Prevalence of latent tuberculosis infection determined by interferon-gamma release assays in patients with immune-mediated diseases

doi:10.21203/rs.3.rs-5018941/v1

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Prevalence of latent tuberculosis infection determined by interferon-gamma release assays in patients with immune-mediated diseases

https://doi.org/10.21203/rs.3.rs-5018941/v1

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Background

Patients with Immune-mediated inflammatory diseases (IMIDs) are at high risk of reactivation of tuberculosis, the risk is determined on the type of drug disease-modifying antirheumatic drugs (DMARDs). The objective of this study was to determine the prevalence of latent tuberculosis infection (LTBI) and associated factors in people who started or who were on DMARDs treatment.

Methods

A cross-sectional study was conducted in Mexico City from January 2021 to June 2024. People ≥ 18 years old, in the clinic of IMIDs, on mainly biological DMARDs treatment or before it was started. The prevalence of LTBI was determined by gamma interferon release assay (QuantiFERON-TB Gold Plus). Categorical data were expressed as frequencies and percentages, quantitative data in median and interquartile ranges, prevalence of LTBI was presented as percentage. A bivariate analysis was performed with x² test to identify associated factors. A multivariate analysis was performed using a logistic regression model.

Results

A total of 304 patients were analyzed, 154 (50.7%) were men, with median age of 53 (IQR 39–61) years. Prevalence of LTBI was 34.2% (95% CI 29.1%-39.7%). The most frequent IMIDs were psoriasis in 123 (40.4%) and, rheumatoid arthritis in 47 (15.4%). The most prescribed biological DMARDs were adalimumab in 132 (43.4%) and secukinumab in 46 (15.1%). After a logistic regression model, prior exposure to contacts diagnosed with tuberculosis OR 4.20 (95% CI 1.74–10.12, p = 0.001) and TST ≥ 5 mm OR 99.3 (95%CI 12.7-773.2) remain statistical significance.

Conclusions

A high prevalence of LTBI was found in patients with IMIDs treated with biological DMARDs. tumor necrosis factor alpha inhibitors were widely prescribed in these patients. The history of exposure to contacts diagnosed with tuberculosis and TST ≥ 5 mm were associated with positive IGRA for LTBI.

Latent tuberculosis

Autoimmune diseases

Antirheumatic Drugs

Disease Modifying Antirheumatic Drug

Interferon-gamma release assay

Tuberculosis (TB) is one of the diseases with the highest mortality rate, it is among the top ten causes of death worldwide, occupying ninth place in developing countries, and being the main cause of all infectious etiologies [1].

Latent tuberculosis infection (LTBI) is a state in which bacterial replication is absent or below an undefined threshold and there are considerable differences in the incidence of LTBI according to the geographic area, epidemiological factors, and clinical risk factors, such as immunosuppression and the presence of Immune-mediated inflammatory diseases (IMIDs) [2]. Disease-modifying antirheumatic drugs (DMARDs), specifically biological DMARDs, increase the risk of reactivation; although, varies depending on the used drug, the highest risk has been associated with tumor necrosis factor alpha inhibitors (TNF-alfa) [3].

The World Health Organization (WHO) recommends the use of tuberculin skin test (TST) or interferon-γ release assay (IGRA) for the detection of LTBI [4]. The estimated prevalence of LTBI in people with IMIDs has been reported with great variability worldwide. In Brazil, the prevalence was 29.5%, in patients with IMIDs screened with TST and in Peru was 29% with TST; however, differences probably are due to the test performed [5–7]. The prevalence has been reported variable in relation to the type of test used, estimating a higher sensitivity and specificity for IGRA [8–9]. To date, global prevalence of LTBI has been estimated using TST [10].

In Mexico, the prevalence of LTBI in IMIDs patients determined by IGRA has only been estimated in rheumatoid arthritis group and not in the other types of IMIDs [11]. The objective of the study was to determine the prevalence of LTBI by IGRA, and associated factors in people with IMIDs before starting DMARDs treatment or in those who have already received them.

