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. 2022 Nov 28;17(11):e0277807. doi: 10.1371/journal.pone.0277807

Tuberculosis in individuals who recovered from COVID-19: A systematic review of case reports

Ayinalem Alemu 1,2,*, Zebenay Workneh Bitew 3, Getachew Seid 1,2, Getu Diriba 1, Emebet Gashu 4, Nega Berhe 2, Solomon H Mariam 2, Balako Gumi 2
Editor: Shampa Anupurba5
PMCID: PMC9704624  PMID: 36441785

Abstract

Background

The emergence of COVID-19 overwhelmed tuberculosis (TB) prevention and control, resulting in a decrease in TB detection rate and an increase in TB deaths. Furthermore, the temporary immunosuppressive effects, lung inflammation, and the corticosteroids used to treat COVID-19, may play a direct role in immunosuppression, leading to reactivation of either previous infection or latent TB or the development of new TB. Thus, the aim of this study was to review TB incidence in individuals who recovered from COVID-19.

Methods

We conducted a systematic search of available databases for previously published studies that reported TB in COVID-19 survivors. The PRISMA checklist was used to guide the review, and the JBI checklist was used to evaluate the study’s quality. The descriptive data were summarized.

Results

Data were extracted from 21 studies conducted in 13 countries having 33 cases. The median age was 44 years (range; 13.5–80), and more than half (18, 54.5%) were males. Twelve patients immigrated from TB endemic settings. All 17 patients assessed for HIV were seronegative, and all 11 patients assessed for BCG vaccination status were vaccinated. The majority (20, 69%) of patients had some type of comorbidity with diabetes (12/29) and hypertension (9/29) being the most common. Four patients (30.77%) had a history of TB. Corticosteroids were used to treat COVID-19 in 62.5% (10) of individuals. Dexamethasone, remdesivir, azithromycin, hydroxychloroquine, and enoxaparin were the most commonly used drugs to treat COVID-19. The most common TB symptoms were fever, cough, weight loss, dyspnea, and fatigue. Twenty, eleven, and two patients developed pulmonary, extrapulmonary, and disseminated/miliary TB respectively. It may take up to seven months after COVID-19 recovery to develop tuberculosis. Data on the final treatment outcome was found for 24 patients, and five patients died during the anti-TB treatment period.

Conclusion

Tuberculosis after recovering from COVID-19 is becoming more common, potentially leading to a TB outbreak in the post-COVID-19 era. The immunosuppressive nature of the disease and its treatment modalities may contribute to post COVID-19 TB. Thus, we recommend a further study with a large sample size. Furthermore, we recommend feasibility studies to assess and treat latent TB in COVID-19 patients residing in TB endemic counties since treatment of latent TB is done only in TB non-endemic countries.

Introduction

COVID-19 caused a huge public health impact across the globe. In addition to its direct impact, COVID-19 exerted many disruptions in the prevention and control of other diseases including tuberculosis (TB) [1, 2]. It is reported that during the COVID-19 epidemic there was a decrease in the global TB detection rate and an increase in TB deaths [3]. Different studies revealed a decrease in TB notification rate due to COVID-19 lockdown [4–8]. A study conducted in Malawi revealed a 35.9% decrease in TB detection rate immediately after the start of the COVID-19 epidemic [5]. In another study conducted in Sierra Leone it was observed that there was an overall 12.7% decrease in presumptive TB cases during the first three quarters of 2020 compared to 2019 [8]. Likewise, in Kenya, there was a 31.8% decrease in people with presumptive pulmonary TB [9]. In addition to the lockdown, the shift of resources from the TB prevention and control program to COVID-19 exerted a huge impact in the TB detection rate [1]. Besides, the pandemic increased TB mortality. For the last decades, the global TB mortality rate was decreasing, however, based on the 2021 Global TB report for the first time in over a decade, TB deaths have increased because of reduced access to TB diagnosis and treatment in the face of the COVID-19 pandemic [3].

Integrating TB and COVID-19 disease programs is important to harmonize the effort to decrease the debilitating effect of both diseases. Assessing COVID-19 patients/suspects/ for TB and vice versa could be important. A pooled estimate revealed that the proportion of active pulmonary tuberculosis among COVID-19 patients was 1.07% (95% CI 0.81%-1.36%) [10]. In addition to the indirect effect of COVID-19 on TB prevention and control programs, it can directly affect TB incidence by making an individual develop TB after recovery from COVID-19 [11–13]. The temporary immunosuppressive effects and lung inflammation caused by COVID-19 along with steroid-induced immunosuppression might lead to reactivation of dormant bacilli to TB disease [14]. COVID-19 affects the immune system by diminishing the total number of T cells, CD4+ and CD8+ T cells [15, 16]. COVID-19 and TB share dysregulation of immune responses that could worsen COVID-19 severity and may favor TB disease progression and reactivation of TB [17]. We anticipate a higher risk of new TB and the potential reactivation of previous TB or latent TB in individuals who recovered from COVID-19. This might result in post COVID-19 TB outbreak in TB endemic settings. Thus, this systematic review aimed to assess TB in individuals who recovered from COVID-19.

Methods

Article searching strategy

The methodology for this systematic review study was designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist [18] (S1 Table). Two independent authors (AA, and GS) conducted systematic article searching from electronic databases such as PubMed, CINAHL, Global Index Medicus, Global Health, and OVID and other gray literature sources such as Google Scholar and Google for studies that reported TB among individuals who recovered from COVID-19 without the time and boundary restrictions. The search was conducted up to 12 June 2022 for studies published in the English language. The third author (ZWB) resolved the inconsistencies that arose between the two authors. The keywords used during article searching were tuberculosis, Mycobacterium tuberculosis, COVID-19, SARS-CoV-2, and reactivation in conjunction with the Boolean operators AND and OR. The search string for the PubMed database was ("Tuberculosis"[MeSH Terms] OR "Latent Tuberculosis"[MeSH Terms] OR "Extensively Drug-Resistant Tuberculosis"[MeSH Terms] OR "tuberculosis, central nervous system"[MeSH Terms] OR "tuberculosis, multidrug resistant"[MeSH Terms] OR "tuberculosis, urogenital"[MeSH Terms] OR "tuberculosis, splenic"[MeSH Terms] OR "tuberculosis, spinal"[MeSH Terms] OR "tuberculosis, renal"[MeSH Terms] OR "tuberculosis, pulmonary"[MeSH Terms] OR "tuberculosis, pleural"[MeSH Terms] OR "tuberculosis, osteoarticular"[MeSH Terms] OR "tuberculosis, oral"[MeSH Terms] OR "tuberculosis, ocular"[MeSH Terms] OR "tuberculosis, miliary"[MeSH Terms] OR "tuberculosis, meningeal"[MeSH Terms] OR "tuberculosis, male genital"[MeSH Terms] OR "tuberculosis, lymph node"[MeSH Terms] OR "tuberculosis, laryngeal"[MeSH Terms] OR "tuberculosis, hepatic"[MeSH Terms] OR "tuberculosis, gastrointestinal"[MeSH Terms] OR "tuberculosis, female genital"[MeSH Terms] OR "tuberculosis, endocrine"[MeSH Terms] OR "tuberculosis, cardiovascular"[MeSH Terms] OR "tuberculosis, bovine"[MeSH Terms] OR "tuberculosis, cutaneous"[MeSH Terms] OR "Mycobacterium tuberculosis"[MeSH Terms]) AND ("COVID-19"[MeSH Terms] OR "SARS-CoV-2"[MeSH Terms]) AND "Case Reports"[Publication Type] (S2 Table).

