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Vol. 29. Issue 6.
Pages 535-539 (November - December 2023)
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Vol. 29. Issue 6.
Pages 535-539 (November - December 2023)
Letter to the Editor
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Long-term sequelae of TB and COVID-19 co-infection: Prospective cohort evaluation after 1 year
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D.R. Silvaa,b,c,
Corresponding author
denise.rossato@terra.com.br

Corresponding author.
, A.P.C. dos Santosb,c, R. Centisd, L. D'Ambrosioe, G.B. Migliorid
a Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
b Programa de Pós-Graduação em Ciências Pneumológicas da Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
c Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
d Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri, IRCCS, Tradate, Italy
e Public Health Consulting Group, Lugano, Switzerland
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Tables (2)
Table 1. General characteristics of patients.
Table 2. Factors associated with mortality in TB-COVID-19 patients.
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Dear Editor,

The coronavirus disease 2019 (COVID-19) pandemic has shown negative effects on tuberculosis (TB) control. Disruptions to the access to TB services have been reported. In fact, the World Health Organization data show that the pandemic has had a substantial effect on TB trends, with an overall decrease in the number of new TB cases, and an increase in the number of deaths between 2019 and 2020.1

TB and COVID-19 coinfection may be associated with more severe clinical conditions than either disease on its own, leading to greater morbimortality during the acute phase.2–4 Additionally, post-TB lung disease (PTLD) and post-COVID-19 disorders account for substantial consequences on the health of survivors and often require rehabilitation.5,6 Pulmonary impairment after TB is identified in more than 50% of patients, and post-COVID-19 sequelae may affect up to 80% of COVID-19 survivors.5,7 However, the sequelae of TB and COVID-19 co-infected individuals are largely unknown, and there are no studies so far that have evaluated long-term lung function in these patients.

We conducted a prospective cohort study at Hospital de Clínicas de Porto Alegre, Brazil in collaboration with Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Maugeri, Tradate, Italy. The study was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre (number 200188). All participants gave their written consent to participation. The study objectives were to assess pulmonary functions tests (PFT, including 6-minute walk test- 6MWT) and quality of life (QoL) in patients with COVID-19 and TB, one year after COVID-19, and to evaluate factors associated with mortality.

Patients ≥18 years of age hospitalized with a concomitant diagnosis of COVID-19 and TB (active or sequelae) were evaluated one year after discharge. Patients underwent PFT: spirometry, plethysmography, diffusing capacity of the lung for carbon monoxide (DLCO), and 6MWT. To assess QoL, the EuroQol-5D scale (EQ-5D) was used. In addition, patients were asked about persistent post-COVID-19 symptoms. Categorical comparisons were performed by chi-square test using Yates's correction if indicated, or Fisher's exact test. Continuous variables were compared using the t-test or Wilcoxon test. A two-sided p value <0.05 was considered significant.

We included 106 patients with COVID-19 and active TB (n = 24) or TB sequelae (n = 82), from March 2020 to December 2022. Forty (37.7%) patients died from COVID-19 during the study period. Of the 66 patients who survived COVID-19, 23 underwent PFT (and 6MWT), and were assessed for QoL and persistence of symptoms. Table 1 shows the cohort characteristics. The most common post-COVID-19 ventilatory impairment was restrictive. A large percentage of patients had impaired QoL in the usual activities, anxiety/depression, mobility and pain/discomfort dimensions. All patients reported at least one persistent post-COVID-19 symptom. Active TB patients were younger and had a higher prevalence of current smoking.

Table 1.

General characteristics of patients.