A cross-sectional study was conducted from January 2021 to June 2024 at the Hospital de Infectología, National Medical Center, “La Raza”; this is a national reference center for infectious diseases, located in Mexico City, where patients of all the country with social security insurance can be attended. The Ethical local health and, Research Committee of the Infectious Diseases Hospital approved this study with number R-2024-3502-133.

People over 18 years old with IMIDs without a previous diagnosis of active TB or LTBI were included. Patients were referred to the infectious diseases clinic as part of a protocol to search for active infections or look for a risk of TBLI reactivation in those patients starting or undergoing treatment of DMARDs. The data were collected from direct assessment and laboratory profile. Patients who lost social security and, those who did not undergo IGRA testing were excluded from the study.

The diagnosis of LTBI was established according to results of IGRA through QuantiFERON-TB Gold Plus (QFT) from the blood plasma sample which was performed in all patients included. Clinical data were type of IMIDs, type of synthetic DMARD used or Janus kinase inhibitor, biological DMARDs prescribed for each patient, previously DMARDs used, comorbidities, tobacco use, and alcohol consumption. Laboratory data such as hepatitis B virus (HBV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) antibodies were also collected. Sociodemographic data such as occupation, educational level, history of vaccination including Bacillus Calmette-Guerin (BCG) vaccine, place of birth, place of residence, and exposure to TB defined as contact with people diagnosed with tuberculosis, whether through family contact, job contact, or staying in overcrowded centers was obtained through direct interview during initial evaluation.

The place of birth/residence were classified according to the estimated incidence for each state from national average calculated in 2021 by the national epidemiological surveillance system of Mexico. The states with higher incidence than the national average (15.7 cases per 100 patient-years) were considered with a high incidence of TB and, those with a lower incidence than the national average were estimated with a low incidence.

The prevalence of LTBI was estimated with the number of patients diagnosed with LTBI divided by the total number of patients included in the analysis. Categorical variables were expressed as frequencies, percentages, or proportions, as appropriate, quantitative variables were reported as mean and standard deviation or median and interquartile range, depending on the distribution of the variables, using the Kolmogorov-Smirnov test. Odds ratio (OR) were obtained through x² or Fisher exact test; OR found with a p-value ≤ 0.25 for developing TBLI were included in a logistic regression model to obtain adjusted OR (aOR). A p value ≤ 0.05 was considered statistically significant. The statistical analysis was performed with the IBM SPSS Statistics 22 program for the macOS Ventura 13.6.4 operating system.

During the study period, 329 patients were attended in the IMIDs clinic; 25 (7.6%) patients were excluded due to history of active TB or TBLI. All patients underwent IGRA testing using QuantiFERON TB Gold Plus.

A total of 304 patients were included (Figure 1), 154 (50.7%) were men. Median age was 53 (IQR 39-61) years. An educational level corresponding to middle-high and professional degree was found in 211 (69.4%) patients. The most reported jobs were merchants in 84 (27.6%), professionals in 60 (19.7%) and, domestic service workers in 35 (11.5%). Regarding the geographic region, 274 (90.1%) patients were from the central region of the country, the states with the highest number of cases were Mexico City 196 (64.4%) and Mexico State 53 (17.4%). Considering the origin regions, 22 (7.2%) patients belong to Veracruz, Guerrero, Oaxaca, Nuevo León; classified with high incidence of TB (>15.7 cases per 100,000 inhabitants). Two naturalized Mexican patients, who were born in Bolivia and Venezuela were included. The most frequently comorbidities were systemic arterial hypertension in 94 (30.9%), diabetes in 68 (22.4%) and, metabolic syndrome in 25 (8.2%) (table 1).

Tobacco use was found in 105 individuals (34.5%) and alcohol consumption in 96 individuals (31.6%). In some people other infections were found HIV in 3 (1.0%) HCV 1 (0.3%) and 1 (0.3%) for HBV.

Cases from Dermatology, Rheumatology, Gastroenterology, and Neurology departments were analyzed. The most frequently IMIDs reported were dermatological in 186 (61.1%) of the cases. Psoriasis was the most common IMIDs 126 (41.4%), rheumatoid arthritis 47 (15.4%), ankylosing spondylitis and hidradenitis suppurativa 31 (10.1%) patients each one (table 2).

