Lymphopenic community acquired pneumonia as signature of severe COVID-19 infection
Authors: Jesús F Bermejo-Martin, Raquel Almansa, Rosario Menéndez, Raúl Mendez, David J Kelvin, Antoni Torres
Journal: Journal of Infection (2020)

As recently commented by Tang and colleagues in this Journal, the novel Coronavirus emerged at the end of 2019 from Wuhan has already spread beyond China [1Tang Julian W. Tambyah Paul A. Hui David S.C. Emergence of a novel coronavirus causing respiratory illness from Wuhan, China.J Infect. 2020; 80: 350-371https://doi.org/10.1016/j.jinf.2020.01.014Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar], which led WHO to declare a public health emergency of international concern by Jan 30, 2020. Infection caused by this virus (COVID-19) courses with severe community acquired pneumonia (CAP) in a minority of the cases, but given its transmission characteristics, this is a further cause of alarm. In two recent articles from Huang C et al. and Yang X in The Lancet [2Chaolin Huang Yeming Wang Xingwang Li Lili Ren Jianping Zhao Yi Hu et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.The Lancet. 2020; 0https://doi.org/10.1016/S0140-6736(20)30183-5Abstract Full Text Full Text PDF Scopus (33292) Google Scholar,3Xiaobo Yang Yuan Yu Jiqian Xu Huaqing Shu Jia'an Xia Hong Liu et al.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.The Lancet. 2020; Google Scholar, 85% of critically ill patients with COVID-19 showed lymphopenia. The presence of lymphopenia as a signature of severe COVID-19 was confirmed by Wang D et al., who, in their study published in JAMA, reported that ICU patients suffering this infection had a median lymphocyte count of 800 cells/mm [3Xiaobo Yang Yuan Yu Jiqian Xu Huaqing Shu Jia'an Xia Hong Liu et al.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.The Lancet. 2020; Google Scholar], with non survivors exhibiting persistent lymphopenia [4Dawei Wang Bo Hu Chang Hu Fangfang Zhu Xing Liu Jing Zhang et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; https://doi.org/10.1001/jama.2020.1585Crossref Scopus (16387) Google Scholar]. ICU patients present also with high levels of plasma cytokines [2Chaolin Huang Yeming Wang Xingwang Li Lili Ren Jianping Zhao Yi Hu et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.The Lancet. 2020; 0https://doi.org/10.1016/S0140-6736(20)30183-5Abstract Full Text Full Text PDF Scopus (33292) Google Scholar]. The existence of hyper-cytokinemia in COVID-19 patients with lymphopenia could indicate a poor control of the pathogen, as showed in severe patients infected with the 2009 Pandemic Influenza virus. Interestingly, hypercytokinemia and lymphopenia were also evident in critical patients with Severe Acute Respiratory Syndrome due to the Coronavirus emerged in 2003 (SARS-CoV) [5Cameron Mark J. Longsi Ran Luoling Xu Ali Danesh Bermejo-Martin Jesus F. Cameron Cheryl M. et al. interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome.J Virol. 2007; 81: 8692-8706https://doi.org/10.1128/JVI.00527-07Crossref PubMed Scopus (312) Google Scholar,6Nelson Lee David Hui Alan Wu Paul Chan Peter Cameron Joynt Gavin M. et al. a major outbreak of severe acute respiratory syndrome in Hong Kong.N Engl J Med. 2003; 348: 1986-1994https://doi.org/10.1056/NEJMoa030685Crossref PubMed Scopus (1988) Google Scholar. These features (lymphopenia + hypercytokinemia) fit the characteristics of a particular immunological phenotype of community acquired pneumonia (CAP), lymphopenic CAP (L-CAP), which, as we recently demonstrated in an article published in the Journal of Infection, is associated with increased severity, mortality and a dysregulated immunological response [7Raúl Méndez Rosario Menéndez Isabel Amara-Elori Laura Feced Alba Piró Paula Ramírez et al.Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality.J Infect. 2019; 78: 423-431https://doi.org/10.1016/j.jinf.2019.04.006Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. In their works, Yang X et al. and Chen N et al. propose a direct cytotoxic action of the virus to explain the low lymphocyte counts observed in the severe cases of COVID-19 [3Xiaobo Yang Yuan Yu Jiqian Xu Huaqing Shu Jia'an Xia Hong Liu et al.Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.The Lancet. 