Researchers from Necmettin Erbakan University-Turkey and the Meram Medical Faculty Hospital-Turkey are warning that based on actual clinical case studies and reports of pediatric patients in their hospital, they are witnessing cases of dormant tuberculosis being reactivated in individuals including children as a result of a COVID-19 infection.
The COVID-19 disease is a viral disease caused by a novel SARS-CoV-2 coronavirus that can lead to severe acute respiratory failure.
Recent studies have shown that aggravating factors in the etiology of COVID-19 disease include genetic defects and autoantibodies against type 1 interferon.
Mycobacterium tuberculosis is an immobile aerobic bacillus that causes tuberculosis disease. SARS-CoV-2 infection and immunosuppressive drugs may temporarily inhibit immunologic system, then may lead to active tuberculosis by reactivation or infection of M. tuberculosis.
The COVID-19-Tuberculosis study team aimed to show that there is a relationship between COVID-19 infection and an increase in the number of tuberculosis patients.
A total of eight pediatric patients diagnosed with tuberculosis in the Pediatric Pulmonology and Pediatric Infectious Diseases Clinics of Necmettin Erbakan University, Meram Medical Faculty between March 2020 and May 2021 were enrolled in this study.
The presence of COVID-19 infection was confirmed by COVID-19 antibody test and patient’s detailed medical history.
The patient with negative antibody test was also included in the study if other family members confirmed for COVID-19 infection by RT-PCR.
The study team evaluated demographic data, laboratory findings, imaging tests and pathology results of all patients.
The remarkable but alarming increase in the number of tuberculosis activation in the recent year suggests the role of COVID-19 infection.
The study team notes that the pathologic structure of the virus may be responsible of the increase, although the mechanism is not fully understood. They insist that further detailed research should be done on this topic.
The study findings were published in a preprint platform for researchers. https://www.authorea.com/doi/full/10.22541/au.163800231.17635204/v1
Mycobacterium tuberculosis is an immobile aerobic bacillus that causes tuberculosis disease (TB). It is transmitted by infected droplets. Whether infection develops after transmission depends on the frequency and duration of the contact, distance to the contact, the amount and virulence of the transmitted pathogen, and the susceptibility of the exposed person.
After inhalation of the bacillus, it usually settles in the better ventilated upper regions of the lungs. In healthy individuals, T-cells inhibit intracellular proliferation of the bacillus 3-4 weeks after the infection. In this way, the disease is brought under control. Clinically significant TB may develop shortly after the disease, particularly in children and immunosuppressed individuals .
Tuberculosis remains a major cause of mortality and morbidity in developing countries.
More than 95% of tuberculosis-related deaths occur in low- and middle-income countries. About one-third of the world’s population has latent tuberculosis infection [8,9].
SARS-CoV-2 infection and immunosuppressive drugs may temporarily inhibit immunologic system, then may lead to active tuberculosis by reactivation or infection of M. tuberculosis .
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Coronaviruses have been known to cause occasional pandemics. The studies in the literature that examined correlations between SARS, MERS, H1N1, and reactivation of tuberculosis during these periods showed that cellular immunity associated with this infection was temporarily suppressed and reactivation of latent tuberculosis or a new TB infection occurred [11-15].
There is no such information on SARS-Cov-2 yet. We have done a retrospective study in our clinic and found that the number of patients diagnosed with TB has increased. Examination of the number of children diagnosed with TB in the pediatric pulmonology and pediatric infectious disease clinics at our hospital by year between 2017 and 2021 shows that three pediatric patients were diagnosed with tuberculosis and received treatment in 2017, four in 2018, eight in 2019, and 23 in 2020- April 2021.
When we scanned the number of pediatric patients diagnosed with tuberculosis in Konya by years, we found that 21 children were diagnosed with tuberculosis in 2017, 21 children in 2018, 27 children in 2019, 33 children in 2020, and 13 children until April 2021. Despite the decrease in the child population in Konya, there was a remarkable increase in the number of pediatric tuberculosis cases (Table 3) [18,19].We checked all our patients with TB by Covid-19 antibody (IgG+IgM) or PCR. Only eigth of the patients was positive.
Of the eight patients with positive PCR or antibody, two (%25) had cavitary lesions, three (%37,5) had pleural effusion, and one (%12,5) had pleural and pericardial effusion. Remaining 15 patients with negative PCR or antibody have mild fenotipe including two (%13,3) had pleural effusion and three (%20) had cavitary lesion.We could not test the presence of autoantibodies against interferon type 1 in any of them.
