comments and Suggested Improvements
Rapid Diagnostic Tests	Includes the tuberculin skin test and tests for specific M. tuberculosis antigens.	Commonly used for quick diagnosis	Maintain availability and enhance accuracy with new antigen tests.
Standard Treatment Regimens	Combine effective, well-tolerated antitubercular drugs, achieving high cure rates for drug-sensitive TB.	Standard practice in treatment	Continue monitoring drug efficacy and side effects.
New Treatment Regimens for Drug-Resistant TB	Involves second-line drugs like bedaquiline and delamanid.	Increasing use in drug-resistant cases	Increase accessibility and monitor resistance patterns.
HRCT (High-Resolution Computed Tomography)	Advanced imaging technique for visualizing TB lesions.	Used in specialized diagnostic settings	Expand access to imaging facilities.
Biomarkers and Novel Biosensors	Emerging technologies like urinary lipoarabinomannan and various biosensors for rapid detection of TB.	Limited use; mostly in research	Further validation and integration into clinical practice.
MALDI-TOF	Uses ionization and mass spectrometry for rapid identification of microorganisms.	Used in specialized laboratories	Improve database for better identification accuracy.

). Traditional Bacilloscopy and cultures remain fundamental methods because they confirm the presence of M. tuberculosis through direct observation and bacterial growth. Genotypic tests are essential for identifying antibiotic-resistant strains, enabling more targeted and effective treatment. These methods form the foundation of TB diagnosis and treatment in the region, though continuous improvement in infrastructure and access to advanced technologies is necessary.

3.2. Management of the Tuberculosis Program in Mexico

Several governments have acquired policies by which they subsidize at least some of the molecules of the first line of the treatment. Nevertheless, as for other diseases, the therapies are usually long, expensive, and inaccessible for a large proportion of the patients. To evaluate the bacterial pharmacological treatment resistance, several methods currently used, such as Xpert^® MTB/RIF, INNO-LIPA Rif TB kit, GenoType MTDRplus and GenoType MTBDRsl [66]. The sequencing process which can also determine the whole order of the nitrogen bases of the microorganism. The current platforms for this analysis include Roche454, MiSeq Illumina, PacBio and IonTorrent and have lately revolutionized our capacity for studying genetics and their applications for microbiology research [67,68].

The treatment of TB has evolved considerably in recent decades, thanks to the advancements in research and the development of new medications. Modern treatments for TB focus on administering a combination of effective and well-tolerated antitubercular drugs, with the goal of achieving cure and preventing drug resistance. The standard treatment regimen for drug-sensitive TB includes the administration of four first-line medications: isoniazid, rifampicin, pyrazinamide, and ethambutol. These medications are given daily during an initial intensive phase, followed by a maintenance phase lasting several months. According to World Health Organization (WHO) guidelines, this treatment has a cure rate of over 90% in cases of drug-sensitive TB. Furthermore, short-course therapies have been developed for the treatment of drug-sensitive TB. For example, the treatment regimen with rifapentine and isoniazid administered once a week for three months has been shown to be as effective as the standard six-month regimen. According to a clinical trial conducted by Njie et al. [69], this short-course treatment regimen has a cure rate of 90% in cases of drug-sensitive TB. Additionally, short-course therapies, such as the rifapentine and isoniazid treatment regimen administered once weekly for three months, have been shown to be as effective as standard six-month regimens. Drug-resistant TB cases and deaths have risen, highlighting the need for new treatments. Current DR-TB treatments have issues like long duration, significant side effects, and drug resistance. Alpibectir (BVL-GSK098) is a promising new drug targeting mycobacterial transcription regulators, enhancing the bioactivation of ethionamide (Eto), reducing the required dose, and minimizing side effects. Alpibectir has shown high solubility, good bioavailability, and a favorable safety profile in preclinical studies. A first-in-human study is underway to assess its safety, tolerability, and pharmacokinetics [70,71]. Bacteriological diagnosis of TB in Mexico relies on the laboratories of the “Red Nacional de Laboratorios de Salud Pública para la Vigilancia de la Tuberculosis,” which has different administrative levels and diagnostic capabilities. This network ensures that diagnostic techniques are uniform and follow the guidelines for tuberculosis surveillance. As said before, the Baja California state is located at the border of the United States of America and presents high incidence of TB [72] and the government subsidizes first-line treatment. In cases of resistance, second-line therapies are administered, which are not funded by the government, making adherence to treatment very difficult for low-income patients. There are also alternatives for some patients to be part of the binational project “Programa Binacional de Tuberculosis Esperanza y Amistad” and the “Comisión de Salud Fronteriza México—Estados Unidos,” which subsidize the second-line treatment.