Article selection procedure

Articles were selected in a phase-wise approach such that all the extracted articles were exported into the EndNote X8 citation manager and the duplicates were removed. Then, the articles were screened by title and abstract before the full-text review (Fig 1). Finally, data were extracted from the articles that passed the full-text review. The PICOS criteria for this study were; population (individuals who recovered from COVID-19), intervention (not applicable), comparator (not applicable), outcome (developing tuberculosis), study design (case reports), and study setting (any setting in any country across the globe). The studies that reported TB (any type of TB whether latent TB or previously treated TB) in individuals who recovered from COVID-19 or reported TB after completing COVID-19 treatment were included. While a study that did not include details of individual patients was excluded.

Fig 1. Flowchart describing the selection of studies for the systematic review of case reports for developing tuberculosis in individuals who recovered from COVID-19.

Fig 1

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Data extraction

Data were extracted independently by two authors (AA, and EG), and the third author (GD) resolved the inconsistencies that arose between the two authors through discussion. The extracted data included the first author name and publication year, country, setting, study design, sex, age, migration status, type of co-morbidities, COVID-19 diagnostic method, treatment modality of COVID-19, time from COVID-19 recovery to TB symptoms developed, types of TB symptoms, TB diagnostic method, anatomical classification of TB, anti-TB drug-resistance category, anti-TB treatment given, previous TB history, smoking status, HIV status, BCG vaccination status, alcohol/drugs consumption status, and mortality status during anti-TB treatment. The data were summarized using Microsoft Excel 2016 spreadsheets (Table 1).

Table 1. Demographic and behavioral characteristics of individuals who developed tuberculosis after COVID-19 recovery included in this systematic review.

Patient code Author year Living country Continent Country origin Study design Study setting Age in years Sex HIV status BCG vaccination Any comorbidity Smoking Alcohol
Patient 1 Khayat et al., 2021 [11] Saudi Arabia Asia Case report King Fahad Armed Forces Hospital 40 Female Negative - - No No
Patient 2 Ntshalintshali et al., 2021 [12] South Africa Africa Case report Stellenbosch University 65 Male Negative - Chronic lung disease - -
Patient 3 Unal et al., 2021 [19] Türkiye Asia One patient migrated from Syria Case report Erbakan University 16 Male Negative Vaccinated Juvenile idiopathic rheumatoid arthritis - -
Patient 4 Türkiye Asia Case report 16 Male Negative Vaccinated No chronic disease - -
Patient 5 Türkiye Asia Case report 17 Female Negative Vaccinated No chronic disease - -
Patient 6 Türkiye Asia Case report 13.5 Female Negative Vaccinated No chronic disease - -
Patient 7 Türkiye Asia Case report 16 Female Negative Vaccinated No chronic disease - -
Patient 8 Türkiye Asia Case report 13.5 Female Negative Vaccinated No chronic disease - -
Patient 9 Türkiye Asia Case report 16 Female Negative Vaccinated No chronic disease - -
Patient 10 Türkiye Asia Case report 13.67 Female Negative Vaccinated Primary ciliary dyskinesia - -
Patient 11 Lee et al., 2021 [20] USA North America Vietnam, 1995 Case report Moulay Ismail Military Hospital, 49 Male - - Past medical history of Mediastinal gray zone lymphoma, hypertension, and malignancy. Current infection with cytomegalovirus - -
Patient 12 Elmoqaddem et al., 2020 [21] Morocco Africa - Case report Moulay Ismail Military Hospital, 59 Female - - DM - -
Patient 13 Pozdnyakov et al., 2021 [22] Canada North America East Asian descent Case report McMaster University 64 Male - - Type 2 DM, hemodialysis, hypertension, dyslipidemia. No -
Patient 14 Garg and Lee, 2020 [23] USA North America - Case report - 44 Male - - Hypertension, DM, atrial fibrillation - -
Patient 15 Aguillón-Durán et al., 2021 [13] Mexico South America Case report Centro Regional de Tuberculosis in Reynosa Tamaulipas 43 Male Negative Vaccinated Type 2 DM for 13 years, peripheral neuropathy No No
Patient 16 Mexico South America Case report 44 Male Negative Vaccinated Type 2 DM for 5 years No Yes
Patient 17 Mexico South America Case report 49 Female Negative Vaccinated Type 2 DM for 6 years, high blood pressure No No
Patient 18 Dahanayake et al., 2021 [24] Sri Lanka Asia - Case report National Hospital for Respiratory Diseases 58 Male - - No comorbidities No -
Patient 19 Zahid et al., 2021 [25] Pakistan Asia - Case report Aga Khan University Hospital 26 Female - - - - -
Patient 20 Podder and Chowdhury, 2020 [26] Bangladish Asia - Case report Debidwar Upazila Health Complex 58 Male - - DM - -
Patient 21 Bangladish Asia - Case report Debidwar Upazila Health Complex 67 Male - - DM, hypertension - -
Patient 22 Bangladish Asia - Case report Debidwar Upazila Health Complex 58 Male - - DM, hypertension - -
Patient 23 Asif et al., 2021 [27] USA North America Guatemala Case report University of Miami Miller School of Medicine 18 Male Negative - No comorbidities - -
Patient 24 Win et al., 2021 [28] USA North America Myanmar Case report University at Buffalo 38 Female - - DM and Renal transplant due to ESRD - -
Patient 25 Noh and Dronavalli, 2021 [29] USA North America China, 50 years ago Case report - 80 Female - - Hypertension, coronary artery disease - -
Patient 26 Elziny et al., 2021 [30] Qatar Asia Nepal Case report Hamad Medical Corporation 29 Male Negative - No known chronic illness No No
Patient 27 Burda etal., 2021 [31] USA North America Southeast Asian Case report Thomas Jefferson University Hospital 55 Male - - - - -
Patient 28 Cutler et al., 2020 [32] USA North America China Case report Weil Cornell Medical College 61 Male - - Past history of Parkinson’s disease - -
Patient 29 Younes et al., 2021 [33] USA North America Brazil Case report New Jersey Medical School 76 Male - - Chronic obstructive pulmonary disease - -
Patient 30 USA North America Columbia Case report 71 Male - - DM - -
Patient 31 Guliani et al., 2021 [34] India Asia Case report A tertiary care hospital of North India 45 Female Negative - Hypertension for 5 years - -
Patient 32 Rahimi et al., 2021 [35] Iran Asia Case report Tehran University of Medical Sciences 25 Female Negative - - - -
Patient 33 Leonso et al., 2022 [36] USA North America Philippines Case report South Florida hospital 74 Female - - Hypertension, Hyperlipidemia, and DM - -
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“-”; Not described, DM; Diabetes Mellitus, USA; United States of America, ESRD; End Stage Renal Disease

Quality assessment

Two independent authors (AA, and ZWB) assessed the study’s quality using the Joanna Briggs Institute (JBI) critical appraisal checklist for case reports, and the inconsistencies were resolved by the third author (GS). The checklist contained eight questions where we gave 12.5 points for each question and rounded to 100%. As per the tool, all queries were filled with “yes”, “no”, “unclear” and “not applicable”. The quality score was graded as a low, medium, and high if the quality score was <60%, 60–80%, and >80% (S3 Table).

