INTRODUCTION

Tuberculosis (TB) infection continues to be a worldwide public health issue in which its incidence and mortality numbers have been declining in the last decade, apparently not fast enough for the targets set by the World Health Organization (WHO).¹During 2021, an increase of 4.5% in the worldwide incidence of TB compared to the previous year was reported, where 10.6 million people got infected and a mortality rate of 20 per 100 000 population was evidenced.¹One of the main possible causes of the increasing number of cases, is the impact of the COVID-19 pandemic on the unprepared healthcare systems for a crisis of this magnitude mirrored in a lack of TB related services.²As for Latin America, other aspects must be taken into account such as the ongoing political, economic, and social crises, a setback in poverty reduction, in addition to the increasing rates of homelessness and prisoners³,⁴,4which reflects in two south American countries with a position in the three global lists of high-burden countries for TB.⁵Brazil accounts for the only south American country included in two of them, the high burden TB list itself as well as in the HIV-associated TB one. In addition, Peru is the other south American country that has gained a spot in the third one, the Multidrug-resistant (MDR) / Rifampicin-resistant (RR) TB list⁶which keeps bringing nothing but concern in all aspects for disease control. It is worth mentioning that following the worldwide trend, Peru also experienced an increase of 5.1% in the incidence of TB between the years mentioned.

Alongside the growth in TB infection and death numbers, drug-resistant TB (DRTB), continues to be a rising problem. Reflected on the steady increase of these cases, several factors play a critical role on the risk to develop DRTB, including demographic and socioeconomic ones such as psychiatric illness, alcohol or drug addiction, homelessness, comorbidities and ages between 18 to 45.⁷On another hand, but still interrelated, history of previous treatment has been more strongly associated⁸with its different scenarios ranging from inadequate treatment for specific situations, as in wrong choice of new drugs for an unsuccessful treatment, discharge of still infected patients, cases of undetected underlying resistance and non-adherence, to genetic predisposition due to permanent or temporary mutations on efflux pump, propionate catabolism, glycerol kinase encoding associated genes, to name a few.⁹It is worth mentioning that Mycobacterium was found as one of the most important multi-antibiotic resistant bacteria (MAR) with the presence of 14 MAR genes.¹⁰

The development of different drug resistance patterns impacts socially and economically as it requires a prolonged and a more expensive treatment regimen involving investment in more resources and infrastructure, which are lacking in the context of low-income countries¹¹due to poor investment from the government in quantity or quality alongside different social factors.¹²This causes a great impact on morbidity and mortality especially in vulnerable communities for the access to health services in general.¹¹From this study we intend to describe the drug resistance patterns of Mycobacterium tuberculosis identified in the period of the year 2022 in our locality and to compare them with those existing in other realities.

MATERIALS AND METHODS

RESULTS

A total of 294 medical histories of patients with a diagnosis of tuberculosis in all its clinical forms were reviewed, of which 18 were excluded for having incomplete clinical-epidemiological-radiological data, in addition to 15 medical histories that did not have sensitivity profile data in the NetLab information system of the National Institute of Health; finally, 261 patients were included for the statistical analysis (Figure 1).

Figure 1: Flow chart 

As it is reported on Table 1, the most frequent age group was the 27-59 years old one and the majority were male (62.1%). Among the diagnostic criteria for patient admission, the most common was bacteriology (49.4%), followed by clinical/epidemiological/radiological (27.97%), histopathology (16.5%), and biochemical (6.13%). Sensitivity profile studies on antituberculosis drugs obtained were performed with Genotype (47.9%), Genexpert (49%), MODS (3.1%) diagnostic tests. Out of the 261 patients evaluated, 89.66% were sensitive to first line antituberculosis drugs; 6.13% were MDR-TB, and 0.77% presented XDR-TB resistance; likewise, 0.77% and 2.68% exhibited monoresistance to rifampicin and isoniazid respectively. Regarding the condition of admission, 83.14% were considered as new patients, this meaning they have never received treatment for TB infection; 15.71% presented relapse, defined by the Peruvian technical standard as presenting a new diagnosis of tuberculosis 6 months after the last diagnosis; and 1.15% were admitted as patients who resumed their treatment after not receiving it for 30 days or more, as established on the previously mentioned document. Most of the patients had no comorbidities (65,52%), although 14.18% had a diagnosis of HIV, 11.5% patients presented another condition that conditioned immunosuppression (diabetes mellitus, pregnancy, treatment with corticoids and chronic renal disease), 1.91% had another disease that did not condition immunosuppression (history of arterial hypertension, stroke, Parkinson's disease, bulimia, gout, human papilloma virus infection), 6.89% patients had unhealthy habits. With respect to last, it was observed that 6.13% of the patients consumed alcohol, 4.6% were drug users, 0.38% had a history of smoking and 91.95% had no harmful habits. In relation to risk factors, patients who had contact with active tuberculosis (19.16%), patients with MDR contact (1.15%), health workers (0.77%), and patients who did not present any risk factor (78.93%) were taken into account.

