A Study of COVID-19 Infected Patients with Tuberculosis as Comorbidity and on Antitubercular Drug Therapy
Corresponding Author: Bhoomika Patel, Department of Respiratory Medicine, Government Medical College, Surat, Gujarat, India, Phone: +91 7567662626, e-mail: firstname.lastname@example.org
Received on: 13 April 2023; Accepted on: 22 July 2023; Published on: 30 October 2023
Background: The coronavirus disease 2019 (COVID-19) infection is considered the most detrimental among patients with comorbid conditions during the prevaccination era. Drugs have been repurposed for the management of COVID-19 infection. An attempt was made to study the morbidity and mortality outcome and the role of anti-TB drug therapy in COVID-19 disease prognosis, in patients of tuberculosis (TB) on anti-TB drug therapy acquiring COVID-19 infection.
Materials and methods: For this study patients diagnosed with COVID-19 infection with TB were divided into three groups. Group I—patients with TB and COVID-19 infection, Group II—patients on anti-TB therapy who acquired COVID-19 infection and Group III—patients suspected with coronavirus disease 2019 (COVID-19) infection, found to be COVID-19 negative and diagnosed with TB from March 2019 to June 2021. All were studied for the duration of hospital stay, clinical symptoms, and associated comorbidity. Kruskal–Wallis and Chi-squared tests were applied.
Result: From records of the designated microscopic center (DMC) of Government Medical College, Surat, a total of 888 patients were diagnosed with TB during the study period, 46 of whom reported to the COVID-19 care center with clinical suspicion. Out of 46 patients, 52.2% had TB, 23.9% had diabetes, 15.2% had hypertension, 4.3% had chronic kidney disease (CKD) with DM & HT, 2.1% had rheumatoid arthritis (RA). Out of a total of 46 patients, 41 recovered, while five died. The median duration of disease among patients from all groups was 15 days. There was a significant association between TB patients on AKT with COVID-19 test results. Those patients who were on AKT had lesser chances of getting an infection with COVID-19 (χ2 = 272.41, p < 0.00001).
Conclusion: The study observation leads toward anti-TB drugs having a protective role against COVID-19 infection.
How to cite this article: Patel B, Sinha A, Verma M, et al. A Study of COVID-19 Infected Patients with Tuberculosis as Comorbidity and on Antitubercular Drug Therapy. Indian J Respir Care 2023;12(3):239–243.
Source of support: Nil
Conflict of interest: None
Keywords: Antituberculous therapy, Coronavirus disease 2019, Rifampicin, Tuberculosis
The coronavirus disease 2019 (COVID-19) infection is created havoc across the globe, increasing morbidity and mortality, and putting tremendous pressure on healthcare systems all over the world. People from every section of society were getting infected across th eglobe as the world came to shocking revelation of pneumonic infections in the city of Wuhan, Hubei province of China, in late December 2019.1,2 It was suspected to be present in China cosiderable time before actually being declared as pandemic by the World Health Organization (WHO) on 11th March 2020. There has been tremendous pressure on people’s lives in terms of economic as well as psychological loss. People have lost their jobs due to the closure of many large and small industries. Shops and offices were closed for a considerable time pushing millions under the poverty line. COVID-19 infection is thought to spread by close physical proximity and via air transmission. It is shown to be detrimental to patients with comorbid conditions, like hypertension, diabetes mellitus, heart disease, or any other disease like kidney disease, or cancer. People living in poverty, overcrowded, increasingly polluted dwellings add to the possibility and were thought to have a very poor prognosis with increased susceptibility to acquiring COVID-19 infection with consequent morbidity and mortality.3 It has been stated by many researchers and seconded by the scientific community all over the globe that patients with tuberculosis (TB) are not only more likely to be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but also likely to have adverse outcomes once infected. The final outcome of more severe forms of COVID-19 in patients who have overcome TB but still have some limitations to normal lung function is likely to be crippling for the patients.3 An early observational study from the main epicenter of the pandemic in Wuhan showed individuals with latent and active TB to be increasingly susceptible to SARS-CoV-2 infection. In this study, infection with Mycobacterium TB (M.tb) was found to be a leading comorbidity for COVID-19 (36%), then diabetes (25%), hypertension (22%), ischemic heart disease (8%), and chronic obstructive pulmonary disease (6%). Patients having coinfection with M.tb were also found to have shown more severe COVID-19 disease and more rapid progression of COVID-19 infection. The study sample was small, but it was the first to show a link between infection with M.tb bacteria and COVID-19.4 A case series by Liu et al., also showed increasing complications related to severe COVID-19 infections in three patients with latent Tb infection (LTBI).5 LTBI is defined as a state of persistent immune response to stimulation M.tb antigens with no evidence of clinically manifested active TB. Looking at these studies, India, with its one of the largest burden of patients infected with TB would be expected to have increasing number of COVID-19 coinfected patients. But this is not the case presently in India as well as in other countries where TB has gained endemic status. A study conducted by Madan et al., from AIIMS, New Delhi, India, on LTBI with COVID-19 as coinfection showed patients with LTBI to be having milder disease.6 Likewise, there were no reports from any other country endemic for TB anywhere worldwide of any severe increase in number of COVID-19 coinfection in patients with latent or overt TB.
