key: cord-0997483-pqlxcrdy
authors: Safarpour., Damoun; Srinavasan., Krishnan; Farooqui., Marwah; Roth., Connor; Ghouse., Masood
title: A case of Covid-Induced Lymphocytosis in a treatment naïve CLL patient. Should It be treated?
date: 2020-09-18
journal: Clin Lymphoma Myeloma Leuk
DOI: 10.1016/j.clml.2020.09.005
sha: 687c32ba577873d620d4e5b35956a5f02cc3d7a3
doc_id: 997483
cord_uid: pqlxcrdy

The COVID-19 pandemic has proven to have significant morbidity and mortality in high risk patient populations including those with cancer. Chronic lymphocytic leukemia (CLL) is an indolent disease and the majority of patients with CLL are under monitoring. Here we present a case of a CLL patient with severe COVID-19 presenting with marked lymphocytosis within 2-3 days of diagnosis. An 80-years old man with treatment naïve CLL was admitted to our hospital for COVID-19 pneumonia. He was intubated due to hypoxic respiratory failure and developed multi-system organ failure requiring hemodialysis and vasopressor therapy. His white blood cell and absolute lymphocyte count rose to more than 3-fold his baseline during hospitalization. This is the second case of ‘COVID-Induced Lymphocytosis’ in treatment naïve CLL patients with severe COVID-19 infection. The ethology and prognosis of this new phenomenon is not clear.

Introduction: The COVID-19 pandemic has proven to have significant morbidity and mortality in many different patient populations. Patients with hematologic malignancies, particularly those with lymphocytic leukemia, are high risk for infections due to underlying immunodeficiency and inadequate immune response to infections. Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in United States (1) . CLL is an indolent disease and the majority of patients with CLL do not benefit from immediate treatment and are under monitoring. At this time, there is very limited data regarding the clinical course in CLL patients with COVID-19.

Here we present a case of a CLL patient with severe COVID-19 presenting with marked lymphocytosis within 2-3 days of the COVID diagnosis.

Case report: This is a case of an 80-years old man with chronic hypertension, controlled asthma, gastroesophageal reflux disease, and stage 0 CLL originally diagnosed in 2002 under active surveillance. He never required treatment for his CLL. Four months prior to current hospitalization, his CLL was stable with a white blood count (WBC) of 43 x 10 3 /uL . He was asymptomatic with no evidence of lymphadenopathy on computed tomography scan. In May 2020, he presented to the emergency room with a 2-day history of productive cough and shortness of breath. His oxygen saturation was 84% on room air and he was placed on BiPap. Chest x-ray showed diffuse bilateral opacities and an arterial blood gas showed that the patient was likely in acute hypoxic respiratory failure. Troponin 243 pg/mL (re: 0-20 pg/ml), Ferritin 761 ng/mL, c-reactive protein: 251 mg/L (ref: >3 mg/l high risk) and D-Dimer markedly elevated at 22,891 ng/mL (ref: <500 ng/ml). Complete blood count showed WBC 32.5 x 10 3 /uL absolute lymphocyte count (ALC) 30.1 x 10 3 /uL, hemoglobin 12.3 g/dL, and platelets 248 x 10 3 /uL . COVID-19 was positive by PCR. He was intubated on day 4 due to worsening hypoxic respiratory failure. In addition, he developed multi-system organ failure with acute kidney injury requiring hemodialysis and septic shock requiring vasopressor therapy. He received tocilizumab 800 mg on day 2, and remdesivir was initiated on day 3 (200 mg day 3 and then 100 mg daily for total of 7 days). On day 8, the WBC rose to 101.5 x 10 3 /uL with an ALC of 81.0 x 10 3 /uL. On day 13, the WBC continued to rise to 127.8 x 10 3 /uL with an ALC of 113.7 x 10 3 /uL (Chart 1). Methylprednisolone was started at a dose of 100 mg every 8 hours on day 13 and tapered to 50 mg every 8 hours (days 19-24), and then 40 mg every 12 hours (days 25-27). Following initiation of steroids, the WBC dropped to 55 x 10 3 /uL, but gradually increased again and reached a peak of 132.4 x 10 3 /uL (ALC of 116 x 10 3 /uL) on day 23. Immunoglobulins during this admission showed low normal IgA and IgG levels and decreased IgM levels (<20 mg/dl). Additional work up showed elevated B2 microglobulin at 0.930 mg/dl (ref: 0.097-0.184), and a peripheral flow cytometry showed monoclonal B-Cell population exhibiting lambda light chain restriction (and comprising 81% of the total live cellular events). FISH study showed deletion of 13q14 and IgVH mutation positive (associated with a more favorable clinical course). After a long period of hospitalization his family decided against resuscitation and sadly, he succumbed to the infection on day 27 of admission.