Anti-TNF-alfa agents were prescribed to 181 (59.5%) patients; of them, 139 (45%) patients had received a biologic DMARDs treatment before the QFT determination; anti-TNF-alfa was the most frequent previously used drug in 114 (37.5%). The most frequently prescribed biologic DMARDs were adalimumab in 132 (43.4%) cases, followed by secukinumab in 46 (15.3%) cases (table 3).

QFT determination was positive in 104 of the 304 patients. The prevalence of LTBI in this population was 34.2% (95% CI 29.1%-39.7%). In some cases, TST result was also available, with a positive test (induration greater than 5 mm for the risk group) in 230 of 304 patients (75%); the prevalence of LTBI by TST was 35.6% (95% CI 29.7%-42.0%). A bivariate analysis that included clinical and sociodemographic characteristics of this population was performed to evaluated possible associated factors with LTBI diagnosis (table 4). A statistically significant association was found for history of exposure to contacts diagnosed with TB OR 4.19 (95% CI 1.79 - 9.78, p = < 0.001), TST ≥5 mm OR 99.3 (95%CI 12.7-773.2) and previous use of anti-TNF-alfa OR 1.40 (95% CI 1.00 – 1.97, p = 0.038). A multivariate analysis was then performed by logistic regression model including associated factors with a P-value ≤0.25 in bivariate analysis. Only prior exposure to contacts diagnosed with TB OR 4.20 (95% CI 1.74 – 10.12, p= 0.001) and TST ≥5 mm OR 99.3 (95%CI 12.7-773.2) remain statistical significance.

In this cross-sectional study, a high prevalence of LTBI was found in patients with IMIDs. Almost two-thirds of patients included had a dermatological condition. The most common IMIDs were psoriasis, followed by rheumatoid arthritis and, the most common prescribed biological DMARDs were anti-TNF-alfa drugs. Prior exposure to contacts diagnosed with active tuberculosis and, TST ≥ 5 mm were found like a significative associated factors to LTBI by IGRA in this group of patients.

Prevalence in this population is higher than global prevalence of LTBI, that has been estimated at 24.8% determined by IGRA, Mexico is classified as a country with an estimated prevalence of tuberculosis of 19–20% [10]. The higher LTBI prevalence described in this study also contrast with findings of other studies that included Latin-American population. In 2017, Garziera et al. [5] found a prevalence of 29.5% in the Brazilian population and Ponce de León et al.,[6] in 2005, found a prevalence of 29% in the Peruvian population; in these studies, LTBI detection was performed only with TST, and patients with diseases such as diabetes, liver or kidney disease, malnutrition, and cancer were not included. The prevalence in this study was higher than previous publications to the fact of performing LTBI detection by using IGRA (QuantiFERON TB Gold plus) to define cases; the prevalence reported in other studies was determinate with TST, which could decrease diagnostic sensitivity [9].

In Mexico, studies have been carried out to determine LTBI in different risk groups such as migrants, hematological malignancies patients, people living with HIV, injectable drug users, older adults, patients with diabetes, and children; however, studies in people with IMIDs who are categorized using IGRA results are scarce. The study by Zavala et al. [11] was conducted only in patients with rheumatoid arthritis in whom LTBI was determined with QFT, finding a prevalence of 14%. That study only included cases from Veracruz, Mexico. It is important to highlight that more than 97% of the population evaluated in our study lives in the central area of Mexico, a region considered to have a low prevalence of TB compared to national average; nevertheless, in population analyzed in this study, the prevalence estimated was similar to that reported in specific areas of the country such as border regions, with a high prevalence of TB, in which the factors related were sociodemographic conditions like proximity to migrant populations, level of nutrition, type of employment, and overcrowding [12–13]. The large proportion of people residing in the central region of the country included in this study, is mainly explained by people assigned to the hospital.

More than a half of patients evaluated in this study have dermatological IMIDs, which is relevant since most clinical studies focus on rheumatologic diseases. This study provides information from an underrepresented population in global prevalence estimates of LTBI.

