Metabolic disorders in patients with post-COVID-19 Tuberculosis: A Peruvian unicentric experience

Introduction

According to the World Health Organization (WHO), on December 31, 2019, the municipal health commission in China notified a conglomerate of cases in Wuhan, Hubei province. Subsequently, the cause is determined, and the presence of SARS-CoV-2 is announced as the etiological agent of coronavirus disease 19 (COVID-19), spreading rapidly throughout the world.^1,2 Humanity was not prepared for this pandemic, currently reaching more than 673 million cases and a mortality of more than 6.8 million globally.³

Due to the high virulence and mutagenicity of the virus, hospitals were closed, causing a dramatic decline in the diagnosis, treatment, control, promotion, and prevention of pathologies with high morbidity and mortality, with tuberculosis perhaps being one of the most affected diseases; since these patients could not be treated promptly at their health center, hospital, or other health establishments.^4,5

It is a chronic bacterial disease that is transmitted mainly through the respiratory route, that is, from person to person when they are expelled into the air in the form of microdroplets or Flügge drops by a person with pulmonary tuberculosis disease; a higher incidence has also been observed in people who are in permanent contact with infected patients, as is the case with health care personnel or the families that surround and care for them.^6,7 Its transmission is generally produced by speaking, sneezing, coughing, or simply exhaling.^8,9 This was demonstrated in 1890 by the German bacteriologist Carl Georg Friedrich Wilhelm Flügge, who, when investigating these microdroplets, discovered that they could also carry other pathogens such as viruses and bacteria. This transmission mechanism also occurs in measles, rubella, chickenpox, leprosy, canine distemper, mumps, and all variants of SARS-CoV-2.¹⁰

TB transmission occurs when Flügge droplets reach the surface of susceptible mucosae, such as the mucosa of the eyes, nose, or mouth. However, it has also been shown that genitourinary TB, observed in 2–20% of those infected, can be transmitted through the genital mucosa. In this way, one of its forms of transmission has to do with sexual customs; that is, it is directly related to infection through infected sputum and semen.^11–13

According to the WHO, for the year 2021, tuberculosis was estimated to affect approximately 10.6 million people (6 million men, 3.4 million women, and 1.2 million children), having increased by 4.5% compared to the year 2020, with a mortality of 1.6 million deaths and more than 4 thousand cases of multidrug-resistant tuberculosis (MDR TB).¹⁴

The regions most affected by TB are Southeast Asia, where 45% of the cases were observed; Africa, with 23%; the Western Pacific, with 18%; and the Americas region, with an estimated 2.9% of all TB infections. TB.¹⁵ In the latter, more than 291 thousand cases of TB were found; which decreased by 14.8% of the cases in 2020 compared to 2019; however, the countries with the highest frequency of TB were Brazil with 33.1% of cases, Peru (13.4%), and Mexico (10.3%). In addition, mortality greater than 3000 deaths was observed at a rate of 1.7 deaths per 100 thousand inhabitants.^16,17

Likewise, coinfections between COVID-19 and tuberculosis have been reported, and some investigations have stated that the lack of preventive measures in the management of patients with TB favored the intrahospital spread of COVID-19, potentially increasing the severity of the disease.^18,19

Investigations have observed important metabolic alterations in patients with TB. For example, the development of hyperglycemia because of first-line drugs against TB is an important risk factor for the severity of the disease.²⁰ It is also relevant to mention the liver injury induced by anti-tuberculosis drugs that considerably alters the concentration of liver and lipid metabolites, proving to be early prediction markers for this type of injury, avoiding complicating the health status of patients.²¹

In this way, the measurement of the glucose, lipid, and liver profiles is relevant; its usefulness lies in the early identification of cases of asymptomatic patients who could develop biochemical alterations of the metabolites due to anti-tuberculosis treatment associated with the presence of the COVID-19 virus, and that this may lead to a possible deterioration in the quality of life of the patient.

The objective of this research was to determine metabolic disorders and their association with TB stage in post-COVID-19 patients with TB at the Félix Torrealva Gutiérrez Hospital in Ica, Peru.

Methods

Results

The results of 80 (100%) patients with post-COVID-19 tuberculosis were collected. The investigation found that the population had an average age of 56.6±1.04 years, 52.5% (42/80) were male, 67.5% (54/80) came from urban areas of the department of Ica, where 90% (72/80) of the patients lived with their family; In addition, the study also inquired about the consumption of addictive substances where it was observed that 13.8% (11/80) consumed tobacco, 42.5% (34/80) consumed alcohol and 3.8% (3/80) consumed drugs. Likewise, the presence of tuberculosis could be classified as sensitive tuberculosis observed in 56.3% (45/80) of the cases, multiresistant tuberculosis in 15% (12/80) of the patients, and recurrent tuberculosis in 28.7%. (23/80). The patients received treatment against tuberculosis, observing an average of 5.94±2.91 months of treatment; patients with susceptible tuberculosis had 4.00±0.32 months of treatment, patients with multidrug-resistant tuberculosis had 10.0±0.01 months, and patients with relapsed tuberculosis had 7.61±0.29 months of treatment (Table 1).

