Introduction

Tuberculosis was one of the leading causes of death in human history and remains one of the leading infectious causes of death in the world.1 Globally, the number of new cases of tuberculosis exceeds 10 million, although the incidence of tuberculosis has fallen slowly over the past decade, and mortality has fallen by almost a third.1

Although there has been a downward trend in the incidence of tuberculosis, the achievements are below the indicators established by the World Health Organization [WHO]. The aim of the “END TB” strategy, is to reduce the global TB incidence and mortality rates by 90% and 95%, respectively, in 2035 when compared to 2015. The COVID-19 pandemic has interfered with the diagnosis and care program for tuberculosis, negatively impacting the progress achieved in combating the disease by 2019. The reported number of people diagnosed with TB in 2020 and 2021 has decreased suggesting growing the number of undiagnosed and untreated people, with an estimated 10.6 million reported TB cases in 2021, compared to 10.1 million in 2020. Over more, the number of deaths increased to 1.6 million in 2021 compared to 1.5 million in 2020.1

COVID-19 has epidemiological similarities with tuberculosis, both infections being airborne, favored by direct contact, crowded environments, and vulnerable biological status. Both tuberculosis and the COVID-19 infection predominantly affect the lung, although extrapulmonary manifestations are also known. The incubation period differs, with variations between 2 and 14 days for COVID-19 and 3–9 weeks for tuberculosis, although they may start with common manifestations, such as cough, chest pain, and asthenia.2 Tuberculosis is an airborne bacterial infection caused by Mycobacterium tuberculosis that can cause extensive destruction of lung tissue, with the formation of cavities, while COVID-19 is a viral infection primarily transmitted person-to-person, caused by SARS-Cov-2 that alters lung cells, triggering inflammation and acute respiratory dysfunction.3,4 The infection of COVID-19 can be diagnosed both before, during active tuberculosis, and post-tuberculosis, but the influence of COVID-19 in the reactivation or worsening of active tuberculosis is still unclear.5,6 Morbidity and mortality risks for COVID-19 and tuberculosis can be influenced by smoking and co-morbidities, such as chronic lung disease, diabetes, or liver failure.7–11 The convergence of these infections constitutes major challenges for public health globally.12

In 2020, of the 33,148 cases of tuberculosis reported by 29 of 30 EU/EEA countries, 23.2% came from Romania. Regarding the number of TB new cases, Romania is at the top ranking of EU countries, though decreasing trend was noted in the last years.13

There are some reports regarding the role of COVID-19 to increase the severity and mortality of tuberculosis.14–16 The purpose of our study is to identify the particularities of the clinical, biological, radiological, and evolutive characteristics on hospitalized patients with tuberculosis-COVID-19 co-infection, from a special hospital of pneumology. To our knowledge, this is the first study on COVID-19 and tuberculosis co-infection from South-East of Romania.

Materials and Methods

We have conducted a descriptive retrospective study on the cases of tuberculosis hospitalized during the COVID-19 pandemic period, from 1.07.2020 to 30.06.2022, from the Clinical Hospital of Pneumophtisiology Galati, located in the South-East of Romania. We specify that the hospital does not have an intensive care unit, and the complicated cases with organ dysfunctions are admitted/transferred to emergency hospitals.

Selection of the Patients

The diagnosis of tuberculosis (TB) was considered according to the case definitions established by the national tuberculosis management guideline, classified into new cases and relapses, according to the TB history and treatment.13 The etiological diagnosis was based on the classical methods of sputum analysis through culture on Loewenstein-Jenssen medium and/or microscopic examination of Ziehl-Nielson colored smears. The laboratory diagnosis of TB was completed by molecular tests by quantitative polymerization reaction in real-time DNA chain - RT-PCR (GeneXpert MTB-Rif-Cepheid). All hospitalized patients with TB were tested for COVID-19 upon admission and during hospitalization, due to clinical or epidemiological suspicion for this infection. The diagnosis of COVID-19 was confirmed by RT-PCR SARS-CoV-2 test. Considering that the average incubation interval of COVID-19 is 7 days, we have classified the cases as community or health care associated infection, depending on the diagnostic data, in the first 7 days of hospitalization or after 7 days, respective. The study was based on the analysis of data from the hospital’s archive of the clinical records, that were selected based on the diagnostic codes ICD-10-CM version 37.1 R1, specified A15 (respiratory tuberculosis), associated or not with U07.1 (COVID-19), for each case of co-infection. The control group included cases of TB mono-infection (A15), selecting a pair with the most proximate hospitalization date of each co-infection case. Two independent researchers, not involved in the patient care or data collection, have selected the patients of the control group.

