key: cord-261240-osbk041e
authors: Bermejo-Martin, Jesús F; Almansa, Raquel; Menéndez, Rosario; Mendez, Raúl; Kelvin, David J; Torres, Antoni
title: Lymphopenic community acquired pneumonia as signature of severe COVID-19 infection
date: 2020-03-05
journal: J Infect
DOI: 10.1016/j.jinf.2020.02.029
sha: 
doc_id: 261240
cord_uid: osbk041e

nan

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 [1] , 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 [2 , 3] , 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 [3] , with non survivors exhibiting persistent lymphopenia [4] . ICU patients present also with high levels of plasma cytokines [2] . 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) [5 , 6] . 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 [7] .

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 [3 , 8] . 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 [4] . 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 [9] . Recent findings from our group have evidenced the interconnection between lymphopenia and endothelial dysfunction in patients with CAP and organ failure [10] . Endothelial dysfunction induces also increased oxidative stress and systemic inflammation, glycocalyx degradation and shedding along with a pro-coagulant and anti-fibrinolytic state [9] . 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 [2] , and 26% in the study of Wang D et al. [4] 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. 

Emergence of a novel coronavirus causing respiratory illness from Wuhan

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome

a major outbreak of severe acute respiratory syndrome in Hong Kong

Lymphopenic community-acquired pneumonia is associated with a dysregulated immune response and increased severity and mortality

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Shared features of endothelial dysfunction between sepsis and its preceding risk factors (Aging and chronic disease)

Simultaneous depression of immunological synapse and endothelial injury is associated with organ dysfunction in community-acquired pneumonia

Letter to the Editor / Journal of Infection 80 (2020) e23-e24

Not applicable