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Vol. 57. Issue S2.
Pages 58-59 (April 2021)
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Vol. 57. Issue S2.
Pages 58-59 (April 2021)
Scientific Letter
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Influence of Cytokine Release Syndrome in Severe COVID-19 Patients Treated With Tocilizumab Over the Quantiferon TB Gold Plus Results
Influencia de la tormenta citoquímica de pacientes COVID-19 graves tratados con tocilizumab sobre los resultados del Quantiferon TB Gold Plus
Francesca Sánchez-Martínez, Mar Arenas-Miras
Corresponding author
, Neus Jové-Caballé, Hernando Knobel-Freud, on behalf of COVID-19 Infectious Disease Team Hospital del Mar 1
Infectious Diseases Service, Hospital del Mar, Barcelona, Spain
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Table 1. Demographic data and results of Quantiferon and CD4+/CD8+ counts in patients receiving TCZ.
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Dear Editor,

During the first COVID-19 peak and after administering it to approximately 500 patients in Wuhan,1 the Chinese health authorities included tocilizumab (TCZ), an interleukin 6 receptor antagonist, for the treatment of severe SARS-CoV-2 pneumonia.

With increasing evidence of its effectiveness in severe COVID-19,2 in Spain the Ministry of Health authorizes TCZ expanded access, prioritizing the inclusion of patients in clinical trials.3,4 As it is an immunosuppressive agent, it is advisable to screen for latent infections caused by intracellular bacteria, parasites and viruses, such as M. tuberculosis, which could be reactivated during treatment with TCZ5 in patients who may be candidates to receive it for long periods. Additionally, a recent, non-peer-reviewed report indicates that, like pandemic influenza, SARS CoV-2 might increase the number of tuberculosis (TB) cases and related mortality.6 Moreover, new cases of coinfection TB-COVID-19 have been drescribed.7 Finally, several original works, reviewed during the first European congress on SARS CoV-2 (ECCVID) held online between September 23 and 25, 2020, coincide in stating that mortality is influenced by SARS CoV-2, as much in patients with a history of TB as in those with active TB.8

From March 15 to May 15 2020, an IGRA test, Quantiferon TB Gold Plus (QFN-Qiagen, Venlo, The Netherlands), was requested9 in our hospital for patients with SARS CoV-2 confirmed by PCR who met clinical (on the COVID-19 severity scales), radiological (new onset or progression of the initial pulmonary infiltrates) and biological (IL-6>40pg/ml) criteria for treatment with TCZ in order to evaluate their immune response to latent tuberculosis infection (LTBI) before starting TCZ. Additional blood tests were done to examine other immune parameters, including CD4+ and CD8+ lymphocyte counts. Patients gave their verbal consent before undergoing treatment and for the use of their clinical data and storage of surplus samples in a biological bank (biobank) for research purposes. Both approval of the Hospital Pharmacy Committee and authorization from the Research Ethics Committee were obtained before treatment began.

Among the 190 patients treated with TCZ, the mean age (±SD) was 59.7(19.6) years and 125 (71%) were male. Seventy-two (38%) required ventilation in Intensive Care (ICU). Twenty-two (30% of those requiring ventilation) and 7 (6% of the non ICU patients) died as a result of refractory distress (ARDS). Valid samples for QFN were obtained in 119 patients (63%). The results were negative in 67 (56.3%), indeterminate in 48 (40.3%) and positive in 4 (3.4%). Upon retesting the patients with indeterminate results after 8 weeks, all but one who tested positive had negative results. The CD4+ and CD8+ counts extracted prior to TCZ administration showed a median of 321cells/mL (IQR: 49–1356) and 171 (IQR: 16–1083), respectively. There were no differences in these T-lymphocyte counts between patients admitted and not admitted to the ICU (Table 1).

Table 1.

Demographic data and results of Quantiferon and CD4+/CD8+ counts in patients receiving TCZ.