Data Collection

Demographic, clinical, biological, radiological, and therapeutic data were collected, used according to current hospital procedures for the diagnosis and treatment of TB and COVID-19, according to the recommendations of national protocols.17–19

The radiological changes were evaluated by three independent radiologists and were validated by the pneumologist physician. The cavitary, ulcerated, caseous, nodular, infiltrative, fibrous, pleural/extrapulmonary forms of TB have been notified. Chest CT examination was available in isolated cases. The BRIXIA radiological scores for severity were evaluated on the date of COVID-19 diagnosis (baseline) and at discharge (end of study). Extent of lung parenchyma damage evaluation by BRIXIA score, consists of division into six sections of the lung radiologic image, in which each section achieves a damage score of 0, 1, 2 or 3, while total score could sum from 0 to 18.20–22

The inclusion criteria were age over 20 years, signing the informed consent for the use of personal data for the purpose of medical statistical studies, according to the standardized form from the clinical observation sheet.

They were excluded the patients vaccinated against COVID-19, patients with HIV infection, with neurocognitive dysfunctions who cannot express their consent, those re-hospitalized for the same episode of the disease of COVID-19 or tuberculosis, as well as cases with incomplete CXR examination of the lung (less than 3 radiological opinions).

Statistical Analysis

The statistical analysis used the XLSTAT.2022.4.5 program. Continuous variables with normal distribution were compared based on t-tests, and categorical variables were compared with chi-squared tests or Fisher exact tests. We calculated the frequency of the variables and the mean ±SD for the data with normal distribution or the median in the case of non-normally distributed data. We used the nonparametric Mann–Whitney U-test for data that did not correspond to the standard distribution.

This non-interventional study complies with the Declaration of Helsinki. The institutional approvement of was endorsed by the Medical Council of the Pneumology Hospital from Galati no 1546/15.01.2024.

Results

We analyzed 90 cases hospitalized with tuberculosis during the 2020–2022 pandemic period, of which 45 had the diagnosis of co-infection with COVID-19 and 45 had TB mono-infection.

Demographic Data

The age of the patients varied between 20 and 86 years, with an average of 52.1±14.69 years, without significant statistical differences between the two groups (Mann Whitney test: p = 0.272). The demographic characteristics indicated the predominance of male patients (78.8%), from rural areas (62.2%), with medium/higher education level (53.3%), professionally active (43.33%). The frequency of patients with a low level of education was significantly higher in the group with co-infection with COVID-19 compared to mono-infection with TB (p < 0.001), without other demographic differences (Table 1).

Table 1 Characteristics of Hospitalized Patients with TB Only Vs COVID-19 Co-Infection

Smoking was reported in 71.11% of the patients, with an average lifetime smoking exposure of 29.48 ± 11.74 packs of cigarettes/year. The alcohol use was reported by 74.33% of patients, with average of 4164±1.82 IU/day. The health risk factors, such as smoking, alcohol consumption or altered nutritional status, did not influence the association with COVID-19.

Associated Chronic Co-Morbidities

Chronic co-morbidities have been associated in 57.77% of patients (Figure 1), mainly chronic lung diseases (41.11%), liver chronic disease (18.88%), hypertension (16.66%), heart chronic diseases (11.11%) (Figure 1).

Figure 1 The frequency of TB related chronic co-morbidities.

Abbreviations: COPD, chronic obstructive pulmonary disease; HTN, hypertension; HCDs, heart chronic diseases; NCDs, neurological chronic disease; CTD, connective tissue disease; CLD, chronic liver disease.

