key: cord-0840369-ugxo8njg
authors: Michot, J.M.; Hueso, T.; Ibrahimi, N.; Pommeret, F.; Willekens, C.; Colomba, E.; Francis, S.; Bayle, A.; Cournède, P.H.; Merad, M.; Foulon, S.; Albiges, L.; Gachot, B.; Barlesi, F.; Soria, J.C.; Ribrag, V.; Griscelli, F.
title: Severe COVID-19 in patients with hematological cancers presenting with viremia.
date: 2021-07-13
journal: Ann Oncol
DOI: 10.1016/j.annonc.2021.07.002
sha: 61c2d0be12145ae40a5d4f090f69a83da25071af
doc_id: 840369
cord_uid: ugxo8njg

nan

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, poses a danger to the health of populations around the world. Cancer is one of the comorbidities identified as being at risk of developing a severe COVID-19 1 . Among cancer patients, those with hematological cancers are particularly at high risk of severe disease or death [2] [3] [4] . However, the reasons for developing severe COVID-19 in patients with hematological cancers remain poorly understood. Here, we investigate clinical factors associated with higher risk for severe COVID-19 in patients with hematological cancers.

Characteristics of all patients with hematological cancers hospitalized for COVID-19 at Gustave Roussy in France from March 20, 2020, to November 17, 2020 were analyzed. Overall, 51 adult patients with lymphoma (n=26; 51%), acute leukemia (n=15; 29%), myeloma (n=9; 18%) or other type (n=1; 2%) were included. The clinical and biological characteristics at day 1 of hospital admission are shown in table S1. During hospitalization, twenty-four (47%) of the 51 patients had progressed to severe COVID-19 as assessed by the 10-points WHO scale 5 . At day 1 of hospitalization, patients who progressed to severe COVID-19 were characterized by significantly lower gammaglobulin levels in their serum (p=0.0312) and tended to have more advanced age (64.7 versus 57.6 years; p=0.0503). Lymphopenia was not significantly associated with increased risk of developing severe COVID-19 (p=0.1006) (table S1).

By linear logistic regression, hypogammaglobulinemia remained the most significant factor associated with progression to severe COVID-19 ( Ten out of 21 patients tested had detectable viremia (42%) at day 1 of hospitalization. Viremia was associated with a relative risk of progression to severe COVID-19 and COVID-19 death of 5.33 (CI95: 1.47-19.30; p=0.0019) and 2.83 (CI95: 1.49-5.39; p=0.0351), respectively ( Figure 1C) .

We compared the Sars-cov2 viremia, on the day of admission to hospital, in patients hospitalized for COVID-19, in patients with hematological cancer versus a control population with solid tumors. Viremia was more often positive in patients with hematologic cancer as compared with patients with solid tumors (47.6% versus 18.2%; p = 0.0099) ( Figure S1 ).