Outcome

The primary outcome of this study was developing TB in individuals who recovered from COVID-19 or completed COVID-19 treatment. While the secondary outcome of the present study was the mortality status of patients during the anti-TB treatment period. The diagnosis of TB in this study was based on either of or the combinations of culture, AFB smear microscopy, molecular method (GeneXpert), pathology, clinically using chest X-ray and chest computed tomography.

Data synthesis and statistical analysis

The extracted data were exported to STATA version 16 for statistical analysis. Simple descriptive statistics such that frequency, proportion, mean/median age and time to develop TB were determined. Descriptive data were summarized by study country, sex, age, immigration status, co-morbidity types, COVID-19 diagnostic method, COVID-19 treatment modality, time from COVID-19 recovery to developing TB, TB symptoms, TB diagnostic methods, anatomical classification of TB, anti-TB drug-resistance category, anti-TB treatments, previous TB history, smoking status, alcohol/drugs consumption status, HIV status, BCG vaccination status, and mortality status during anti-TB treatment.

Results

From the whole search, 2653 studies were identified, and 316 duplicates were removed. Then, the remaining 2337 studies were screened by title and abstract. Full-text screening was conducted for 23 studies, and finally, data were extracted from 21 studies comprising [11–13, 19–36] 33 individual cases (Fig 1). The studies were reported from 13 countries with the highest frequency from the United States of America (10 patients), and Türkiye (eight patients) followed by Bangladesh (three patients), and Mexico (three patients). The other countries were Canada, India, Iran, Morocco, Pakistan, Qatar, Saudi Arabia, South Africa, and Sri Lanka. Per continent, 17, 11, 3, and 2 cases were reported from Asia, North America, South America, and Africa respectively. Twelve patients immigrated from TB endemic settings. The median and mean age of individuals were 44 years (Min; 13.5 years, Max; 80 years), and 42.96 years (SD = 21.54 years) respectively. Of 33 patients, more than half (18, 54.55%) were males. In a study conducted by Tadolini et al. (2020) [37], among 49 patients with COVID-19 and TB co-infection, in 14 patients COVID-19 preceded TB by a median (range) time of four (2–10) days. However, the authors revealed that they could not report on the potential contribution of COVID-19 towards development of active TB disease because they did not follow individuals with latent TB infection overtime. Besides, the details of each patient was not reported so that we were unable to find each patient’s data for the current systematic review.

Seventeen patients were HIV seronegative however, HIV serostatus was not determined for the remaining 16 patients. BCG vaccination status were available for only 11 cases and all were vaccinated. More than half of (20/29) patients had some type of one or more comorbidities other than COVID-19. The most frequent comorbidities were diabetes mellitus (12 cases), followed by hypertension (nine cases), and hemodialysis/ renal transplantation (two cases) (Table 1).

Among 13 patients assessed for the previous TB history, four patients had previous TB treatment history with three active TB cases and one latent TB case, one case had home-based TB contact history, and eight patients were new TB cases. COVID-19 was confirmed in 13 cases by RT-PCR, while in nine cases it was confirmed by SARS-CoV-2 antibody tests. Two cases were treated for COVID-19 by considering the chest X-ray result. The COVID-19 treatment modalities were reported in 16 cases. Per group of drugs, ten six, six, five, and five patients took steroids, antibiotics, anticoagulants, anti-viral, and anti-malarial drugs respectively approved for COVID-19. The remaining treatment anti-parasites (2), cough suppressants (2), immunosuppressant (2), anti-allergies (1), and monoclonal antibody (1). Specific to the drugs, dexamethasone (7), remdesivir (5), azithromycin (4), hydroxychloroquine (4), enoxaparin (4), tocilizumab (2), ivermectin (2), doxycycline (2), unspecified antitussives (2), unspecified steroids (2), Plaquenil (1), ceftriaxone (1), heparin (1), unspecified anticoagulant (1), unspecified antibiotic (1), oral prednisolone (1), unspecified antihistamine (1), and bamlanivimab (1). Four patients also took oxygen (Table 2).

Table 2. Clinical characteristics of individuals who developed tuberculosis after COVID-19 recovery included in this systematic review.