Clinical Presentation and Diagnostic

The inventory of clinical symptoms identified manifestations exclusively associated with COVID-19, such as headache (44.4%), myalgias (35.5%), arthralgias (24.4%), as well as manifestations common to the two groups of patients, but with a higher frequency in the case of co-infection COVID-19/TB: fever (71.1% vs 22.2%), chest pain (82.2% vs 28.8%), shortness of breath (73.3% vs 44.4%), decreased appetite (77.7% vs 60%). Other manifestations had equal frequencies, for example, cough (100%), sweating (88.8%), weight loss (73–74%). Hemoptysis was reported in 22.2%, but the frequency was higher in patients with TB only (Figure 2).

Figure 2 Frequency of Symptoms on patients with TB+ COV- comparative with TB+COV+.

The source of COVID-19 was community acquired in 62.2% of cases and healthcare-associated in 37.7%.

Recurrences constituted 30% of TB cases, more frequent in patients with COVID-19 co-infections compared to TB mono-infections (38% vs 22%). The microscopic examination of acid-alcohol-resistant bacilli (AARB) was positive in 91.1% of the cases.

The majority of cases (86.66%) had complex radiological images, highlighting 46.66% cavitary forms, 40% caseous, 26.66% ulcerated, 21.11% infiltrative, 36.66% fibrous, 43.33% nodular, and 7.7% pleurisy or associated extrapulmonary locations (Table 2).

Table 2 Classification Criteria of in TB Only in Comparison with TB-COVID-19 Co-Infection

The biological picture evidenced higher values of inflammation markers and of the Neutrophils/Lymphocytes ratio in patients with co-infection with COVID-19. Overmore, significantly higher differences of values in creatinine, ALT and Brixia scores, both at baseline and during the follow-up examination, were found in COVID-19 group (Table 3).

Table 3 Comparative Features of Biological Data and Radiologic Scores in TB Only and TB-COVID-19 Co-Infection

Non-TB bacterial examination of sputum was performed in 17.77% of patients, with 43.75% showing negative results. Isolates from sputum included Streptococcus spp (3), Moraxella catharalis (1), Klebsiella spp (3), Pseudomonas spp (1), and E. coli (1). A higher number of Gram-negative bacteria (BGN) isolates were observed in cases with COVID-19 (3:1), while TB monoinfection had a higher proportion of Gram-positive bacteria (CGP) (3:2).

Drug Therapy and Outcomes

Treatment with the combination of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol, was administered to 96.6% of TB patients. Individualized antituberculous regimens were provided for 2 patients with TB-MDR and for one case of TB rifampicin resistance detected in the GeneXPERT test.

Antibiotics for non-tuberculous infections were used in 33.3% of patients, including ceftriaxone (14.4%), amoxicillin (2.2%), tienamicin (3.3%), moxifloxacin (3.3%), levofloxacin (2.2%), linezolid (1.1%), gentamicin (1.1%), sulfamethoxazole (1.1%). Vancomycin (14.4%) and metronidazole (6.6%) were used for the treatment of patients with Clostridioides difficile-associated diarrhea.

Oxygen support via nasal cannula or face mask was provided to 31.1% of patients with COVID-19, compared to 6.6% in patients with TB monoinfection. Patients with COVID-19 received antivirals (77.7%) with favipiravir or remdesivir, dexamethasone (51.1%), and anticoagulants (62.2%).

Complications associated with the severe evolution of COVID-19 were observed in 8.8% of cases (coma, sepsis, and pleuropneumothorax), and medication toxicity was reported in 20% of patients (hyperuricemia, renal failure, toxic hepatitis, and anemia). Clostridioides difficile associated diarrhea occurred in 27.7% of cases, more frequently in the group with COVID-19 (16/9 vs.), but the difference was not statistically significant (Figure 3).

Figure 3 Comparative Complications in Patients Hospitalized with Co-infection TB-COVID-19 and TB only.

Abbreviations: PL-PN, pleuropneumonia; AKF, acute kidney failure; CDD, Clostridioides difficile diarrhea.

The outcomes were favorable in 92.2% of patients who were discharged with improved conditions. However, 5.5% of patients with COVID-19 deteriorated, requiring transfer to intensive care units in emergency hospitals, and 2.2% of patients died (1 case of TB-COVID co-infection and 1 case of monoinfection).