Figure 2:  Distribution of clinical forms of tuberculosis 

Distribution of the clinical forms of tuberculosis are shown on Figure 2. Most patients were diagnosed with pulmonary tuberculosis (49.04%), followed by pleural TB (21.84%). It was observed that 7.66% were diagnosed with multisystemic TB, 5.75% with mammary TB, 3.07% with ganglionar TB, TB of the central nervous system, osteoarticular and pleuro-parenchymal each accounting for 2.68% of the population; miliary and gastrointestinal forms where each constitutes 1.15% of the population; cases of genitourinary and cutaneous TB were each amounting to 0.77% and finally only 0.38% presented nasopharyngeal TB.

Table 2 indicates that 65.67% of patients between the ages of 27-59 years were diagnosed with extrapulmonary tuberculosis. Similarly, 62.69% of the patients with extrapulmonary tuberculosis were male. A significant p-value was obtained when evaluating the variables of diagnostic criteria, admission condition, type of diagnostic test used for the sensitivity profile. Most of the patients with a diagnosis of extrapulmonary tuberculosis had never been treated (90.30%). Regarding the sensitivity profile, 94.03% of patients with extrapulmonary tuberculosis were sensitive to first-line drugs; in contrast, patients with pulmonary tuberculosis presented more cases of MDR tuberculosis (9.45%).

The sensitivity profile observed in each group of patients is described on Table 3. Overall, the majority of patients were sensitive to first-line antituberculosis drugs. Statistically significant results were obtained when evaluating the sensitivity profile according to age as well as unhealthy habits. Most patients with MDR tuberculosis were between 27-59 years of age; however, 61.5% of patients sensitive to first-line drugs were also in the same age group. 42.86% of the patients who presented resistance to isoniazid consumed alcohol, likewise 18.75% of the MDR patients were drug users.

No statistically significant differences were obtained when evaluating sensitivity in relation to the clinical forms of tuberculosis, sex, nationality and comorbidities; however, it was found that among patients with the diagnosis of MDR tuberculosis, 62.5% were male, 75% were diagnosed with pulmonary tuberculosis and 31.3% had relapsed after previous treatment. Finally, in relation to comorbidities, 50% did not have them and 18.8% had some type of immunosuppression rather than HIV.

DISCUSSION

In the present study we sought to determine the different TB drug resistance patterns of TB diagnosed patients in a public hospital in Lima, Peru. The majority of patients were sensitive to first-line antituberculosis drugs, nevertheless a lower percentage of patients with MDR and XDR tuberculosis and with resistance to rifampicin or isoniazid were also observed. Around the world there are different reports of the prevalence of tuberculosis and their respective sensitivity profiles. A systematic review by Lohiya et al. reported the prevalence of MDR, Any Drug Resistance and XDR patients to be 3.5%, 24.9% and 0.06%, respectively.¹³Likewise, in the study by Ahmad et al. regarding the prevalence of tuberculosis and drug resistance in the Middle East, regions such as Saudi Arabia, had variations in the MDR-TB prevalence according to the time period in which the studies were conducted, with an average of 6.7%.¹⁴Similarly, Tengan et al. studied the prevalence of MDR-TB in Latin America among never treated patients was 7.0% and previously treated cases was 26.5%.¹⁵

Additionally, as in our study, it has been reported that monoresistance was higher for isoniazid compared to rifampicin.^14),(15Our findings align with those reported in the international literature, likely due to shared local factors associated with tuberculosis. Poverty, for instance, has been identified as a contributing factor, with higher incidence observed in middle and low-income countries by Furin et al.¹⁶Moreover, under-diagnosis of resistant forms of tuberculosis can delay treatment initiation, potentially explaining the unchanged or increasing prevalence rate of MDR tuberculosis as reported by Tengan et al.¹⁵

The most common age group in the present study was the 17-59 years old one, with a predominance in the male sex, results consistent with those from similar studies that also concluded the adult group to be the most frequently affected, and also the one in which coinfection with HIV is more common.^17),(18Similar findings were reported by Bonin, et al. who found that 76% of the patients they studied were male.¹⁸