Patient code Previous TB history COVID-19 diagnostic method COVID_19 treatment mechanism TB symptoms TB Diagnostic method Drug-resistance Type of TB Time from COVID-19 recovery to TB Anti-TB treatment Mortality status
Patient 1 No RT-PCR - Right-side pleuritic chest pain, cough, subjective fever and anorexia GeneXpert Positive, culture positive, smear negative Susceptible PTB Seven weeks - -
Patient 2 PTB in 2017 RT-PCR - Productive cough, dyspnea, left-sided pleuritic chest pain, loss of weight and appetite. GeneXpert Positive, Smear positive Susceptible PTB Immediately after starting COVID-19 treatment RIPE Died
Patient 3 - Antibody positive in 6 cases - Fever = 6, cough = 3, side pain = 3, swelling at neck = 1 Pathology - Pleural TB - RIPE alive
Patient 4 - Clinically - Pleural TB - RIPE alive
Patient 5 - Clinically - Pleural TB - RIPE alive
Patient 6 - Pathology - Pleural TB - RIPE alive
Patient 7 - Clinically - TB Lymphadenitis - RIPE alive
Patient 8 - Pathology, GeneXpert Positive - TB Lymphadenitis - RIPE alive
Patient 9 - Smear positive, culture positive Susceptible TB Lymphadenitis - RIPE alive
Patient 10 - GeneXpert Positive - EPTB (congenital TB) - RIPE alive
Patient 11 - RT-PCR Remdesivir and dexamethasone Diarrhea, hematochezia, hypoxic, acidotic, and septic Culture positive, smear positive, GeneXpert Positive Susceptible PTB 20 days RIPE Died
Patient 12 PTB before 15 years RT-PCR Hydroxychloroquine, azithromycin, enoxaparin Cough, respiratory difficulty with episode of hemoptysis. Gene Xpert positive - PTB 5 days - -
Patient 13 No RT-PCR - Persistent fever Smear positive, GeneXpert Positive, culture positive Susceptible PTB 40 days RIPE Died
Patient 14 - RT-PCR Plaquenil, ceftriaxone, azithromycin, anticoagulation, dexamethasone, tocilizumab Fever Culture positive, smear positive - PTB 10 days RIPE alive
Patient 15 No Anti-SARS-CoV-2 IgG titers - Cough, fever, chills, chest pain, weight loss Abnormal chest x-ray, smear positive, culture positive - PTB 3 months - -
Patient 16 No Anti-SARS-CoV-2 IgG titers - Cough, fever, chills, weight loss Abnormal chest x-ray, smear positive, culture positive - PTB 6 months - -
Patient 17 TB before 2 years Anti-SARS-CoV-2 IgG titers - Cough, productive cough, fever, chills, weight loss, fatigue Abnormal chest x-ray, Smear positive, culture positive - PTB 4 months - -
Patient 18 No The Chest X-ray showed bilateral shadows of COVID pneumonitis Dexamethasone, enoxaparin, oxygen Dry cough Enhanced CT chest - Pleural TB 2 weeks RIPE alive
Patient 19 - RT-PCR Antibiotics, oral prednisolone 2, azithromycin High grade fever, hoarseness of voice, dry cough. Smear negative, GeneXpert Positive, culture positive Susceptible PTB - RIPE alive
Patient 20 - RT-PCR Ivermectin, doxycycline, antitussives, antihistamines High grade fever, breathlessness and productive distressing cough Smear positive - PTB 1 week Anti-TB chemotherapy alive
Patient 21 - RT-PCR Enoxaparin, doxycycline, ivermectin, antitussives Low grade fever, productive cough, 3 kg of weight loss. Smear positive, GeneXpert positive - PTB 2 weeks Anti-TB chemotherapy alive
Patient 22 - RT-PCR Enoxaparin, steroids oxygen Anosmia, low grade intermittent fever, unexplained fatigue Smear positive - PTB Immediately after startingCOVID-19 treatment Anti-TB chemotherapy alive
Patient 23 No - - Dyspnea, fever, and cough productive of sputum. Smear positive, Culture positive, GeneXpert Positive Susceptible PTB 1 month RIPE Died
Patient 24 Treated latent TB - - Nocturnal fever, fatigue, nausea, sore throat, appetite and weight loss, dysphagia, neck swelling, dyspnea, and watery diarrhea. Smear positive - Thyroid TB 7 months RIPE Died
Patient 25 - - Tocilizumab, remdesivir, steroids, hydroxychloroquine Fever, cough, altered mental status, hypoxemic Smear positive, GeneXpert Positive, culture positive - PTB, 3 months RIPE -
Patient 26 No RT-PCR Azithromycin, hydroxychloroquine Tired, shortness of breath, febrile GeneXpert Positive Susceptible PTB 2 weeks RIPE, AMK, piperacillin–tazobactam alive
Patient 27 - - - Acute progressive encephalopathy. GeneXpert Positive, culture positive - Bone and Lymphnode TB 3 weeks RIPE -
Patient 28 - RT-PCR Hydroxychloroquine, oxygen High grade fever, cough. Smear positive, GeneXpert positive Susceptible PTB Immediately after startingCOVID-19 treatment RIPE, AMK, piperacillin–tazobactam alive
Patient 29 - - Bamlanivimab Generalized weakness, fever and cough GeneXpert Positive - PTB 1 month - -
Patient 30 - - Dexamethasone and remdesivir Dyspnea, fever, and productive cough. GeneXpert Positive - PTB 3 months - -
Patient 31 No RT-PCR Remdesivir, dexamethasone, and low molecular weight heparin cough and fever Clinical - Miliary TB Immediately after COVID-19 treatment Anti-tubercular therapy alive
Patient 32 No - Dexamethasone Headache, decreased level of consciousness, nausea, vomiting, diplopia, back pain and bladder incontinency, lower limb weakness, lost 5 kg GeneXpert Positive Susceptible Disseminated TB, miliary TB pulmonary, TB meningitis and TB spondylodiscitis 3 months RIPE alive
Patient 33 - Chest X-ray with multifocal ground glass infiltrates Dexamethasone, remdesivir, oxygen Generalized weakness, shortness of breath, fever Culture positive, Smear positive, GeneXpert Positive - PTB 3 months RIPE, then second-line therapy (Linezolid, INH, Levo), then Rifabutin, then ethambutol, rifabutin, and levofloxacin alive
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“-”; Not described, RT-PCR; Real Time Polymerase Chain Reaction, TB; Tuberculosis, PTB; Pulmonary Tuberculosis, EPTB; Extrapulmonary Tuberculosis, R; Rifampicin, I; Isoniazid, P; Pyrazinamide; E; Ethambutol, AMK; Amikacin, Levo; Levofloxacin, Clatro; clarithromycin

The symptoms identified before TB diagnosis were fever (25/33), cough (19/33), weight loss (7/33), dyspnea (7/33), fatigue 6/33), chest pain (3/33), chills (3/33), side pain (3/33), anorexia (3/33), swelling at the neck (2/33), diarrhea (2/33), hypoxic (2/33), hematochezia (1/33), acidotic (1/33), septic (1/33), hemoptysis (1/33), hoarseness of voice (1/33), anosmia (1/33), nausea (1/33), sore throat (1/33), dysphagia (1/33), altered mental status (1/33), headache (1/33), and acute progressive encephalopathy (1/33). Tuberculosis was confirmed bacteriologically (26 cases), clinically (four cases), pathology (two cases), and one case had an abnormal chest X-ray, abnormal Contrast-Enhanced CT chest, high ESR count, and high adenosine deaminase activity of pleural fluid. Specific to the bacteriological diagnostic methods, in 18, 15, and 13 cases GeneXpert, smear microscopy, and culture were positive. Anti-TB drug susceptibility status was determined in ten cases where all were susceptible to anti-TB drugs. However, keeping in mind 20 patients who took first line anti-TB drugs we assumed the cases were susceptible to anti-TB drugs. However, one case took different anti-TB drugs: rifampicin, isoniazid, pyrazinamide, ethambutol, linezolid, rifabutin, levofloxacin and finally took six month treatment with rifabutin, levofloxacin, and ethambutol. Regarding the anatomical site of TB, 20 cases developed PTB. Eleven cases developed EPTB with different sites; pleural TB (five cases), TB lymphadenitis (three cases), Congenital TB (one case), Thyroid TB (one case), and both bone TB and lymph node TB (one case). The remaining two cases developed disseminated/miliary TB. From 20 PTB cases, three cases were reported from the high TB burden countries, while all the 11 EPTB cases were reported from the countries that are not included in the list of high TB burden countries. For the remaining 2 cases, 1 miliary TB case was reported from a high TB burden country, while 1 disseminated case was reported from a country not included in the high TB burden countries list. The time of developing TB from COVID-19 recovery was reported in 24 studies that extends up to seven months with a median of 25.5 days. The TB treatment modalities were described for 26 cases such that 20 patients exclusively took first-line anti-TB drugs, one patient took first-line anti-TB drugs, amikacin, and piperacillin-tazobactam, one patient took first-line and second-line anti-TB drugs, while in the remaining four cases, the type of anti-TB drug was not specified rather described as anti-TB chemotherapy. The mortality status of the patients was described in 24 cases, where 19 were alive and five died during the anti-TB treatment period. While for the remaining 9 cases, their anti-TB treatment outcome is not described in the studies (Table 2).