The first-ever global cohort of current or former TB patients (post-TB treatment sequelae) with COVID-19, recruited by the Global TB Network in eight countries and three continents, was also conducted recently. No analysis for determinants of outcome was attempted. A specific nested database was created in collaboration with the eight countries reporting patients with TB and COVID-19.7 Presently, there is no study available in relation to patients of COVID-19 infection also suffering from TB as a comorbidity and being treated with anti-TB drugs (before or after getting infected with COVID-19 virus). There is virtually no such study that shares the outcomes of TB-infected patients on anti-TB therapy being infected with the COVID-19 virus. India already has a huge burden of TB population on antitubercular therapy.8 So, it was logical to go for the present study.
Aims and Objectives
To study the rate of COVID-19 infection in patients already having TB infection as comorbidity and taking anti-TB drug therapy.
To correlate patients’ treatment history of anti-TB drugs with COVID-19 infection.
To correlate the morbidity and mortality outcomes of the patients infected with COVID-19 and TB and also on anti-TB drug therapy.
To correlate the pharmacological action of anti-TB drug treatment with the infection status, morbidity, and mortality of COVID-19 patients.
MATERIALS AND METHODS
The study was approved by the institutional review board vide number GMCS/STU/ETHIC/Approval/13203/20 & dated 18/07/2020. The study was performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. The study population was of patients of suspected cases of COVID-19 infected with/without TB and/or on anti-TB therapy. Of the total of 11521 cases of patients visiting the tertiary care New Civil Hospital (NCH), Surat, Gujarat, India, during the pandemic time (March 2020 to June 2021, including both first and second wave with confirmed COVID-19 infection), only 888 were of TB during March 2020 to June 2021 (lockdown effect). Of these, only 46 patients came out suspected to be coinfected with COVID-19 and TB [with or without antituberculosis treatment (ATT)]. From these 46, three groups of patients were formed after evaluation for both TB & COVID-19 infection.
Group I, where the patients were simultaneously coinfected with COVID-19 and TB, and presented with common symptomatology but were not on any drug treatment.
Group II, where the patients were already on antitubercular therapy for any form of TB and were also diagnosed with COVID-19 coinfection.
Group III, where the patients were suspected to be infected with COVID-19 but later diagnosed with TB (COVID-19 negative).
Other comorbid conditions were also noted and treated accordingly.
Study design and sampling methodology: Retrospective and prospective observational study with purposive sampling.
Study period: March 2020 to June 2021.
Study site: Government Medical College (GMC) and NCH, Near Majura Gate Cross Road, Surat, Gujarat, India.
Control of hospital data for a similar period of TB patients on anti-TB therapy in the previous year (non-COVID-19 year) has been taken for comparison purposes.