Demographic data  Active TB (n = 24)  TB sequelae (n = 82)  p value 
Age (years)  51.3 ± 16.3  60.3 ± 14.9  0.013 
Male sex  15 (62.5)  45 (54.9)  0.668 
Smoking status       
Current smoker  9 (37.5)  8 (9.8)  0.005
Former smoker  9 (37.5)  48 (58.5) 
Never smoker  6 (25.0)  26 (31.7) 
Alcohol abuse  7 (29.2)  20 (24.4)  0.837 
Intravenous drug user  5 (20.8)  7 (8.5)  0.137 
HIV positive  9 (37.5)  15 (18.3)  0.089 
TB data       
CXR at TB diagnosis       
Unilateral pulmonary cavitary lesions  1 (4.2)  3 (3.7)  0.999 
Bilateral pulmonary cavitary lesions  1 (4.2)  0.226 
Unilateral pulmonary infiltrates (no cavities)  4 (16.7)  38 (46.3)  0.017 
Bilateral pulmonary infiltrates (no cavities)  14 (58.3)  32 (39.0)  0.149 
PFT pre-COVID-19 (n = 29)       
Post-BD FEV1 (L)  2.23 ± 0.21  2.13 ± 0.98  0.892 
Post-BD FEV1 (%)  97.0 ± 37.8  71.0 ± 29.5  0.248 
Post-BD FVC (L)  2.97 ± 0.64  2.88 ± 0.95  0.902 
Post-BD FVC (%)  92.9 ± 32.0  77.1 ± 25.4  0.410 
Post-BD FEV1/FVC  83.6 ± 1.13  72.6 ± 18.2  0.007 
TLC (L)  –  4.93 ± 1.52  – 
TLC (%)  –  82.8 ± 24.8  – 
RV (L)  –  2.17 ± 1.13  – 
RV (%)  –  90.6 ± 33.8  – 
DLCO (L)  –  4.76 ± 2.61  – 
DLCO (%)  –  54.1 ± 25.2  – 
6MWT (m)  –  385.3 ± 119.7  – 
Desaturation in 6MWT  –  6 (35.3)  – 
Ventilatory defect pre-COVID-19       
Obstructive  6 (23.1)  0.541
Restrictive  1 (33.3)  10 (38.5) 
Normal  2 (66.7)  10 (38.5) 
COVID-19 data       
CXR at COVID-19 diagnosis       
Unilateral pulmonary cavitary lesions  1 (4.2)  1 (1.2)  0.403 
Bilateral pulmonary cavitary lesions  1 (4.2)  0.226 
Unilateral pulmonary infiltrates (no cavities)  9 (11.0)  0.204 
Bilateral pulmonary infiltrates (no cavities)  8 (33.3)  27 (32.9)  0.999 
CT at COVID-19 diagnosis       
Typical ground glass opacity, unilateral  4 (16.7)  7 (8.5)  0.265 
Typical ground glass opacity, bilateral  7 (29.2)  20 (24.4)  0.837 
Atypical  12 (50.0)  35 (42.7)  0.688 
Supplemental oxygen during COVID-19  16 (66.7)  53 (64.6)  0.999 
Type of ventilation used during COVID-19       
Invasive  9 (37.5)  28 (34.1)  0.436
Non-invasive  2 (8.3)  16 (19.5) 
No ventilation  13 (54.2)  38 (46.3) 
COVID-19 outcome       
Discharge  18 (75.0)  48 (58.5)  0.221
Death  6 (25.0)  34 (41.5) 
PFT post-COVID-19 (n =23)a       
Post-BD FEV1 (L)  3.10 ± 0.74  2.24 ± 1.09  0.156 
Post-BD FEV1 (%)  83.1 ± 9.1  70.6 ± 30.1  0.149 
Post-BD FVC (L)  3.61 ± 0.81  3.02 ± 1.22  0.370 
Post-BD FVC (%)  78.6 ± 8.9  76.3 ± 26.8  0.767 
Post-BD FEV1/CVF  85.9 ± 2.3  73.6 ± 15.7  0.004 
TLC (L)  4.88 ± 0.35  5.38 ± 1.15  0.410 
TLC (%)  77.8 ± 10.7  93.5 ± 20.3  0.155 
RV (L)  1.54 ± 0.41  2.24 ± 0.85  0.133 
RV (%)  84.4 ± 30.8  113.9 ± 43.9  0.222 
DLCO (L)  5.79 ± 0.57  4.76 ± 2.41  0.175 
DLCO (%)  57.5 ± 7.4  54.8 ± 21.4  0.709 
6MWT (m)  416.7 ± 77.1  384.2 ± 107.6  0.627 
Desaturation in 6MWT  6 (35.3)  0.521 
Ventilatory defect post-COVID-19       
Obstructive  3 (15.8)  0.074
Restrictive  4 (100)  9 (47.4) 
Normal  7 (36.8) 
EuroQol-5D mobility       
I have no problems walking  4 (36.4)  16 (59.3)  0.494
I have slight problems walking  2 (18.2)  3 (11.1) 
I have moderate problems walking  4 (36.4)  4 (14.8) 
I have severe problems walking  1 (9.1)  3 (11.1) 
I am unable to walk  1 (3.7) 
EuroQol-5D self-care       
I have no problems washing or dressing myself  9 (81.8)  19 (70.4)  0.783
I have slight problems washing or dressing myself  1 (9.1)  2 (7.4) 
I have moderate problems washing or dressing  1 (9.1)  4 (14.8) 
I have severe problems washing or dressing  1 (3.7) 
I am unable to wash or dress myself  1 (3.7) 
EuroQol-5D usual activities       
I have no problems doing my usual activities  4 (36.4)  15 (55.6)  0.507
I have slight problems doing my usual activities  2 (18.2)  6 (22.2) 
I have moderate problems doing my usual activities  3 (27.3)  3 (11.1) 
I have severe problems doing my usual activities  2 (18.2)  2 (7.4) 
I am unable to do my usual activities  1 (3.7) 
EuroQol-5D pain and discomfort       
I have no pain or discomfort  4 (36.4)  16 (59.3)  0.194
I have slight pain or discomfort  5 (45.5)  4 (14.8) 
I have moderate pain or discomfort  3 (11.1) 
I have severe pain or discomfort  1 (9.1)  1 (3.7) 
I have extreme pain or discomfort  1 (9.1)  3 (11.1) 
EuroQol-5D anxiety/depression       
I am not anxious or depressed  5 (45.5)  14 (51.9)  0.687
I am slightly anxious or depressed  2 (18.2)  4 (14.8) 
I am moderately anxious or depressed  2 (7.4) 
I am severely anxious or depressed  2 (18.2)  2 (7.4) 
I am extremely anxious or depressed  2 (18.2)  5 (18.5) 
EuroQol-5D - your health today  68.5 ± 17.7  66.7 ± 22.3  0.818 
Persistent symptoms post-COVID-19 (most common)       
Olfactory disorders  2 (40.0)  11 (52.4)  0.999 
Dyspnea  1 (20.0)  10 (47.6)  0.356 
Arthralgia  2 (40.0)  7 (33.3)  0.999 
Mylagia  7 (33.3)  0.278 
Fatigue  6 (28.6)  0.298 
a