Discussion

This study is a systematic review of case reports that reported TB in individuals who recovered from COVID-19. The study revealed that TB reactivation or new TB infection is becoming a common phenomenon in individuals who recovered from COVID-19. Post COVID-19 recovery TB was happening in all age groups. The study also revealed that TB in COVID-19 recovered individuals was reported from 13 countries found in four continents. This suggests that post COVID-19 recovery may become the potential risk factor for TB outbreak across the globe mainly in high TB burden countries. The prevalence of latent TB is high in individuals residing in high TB prevalence settings [38]. Thus, the impact of COVID-19 in these settings might be significant. However, the number of studies from high TB endemic settings are limited with only 6/33 cases reported in individuals residing in high TB burden countries. Many cases may have been missed because endemic countries’ scientists/doctors did not bother to report common TB cases. The current study also revealed that 12 patients immigrated from high TB settings who might have latent TB. This reflects the potential reactivation of latent TB to active TB in individuals who recovered from COVID-19. In the present study, relatively the number of men is higher than women in line with the global TB report where there are more TB cases among men than women [3].

The current study also revealed that, all the 17 cases assessed for HIV status were sero-negative. This revealed the diminished immune status of COVID-19 patients might lead to developing TB. Another important finding observed in the present study is, though 11 patients were BCG vaccinated (eight were <17 years and three were 43–49 years of age), they developed TB after COVID-19 recovery. This highlights two things, first the immunogenicity of BCG vaccination in general, and second the effect of COVID-19 on the immunogenicity of BCG to protect against TB. However, this needs further investigations in future studies. We hypothesized the potential for low reactivation in countries where BCG is routinely administered. The other factor observed in this study was the presence of any type of co-morbidity. Presence of co-morbidity may be potential confounding factor. In the current study, more than half of (20/29) patients had any type of one or more comorbidities mainly DM and hypertension. It is well known that DM increases TB risk by two to three times [39] however, we anticipated more TB risk in DM patients who infected with SARS-CoV-2 that needs further investigation. This study also revealed that patients on hemodialysis and with renal transplantation had TB after COVID-19 recovery. There are also other identified comorbid conditions in this study. Generally, this study revealed that patients with underlined comorbidities mainly chronic diseases had a higher risk of developing TB after COVID-19 recovery that needs a close follow-up.

The current study also revealed that among 13 patients with data on previous TB history, four patients had previous TB treatment history that might be due to the potential reactivation of TB after COVID-19 recovery. However, we are not sure whether it was due to endogenous reactivation or due to exogenous reinfection. The other factor assessed in the present study is the type of treatment modality given to COVID-19. The most frequent treatment modality given was corticosteroids (dexamethasone, and oral prednisolone) in eight cases. Corticosteroids given to COVID-19 patients can cause immunosuppression and are associated with TB susceptibility [40]. Besides, two patients took tocilizumab which is an immunosuppressant, and reported to increase TB susceptibility [41]. Thus, assessing for latent TB or previous TB history before giving steroids and tocilizumab for COVID-19 treatment may be important to decrease TB reactivation in this group of individuals. However, due to short window of decision making, it may not be possible to rule out tuberculosis before starting treatment for COVID-19.

This study also revealed the most common TB symptoms identified in individuals who recovered from COVID-19 include fever, cough, weight loss, dyspnea, and fatigue. However, there are also other symptoms identified in this study. Thus, assessing these identified symptoms may be important to early detect TB in this group of individuals. This study also revealed that about 36.36% (11/33) of TB cases identified were EPTB with different sites, and two cases developed disseminated/miliary TB that indicated the importance of assessing COVID-19 recovered patients for non-respiratory symptoms. However, this needs to be further investigated in future studies. Per the high TB burden category, all the 11 the EPTB cases were reported from the countries that are not included in the high TB burden category. The study also revealed that the time to develop TB in individuals who recovered from COVID-19 extends up to 7 months. This emphasizes the importance of long-term follow-up in this group. Even though the overall sample size is low in the current review, 20.83% (5/24) of COVID-19 recovered patients died during their anti-TB treatment which is higher compared to the global TB mortality in 2020 [3]. However, we hypothesized more deaths since the mortality in this study is determined in the early phase of anti-TB treatment where the final TB treatment outcome is not assessed for all cases. Finally, this study is an early and rapid systematic review that might have limited evidence due to limited number of available studies included in the review.

Conclusion

The findings of this study revealed that developing TB among individuals who recovered from COVID-19 might result in a TB outbreak in the post-COVID-19 era. The risk of TB in COVID-19 recovered individuals might be due to the immune suppressive nature of COVID-19, and the treatments used to treat COVID-19. Those individuals who recovered from COVID-19 having certain types of comorbidities might have a higher risk of developing TB. In addition, a considerable proportion of the TB cases were EPTB and the mortality rate is higher than the global mortality rate. Thus, we recommend a further cohort study assessing the incidence of TB post-COVID-19 recovery. Besides, since treatment of latent TB is done only in TB non-endemic countries, feasibility studies to assess and treat latent TB in COVID-19 patients residing in TB endemic countries may be considered in future studies.

Supporting information

S1 Table. Completed PRISMA 2009 checklist.

(DOCX)

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S2 Table. Search engines.

(DOCX)

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S3 Table. Quality assessment for the included studies in meta-analysis.

(DOCX)

Click here for additional data file. (31.2KB, docx)

Acknowledgments

We would like to acknowledge the Ethiopian Public Health Institute for the non-financial help such that for internet searching. Our acknowledgement also goes to primary authors.

Abbreviations

BCG

Bacille Calmette-Guerin

COVID-19

Coronavirus Disease 2019

DM

Diabetes Mellitus

EPTB

Extra Pulmonary Tuberculosis

HIV

Human Immunodeficiency Virus

JBI

Joanna Briggs Institute

MTBC

Mycobacterium Tuberculosis Complex

PCR

Polymerase Chain Reaction

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-analyses

PTB

Pulmonary Tuberculosis

SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

TB

Tuberculosis

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

References

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Decision Letter 0

Shampa Anupurba

19 Sep 2022

PONE-D-22-18569

Tuberculosis in individuals who recovered from COVID-19: A Systematic Review of Case Reports

PLOS ONE

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Additional Editor Comments:

The language has to be thoroughly revised. A few corrections in additions to comments made by reviewer have been pointed out as follows:

Line 58- 'caused' in place of causes

Line 59 to 60-'... the others disease prevention and control programs including the tuberculosis' may be replaced by '...prevention and control of other diseases including tuberculosis'.