Management Plan of Patients
Patients admitted to the triage intensive care unit, whose molecular test for COVID-19 was negative and whose X-ray chest if found to be inconclusive of COVID-19, were offered high-resolution computed tomography (HRCT) thorax and accordingly shifted to designated wards (isolation ward for both TB and COVID-19, COVID-19 wards—reverse transcription polymerase chain reaction (RT-PCR) positive ward and RT-PCR negative ward and TB wards, respectively). All these patients were approached for consent for participation in the study. The basic profile (gender and age), the average duration of stay in hospital, the average duration of disease and clinical symptoms, associated comorbidity, and treatment being offered for their present condition other than anti-TB therapy were noted. Information regarding treatment status related to TB & the drugs they were taking, duration of treatment with anti-TB drugs, past history of TB, etc was obtained from the patients who were on anti-TB therapy. Patient adherence to therapy, on first-line anti-TB therapy or being treated for drug-resistant anti-TB therapy, etc., was also ascertained. Their case sheets were examined for supportive drug therapy for COVID-19 infection and investigations. Mortality, if any, with causation was also documented. Any posttreatment/discharge complications were noted. The collected information is shown by means of figures and tables.
Statistical Analysis Plans
Univariate analysis was done by calculating frequencies and percentages for categorical data and by the mean and standard deviation for continuous data. Bivariate analysis was done with Chi-squared tests for categorical data. In the case of nonnormal distribution, nonparametric tests were applied appropriately. Arbitrarily a p-value of <0.05 was considered to be significant.
From records of the designated microscopic center (DMC) of GMC, Surat, Gujarat, India, 888 patients were diagnosed with TB during the study period, 46 of them reported to the COVID-19 care center with clinical suspicion. Thus, the total sample size for the study was 46 patients, 14 (30.43%) of whom were female patients, and 32 (69.56%) male patients. Pulmonary and extrapulmonary TB were found among 41 (89.13%) and five (10.87%) patients, respectively. The average age of study participants was 42.69 years. The average duration of hospital stays in group I patients (simultaneous COVID-19, TB infection, and not on AKT) was 27 days. These patients were not on AKT, which was started later upon diagnosis of TB. The average duration among group two patients with COVID-19 and TB coinfection and on anti-TB therapy was 8.4 days, while it was 10.9 days among group III patients (COVID-19 suspected RT-PCR negative patients with TB). So AKT was started after diagnosis of TB in groups I and III patients Kruskal–Wallis test was applied to compare the average duration of hospital stay in three groups. Test statistic value of 2 and p-value of 0.368 reflect no significant difference in the average duration of hospital stay between the three groups.
Out of a total of 46 patients, 41 recovered from COVID-19 infection, while five patients could not survive. The death of four patients was due to acute respiratory distress syndrome, while one patient was lost due to multiorgan dysfunction. Three patients were lost from groups I and 2 patients from group II. The median duration of disease among patients from all groups was 15 days. In (Table 1) which shows the clinical presentation of all the patients suspected to be infected with COVID-19, out of 46 patients, 24 (52.2%) patients did not have any comorbidity other than TB. A maximum number of patients, 12 (23.9%) had diabetes as comorbidity, two patients had chronic kidney disease (CKD), along with diabetes and hypertension (4.3%), eight were patients of hypertension (15.2%), one had rheumatoid arthritis (RA) (2.17%), and one case was of hypothyroidism (2.17%). Amongst recovered patients of TB with COVID-19 coinfection, pulmonary arterial hypertension was found to be the only post COVID-19 complication found in one patient. The patient was put on oral anticoagulant therapy, tab rivaroxaban (according to standard pulmonary embolism protocol) before discharge along with anti-TB therapy. After discharge, on a routine 6-month follow-up, the patient was not having any symptoms of pulmonary arterial hypertension. Another patient had symptoms suggestive of airway disease. Rest of the patients did not have any other complications. A total of 44 patients diagnosed with gene expert cartridge-based nucleic acid amplification test testing were found to be of drug-sensitive TB. Two