Discussion Impact of COVID-19 on Tuberculosis Outcomes

Mycobacterium tuberculosis, a well-adapted pathogen to humans, has coexisted throughout human history. Approximately 2 billion people worldwide carry latent tuberculosis infections, with an estimated 10% risk of developing active disease during their lifetime, varying geographically and with comorbidities.23

COVID-19 induces pulmonary lesions but also affects other compartments of the immune system. In this context, tuberculosis reactivation can be attributed to various mechanisms, such as the immunosuppressive effects of corticosteroid therapy, cytokine storms, and T lymphocyte depletion.24 An observational case-control study in China highlighted that both active and latent tuberculosis are risk factors for the progression of COVID-19.25

Conversely, studies from the early pandemic period provided evidence that COVID-19 increases the frequency and severity of tuberculosis.18,21,22 The mortality rate in our study for patients with co-infection was 2.2%, comparable to the monoinfection TB group. This hospital mortality rate was lower than reported in some multicenter studies, where rates ranged from 9.2% to 14.2%.26–28 It should be counting that 5.5% cases with severe evolution were transferred to intensive care units and probably died, increasing the mortality reported per case, and consequent decreasing discrepancy versus other studies. Most radiological lesions observed in our study were cavitary, evenly distributed between the co-infection and monoinfection TB groups, constituting 46.6%. Over 60% of these were new cases of tuberculosis, suggesting that the lesions had been present for at least one month before the onset of the COVID infection, whose incubation period is short.28

In view of these observations, our study results in line with the patterns observed in countries with a high prevalence of tuberculosis. In such settings, the diagnosis of COVID-19 might be more of a coincidental revelation of tuberculosis rather than a causative factor for reactivating latent tuberculosis.23,27,29,30

Considerations of COVID-19 Impact on Tuberculosis Appearance in Romanian Patients

In comparison with a report from Serbia, patients with tuberculosis-COVID-19 co-infection in our study exhibited more intense symptoms, with a higher frequency of cough (100% vs 69.8%), fever (71.1% vs 30.2%), and shortness of breath (73.3% vs 30.2%). However, the frequency of cases diagnosed with COVID-19 following tuberculosis was lower in our study (37.7% vs 45%).31 A noteworthy proportion of patients in both the monoinfection TB and co-infection COVID-19 groups received non-tuberculosis antibiotics. Despite the global alert on excessive antibiotic use for COVID-19 without clear evidence of bacterial infections, our study reported lower antibiotic utilization rates compared to other studies.32

Demographic characteristics and risk factors such as alcohol and smoking did not influence the occurrence of COVID-19 co-infection. Nevertheless, lower adherence to COVID-19 prevention rules could be related to lower education level that was found more prevalent in co-infected group. Chronic comorbidities, especially chronic obstructive pulmonary disease (COPD), hypertension, chronic liver diseases, or neurological chronic diseases (NCDs), were more frequent in patients with COVID-19 co-infection, consistent with previous findings.33,34 Most statistics on tuberculosis has reported more frequent the males, according to our findings.35,36 A slightly higher rate of male/ female was found in co-infection group, probably related to additional risks of comorbidities and smoking that are considered in COVID-19, but are as well in generally observed between males and females.37–39

Clinical symptoms highlighted an overlap between manifestations typical of both COVID-19 and tuberculosis, such as cough, sweating, and weight loss. Fever, chest pain, shortness of breath, and loss of appetite were more common in patients with COVID-19 co-infection, whereas hemoptysis was more frequent in TB alone. The pain syndrome was characterized by headache, myalgia, and arthralgia, and has been mentioned exclusively in patients with COVID-19 co-infection. However, the specificity of clinical manifestations for COVID-19 is limited, with none of the symptoms having the accuracy to confirm or rule out this infection.40 Moreover, the clinical spectrum of COVID-19 varies from asymptomatic to severe forms, correlated with epidemiological factors and host characteristics.41 Hemoptysis is an uncommon manifestation of COVID-19, reported with frequencies between 0.9% and 3.3%.41,42 Hemoptysis in tuberculosis can be caused by bronchiectasis, bronchial artery erosions, and, more rarely, pulmonary artery erosions.43 The proportion of hemoptysis revealing the onset of tuberculosis and/or the unfavorable evolution of fibrocavitary secondary TB was 20.71%, in line with recent studies in Romania.44