Line 60- Delete 'prevention and control program'

Line 62- Delete 'Studies conducted in'

Line 69- 'increases' to be replaced by 'increased'

Line 74- Insert 'versa' after vice

Line 122- 'included' instead of include

Line 132- 'contained' instead of contains

Line 163- 'males' instead of male

Lines 170-172- May be deleted as there is no relevance of smoking and alcohol consumption. 

Line 172- 'HIV' need not be written in italics.

Line 173- Eleven cases were BCG vaccinated or vaccination status was available for only eleven cases?

Line 183- 'COVID-19 was confirmed in 14 cases by PCR'- Please check whether it was  PCR or RT-PCR as  COVID-19 has always been diagnosed by RT-PCR. 

Line 185- 'confirmed by chest X-ray.' Chest X-ray could be suggestive of COVID-19.

Line 254- 'previous TB treatment history that indicated the potential reactivation of TB'- cannot be proven whether it was endogenous reactivation or exogenous reinfection.

Table 2- TB DNA, PCR have been mentioned separately in diagnostic methods for TB. Also Xpert MTB/RIF and Gene Xpert are actually the same.In Patient 13, NAT positive could also be Gene Xpert. In fact all the PCR should be checked whether they were in house PCR or a commercial assay or Gene Xpert 'Clatro' should be expanded to 'clarithromycin' in the footnote under Table 2.'

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

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Reviewer #1: Yes

**********

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Reviewer #1: Yes

**********

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: I congratulate the authors for taking up an interesting topic. The occurrence of TB post-COVID-19 recovery has been commonly observed since the start of the pandemic. It is surprising how little literature is still there on the topic; so, the authors’ effort is praiseworthy. I also appreciate the supplementary material that they have provided which lends further credence to the study. However, there are some suggestions that I have for improving the article.

Major Comments

1. Why did the authors focus only on reactivation in search terms? New onset tuberculosis cases following COVID-19 may be missed in such a strategy. This is more so as the authors themselves write about new cases in lines 222-223.

2. Some perspective must be shared on the difference between the current study and the Tadolini study which the authors have rightly pointed out. In lines 168-169, since Tadolini’s study was also a systematic review, did you attempt to identify the individual case reports and see if any of those were missing in your study? Then the same may be added.

3. In line 210, how is situs inversus totalis a type of TB?

4. Some discussion is warranted on the relative prevalence of PTB and EPTB in the study as compared to world literature. Also, is this differential distribution seen only in the TB non-endemic country cases or even in the cases reported by the authors from TB-endemic countries? This information may be useful.

5. In lines 229-231, discuss the relevance of the low reporting from endemic countries. Many cases may have been missed because endemic countries’ scientists/doctors did not bother to report common TB cases. Another aspect worth discussing is the potential for low reactivation in countries where BCG is routinely administered. Both these angles need to be discussed.

6. The Discussion needs to be shortened and only the major findings need to be analyzed. Discussion on smoking and alcohol status may be removed as no salient features found. Similarly, the discussion on HIV status must be shortened to 1 sentence. The phrase, “The current study also revealed…” or similar phrases have been used many times. Please improve the English language in the Discussion and make it better to read.

7. Please check the tables provided carefully for appropriateness of all data. There may be minor mistakes. Example- In Table 1, for patient code 3-10, in second column with name of authors Unal et al, Patient 1 is written which makes it unclear. Similarly, which patient migrated from Syria is unclear. For the reference of Lee et al (Patient 11), country of origin is written as Vietennam which seems to be wrong spelling. In column on comorbidities it needs to be mentioned which comorbidity was there in the past so as not to confuse with current ones. For example, in the case of the Lee et al, lymphoma history was in past whereas cytomegalovirus was co-existent with COVID. Clarify such details for every case (all 34 cases). Please go through both tables carefully and check all the data and synchrony of lines and columns once more. (Very important as this is backbone of a systematic review of case reports)

Minor Comments:

1. In line 41, write ‘…all 11 patients assessed for BCG vaccination status..’.

2. In line 48, write ‘It may take up to 7 months…’.

3. In line 49, 5/25 patients died. Was information missing for the remaining 9 patients? Please clarify.

4. In line 55, since treatment of latent TB is done only in TB non-endemic countries, please add this as a rejoinder. Same for lines 288-289.

5. The English language is inappropriate at many places in the manuscript. A thorough English editing is needed. For example, in line 58, it should start with “COVID-19 has caused a huge…”; in line 61, it should be “the COVID-19 epidemic..” instead of “epidemics”. Many such corrections need to be done throughout.

6. Lines 100-101- Please check. It seems “tuberculosis” has been repeated multiple times.

7. In line 176, mention the type of transplantation- kidney?

8. Lines 176-180 is repetition of Table 1 data and may be deleted.

9. In lines 217-218, why is M.simiae case described with MTB cases?

10. In lines 218-219, 19+5 is 24. What about the other patient?

11. In Supplementary Tables, numbering is S1,S2,S4. Shouldn’t it be S3?

12. In line 228, change the word ‘magnificent’ to ‘significant’.

13. Lines 237-238 needs to be deleted as this is not a finding of the current study where none of the patients were HIV positive.

14. Lines 260-262 may be modified as due to short window of decision making, it may not be possible to rule out tuberculosis before starting treatment for COVID.

**********

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Reviewer #1: No

**********

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PLoS One. 2022 Nov 28;17(11):e0277807. doi: 10.1371/journal.pone.0277807.r002

Author response to Decision Letter 0

4 Oct 2022

Revisions based on the Editor’s and the reviewers’ comments and suggestions

Title: Tuberculosis in individuals who recovered from COVID-19: A Systematic Review of Case Reports (PONE-D-22-18569)

Editor Comments and suggestions

We would like to thank the editor and the reviewer for giving pertinent comments and suggestions that improve the quality of the paper.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

• Response: Thank you, we have uploaded all required documents.

2. We note that this manuscript is a systematic review or meta-analysis; our author guidelines therefore require that you use PRISMA guidance to help improve reporting quality of this type of study. Please upload copies of the completed PRISMA checklist as Supporting Information with a file name “PRISMA checklist”.

• Response: Thank you. The completed PRISMA checklist was already uploaded fin the supplementary file and at this stage we have uploaded it separately.

Additional Editor Comments:

The language has to be thoroughly revised. A few corrections in additions to comments made by reviewer have been pointed out as follows:

Line 58- 'caused' in place of causes

• Response: Thank you. It is revised accordingly.

Line 59 to 60-'... the others disease prevention and control programs including the tuberculosis' may be replaced by '...prevention and control of other diseases including tuberculosis'.

• Response: Thank you. It is revised accordingly.

Line 60- Delete 'prevention and control program'

• Response: Thank you. It is deleted.