The limits in the interpretation of our results are to focus on a reduced population size presenting hematologic malignancies. However, our results suggest hypogammaglobulinemia and Sars-CoV-2 viremia were two relevant determinants of COVID-19 severity in patients with hematological cancers. Viremia was recently reported as correlating with disease severity 6 . Our findings suggest that in patients with hematological cancers, the coronavirus infection itself, rather than cytokine storm, lead to severe and lethal COVID-19. We suggest that humoral immunocompromised patients may be considered as a specific population to manage for COVID-19. Thus, corticosteroids or anti-cytokines drugs such as anti-IL-6 receptor therapies may worsen immunosuppression and should be probably used with caution in such patients. Therapeutics supporting immunity against Sars-CoV-2 such as hyperimmune convalescent plasma deserves to be specifically investigated for immunocompromised patients. Figure 1A : Correlation matrix between the quantitative variables observed in patients included in the study. The correlation matrix computed 14 numeric variables using the statistical Pearson method (*p value for interaction <0.05). The positive correlation between two variables was illustrated by a blue color, whereas a negative correlation was in red. A thin ellipse meant that the relationship between the two variables was linear. The severity of COVID-19 evaluated by WHO score, as emphasized by the black rectangle, top negatively correlated with gammaglobulins (r=-0.43; p=0.0018), SARS-CoV-2 RT-PCR nasopharyngeal swabs at day 1 of hospitalization cycle threshold (Ct) (r=-0.30, p=0.0482) and absolute lymphocyte count (r=-0.21, p=0.1428). The severity of COVID-19 evaluated by WHO score top positively correlated with LDH (r=+0.37, p=0.0073), age (r=+0.34, p=0.0154), duration of positive viral carriage by nasopharyngeal SARS-CoV-2 RT-PCR (r =+0.28; p=0.0540) and serum procalcitonin (r=+0.28; p=0.0550). Figure 1B : This figure indicates the kinetics of cycle threshold (Ct) in nasopharyngeal SARS-CoV-2 RT-PCR, in patients with hematological cancers and hospitalized for COVID-19, according to the serum level of gammaglobulins (with a threshold of 6 g/L for gammaglobulins) (n=49 patients evaluated for gammaglobulins). All positive PCR by nasopharyngeal swabs performed in the patients included in the study are indicated. Each point represents one PCR by nasopharyngeal swab done. Number of Ct Sars-CoV-2 PCR RT points analyzed were 86 points in patients with gammaglobulins <6 g / L and 56 points in patients with gammaglobulins ≥ 6g / L. Colored lines represented polynomial trend lines, by second order polynomial, for patients with gammaglobulins levels < 6 g/L (red line) and ≥ 6 g/L (blue line). To compare all Ct Sars-CoV-2 PCR RT values in patients with gammaglobulins < 6 g/L and ≥ 6 g/L, XY analyzes was performed with nonlinear regression. Comparison method was extra sum-of-squares F test and the p-value was 0.05. The SARS-CoV-2 RT-PCR representing curves for each data set were different with p value = 0.0033. The red curve above blue curve shown that patients with hypogammaglobulinemia in their serum have more intense and prolonged SARS-CoV-2 nasopharyngeal virus replication assessed by SARS-CoV-2 RT-PCR nasopharyngeal. Figure 1C . SARS-CoV-2 viremia in patients with hematological cancers. This figure shows the clinical and biological parameters associated with viremia in patients with hematological cancers. Viremia was performed by SARS-CoV-2 RT-PCR on blood (as indicated in method appendix), at day 1 of hospitalization. Overall, 21 patients were investigated for viremia, 10 were positive and 11 were negative. For each factor, the median value calculated over the entire population (n=51 patients) was used to determine the cut-off for each variable in subgroups. The relative risk and its 95% confidence interval (95% CI) as well as the p-value for the interaction, calculated by Fisher's exact test, are shown for each parameter in the table. Gray bars in figure indicate 95% confidence intervals. Abbreviations: naso.: Nasopharyngeal. ANC: Absolute neutrophils count. BMI: Body mass index. CRP: C-reactive protein. LDH: Lactate dehydrogenase. Ct: Cycle threshold. NA: Not available. RT-PCR: Real-time polymerase chain reaction. 

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

COVID-19 in persons with haematological cancers

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Prolonged SARS-CoV-2 Infection in a CAR T-Cell Therapy Recipient

A minimal common outcome measure set for COVID-19 clinical research. The Lancet Infectious Diseases

Highly sensitive quantification of plasma SARS-CoV-2 RNA shelds light on its potential clinical value

Data presented are n (%) unless otherwise stated. Data are presented by median (range), unless otherwise stated. CT: Cycle threshold; COVID-19: Coronavirus disease 2019; NT: not tested; WHO: World health organization on 10-points scale. RT-PCR: Real-time polymerase chain reaction † Based on the WHO international scale of clinical studies relating to COVID-19, have been established (10-point scale), [http://www.who.int/blueprint/priority-diseases/key-action/en/]. ¶ Non-parametric tests were performed for all comparisons in the table presented. P value was calculated by Mann Whitney test.  The duration of SARS-cov2 positivity by SARS-CoV-2 RT-PCR nasopharyngeal swabs was the period between the first positive PCR and the first negative PCR. Patients who remained with a positive PCR at the last sample were not included in this analysis. Patients who died with a positive PCR as their last timepoint were not included in this analysis. β nadir of CT was the lowest CT point in each patient, among all PCRs performed on a nasopharyngeal swab during and after hospitalization.