Bilateral lung lesions were significantly more frequent in the COVID-19 group compared to monoinfection TB (p = 0.003), consistent with a higher BRIXIA radiologic score. Although the BRIXIA score decreased in both groups upon discharge, the difference in values accentuated, likely due to the slow regression of COVID-19 pulmonary lesions. Prospective evaluation of these cases may be useful to clarify whether there is an additional risk for post-COVID fibrosis and respiratory dysfunction in the case of tuberculosis co-infection.

The average NLR was elevated in most patients in our study, but the differences between the COVID-19 co-infection and monoinfection TB groups were not significant, possibly because critical COVID-19 pattern were not evaluated in the study.45,46

Clostridioides difficile infection was reported in 27.7% of tuberculosis patients, possibly favored by rifampicin use, listed as one of the antibiotics that can induce diarrhea with this etiology, especially in elderly individuals with chronic comorbidities (underlying conditions).29 The frequency of Clostridioides difficile-associated diarrhea was higher in the COVID-19 co-infection group (35.5% vs 20%), likely explained by the twice as frequent use of non-tuberculosis antibiotics and the occurrence of this type of diarrhea. It could be favored by rifampicin or broad-spectrum antibiotics use, as well as by changes in the intestinal microbiome during COVID-19 infection (fecal microbiota disruption by SARS-CoV-2 infection).47

Limitations of the Study

The retrospective design of the study could have limited the accuracy of collecting the data. The number of cases is small, limiting the statistical significance of the results. There were only hospitalized TB cases, with symptomatic COVID-19 during the first 4 to 8 weeks from the admission. Symptomatic or asymptomatic COVID-19 cases preceding tuberculosis were not analyzed. The potential impact of prior asymptomatic COVID-19 infections on tuberculosis, with potential effects on the biological and radiological changes found in the monoinfection TB group, could not be assessed. Intensive care unit was not available and some patients with severe evolution were transferred to other hospitals, with unknown state, that could distort the rate of mortality per case.

Conclusion

Symptomatic non-severe infection COVID-19 had a mild impact on the clinical and biological expression of tuberculosis diagnosed in the pandemic context. The hospital mortality of patients with tuberculosis was not influenced by COVID-19 co-infection in a country with a high tuberculosis prevalence. Persistent structural lung damage is suggested by radiological lesions according to the BRIXIA score and could be an indicator for COVID-19 additional risk on tuberculosis sequelae. Co-infection Covid-19 - tuberculosis should be care by multidisciplinary teams, covering at least specialties as pneumology, infectious diseases, intensive care, microbiology, imagistic, epidemiology. Tuberculosis control strategies should consider intensifying efforts to evaluate tuberculosis in COVID-19 patients, as common clinical manifestations and some pathogenic mechanisms continue to pose challenges for medical research and public health.

Abbreviations

AFB, acid fast bacteria; ALT, Alanine-amino transferase; AKF, acute kidney failure; AST, Aspartate amino transferase; CI, confidence interval; CDD; Clostridioides difficile diarrhea; COPD, chronic obstructive pulmonary disease; HCDs, heart chronic diseases; CLD, chronic liver disease; CRP, C-Reactive Protein; CTD, connective tissue disease; ESR, Erythrocytes Sedimentation Rate; GNB, Gram-negative bacilli; GPC, Gram-positive cocci; HTN – hypertension; NCDs, neurological chronic disease; NRV, Normal Reference Values; N/Ly, Neutrophils/Lymphocytes Ratio; OR, Odds Ratio; PL-PN, pleuropneumonia; TB-tuberculosis; WHO, World Health Organization.

Acknowledgments

We kindly acknowledge the board of “Dunarea de Jos” University from Galati for the financial support for publication. This paper has been uploaded to [https://www.preprints.org] as a preprint: https://doi.org/10.20944/preprints202401.1145.v1

Disclosure

The authors report no conflicts of interest in this work.

References

1. World Health Organization. Global tuberculosis report 2022; 2022. Available from: https://iris.who.int/bitstream/handle/10665/363752/9789240061729-eng.pdf?sequence=1. Accessed 11, December 2023.