It was also found that the stage of tuberculosis in post-COVID-19 patients was associated with the patient’s sex (p=0.011), the male sex was more frequent in sensitive tuberculosis (36.3%) and women had a higher frequency multiresistant tuberculosis (12.5%) and recurrent tuberculosis (15%). In addition, the stages of tuberculosis present significant differences with the time of treatment (p˂0.001).

All patients underwent biochemical tests to determine metabolic alterations. In the total population, it was obtained that the blood glucose concentration was 123.64±5.42 mg/dl (95% CI; 112.8-134.4 mg/dl), total cholesterol was 183.8 ± 4.46 mg/dl (95% CI; 175.0-192.7 mg/dl), triglycerides presented concentrations of 160.73±6.25 mg/dl (95% CI; 148.3-173.2 mg/dl), HDL cholesterol obtained 39.3±0.63 mg/dl (95% CI; 38.1-40.6 mg/dl), LDL cholesterol obtained 140.63±3.05 mg/dl (95% CI; 134.5-146.7 mg/dl), albumin presented a mean of 43.04±1.47 g/dl (95% CI; 40.1-46.0 mg/dl). dl), total bilirubin obtained 84.28±6.58 mg/dl (95% CI; 71.2-97.4 mg/dl), direct bilirubin obtained values of 16.20±0.97 mg/dl (95% CI; 14.3-18.1 mg/dl), the TGO concentrations were 34.08±1.40 IU/L (95% CI; 112.8-134.4 IU/L), the TGP presented an average concentration of 68.9±5.09 IU/L (95% CI; 31.3-36.9 IU/L), alkaline phosphatase had a mean of 152.0±5.08 IU/L (95% CI; 141.9-162.1 IU/L), GGTP had a mean value of 53.79±3.13 IU/L (95% CI; 47.6-60.1 IU/L) and total proteins presented an average concentration of 70.84±1.20 g/dl (95% CI; 68.5-73.2 g/dl) (Table 2).

Statistically significant differences were found in total cholesterol in relation to the stage of tuberculosis (p=0.025), where sensitive and multiresistant tuberculosis presented higher concentrations than recurrent tuberculosis. No significant differences were found with the rest of the metabolites (p˃0.05).

The investigation has presented alterations in the metabolites analyzed. Elevated blood glucose concentration (>110 mg/dl) was observed in 36.3% (29/80) of the cases. Within the lipid profile, 31.3% (25/80) of the patients presented total cholesterol levels greater than 200 mg/dl, triglyceride values increased (>150 mg/dl) in 52.5% (42/80) of the cases, values ≤40 mg/dl of HDL cholesterol were observed in 52.5% (42/80) of the patients and concentrations greater than 150 mg/dl of LDL cholesterol were observed in 53.8% of the cases. Likewise, an association was only observed between the stage of tuberculosis and total cholesterol (p=0.021), where an increase in total cholesterol levels was found when the tuberculosis was multiresistant (Figure 1).

Figure 1. Association between tuberculosis stage with glucose and lipid profile.

Metabolic alterations have also been observed in the liver profile. Albumin presented values greater than 5.4 g/dL in 32.5% (26/80) of the cases. Regarding bilirubin, it was found that total bilirubin obtained concentrations greater than 1.4 mg/dL in 46.3% (37/80) of the patients, and 5% presented values greater than 0.3 mg/dL of direct bilirubin. About transaminases, the TGO presented values >40 UI/L in 30.0% (24/80) of the patients and the TGP also achieved values >40 UI/L in 56.3% (45/80). Alkaline phosphatase was found elevated (>170 U/L) in half of the total population (40/80), 46.3% (37/80) presented GGTP concentrations greater than 50 U/L, and total protein was found. increased (>8 g/dl) in 22.5% (18/80) of patients with post-COVID-19 tuberculosis. As observed in Figure 2, no relationship was observed between the stage of tuberculosis and the metabolites of the liver profile (p>0.05).

Figure 2. Association between tuberculosis stage and liver profile.