Both innate and acquired immunity play important roles in the immune response against Mycobacterium tuberculosis. T lymphocytes, dendritic cells, Toll-like receptors, IFN-gamma, TNF-alpha, and IL-12 play important role immune response to Mycobacteria .
There is an increased susceptibility to tuberculosis in primary immunodeficiencies with defects in these cells and pathways.The primary immunodeficiencies known to predispose to tuberculosis are T-cell deficiencies, chronic granulomatous disease and Mendelian susceptibility to mycobacterial diseases.
The unexpectedly severe clinical findings of tuberculosis in our patients suggested primary immunodeficiency, while the immunological evaluation revealed a CVID diagnosis in one patient (patient #1) and mild immunological defects in the other patients that did not meet ESID criteria for a primary immunodeficiency.
Lymphopenia was present in only one of our patients, and improvement at the follow-up suggested a temporary situation secondary to the infection.Physical activity can affect NK cells; their number can change even throughout the day. We do not yet know the importance of the low NK cell count detected in four of our patients during the disease. but turn to normal levels at follow up (except in the # 1 patient).
Consequently, the activation of TB seems to be due to the structure of the COVID-19 virus and its pathological characteristics.There are few studies on COVID-19 and tuberculosis. Jain et al. showed that the risk of SARS-CoV-2 infection is increased in patients with latent tuberculosis and there is a susceptibility to severe COVID-19 pneumonia.
Additionally, it is indicated that the COVID-19 pandemic leads to a decrease in admission to health facilities and to a delay in diagnosing tuberculosis . Can Sarinoğlu et al.’ simultaneously requested COVID-19 and tuberculosis tests in 30 patients since March 2020 and found that 26.6% of 30 patients was immunosuppressed (malignancy, hematopoietic stem cell transplantation, positive HIV test).
Two out of 30 patients had both COVID-19 PCR and tuberculosis test positive. One of these two patients had diabetes, hypertension, chronic obstructive lung disease, and chronic renal failure. The other patient had no underlying disease . Our study also supports that a COVID-19 infection changes the individual’s immune system and causes tuberculosis infection.In previous studies and case reports, it has been shown that covid-19 causes TB reactivation and newly diagnosed TB, but all the patients in this study were adult except one patient diagnosed with congenital TB.
There have been no studies on children since the beginning of the pandemic period. Our patients had comorbidities such as immunodeficiency, however, none of our patients died [23-27].The remarkable increase in the number of tuberculosis activation in the recent year suggests the role of COVID-19 infection.
The clinical findings of the respiratory diseases that are secondary to infections progress similar to TB. Therefore, the diagnosis of TB may easily be missed. Since TB is a slowly progressing infection, there may be delays in diagnosis. It has been observed that latent TB infection can be activated even if the covid-19 infection is mild in children. Covid-19 infection is not as innocent as it seems for children either.
The experiences of our clinic and our country support the impression that the increase in recent year is due to increased TB cases associated with the pandemic. This should be kept in mind in case of cavity lesions and pleurisy. Moreover, the presence of a possible underlying immunodeficiency should be investigated in the case of complicated respiratory infections.