2. Cioboata R, Biciusca V, Olteanu M, Vasile CM. COVID-19 and Tuberculosis: unveiling the Dual Threat and Shared Solutions Perspective. J Clin Med. 2023;12:4784. doi:10.3390/jcm12144784

3. Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust. 2020;213(2):54–56.e51. doi:10.5694/mja2.50674

4. Mocanu AI, Mocanu H, Moldovan C, et al. Some Manifestations of Tuberculosis in Otorhinolaryngology - Case Series and a Short Review of Related Data from South-Eastern Europe. Infect Drug Resist. 2022;15:2753–2762. doi:10.2147/IDR.S367885

5. Brosnahan SB, Jonkman AH, Kugler MC, Munger JS, Kaufman DA. COVID-19 and Respiratory System Disorders: current Knowledge, Future Clinical and Translational Research Questions. Arterioscler Thromb Vasc Biol. 2020;40(11):2586–2597. doi:10.1161/ATVBAHA.120.314515

6. Visca D, Ong CWM, Tiberi S, et al. Tuberculosis and COVID-19 interaction: a review of biological, clinical and public health effects. Pulmonology. 2021;27(2):151–165. doi:10.1016/j.pulmoe.2020.12.012

7. Al Maqbali M, Al Badi K, Al Sinani M, Madkhali N, Dickens GL. Clinical Features of COVID-19 Patients in the First Year of Pandemic: a Systematic Review and Meta-Analysis. Biol Res Nurs. 2022;24(2):172–185. doi:10.1177/10998004211055866

8. Biswas SS, Awal SS, Awal SK. COVID-19 and pulmonary tuberculosis - A diagnostic dilemma. Radiol Case Rep. 2021;16(11):3255–3259. doi:10.1016/j.radcr.2021.07.079

9. Vasile MC, Arbune AA, Lupasteanu G, Vlase CM, Popovici GC, Arbune M. Epidemiologic and Clinic Characteristics of the First Wave of the COVID-19 Pandemic in Hospitalized Patients from Galați County. J Clin Med. 2021;10:18. doi:10.3390/jcm10184210

10. Kumar R, Rai AK, Phukan MM, et al. Accumulating Impact of Smoking and Co-morbidities on Severity and Mortality of COVID-19 Infection: a Systematic Review and Meta-analysis. Curr Genomics. 2021;22(5):339–352. doi:10.2174/1389202922666210921101728

11. Vidyasagaran AL, Readshaw A, Boeckmann M, et al. Is Tobacco Use Associated With Risk of Recurrence and Mortality Among People With TB?: a Systematic Review and Meta-Analysis. Chest. 2024;165(1):22–47. doi:10.1016/j.chest.2023.08.021

12. Herrera MT, Guzmán-Beltrán S, Bobadilla K, et al. Human Pulmonary Tuberculosis: understanding the Immune Response in the Bronchoalveolar System. Biomolecules. 2022;12(8). doi:10.3390/biom12081148

13. European Centre for Disease Prevention and Control, WHO Regional Office for Europe. Tuberculosis Surveillance and Monitoring in Europe 2022 – 2020 Data. Copenhagen: WHO Regional Office for Europe and Stockholm: European Centre for Disease Prevention and Control; 2022.

14. Patra K, Batabyal S, Mandal K, Ghose D, Sarkar J. Tuberculosis and COVID-19: a combined global threat to human civilization. Clin Epidemiol Glob Health. 2022;15:101031. doi:10.1016/j.cegh.2022.101031

15. Gong W, Mao Y, Li Y, Qi Y. BCG Vaccination: a potential tool against COVID-19 and COVID-19-like Black Swan incidents. Int Immunopharmacol. 2022;108:108870. doi:10.1016/j.intimp.2022.108870

16. Harries AD, Kumar AMV, Satyanarayana S. TB and COVID-19: measuring key risk factors that affect treatment outcomes. Int J Tubercul Lung Dis. 2021;25(4):329–331. doi:10.5588/IJTLD.21.0061