Among the 66 survivors, 21 patients could not undergo PFT due to contraindications: 13 due to active respiratory infection; 3 due to tracheostomy; 3 due to recent myocardial infarction; 1 due to aortic aneurysm and 1 due to a recent surgical procedure in the eye region.

Ten patients had PFT pre- and post-COVID-19. There was a reduction in all lung function parameters, but not statistically significant (p > 0.05 for all comparisons; data not shown). The 6MWT final test was in average 39.4 m lower than the initial test (although not significant, patients lost about 10% of the performance).

Table 2 shows the factors associated with mortality. TB sequelae patients who were older, needed supplemental oxygen and invasive ventilation, and those who had lower total lung capacity (TLC) (%) and DLCO (%) had higher mortality. Active TB patients who needed invasive ventilation had higher mortality.

Table 2.

Factors associated with mortality in TB-COVID-19 patients.

Demographic dataActive TBp valueTB Sequelaep value
Survivors(n = 18)  Non-survivorsa(n = 6)  Survivors(n = 48)  Non-survivorsa(n = 34) 
Age (years)  49.6 ± 13.9  56.3 ± 22.9  0.393  55.1 ± 15.4  67.5 ± 10.9  <0.0001 
Male sex  11 (61.1)  4 (66.7)  0.999  24 (50.0)  21 (61.8)  0.407 
Smoking status             
Current smoker  8 (44.4)  1 (16.7)  0.2304 (8.3)  4 (11.8)  0.189
Former smoker  5 (27.8)  4 (66.7)  25 (52.1)  23 (67.6) 
Never smoker  5 (27.8)  1 (16.7)  19 (39.6)  7 (20.6) 
Alcohol abuse  5 (27.8)  2 (33.3)  0.999  12 (25.0)  8 (23.5)  0.999 
Intravenous drug user  3 (16.7)  2 (33.3)  0.568  4 (8.3)  3 (8.8)  0.999 
HIV positive  7 (38.9)  2 (33.3)  0.999  7 (14.6)  8 (23.5)  0.458 
TB data             
PFT pre-COVID-19             
Post-BD FEV1 (L)  2.23 ± 0.21  –  –  2.29 ± 1.09  1.91 ± 0.84  0.358 
Post-BD FEV1 (%)  97.0 ± 37.8  –  –  75.2 ± 30.8  65.7 ± 28.4  0.436 
Post-BD FVC (L)  2.97 ± 0.64  –  –  3.04 ± 0.96  2.69 ± 0.94  0.373 
Post-BD FVC (%)  92.9 ± 32.0  –  –  80.9 ± 26.4  72.2 ± 24.4  0.398 
Post-BD FEV1/FVC  83.6 ± 1.1  –  –  75.3 ± 19.6  69.2 ± 16.4  0.418 
TLC (L)  –  –  –  5.57 ± 1.49  4.39 ± 1.43  0.179 
TLC (%)  –  –  –  99.1 ± 25.1  68.9 ± 14.6  0.020 
RV (L)  –  –  –  2.55 ± 1.42  1.84 ± 0.76  0.279 
RV (%)  –  –  –  94.4 ± 35.0  86.9 ± 35.5  0.721 
DLCO (L)  –  –  –  5.50 ± 3.08  4.12 ± 2.12  0.325 
DLCO (%)  –  –  –  68.4 ± 21.5  41.7 ± 22.2  0.035 
6MWT (m)  –  –  –  394.1 ± 131.4  377.4 ± 115.8  0.786 
Desaturation in 6MWT  –  –  –       
Ventilatory defect post-TB             
Obstructive  –  –  4 (28.6)  2 (16.7)  0.148
Restrictive  –  –  3 (21.4)  7 (58.3) 
Normal  2 (66.7)  –  7 (50.0)  3 (25.0) 
COVID-19 data             
CXR at COVID-19 diagnosis             
Unilateral pulmonary cavitary lesions  1 (16.7)  0.250  1 (2.1)  0.999 
Bilateral pulmonary cavitary lesions  1 (16.7)  0.250  –  –  – 
Unilateral pulmonary infiltrates (no cavities)  –  –  –  5 (10.4)  4 (11.8)  0.999 
Bilateral pulmonary infiltrates (no cavities)  4 (22.2)  4 (66.7)  0.129  17 (35.4)  10 (29.4)  0.740 
CT at COVID-19 diagnosis             
Typical ground glass opacity, unilateral  4 (22.2)  0.539  3 (6.3)  4 (11.8)  0.441 
Typical ground glass opacity, bilateral  4 (22.2)  3 (50.0)  0.307  12 (25.0)  8 (23.5)  0.999 
Atypical  10 (55.6)  2 (33.3)  0.640  18 (37.5)  17 (50.0)  0.368 
Supplemental oxygen during COVID-19  10 (55.6)  6 (100)  0.066  22 (45.8)  31 (91.2)  <0.0001 
Type of ventilation used during COVID-19             
Invasive  4 (22.2)  5 (83.3)  0.0038 (16.7)  20 (58.8)  <0.0001
Non-invasive  1 (5.6)  1 (16.7)  6 (12.5)  10 (29.4) 
No ventilation  13 (72.2)  34 (70.8)  4 (11.8) 