Discussion

The present study was able to investigate disorders in post-COVID-19 tuberculosis patients. Because tuberculosis has a high incidence and prevalence in the Peruvian territory with more than 25,000 new cases of TB by the year 2021.²⁴ The COVID-19 pandemic has led to coinfections in tuberculosis patients, where TB patients are at high risk of SARS-CoV-2 infection and have the predisposition to generate serious complications from COVID-19 with an unfavorable prognosis.^25,26 This coinfection leads health personnel to adopt new surveillance and follow-up strategies in order to avoid clinical complications, and it is essential to take into account the metabolic consequences of these coinfected patients.

The investigation found an increase in blood glucose concentration in 36.3% of cases. In Japan, a study by Hayashi et al.²⁷ indicated that the development of TB is related to glucose intolerance, the investigation found significant differences between TB patients and controls (34.2% versus 14.4% for men and 18.3% versus 10.0% for women). Thus, as the review by Cadena et al.²⁸ there is a high risk of developing diabetes mellitus in individuals with a chronic history of TB. An observational population-based study showed that the prevalence of TB infection was 4.1% in non-diabetics, 5.5% pre-diabetics, and 7.6% in diabetics, where diabetes was associated with TB infection (p=0.012).²⁹ However, diabetes also increases the risk of COVID-19 and vice versa; SARS-CoV-2 infection can cause hyperglycemia in patients without diabetes.^26,30 Lima-Martinez et al.³¹ indicated that SARS-CoV-2 can generate direct damage to the pancreas because this organ expresses ACE2 (SARSCoV-2 receptor) causing cell dysfunction with acute hyperglycemia.

Regarding the lipid profile, the study found alterations in total cholesterol levels in 31.3% of patients with post-COVID-19 tuberculosis, in triglycerides (52.5%), in HDL (52.5%), and LDL (53.8%). It is known that Mycobacterium tuberculosis is capable of metabolizing host-derived lipids such as fatty acids and cholesterol, being used for the growth and persistence of the micro-organism.³¹ Likewise, hyperglycemia is usually accompanied by hyperlipidemia, but it has also been observed that diabetics with TB tend to present mainly an increase in triglyceride levels.³² However, there is evidence that high cholesterol is protective in the context of TB; that is, elevated cholesterol concentrations are related to a lower frequency of mortality and severity of the disease.^32,33

In the liver profile, alterations were observed mainly in transaminases, with alterations of TGP and TGO in 56.3% and 30% of the cases, respectively. Albumin was found to be altered in 32.5% of the samples and relation to bilirubin, total bilirubin (46.3%) presented greater alteration than direct bilirubin (5%). In this regard, recent findings have determined that some liver biomarkers (albumin, direct bilirubin, and transaminases) are associated with the risk of developing a more severe SARS-CoV-2 infection.³⁴ A meta-analysis where 64 investigations were analyzed with a total of 11,245 patients with COVID-19, showed that some liver enzymes increased considerably during the infection such as TGO (23.2%), TGP (21.2%), bilirubin (9.7%), GGTP (15%) and alkaline phosphatase (4%).³⁵

Our investigation presented more cases of alteration in the liver profile, and it is mainly because these patients also presented tuberculosis. While it is true that Myco-bacterium tuberculosis infection does not significantly alter these liver enzymes; how-ever, there is susceptibility to liver damage induced by anti-tuberculosis drugs, being one of the main adverse drug reactions during tuberculosis treatment.^36,37

The present study addresses a relevant topic for global public health, focused on tuberculosis and COVID-19. Additionally, different metabolites were analyzed, which allows obtaining detailed information about metabolic alterations in patients with post-COVID-19 tuberculosis. However, the research presents an observational, descriptive-correlational, and cross-sectional design, which means that a causal relationship between metabolic alterations and post-COVID-19 tuberculosis cannot be established. Furthermore, the sample is limited to patients from a single hospital, which may limit the generalization of the results to other populations and places.

To advance in this field of research, it is necessary to carry out future studies that allow for long-term follow-up of patients with post-COVID-19 tuberculosis and to evaluate the type of anti-tuberculosis treatment employed. This will allow for a more precise evaluation of the relationship between metabolic alterations and post-COVID-19 tuberculosis, as well as the effectiveness of anti-tuberculosis treatments in patients with metabolic alterations. Additionally, other important variables that can influence metabolic alterations in patients with post-COVID-19 tuberculosis, such as body mass index, level of physical activity, and diet, should be considered. These factors can have a significant impact on metabolic health and should be considered in future research.

Conclusions

There are post-COVID-19 metabolic disorders in patients with tuberculosis at the Félix Torrealva Gutiérrez Hospital in Ica, Peru. The most relevant alterations were observed in the levels of TGP, LDL, HDL, and triglycerides. People with sequelae after TB treatment and post-COVID-19 deserve further investigation and evaluation, since the consequences of both TB and COVID-19 on the patient’s quality of life and need for rehabilitation are relevant.