2020; Google Scholar,8Nanshan Chen Min Zhou Xuan Dong Jieming Qu Fengyun Gong Yang Han et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; https://doi.org/10.1016/S0140-6736(20)30211-7Abstract Full Text Full Text PDF Scopus (14520) Google Scholar. But, in our opinion, host factors could also contribute to induce lymphopenia in these cases. Compared with those patients not requiring intensive care, COVID-19 patients admitted to the ICU are older and are more likely to have hypertension, diabetes, cardiovascular and cerebrovascular disease [4Dawei Wang Bo Hu Chang Hu Fangfang Zhu Xing Liu Jing Zhang et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; https://doi.org/10.1001/jama.2020.1585Crossref Scopus (16387) Google Scholar]. Aging and chronic diseases induce chronic endothelial dysfunction. As we recently reviewed in J Clin Med, endothelial dysfunction induces disassembly of intercellular junctions, endothelial cell death and blood-tissue barrier disruption, along with enhanced leukocyte adhesion and extravasation, which could contribute to explain the lymphopenia observed in severe COVID-19 patients [9Bermejo-Martin Jesus F. Marta Martín-Fernandez Cristina López-Mestanza Patricia Duque Raquel Almansa Shared features of endothelial dysfunction between sepsis and its preceding risk factors (Aging and chronic disease).J Clin Med. 2018; 7https://doi.org/10.3390/jcm7110400Crossref PubMed Scopus (82) Google Scholar]. Recent findings from our group have evidenced the interconnection between lymphopenia and endothelial dysfunction in patients with CAP and organ failure [10Rosario Menéndez Raúl Méndez Raquel Almansa Alicia Ortega Ricardo Alonso Marta Suescun et al.Simultaneous depression of immunological synapse and endothelial injury is associated with organ dysfunction in community-acquired pneumonia.J Clin Med. 2019; 8https://doi.org/10.3390/jcm8091404Crossref Scopus (16) Google Scholar]. Endothelial dysfunction induces also increased oxidative stress and systemic inflammation, glycocalyx degradation and shedding along with a pro-coagulant and anti-fibrinolytic state [9Bermejo-Martin Jesus F. Marta Martín-Fernandez Cristina López-Mestanza Patricia Duque Raquel Almansa Shared features of endothelial dysfunction between sepsis and its preceding risk factors (Aging and chronic disease).J Clin Med. 2018; 7https://doi.org/10.3390/jcm7110400Crossref PubMed Scopus (82) Google Scholar]. In aged individuals with chronic diseases, these features could represent predisposing factors for presenting a severe respiratory failure following COVID-19 infection. In the Huang et al. report, 32% of the hospitalised patients required admission to the ICU [2Chaolin Huang Yeming Wang Xingwang Li Lili Ren Jianping Zhao Yi Hu et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.The Lancet. 2020; 0https://doi.org/10.1016/S0140-6736(20)30183-5Abstract Full Text Full Text PDF Scopus (33292) Google Scholar], and 26% in the study of Wang D et al.[4Dawei Wang Bo Hu Chang Hu Fangfang Zhu Xing Liu Jing Zhang et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; https://doi.org/10.1001/jama.2020.1585Crossref Scopus (16387) Google Scholar] Co-circulation of the novel Coronavirus in China is coincident with the winter season, a period of high demand for ICU resources due to influenza and other respiratory infections. Finding new biomarkers that can be used at the earliest stages of hospitalization to identify those individuals with COVID-19 who will become critically ill will be important for efficient management of ICU resources. Lymphocyte count can easily be obtained at admission to the emergency room. In areas with sustained circulation of the new Coronavirus, evaluation of lymphocyte counts in patients with CAP could help to identify and prioritize those individuals who require or will shortly require critical care. In conclusion, there is growing evidence suggesting that severe infection caused by the novel Coronavirus emerged in 2019 induces l-CAP. The presence of l-CAP suggests the existence of immunological dysregulation as an accompanying event of the critical illness caused by this virus. Early recognition of this immunological phenotype could be useful to assist prompt recognition of severe patients. Should lymphopenia play a role in the pathogenesis of the disease, drugs targeting lymphocyte proliferation or apoptosis (IL-7, PD1/PD-L1 inhibitors) could help to prevent lymphopenia or restore lymphocyte counts in severe patients suffering COVID-19. The potential role of endothelial dysfunction as predisposing and pathogenic actor in this disease merits investigation. Biomarkers / tests assessing endothelial function could also help to early identify severe cases of COVID-19. Drugs improving endothelial dysfunction such adrecizumab could play a role in its treatment. Preclinical works on animal models should contribute to elucidate the true role of lymphopenia and endothelial dysfunction in this disease. none All the authors participated in generating the idea. Jesús F Bermejo-Martin wrote the initial version of the letter. Raquel Almansa, Rosario Menéndez, Raúl Mendez, David J Kelvin and Antoni Torres critically reviewed and edited it with their comments. none