patients were of old drug-resistant TB. All 46 patients were receiving adequate doses of anti-TB therapy and all were adherent to the drug regimen. RT-PCR positive for COVID-19 was found in 16 patients and 30 patients were found to be RT-PCR negative for COVID-19. The laboratory parameters like hemogram, renal & liver function tests, blood glucose level, erythrocyte sedimentation rate, prothrombin time as well as inflammatory markers like D-dimer, C-reactive protein and interleukin-6 of all patients are shown in Table 2. Chest X-ray findings of 37 patients showed bilateral infiltrations, cavitations in two patients, consolidation in one, which was found to be normal, and the rest five with some radiological changes suggestive of TB. Of the total number of HRCT thorax, one patient showed positive findings of COVID-19 infection, 25 patients had positive findings of TB only, and three patients had positive findings of both TB and COVID-19. In the rest of 17 patients, HRCT thorax could not be done. As shown in Fig. 1, the overall number of TB cases reported during the COVID-19 pandemic was less for each month from March 2020 to February 2021 as compared to March 2019 to February 2020, when COVID-19 was not present at NCH, Surat, Gujarat, India. Out of 888 recorded patients under National Tuberculosis Elimination Programme(NTEP) at DMC, Surat, Gujarat, India, nine confirmed cases of COVID-19 positive with TB & on AKT were diagnosed. And further 18 cases of COVID-19 positive with TB who were not on AKT were also diagnosed. There was a significant association between TB patients on AKT with COVID-19 test results. Those patients who were on AKT had lesser chances of getting an infection with COVID-19 (χ2 = 272.41, p <0.00001). Accordingly, as seen in Fig. 2, initially, there was a declining trend of COVID-19 cases, then an increase in the number of cases and then again decline followed by an increase in number of cases. There was a decline in TB cases reporting to NCH, Surat, Gujarat, India, TB and the chest outpatient department from March to August 2020; then, again rise in the number of TB cases was seen from September 2020 onward till March 2021. It is to be noted that in the months of April and May 2021, reported cases of TB were low and reported COVID-19 cases were at their peak (during the second wave).
|Symptoms (n = 12)||Number (percent)|
|(Headache and weakness) (5 and 21, respectively)|
*Multiple symptoms among patients
|Investigations findings||Frequency (percent)|
|Hemoglobin level gm/dL|
|ALT levels mg/dL|
|Out of range||16|
|PT levels (in seconds)|
|PT levels not checked||03|
TC/cmm, total count per cubic; RBS, random blood sugar; ALT, alanine transaminase; PT, prothrombin time.
During the first and second waves of COVID-19 and before the start of vaccination in India (2020 and 2021), management of all patients with COVID-19 (with or without comorbid conditions) admitted at NCH, Surat, Gujarat, India, was according to the prescribed Indian Council of Medical Research (ICMR) guidelines9 for that period. A meta-analysis of eight studies and 46,248 patients with confirmed COVID-19 infections by molecular diagnostics showed patients with preexisting chronic respiratory disease were two times more likely to be infected with COVID-19 (odds ratio of 2.46).10 In the observational study from the epicenter of the pandemic in Wuhan, China, individuals with latent or active TB were found to be more susceptible to SARS-CoV-2 infection, which is approximately 15–18%.4 Here in our study of a total of 46 patients with COVID-19 infection, 22 patients suffered comorbidities of diabetes, essential hypertension CKD, hypothyroidism, and RA; the remaining 24 patients had TB as the only coinfection along with COVID-19 In our study chances of getting COVID-19 infection among patients of TB on anti-TB therapy was found to be less compared to any other study. (There are very few studies on patients of TB infected with COVID-19). India notified 18 lakh cases of TB during that period, a decline of 25% from that notified in 2019, in the process affecting the TB Millennium Goal to end TB by 2035.11 The results of a study by Vadgama et al., in 2021 suggests no additional impact on indicators of the continuum of care, such as the treatment success rates and case fatality rate during the lockdown as well as satisfaction with the amount of care received in Surat, Gujarat, India during the same period.12 In our study overall, the number of TB cases reported during the COVID-19 pandemic was less each month from March 2020 to February 2021 as compared to March 2019 to February 2020 (pre-COVID-19 era at Surat, Gujarat, India).