Median time do death: Active TB group (13 days [5–27.8 days]) and TB sequelae group (15.5 days [6.8–29.3 days], p = 0.691.

a

Causes of death: Active TB group (3 deaths for COVID-19 and 3 deaths for TB + COVID-19); TB sequelae group (all 34 deaths for COVID-19).

In this prospective cohort study, we demonstrated that, one year after COVID-19, patients with TB and COVID-19 had abnormal PFT, reduced 6MWT performances, impaired QoL, and persistent symptoms. Furthermore, the mortality of these patients was high (almost 40%).

In the largest cohort of patients with TB and COVID-19,2 mortality was 11%, and the factors associated with death were older age, male gender and invasive ventilation. In a previous study,3 the case fatality rate was 12.3% and deaths were mostly in patients >60 years, with at least one comorbidity. Older age and invasive ventilation were also risk factors for mortality in the present study. However, we identified a higher mortality, probably because we included only hospitalized patients.

Patients with TB sequelae and COVID-19 who died had lower TLC (%) and DLCO (%) pre-COVID-19, emphasizing the mortality related to PTLD. In fact, PTLD patients have twice the risk of spirometry abnormalities than the general population, and patients surviving COVID-19 may have persistent abnormalities in PFT, such as restrictive ventilatory defects and diffusion impairment.5 In the present study, a large percentage of patients had restrictive ventilatory pattern, although part of this may be due to sequelae from TB. Although not significant, the loss in 6MWT performances in the final test (about 10%) was relevant.

This study has some limitations. We did not evaluate COVID-19 radiological sequelae, nor pre-COVID-19 QoL. The relatively small sample size of patients with pre- and post-COVID-19 PFT (several patients had severe clinical conditions contraindicating PFT) may have prevented us from finding statistically significant differences.

In conclusion, this study describes the combination of PTLD and post-COVID-19 sequelae, evaluated through PFT (including 6MWT) and QoL. Further studies should evaluate comprehensive strategies to assessment/follow-up and determine the need for pulmonary rehabilitation to improve lung health of patients with these two diseases overlapping.

References
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World Health Organization. Global tuberculosis report 2022. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022; 2022 [Accessed 01 March 2023].
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Tuberculosis and COVID-19 co-infection: description of the global cohort.
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Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases.
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Tuberculosis and COVID-19 interaction: a review of biological, clinical and public health effects.
Pulmonology, 27 (2021), pp. 151-165
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Breathing back better! A state of the art on the benefits of functional evaluation and rehabilitation of post-tuberculosis and post-COVID lungs.
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Functional impairment during post-acute COVID-19 phase: preliminary finding in 56 patients.
Pulmonology, 27 (2021), pp. 452-455
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Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.
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