The pathologic structure of the virus may be responsible of the increase, although the mechanism is not fully understood. Further research should be done on this topic.Table 1. Demographic and clinical results
|Patient no||Age (year)||Sex||PPD||Quantiferon||Tomography||Pathology||Diagnosis||Medication|
|p1||16||Male||Negative||Positive||Paratrecheal lymphadenopathy, pleural effusion, Pneumonic consolidation||Necrotizing Granulamatous inflammation||Pathology||H,R,Z,E|
|p2||16||Female||30mm||Positive||Pleural effusion, atelectasis||–||Clinically||H,R,Z,E|
|p3||17||Female||Negative||Positive||Pleural effusion||lymphocyte-rich fluid||Clinically||H,R,Z|
|p4||13,5||Female||1mm||Negative||Pleural, pericardial effusion||active chronic inflammation||Pathology||H,R,Z,E|
|p5||16||Female||6mm||İnderteminate||Cavity, mediastinal lymphadenopathy,,Pneumonic consolidation||–||Clinically||H,R,Z|
|p6||13,5||Female||17mm||Positive||Thorax CT: Normal Neck CT: central necrotic conglomerate lymphadenopathy||necrotizing granulomatous lymphadenitis||Pathology TB DNA(+)||H,R,Z|
|p7||16||Female||7mm||–||Cavity, budding tree appearance, Mediastinal calcified and noncalcified lap||–||ARB(+) Culture(+)||H,R,Z,E|
|8||13 year 8 month||Female||Negative||–||Situs inversus totalis||–||TB DNA(+)||H,R,Z,E|
H: Isoniazid, R: Rifampicin, Z: Pyrazinamide, E: EthambutolTable 2. Laboratory results
|8/13, 7||7/13||6/13,5||5/16||4/13,5||3/17||2/16||1/16||Patient No/Age(year)|
|887 (851-1323)||1230 (913-1884)||1350 (605-1430)||1630 (913-1884)||823 (605-1430)||1040 (913-1884)||1660 (913-1884)||421 (913-1884)||IgG mg/dl|
|669 (519-1226)||996 (643-1071)||1120 (518-1226)||1000 (643-1071)||571 (518-1226)||591 (643-1071)||1340 (643-1071)||257 (643-1071)||IgG1 mg/dl|
|255 (145-413)||291 (179-435)||431 (145-413)||493 (179-435)||281 (145-413)||236 (179-435)||439 (179-435)||183 (179-435)||IgG2 mg/dl|
|27,3 (24-136)||37/ (17-83)||33 (24-136)||36 (17-83)||62 (24-136)||25 (17-83)||68 (17-83)||20 (17-83)||IgG3 mg/dl|
|21,9 (6-96)||230 (15-80)||212 (6-96)||286 (15-80)||111 (6-96)||49 (15-80)||21 (15-80)||11 (15-80)||IgG4 mg/dl|
|51 (47-484)||820 (88-322)||97 (83-282)||206 (88-322)||93 (83-282)||64 (88-322)||200 (88-322)||184 (88-322)||IgM mg/dl|
|88,3 (67-433)||377 (139-378)||212 (96-465)||272 (139-378)||227 (96-465)||287 (139-378)||248 (139-378)||158 (139-378)||IgA mg/dl|
|76,3 (58-82)||68 (58-82)||74 (58-82)||71 (58-82)||76,4 (58-82)||83 (58-82)||83,4 (58-82)||76 (58-82)||CD3|
|43,9 (27-57)||36 (27-57)||47 (27-57)||40 (27-57)||32,5 (27-57)||60 (27-57)||50 (27-57)||33 (27-57)||CD4|
|36,9 (19-38)||31 (19-38)||21 (19-38)||22 (19-38)||34,2 (19-38)||20 (19-38)||32,7 (19-38)||28 (19-38)||CD8|
|14,1 (10-30)||18 (10-30)||19 (10-30)||21 (10-30)||10,8 (10-30)||10 (10-30)||8,2 (10-30)||18 (10-30)||CD19|
|8,8 (8-30)||10 (8-30)||6 (8-30)||5 (8-30)||10,1 (8-30)||4,8 (8-30)||7,8 (8-30)||3 (8-30)||CD 16-56|
Table 3. Demographic data
|Year||Population of Konya (total)||child population (0-19 year)||total number of TB cases (in Konya)||Number of pediatric TB cases (in Konya)||Number of pediatric TB cases (in our clinic)|
Figüre 1 radiography and torax tomography
A: Mediastinal window on axial contrast-enhanced thoracic CT: Pneumonic consolidation with air bronchograms and cavitation in the left lower lobe and LAP in the left infrahilar region. Lung X-ray: Cavitation and left hilar LAP in consolidation located in the left lower lobe B: Non-contrast Thorax CT, axial parenchymal window, cavitation and bronchiectasis, fibroproductive lesions together, calcification, cavitation, consolidation and budding tree views. C: Contrast-enhanced axial CT, left massive tbc pleurisy and drain.Figüre 2. Pathological results
A: Granuloma formation consisting of multinuclear giant cells (stars), epithelioid histiocytes and lymphocytes with a small focus of necrosis (arrow) in the central part is seen (Hemotoxylin/Eosin, 100x). B: Immunohistochemical CD68 shows a positive reaction in histiocytes and giant cells forming granulomas (CD68, 40x).
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Past published studies have shown that the correlation between viral infections by viruses such as SARS, MERS, H1N1 and the reactivation of tuberculosis during certain pandemic periods.
These studies showed that cellular immunity associated with these infections temporarily suppressed and the manifestation of reactivation of latent tuberculosis or a new TB infection occurring.
However, to date, there is no studies with regards to SARS-CoV-2 and the correlation with Tuberculosis.