Line 62- Delete 'Studies conducted in'

• Response: Thank you. It is deleted.

Line 69- 'increases' to be replaced by 'increased'

• Response: Thank you. It is revised accordingly.

Line 74- Insert 'versa' after vice

• Response: Thank you. It is revised accordingly.

Line 122- 'included' instead of include

• Response: Thank you. It is revised accordingly.

Line 132- 'contained' instead of contains

• Response: Thank you. It is revised accordingly.

Line 163- 'males' instead of male

• Response: Thank you. It is revised accordingly.

Lines 170-172- May be deleted as there is no relevance of smoking and alcohol consumption.

• Response: Thank for the comment. We have deleted in the current version.

Line 172- 'HIV' need not be written in italics.

• Response: Thank you. It is revised accordingly.

Line 173- Eleven cases were BCG vaccinated or vaccination status was available for only eleven cases?

• Response: Thank you. It is revised

Line 183- 'COVID-19 was confirmed in 14 cases by PCR'- Please check whether it was PCR or RT-PCR as COVID-19 has always been diagnosed by RT-PCR.

• Response: Thank you. It was a clerical error and now revised accordingly.

Line 185- 'confirmed by chest X-ray.' Chest X-ray could be suggestive of COVID-19.

• Response: Thank you for the comment. The two cases were treated for COVID-19 by considering the chest X-ray result.

Line 254- 'previous TB treatment history that indicated the potential reactivation of TB'- cannot be proven whether it was endogenous reactivation or exogenous reinfection.

• Response: Thank you for this valuable comment. We have revised it accordingly. “The current study also revealed that among 14 patients with data on previous TB history, five patients had previous TB treatment history that might be due to the potential reactivation of TB after COVID-19 recovery. However, we are not sure whether it was due to endogenous reactivation or due to exogenous reinfection.”

Table 2- TB DNA, PCR have been mentioned separately in diagnostic methods for TB. Also Xpert MTB/RIF and Gene Xpert are actually the same. In Patient 13, NAT positive could also be Gene Xpert. In fact all the PCR should be checked whether they were in house PCR or a commercial assay or Gene Xpert 'Clatro' should be expanded to 'clarithromycin' in the footnote under Table 2.'

• Response: Thank you for the pertinent comments. We were directly presented what the primary authors described. Now, it is revised and a uniform naming is used (GeneXpert).

Reviewers' comments:

Reviewer #1: I congratulate the authors for taking up an interesting topic. The occurrence of TB post-COVID-19 recovery has been commonly observed since the start of the pandemic. It is surprising how little literature is still there on the topic; so, the authors’ effort is praiseworthy. I also appreciate the supplementary material that they have provided which lends further credence to the study. However, there are some suggestions that I have for improving the article.

Major Comments

1. Why did the authors focus only on reactivation in search terms? New onset tuberculosis cases following COVID-19 may be missed in such a strategy. This is more so as the authors themselves write about new cases in lines 222-223

• Response: Thank you for the valuable comment. We have performed data base searching again using the key words; tuberculosis, COVID-19, SARS-CoV-2 and Case report. However, we didn’t get any other study to be eligible in the current systematic review.

2. Some perspective must be shared on the difference between the current study and the Tadolini study which the authors have rightly pointed out. In lines 168-169, since Tadolini’s study was also a systematic review, did you attempt to identify the individual case reports and see if any of those were missing in your study? Then the same may be added.

• Response: Thank you for the comment. The study is not a systematic review rather it is the first-ever global cohort of current or former TB patients (post-TB treatment sequelae) with COVID-19, recruited by the Global Tuberculosis Network (GTN) in eight countries and three continents. https://erj.ersjournals.com/content/erj/56/1/2001398.full.pdf

In this study, among 49 patients with COVID-19 and TB co-infection, in 14 patients COVID-19 preceded TB. However, the authors revealed that they could not report on the potential contribution of COVID-19 towards development of active TB disease because they did not follow individuals with latent TB infection overtime. Besides, the details of each patient is not reported that we were unable to find each patient’s data for the current systematic review.

3. In line 210, how is situs inversus totalis a type of TB?

• Response: Thank you for the valuable comment. It was to describe there was a congenital TB in a child with situs inversus totalis. We revised it accordingly.

4. Some discussion is warranted on the relative prevalence of PTB and EPTB in the study as compared to world literature. Also, is this differential distribution seen only in the TB non-endemic country cases or even in the cases reported by the authors from TB-endemic countries? This information may be useful.

• Response: Thank you for the pertinent comment. We have revised it accordingly both in the result section and discussion section. From 20 PTB cases, three cases were reported from the high TB burden countries, while all the 11 EPTB cases were reported from the countries that are not included in the list of high TB burden countries. For the remaining 2 cases, 1 miliary TB case was reported from a high TB burden country, while 1 disseminated case was reported from a country not included in the high TB burden countries list.

5. In lines 229-231, discuss the relevance of the low reporting from endemic countries. Many cases may have been missed because endemic countries’ scientists/doctors did not bother to report common TB cases. Another aspect worth discussing is the potential for low reactivation in countries where BCG is routinely administered. Both these angles need to be discussed.

• Response: Thank you for the valuable comment, we have included sentences based on the given suggestion.

6. The Discussion needs to be shortened and only the major findings need to be analyzed. Discussion on smoking and alcohol status may be removed as no salient features found. Similarly, the discussion on HIV status must be shortened to 1 sentence. The phrase, “The current study also revealed…” or similar phrases have been used many times. Please improve the English language in the Discussion and make it better to read.

• Response: Thank you for your important comment. We have revised it accordingly. At this stage, the English language was revised by some one with better English language understanding and skills.

7. Please check the tables provided carefully for appropriateness of all data. There may be minor mistakes. Example- In Table 1, for patient code 3-10, in second column with name of authors Unal et al, Patient 1 is written which makes it unclear. Similarly, which patient migrated from Syria is unclear. For the reference of Lee et al (Patient 11), country of origin is written as Vietennam which seems to be wrong spelling. In column on comorbidities it needs to be mentioned which comorbidity was there in the past so as not to confuse with current ones. For example, in the case of the Lee et al, lymphoma history was in past whereas cytomegalovirus was co-existent with COVID. Clarify such details for every case (all 34 cases). Please go through both tables carefully and check all the data and synchrony of lines and columns once more. (Very important as this is backbone of a systematic review of case reports)

• Response: Thank you for the valuable comments and suggestions. We have revised the table and revised accordingly. In the Unal et al., 2021 study, the patient migrated from Syiria was not specified, rather they reported as one patient migrated from Syria. The Vietennam is now corrected to Vietnam. Regarding the co-morbidities, since almost all cases are chronic diseases the co-morbidities were present during TB detection. We have revised both tables for every case (all 33 cases). Since one M.simiae case is excluded in the current analysis, the cases become 33 in number.