The risk of active TB varies depending on immunosuppressive used drug. In this population, almost half of the patients were going to start an anti TNF-alfa agent and, almost a third of the cases had history of prior prescription of these drugs. It is relevant to identified that in study population with a high prevalence of LTBI, anti-TNF-alfa drugs remain the most frequently prescribed therapy, despite the already known risk of TB reactivation associated with its use [14]. Other immunomodulatory therapies with a better safety profile regarding tuberculosis reactivation were used less frequently, like anti-IL-17 (Secukinumab and Ixekizumab) or anti-IL-23 (Guselkumab and Risankizumab) [15, 16].

Prior exposure to contacts with a patient diagnosed with TB is a well-known risk factor for TB infection and, maybe is the main mechanism for which people acquire TB and first degree relatives are particularly at a heightened risk [17–18].

TST ≥ 5 mm was a factor associated to positive IGRA, both had a high concordance to predict TBLI and it shows that in absence of IGRA, TST could help clinicians to detect TBLI in this group of people; although, TST is affected by treatment with glucocorticoids and conventional synthetic DMARDs, its performance is inferior to IGRA. Agreement between TST and IGRA is moderate to low [19].

This study has some limitations. First, the cross-sectional design limits exploration of other factors for TBLI. Second, some data relies on patients recall-memory, such as history of contacts with chronic cough, leading to possible information bias. Third, in some cases, patients were already receiving a biological DMARDs, so we cannot exclude impact of this drugs in performance of diagnostics test and, immunosuppression with prednisone could impact results of TST and IGRA.

A strength of this study is that we were able to categorize cases with the use of QFT. To date, few studies estimate prevalence of LTBI in both the general population and, in patients with IMIDs basing analysis on the use of IGRA, since it is not a test routinely available in most centers of Latin-America. Studies in immunocompromised patients often omit data on the history of BCG vaccination, as well as associated sociodemographic factors, which were described in this study.

A high prevalence of LTBI was found in people with IMIDs in this study, higher than the prevalence in the rest of the country. These emphasizes relevance of initial approach in patients that are candidates to biological DMARDs. Evaluation by an infectious disease physician in this group of patients should be considered essential due to the risk of reactivation of TB and consequently, increase in morbidity and mortality. Further studies of tuberculosis infection in populations from other regions of the country are needed, as well as analysis of risk factors in a prospective cohort in this population with IMIDs.

Tuberculosis

LTBI

Latent tuberculosis infection

DMARDs

Disease-modifying antirheumatic drugs

Anti-TNF-alfa

Anti-Tumor Necrosis Factor alfa

WHO

World Health Organization

TST

Tuberculin skin test

IGRA

Interferon-γ release assay

HBV

Hepatitis B virus

HIV

Human immunodeficiency virus

HCV

hepatitis C virus

BCG

Bacillus Calmette-Guerin

QFT

QuantiFERON™-TB Gold Plus

Clinical trial number: not applicable.

Ethics

This research was approved by the Committee for Scientific Research of the Mexican Institute of Social Security (R-2024-3502-133), the Research Committee, and the Research Ethics Committee of the Instituto Mexico del Seguro Social. According to the regulations of the Mexican General Health Law on Health Research, Article 17, for the above, this research was considered without risk, because it did not require the direct participation of patients and because the data were obtained from electronic records, an informed consent was not necessarily due to the non-interventional design of this study. An exception to consent was requested from the ethics and research committee and it was accepted.

Funding

This protocol did not require external funding because the infectious diseases department has the necessary resources for the development of the research. The institute's computer equipment was used to review electronic files. The Infectious disease hospital has the necessary resources to process samples in its laboratory for the determination of QuantiFERON-TB Gold Plus and test for other infections.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests

Authors' contributions

JAMM design of work, analysis, interpretation of data, drafting the work and reviewing; MAI design of work, data acquisition and analysis, interpretation of data, drafting the work; JPSN data acquisition; DEFM drafting the work and reviewing; GBA data acquisition; S.T.G data acquisition, drafting the work and reviewing; ALCD data acquisition, drafting the work and reviewing; JEGM data acquisition, drafting the work and reviewing. All authors read and approved the final manuscript

Acknowledgments

Not applicable

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Table 1 to 4 are available in the Supplementary Files section.

No competing interests reported.

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Prevalence of latent tuberculosis infection determined by interferon-gamma release assays in patients with immune-mediated diseases

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