17. MINISTERUL SĂNĂTĂȚII ORDIN nr. 956 din 31 martie 2022 privind modificarea Ordinului ministrului sănătății nr. 1.171/2015 pentru aprobarea unor reglementări privind controlul tuberculozei: GHID METODOLOGIC DE IMPLEMENTARE A PROGRAMULUI NAŢIONAL DE PREVENIRE, SUPRAVEGHERE ȘI CONTROL AL TUBERCULOZEI ȘI ALTOR MICOBACTERIOZE. MONITORUL OFICIAL AL ROMÂNIEI, PARTEA I, Nr. 326 bis 4.IV.2022. Available from: https://legislatie.just.ro/Public/DetaliiDocument/253597?msclkid=09174c29c24711ec95524134f8dfd6f2. Accessed October21, 2023.

18. Ministerul Sănătății. ORDIN nr. 487 din 23 martie 2020 pentru aprobarea protocolului de tratament al infecției cu virusul SARS-Cov-2. MONITORUL OFICIAL nr. 242 din 24 martie 2020. Available from: https://legislatie.just.ro/Public/DetaliiDocument/224341. Accessed October21, 2023.

19. Ministerul Sănătății. ORDIN nr. 533 din 22 aprilie 2021 privind modificarea anexei la Ordinul ministrului sănătății nr. 487/2020 pentru aprobarea protocolului de tratament al infecției cu virusul SARS-CoV-2. MONITORUL OFICIAL nr. 434 din 23 aprilie 2021. Available from: https://legislatie.just.ro/Public/DetaliiDocumentAfis/241318. Accessed October21, 2023.

20. Nukovic JA, Opancina V, Zdravkovic N, et al. Brixia Chest X-ray Score, Laboratory Parameters and Vaccination Status for Prediction of Mortality in COVID-19 Hospitalized Patients. Diagnostics (Basel). 2023;13:12. doi:10.3390/diagnostics13122122

21. Au-Yong I, Higashi Y, Giannotti E, et al. Chest Radiograph Scoring Alone or Combined with Other Risk Scores for Predicting Outcomes in COVID-19. Radiology. 2022;302(2):460–469. doi:10.1148/radiol.2021210986

22. Little BP. Disease Severity Scoring for COVID-19: a Welcome Semiquantitative Role for Chest Radiography. Radiology. 2022;302(2):470–472. doi:10.1148/radiol.2021212212

23. Mousquer GT, Peres A, Fiegenbaum M. Pathology of TB/COVID-19 Co-Infection: the phantom menace. Tuberculosis (Edinb). 2021;126:102020. doi:10.1016/j.tube.2020.102020

24. Shariq M, Sheikh JA, Quadir N, Sharma N, Hasnain SE, Ehtesham NZ. COVID-19 and tuberculosis: the double whammy of respiratory pathogens. Eur Respir Rev. 2022;31:164. doi:10.1183/16000617.0264-2021

25. Feldman C, Anderson R. The role of co-infections and secondary infections in patients with COVID-19. Pneumonia (Nathan). 2021;13(1):5. doi:10.1186/s41479-021-00083-w

26. Tadolini M, Codecasa LR, García-García JM, et al. Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases. Eur Respir J. 2020;56:1. doi:10.1183/13993003.01398-2020

27. Motta I, Centis R, D’Ambrosio L, et al. Tuberculosis, COVID-19 and migrants: preliminary analysis of deaths occurring in 69 patients from two cohorts. Pulmonology. 2020;26(4):233–240. doi:10.1016/j.pulmoe.2020.05.002

28. Group TC-GS. Tuberculosis and COVID-19 co-infection: description of the global cohort. Eur Respir J. 2022;59:3. doi:10.1183/13993003.02538-2021

29. Khurana AK, Aggarwal D. The (in)significance of TB and COVID-19 co-infection. Eur Respir J. 2020;56(2). doi:10.1183/13993003.02105-2020

30. Stochino C, Villa S, Zucchi P, Parravicini P, Gori A, Raviglione MC. Clinical characteristics of COVID-19 and active tuberculosis co-infection in an Italian reference hospital. Eur Respir J. 2020;56:1. doi:10.1183/13993003.01708-2020