We emphasize adequate control over unhealthy habits on TB patients, as 60% of these habits was described on patients admitted in a Brazilian referral hospital with significant correlation of the use of illicit drugs with drug-resistant TB.¹⁸

Despite, finding less frequency than previously described,¹⁹alcohol drinking was found to be associated with drug-resistance. Indeed, it has been related with rising risk of transmission and disease severity, by increasing pulmonary oxidative stress, impairing mucociliary function, alveolar epithelium and macrophage action.²⁰

Smoking is also described as a major driver of TB. Thereby, De Vargas, et al. concluded that self-reported active smokers, with 32% prevalence, had minor chances to cure and more to abandon treatment.²¹In contrast, despite evaluating more patients, we found less prevalence of smoking habit and could not establish its association with drug-resistance TB.

The impact caused by these conditions, as mentioned by Song W, et al. in their retrospective cohort study, needs to be taken into consideration because of its effect over TB-resistance.²²

Furthermore, most of the patients with a diagnosis of tuberculosis in our study, were sensitive to first-line antituberculosis drugs regardless of the presence of any comorbidity, in contrast to different studies that show HIV infection as a disease that generally conditions patients to present resistance to first-line antituberculosis drugs. Both share predisposing factors such as poverty, which has been shown to be a risk factor for MDR-TB in HIV patients due to overcrowding in the home, overcrowding in transportation and weak immune systems associated with malnutrition.^16)-(23That is why studies such as the systematic review and meta-analysis by Sultana et al. reports the odds of MDR-TB infection among HIV-positive cases to be 1.42 times higher.²⁴

There are other immunosuppressive conditions predisposing the patient to TB infection such as diabetes mellitus which has been reported to triple the risk for disease development and have a 2-fold higher risk of developing MDR TB than patients without it.^25),(26Although the association between comorbidities that generate immunosuppression and MDR TB is still inconsistent as mentioned by Hamada et al, in their review article, there is still a limitation when evaluating the sensitivity profile in different parts of the world.²⁷Sensitivity profiles are often performed only when there is first-line treatment failure, and this could be the reason why in our study the results of resistance and comorbidities are not related to the previously mentioned international studies. Other conditions that generate immunosuppression and consequently are associated with tuberculosis have been described in the international literature.^28)-(30In our study we considered other factors such as pregnancy, patients with chronic renal disease, neoplasias and treatment with corticoids.²⁸

Patients who had no contact with a TB infected person presented a higher prevalence of drug resistance than those who were. However, only one case of TB MDR was reported out of the 3 patients with TB MDR exposure while the other two were susceptible to first line treatment. According to a systematic review which included studies from around the world, the resistance pattern concordance between infected patients and their household contacts was of 54.3% meaning more than half of the secondary cases had the same resistance pattern of the index cases.³¹Out of the 33 articles included, 2 were performed in the Peruvian population. Bayona et.al. studied MDR-TB patients from 1996 to 1999 where 8% of the contacts developed TB infection, and out of those who developed the disease, 84% were MDR-TB with 17% sharing the same drug-resistance pattern.³²Similarly, Parr included patients from 1996 to 2003 revealing that almost 90% were resistant to isoniazid and rifampin showing the importance of TB contact investigation, which lies in the reduction of its related mortality associated with a late diagnosis especially in high-burden settings.^33)-(35On another hand, the relationship between drug-resistance and TB relapse or abandonment.

Our study has inherent limitations that should be considered in its interpretation. We analyzed patients diagnosed with tuberculosis solely in 2022 at María Auxiliadora Hospital, with no data from previous years to determine prevalence tendencies. Furthermore, the transfer of patients to local health centers hindered follow-up and monitoring of treatment response. Additionally, there was a delay in sensitivity profile requests, resulting in resistance evaluations typically occurring only after first-line treatment had failed. Nonetheless, it is important to remark that this study was performed in an academic medical center, a third level and referral hospital in Peru.

CONCLUSIONS

Tuberculosis is a worldwide condition whose drug-resistance patterns continue evolving. However, in our hospital, a southern Peru reference Center, most TB patients are still sensitive to first line drugs. Only a small amount of MDR and XDR patients were found. Moreover, the most common clinical presentation was pulmonary followed by pleural tuberculosis. Nevertheless, a close follow-up of Mycobacterium tuberculosis-resistance patterns is crucial to prevent the spread of this infection. Monitoring of high-risk patients is required for optimal control because MDR and XDR tuberculosis is a serious public health issue around the world.

As this investigation was done during COVI-19 pandemic, we recommend carrying out some studies that consider pre- and post-COVID-19 pandemic information.