  TCZ (NMean age (±SD)  Sex (N)T cell (median)*Quantiferon N (%)Exitus (%) 
      CD4+  CD8+  Pos  Neg  Ind   
ICU admitted  72  59.3 (±22.6)  46  26  293  129  2 (6)  20 (59)  12 (35)  22 (30) 
Non ICU  118  60.0 (±10.6)  79  39  347  191  2 (3)  47 (55)  35 (41)  7 (6) 
Total  190  59.7 (±19.6)  125  65  321  171  4 (3.4)  67 (56.3)  48 (40.3)  29 (15) 

Glossary: ICU=Intensive Care Unit; N=cases; M=male; F=female; Pos=Positive; Neg=Negative; Ind=Indeterminate. *P value non significant between ICU and non ICU (>0.05).

These data illustrate that SARS CoV-2, while producing an exacerbated inflammatory response, may be associated with T-lymphocyte depletion-dysfunction, which may reduce the capability of Quantiferon TB Gold Plus to identify the LTBI response in patients with moderate and severe COVID- 19. In our cohort, severe COVID-19 patients with cytokine release syndrome, showed medians of CD4+ and CD8+ below 350 and 200cells/mL, respectively, which were probably the cause of the higher-than-expected indeterminate QFN values (40.3%). Similar results have been seen in several IGRA-based LTBI studies in immunosuppressed individuals.10,11

Since SARS CoV-2 could influence the dynamics of M. tuberculosis, specific follow-up of recovered COVID-19 patients at high risk factors of developing active TB should be considered independently of the results of QFN.

Appendix A
COVID-19 Infectious Disease Team Hospital del Mar are:

Itziar Arrieta, Joan Gómez-Junyent, Silvia Gómez-Zorrilla, Alicia González, Ana Guelar, Roberto Güerri, Elisabeth Lerma, Emili Letang, Inmaculada López-Montesinos, María Milagro Montero, Nuria Prim, Helena Sendra, Ana Siverio, Luisa Sorlí, Judit Villar and Juan Pablo Horcajada.

X. Xu, M. Han, T. Li, W. Sun, D. Wang, B. Fu, et al.
Effective treatment of severe COVID-19 patients with tocilizumab.
Proc Natl Acad Sci USA, 117 (2020), pp. 10970-10975
Lan SH, Lai CC, Huang HT, Chang SP, Lu LC, Hsueh PR. Tocilizumab for severe COVID-19: a systematic review and meta-analysis. Int J Antimicrob Agents. 2020;56:106103.
Y. Fu, Y. Cheng, Y. Wu.
Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools.
Virol Sin, 35 (2020), pp. 266-271
A. Huertas, D. Montani, L. Savale, J. Pichon, L. Tu, F. Parent, et al.
Endothelial cell dysfunction: a major player SARS-CoV-2 infection (COVID-19)?.
Eur Respir J, 56 (2020), pp. 2001634
K.L. Winthrop, X. Mariette, J.T. Silva, E. Benamu, L.H. Calabrese, A. Dumusc, et al.
Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors.
Clin Microbiol Infect, 24 (2018), pp. S21-S40
Pathak L, Gayan S, Pal B, Talukdar J, Bhuyan S, Sandhya S, et al. Coronavirus activates a stem cell-mediated defense mechanism that reactivates dormant tuberculosis: implications in COVID-19 pandemic. bioRxiv 2020.05.06.077883.
M. Luciani, E. Bentivegna, V. Spuntarelli, P. Amoriello Lamberti, L. Guerritore, D. Chiappino, et al.
Coinfection of tuberculosis pneumonia and COVID-19 in a patient vaccinated with Bacille Calmette-Guérin (BCG): case report.
SN Compr Clin Med, (2020), pp. 1-4
M. Santin, J.M. García-García, J. Domínguez, D. Rigau, N. Altet, L. Anibarro, et al.
Guidelines for the use of interferon-γ release assays in the diagnosis of tuberculosis infection.
Enferm Infecc Microbiol Clin, 34 (2016),
I. Solovic, M. Sester, J.J. Gomez-Reino, et al.
The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement.
Eur Resp J, 36 (2010), pp. 1185-1206
M. Pai, C.M. Denkinger, S.V. Kik, et al.
Gamma interferon release assays for detection of Mycobacterium tuberculosis infection.
Clin Microbiol Rev, 27 (2014), pp. 3-20

Please see a list of the members of the COVID-19 Infectious Disease Team Hospital del Mar in Appendix A.

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Archivos de Bronconeumología

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