31. Adzic-Vukicevic T, Stosic M, Antonijevic G, Jevtic M, Radovanovic-Spurnic A, Velickovic J. Tuberculosis and COVID-19 co-infection in Serbia: pandemic challenge in a low-burden country. Front Med Lausanne. 2022;9:971008. doi:10.3389/fmed.2022.971008

32. Vaughn VM, Gandhi TN, Petty LA, et al. Empiric Antibacterial Therapy and Community-onset Bacterial Coinfection in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19): a Multi-hospital Cohort Study. Clin Infect Dis. 2021;72(10):e533–e541. doi:10.1093/cid/ciaa1239

33. Parolina L, Pshenichnaya N, Vasilyeva I, et al. Clinical characteristics of COVID-19 in patients with tuberculosis and factors associated with the disease severity. Int J Infect Dis. 2022;124(Suppl 1):S82–S89. doi:10.1016/j.ijid.2022.04.041

34. Song B, Sheng X, Justice JL, et al. Intercellular communication within the virus microenvironment affects the susceptibility of cells to secondary viral infections. Sci Adv. 2023;9(19):eadg3433. doi:10.1126/sciadv.adg3433

35. European Centre for Disease Prevention and Control, WHO Regional Office for Europe. Tuberculosis Surveillance and Monitoring in Europe 2021 – 2019 Data. Copenhagen: WHO Regional Office for Europe; 2021.

36. Shaweno D, Horton KC, Hayes RJ, Dodd PJ. Assortative social mixing and sex disparities in tuberculosis burden. Sci Rep. 2021;11(1):7530. doi:10.1038/s41598-021-86869-w

37. Bwire GM. Coronavirus: why Men are More Vulnerable to Covid-19 Than Women? SN Compr Clin. Med. 2020;2(7):874–876. doi:10.1007/s42399-020-00341-w

38. Kharroubi SA, Diab-El-Harake M. Sex-differences in COVID-19 diagnosis, risk factors and disease comorbidities: a large US-based cohort study. Front Public Health. 2022;10:1029190. doi:10.3389/fpubh.2022.1029190

39. Peer V, Schwartz N, Green MS. Gender differences in tuberculosis incidence rates-A pooled analysis of data from seven high-income countries by age group and time period. Front Public Health. 2022;10:997025. doi:10.3389/fpubh.2022.997025

40. Martínez Orozco JA, Sánchez Tinajero Á, Becerril Vargas E, et al. COVID-19 and Tuberculosis Coinfection in a 51-Year-Old Taxi Driver in Mexico City. Am J Case Rep. 2020;21:e927628. doi:10.12659/AJCR.927628

41. Baj J, Karakuła-Juchnowicz H, Teresiński G, et al. COVID-19: specific and Non-Specific Clinical Manifestations and Symptoms: the Current State of Knowledge. J Clin Med. 2020;9:6. doi:10.3390/jcm9061753

42. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720. doi:10.1056/NEJMoa2002032

43. Quigley N, Gagnon S, Fortin M. Aetiology, diagnosis and treatment of moderate-to-severe haemoptysis in a North American academic centre. ERJ Open Res. 2020;6(4). doi:10.1183/23120541.00204-2020

44. Chirana C, Vlase I. Hemopthisis in Patients with Lung Tuberculosis. ARS Medica Tomitana. 2021;27(3). doi:10.2478/arsm-2021-0025

45. Kim MA, Park YE, Chong YP, Shim TS, Jo KW. Neutrophil-Lymphocyte Ratio and Monocyte-Lymphocyte Ratio According to the Radiologic Severity of. J Korean Med Sci. 2022;37(40):e292. doi:10.3346/jkms.2022.37.e292

46. Sarkar S, Khanna P, Singh AK. The Impact of Neutrophil-Lymphocyte Count Ratio in COVID-19: a Systematic Review and Meta-Analysis. J Intensive Care Med. 2022;37(7):857–869. doi:10.1177/08850666211045626

47. Lewandowski K, Rosołowski M, Kaniewska M, et al. Clostridioides difficile infection in coronavirus disease 2019 (COVID-19): an underestimated problem? Pol Arch Intern Med. 2021;131(2):121–127. doi:10.20452/pamw.15715