In our present study, the patients of TB, whether sensitive to first-line antitubercular therapy or second-line anti-TB treatment (drug resistance TB), were found to have less chance of COVID-19 infection during the first wave and second waves despite lockdown restrictions. Present study is the first of its kind where we have attempted to analyze the effect of antitubercular drug therapy on patients who also become infected with SARS-CoV-19 while being treated for TB. Despite an extensive literature review, no concrete evidence for an association between COVID-19 and TB morbidity and mortality was obtained, as feared by the scientific community all over the globe.3,4,7
Most of the patients were drug-sensitive TB cases on rifampicin, isoniazid, ethambutol, and pyrazinamide. Only two patients were of drug-resistant TB, of which one patient was on salvage therapy for drug-resistant pulmonary TB without bedaquiline, according to the national TB elimination program. COVID-19 infection management includes only supportive and symptomatic management like plain acetaminophen for reducing fever antiplatelet agent aspirin, anticoagulants like heparin, and antiviral agents like fevipiravir and remdesivir to cater to cytokine storm. Many drugs are being used on the presumption of being useful to one or other aspects of COVID-19 disease manifestation according to the March 2020 guideline of ICMR, which is updated periodically.9
In a review paper by Sanders et al., regarding the pharmacological management of COVID-19 in Journal of American Medical Association (JAMA), various drugs being repurposed to be used for the management of COVID-19 patients states remdesivir (RNA polymerase inhibitor) as one of the fore runner drugs being used. Fevipiravir which is a prodrug of purine nucleotide, was advocated for use in mild case of COVID-19 in India. These antiviral drugs, although they do show some effect are not stated to be conclusive therapy for COVID-19.13 To date, many ongoing clinical trials have been registered for finding the appropriate drug which could be repurposed for COVID-19 therapy. In this respect, in silico studies needs particular attention. In studies using the computer-aided approach to drug discovery called “in silico study,” rifampicin has been found to be the most promising existing drug for repurposing and has the maximum potential to be effective against COVID-19.14,15 Being on WHO list of approved drugs as well as clinically efficacious since 1969–1971, rifampicin was found to have RNA polymerase causing inhibition of late viral protein synthesis, assembly of virion particles and the viral polymerase as well as effect on “cytokine storm.” This further indicated rifampicin as one of the most promising drugs for the treatment of COVID-19 together with letermovir and it depends upon the route of drug administration.14,16,17
Our study further strengthens the evidence for rifampicin to have a protective effect in cases of TB patients coinfected with COVID-19 virus. Our take on this is that anti-TB drugs and rifampicin, in particular, have a protective role against COVID-19 infection as in spite of the comorbid condition of TB not many patients of TB on therapy contracted the much infectious COVID-19 infections as shown by our sample size which was from 18 months of COVID-19 epidemy including the two peak-period of COVID-19 infection unlike other patients suffering from comorbidities. To sum up, our preliminary study and findings from in silico studies suggest rifampicin might be used as a repurposed drug for the treatment of COVID-19. However, it warrants further studies both in vitro and clinical trials with larger sample sizes to arrive at any definitive conclusion.
Bhoomika Patel https://orcid.org/0000-0002-8501-9872
We are thankful to all those who have contributed directly or indirectly to completing this research. We are thankful to all patients and their relatives for cooperating in getting the required information.
1. Awadasseid A, Wu Y, Tanaka Y, et al. Initial success in the identification and management of the coronavirus disease 2019 (COVID 19) indicates human-to-human transmission in Wuhan, China. Int J Biol Sci 2020;16(11):1846–1860. DOI: 10.7150/ijbs.45018
8. Global TB Report 2020. https://apps.who.int/iris/bitstream/handle/10665/336069/9789240013131-eng.pdf.[Internet]. 2554. Available from: http://library1.nida.ac.th/termpaper6/sd/2554/19755.pdf
9. Government of India Ministry of Health & Family Welfare Directorate General of. Health, Services (EMR Division) Revised Guidelines on Clinical Management of COVID – 19, 31 March, 2020(ICMR)
10. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis 2020;94:91–95. DOI: 10.1016/j.ijid.2020.03.017
12. Vadgama P, Patel B, Kosambiya J, et al. Impact of lockdown on TB management during SARS-Cov-2 pandemic: urban & rural scenario of Surat. Healthline 2021;12(2):13–20. DOI: 10.51957/HEALTHLINE_217_2021
15. Bouaré F, Laghmari M, Etouche FN, et al. Unusual association of COVID 19, pulmonary TB and human immunodeficiency virus, having progressed favorably under treatment with chloroquine and rifampin. Pan Afr Med J 2020;35(2):110. DOI: 10.11604/pamj.supp.2020.35.2.24952
16. Pathak Y, Mishra A, Choudhir G, et al. Rifampicin and Letermovir aspotential repurposed drug candidate for COVID 19 treatment: insights from an in-silico study. Pharmacol Rep 2021;73(3):926–938. DOI: 10.1007/s43440-021-00228-0
© The Author(s). 2023 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.