Minor Comments:

1. In line 41, write ‘…all 11 patients assessed for BCG vaccination status..’.

• Response: Thank you. It is corrected accordingly.

2. In line 48, write ‘It may take up to 7 months…’.

• Response: Thank you. It is corrected accordingly.

3. In line 49, 5/25 patients died. Was information missing for the remaining 9 patients? Please clarify.

• Response: Thank you, we revised it. “Data on the final treatment outcome was found for 25 patients, and 5 patients died during the anti-TB treatment period.”

4. In line 55, since treatment of latent TB is done only in TB non-endemic countries, please add this as a rejoinder. Same for lines 288-289.

• Response: Thank you for the pertinent comment and suggestion. Now it is revised as per the suggestion.

5. The English language is inappropriate at many places in the manuscript. A thorough English editing is needed. For example, in line 58, it should start with “COVID-19 has caused a huge…”; in line 61, it should be “the COVID-19 epidemic..” instead of “epidemics”. Many such corrections need to be done throughout.

• Response: Thank you for your important comment. At this stage, the English language was revised by some one with better English language understanding and skills.

6. Lines 100-101- Please check. It seems “tuberculosis” has been repeated multiple times.

• Response: Thank you. At this stage, we performed the search again based on the given suggestion and we presented the new search string.

7. In line 176, mention the type of transplantation- kidney?

• Response: Thank you, it is revised.

8. Lines 176-180 is repetition of Table 1 data and may be deleted.

• Response: Thank you for the comment. Now we deleted it.

9. In lines 217-218, why is M.simiae case described with MTB cases?

• Response: Thank you for the critical comment. Now, we excluded the study from this review and the whole manuscript is revised accordingly.

10. In lines 218-219, 19+5 is 24. What about the other patient?

• Response: Thank you for the critical comment. It was due to clerical error. Now it is revised. “The mortality status of the patients was described in 25 cases, where 20 were alive and five died during the anti-TB treatment period. While for the remaining 9 cases, their anti-TB treatment outcome is not described in the studies.”

11. In Supplementary Tables, numbering is S1,S2,S4. Shouldn’t it be S3?

• Response: Thank you, now it is revised.

12. In line 228, change the word ‘magnificent’ to ‘significant’.

• Response: Thank you, now it is revised.

13. Lines 237-238 needs to be deleted as this is not a finding of the current study where none of the patients were HIV positive.

• Response: Thank you. We have deleted the sentence

14. Lines 260-262 may be modified as due to short window of decision making, it may not be possible to rule out tuberculosis before starting treatment for COVID.

• Response: Thank you, now it is revised.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (22.1KB, docx)

Decision Letter 1

Shampa Anupurba

19 Oct 2022

PONE-D-22-18569R1Tuberculosis in individuals who recovered from COVID-19: A Systematic Review of Case ReportsPLOS ONE

Dear Dr. Alemu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Shampa Anupurba, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

All queries have been addressed. However, there are some minor corrections.

Line 28- 'resulted' may be replaced by 'resulting'

Lines 28/29- delete 'due to'

Line 30- delete 'it'

Line 39, 239- delete 'were'

Line 39- HIV need not be in italics

Line 41, 180- 'any' to be replaced by 'some'

Line 64- insert 'it was' before 'observed'

Line 77- 'recovery' instead of 'recovered'

Line 176- 'is' to be replaced by 'was', 'so' to be inserted before 'that'

Line 179- It should be '16' patients instead of '17' as total number of patients is 33

Line 186- Instead of 'nine', antibody to SARS CoV2 was positive in '11' cases.As per your Table 2.

Line 245- It is not clear how being HIV seronegative indicates diminished immune status

Line 249- 'as a' may be replaced by 'in'

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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PLoS One. 2022 Nov 28;17(11):e0277807. doi: 10.1371/journal.pone.0277807.r004

Author response to Decision Letter 1

20 Oct 2022

PONE-D-22-18569R1

Tuberculosis in individuals who recovered from COVID-19: A Systematic Review of Case Reports

Editor comments

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: Thank you for the pertinent comment. All the included references are available in the web and in the revised manuscript we have included the link (DOI) for the studies.

Additional Editor Comments:

All queries have been addressed. However, there are some minor corrections.

Line 28- 'resulted' may be replaced by 'resulting'

Response: Thank you, it is replaced.

Lines 28/29- delete 'due to'

Response: Thank you, it is deleted.

Line 30- delete 'it'

Response: Thank you, it is deleted.

Line 39, 239- delete 'were'

Response: Thank you, it is deleted.

Line 39- HIV need not be in italics

Response: Thank you, it is corrected

Line 41, 180- 'any' to be replaced by 'some'

Response: Thank you, we made a replacement

Line 64- insert 'it was' before 'observed'

Response: Thank you, we made a change accordingly

Line 77- 'recovery' instead of 'recovered'

Response: Thank you, we changed it

Line 176- 'is' to be replaced by 'was', 'so' to be inserted before 'that'

Response: Thank you, revised per the suggestion.

Line 179- It should be '16' patients instead of '17' as total number of patients is 33

Response: Thank you, it was a clerical error. Now, it is corrected.

Line 186- Instead of 'nine', antibody to SARS CoV2 was positive in '11' cases. As per your Table 2.

Response: Thank you. Antibody to SARS CoV2 was positive in 11 cases. As displayed in table 2 among 8 patients in the same study (patient 3-patient 10), antibody was positive in 6 patients and for the remaining 2 cases it was not described. Thus including the remaining 3 cases it becomes nine.

Line 245- It is not clear how being HIV seronegative indicates diminished immune status

Response: Thank you, we have revised it. Our assumption was that the immune suppressed status of COVID-19 infected individuals might led to developing TB. This is a common phenomenon in HIV positive individuals.

Line 249- 'as a' may be replaced by 'in'

Response: Thank you, we made a replacement per the comment.

Attachment

Submitted filename: Response to reviewers.docx

Click here for additional data file. (14.9KB, docx)

Decision Letter 2

Shampa Anupurba

4 Nov 2022

Tuberculosis in individuals who recovered from COVID-19: A Systematic Review of Case Reports

PONE-D-22-18569R2

Dear Dr. Alemu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Shampa Anupurba, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

**********

Acceptance letter

Shampa Anupurba

7 Nov 2022

PONE-D-22-18569R2

Tuberculosis in individuals who recovered from COVID-19: A Systematic Review of Case Reports

Dear Dr. Alemu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Shampa Anupurba

%CORR_ED_EDITOR_ROLE%

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Completed PRISMA 2009 checklist.

    (DOCX)

    Click here for additional data file. (37.4KB, docx)
    S2 Table. Search engines.

    (DOCX)

    Click here for additional data file. (503.9KB, docx)
    S3 Table. Quality assessment for the included studies in meta-analysis.

    (DOCX)

    Click here for additional data file. (31.2KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (22.1KB, docx)
    Attachment

    Submitted filename: Response to reviewers.docx

    Click here for additional data file. (14.9KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting information files.

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