Furthermore, most private primary care clinics consider the implementation of TB screening in T2DM patients acceptable and practicable. In fact, a great number of diabetic patients enthusiastically accept TB–T2DM screening services. T2DM prevalence was 10.6% in 2020, and as mentioned before, previous studies have identified factors associated with TB–T2DM duality in rural populations of Mexico, where factors such as low income or insufficient income for basic needs, obesity and migration (central American migrants aiming to reach the U.S.) contribute to the problem [73]. The increasing link between this pathology and diabetes, higher incidence, mortality rates, and the need for tailored interventions are specific challenges faced in the region [74]. In addition, healthcare professionals in clinics or hospitals are aware of the nature of the intervention and demonstrate a positive attitude to combating this burden. The stigma associated with other infectious diseases like COVID-19 has emerged as new implementation barriers, joining TB stigma, lack of resources, and regulatory issues. Gradual and analytical screening is a potential method for enhancing the implementation of TB-DM screening [75]. The importance of national and binational programs needs to be emphasized and encouraged by governments and health authorities along with the internal sector links to consolidate strategies for combating TB, especially along the northern border of Mexico, due to the T2DM and migration phenomena.

Table 3. Comparison of World Health Organization (WHO) recommendations and Mexican tuberculosis (TB) management practices.

Aspect	WHO Recommendations	Practices in Mexico	Comments and Suggestions for Improvement
First-Line Treatment Subsidy	The WHO recommends subsidizing essential TB medications to ensure accessibility.	The government subsidizes some first-line medications, but many therapies remain expensive and inaccessible.	Increase subsidies and make all essential medications more accessible to patients.
Diagnostic Methods	The WHO promotes the use of modern diagnostic tools like Xpert® MTB/RIF, INNO-LIPA Rif TB kit, GenoType MTBDRplus, and sequencing technologies.	Uses advanced diagnostic tools, including Xpert® MTB/RIF and genotypic tests, but access varies across regions.	Expand access to advanced diagnostics, especially in underserved areas.
Treatment of Drug-Sensitive TB	The standard treatment regimen includes isoniazid, rifampicin, pyrazinamide, and ethambutol, with short-course therapies as an alternative.	Follows the WHO regimen for drug-sensitive TB with high cure rates, including short-course therapies where applicable.	Maintain adherence to the WHO guidelines and consider expanding short-course therapy access.
Treatment of Drug-Resistant TB (DR-TB)	The WHO recommends using second-line drugs and developing new medications.	Second-line therapies for DR-TB are not government funded, making them inaccessible for many low-income patients.	Increase government support for second-line treatments and explore new drug options.
National Laboratory Network	The WHO emphasizes a standardized and coordinated national laboratory network for TB diagnosis.	The “Red Nacional de Laboratorios de Salud Pública para la Vigilancia de la Tuberculosis” follows standardized practices.	Strengthen and expand the capabilities of the national laboratory network.
Special Programs and Binational Cooperation	The WHO encourages international cooperation and targeted interventions for TB, especially in high-risk areas.	Participates in the “Programa Binacional de Tuberculosis Esperanza y Amistad” and other cross-border initiatives.	Enhance binational collaboration and increase funding for these programs.

recapitulates the recommendations of the WHO [76] and contrasts it with Mexican TB management practices.

4. Conclusions

During the COVID-19 pandemic, there was an increase in tuberculosis cases and deaths, as well as its transmission. This was partially due to a decrease in the notification of tuberculosis cases in all forms during the pandemic but not yet of its existence. In fact, focus group discussions and interviews revealed that the primary causes of this were a reduction in tuberculosis case notifications and less interest in its surveillance, thus its transmission continued even without being well detected and/or treated. Other causes include the disruption of TB services and restrictions on patient movement, consequently increasing TB-related deaths. Also, a decrease in case-finding efforts of community health workers and outreach workers, delays in tuberculosis diagnosis, and limited access to tuberculosis supplies and services were found. As for other important pathologies for the population such as metabolic diseases like diabetes mellitus, hypertension or hyperlipemia, they were also found to be a second-level cause—in fact, COVID-19 was the most important statistically and acutely affected several people.

Particularly in border cities in Baja California, Mexico, such as Mexicali and Tijuana, the migrant population faces serious public health challenges, particularly concerning tuberculosis. The vulnerability of this population, often housed in shelters or wandering the city, contributes to frequent treatment abandonment, which exacerbates the transmission of the disease. This problem is further compounded by a poor nutritional and health status and treatment resistance, making the control of tuberculosis even more difficult. The lack of access to adequate diagnosis and treatment in a potentially overburdened and resource-limited health jurisdiction transforms this issue into a public health crisis that requires urgent and coordinated attention. It is crucial to reduce the costs of diagnostic techniques to detect resistant strains to first-line tuberculosis treatments, as this will enable early and accurate disease detection. The implementation of more affordable and accessible technologies will not only facilitate tuberculosis monitoring and control but also ensure that all individuals, regardless of their economic situation or geographic location, can access these vital diagnostics. In this way, the response to resistant tuberculosis can be significantly improved, reducing the spread of the disease, and improving global health outcomes.