J o u r n a l P r e -p r o o f Discussion: Lymphopenia, in contrast to leukocytosis, is a common lab finding of COVID-19 patients. It is more significant among those with severe disease and it is found to be a poor prognostic factor (2, 3) . In severe COVID-19 patients, Liu et al. found an initial phase of lymphocyte count drop followed by a gradual increase in the lymphocytes from day 7 to 15 after disease onset. Elevation of lymphocyte count in their study was towards resolution of lymphopenia, without apparent leukocytosis. However, the chronicle and severity of lymphocyte count elevation in our patient did not follow the same pattern.

One hypothesis for our patient's lymphocytosis was from the effect of the antiviral (remdesivir) and interleukin-6 receptor antagonist (tocilizumab) treatment on lymphocyte count. In a recent randomized trial for efficacy of remdesivir in 233 patients with severe COVID-19, there was no difference in the rate of remdesivir induced increased white cell count when compared to placebo (7% in remdesivir group vs. 8% in placebo group) (4). Of note, 68% of patients in this trial had COVID-19 related leukopenia prior to administration of remdesivir.

A prospective, single-arm study reported minimal improvement in lymphopenia in severe COVID-19 patients after receiving tocilizumab (5) . However, when compared to nontocilizumab groups in the SMACORE trial (for patients with severe COVID-19 pneumonia) no significant difference was detected (6) . Based on these studies, marked elevation of lymphocyte counts in our patient (> 3 times his baseline) cannot be attributed to either tocilizumab or remdesivir. Liu et al. found a nonsignificant elevation in lymphocyte count and a nonsignificant decrease in neutrophil count of COVID-19 patients after receiving methylprednisolone (7) . The effect of methylprednisolone in our patient was in the opposite direction and his lymphocyte count dropped suddenly after first dose of methylprednisolone, but gradually increased again.

Interestingly, a recent report at University of Birmingham, UK documented a 3-4-fold increase in lymphocyte counts of four treatment naïve CLL patients with severe COVID-19 infection (8) and authors described this phenomenon as 'COVID-Induced Lymphocytosis'. All patients in their study received supportive care including antibiotics. In the first patient in their study, the ALC rose 6-fold to 202 x 10 3 /uL at day 3, but it declined to baseline at day 10 and the patient improved. Other patients had 3-4-fold rise in their ALC and they died. In one of them ALC increased from 2.8 x 10 3 /uL at baseline to 8 x 10 3 /uL. Underlying mechanism of this phenomenon is yet to be explained.

It is not clear if sudden rise in lymphocyte count can be a prognostic factor in treatment naïve CLL patients with acute COVID-19 infection. Also, not all treatment naïve CLL patients have similar outcomes. A report from a hospital in Barcelona described four CLL patients with acute COVID-19 infection of which two of them never received treatments before (9) . Although no comparison with baseline lymphocyte count was provided in their review, both patients recovered from acute COVID-19 infection.

Deletion of 13q is the only chromosomal abnormality in CLL patients associated with favorable prognosis and the longest median survival (10) . Despite early stage of disease, treatment naïve status, absence of lymphadenopathy, favorable cytogenetics, and stable count prior to contraction of COVID-19, our patient's lymphocyte counts increased more than 3-fold and had a poor outcome. This is the second report of a new phenomenon 'COVID-Induced Lymphocytosis' (or 'COVID-Induced Hyperlymphocytosis'). Of note, elevated B2 macroglobulin in our patient was at the time acute kidney injury and rise in creatinine number and cannot be used as a disease severity index.

When it comes to continuation of CLL therapy, some experts agree to continue only Bruton tyrosine kinase inhibitors (BTKi) while holding other CLL therapies, even in cases of active COVID-19 infection (11) . However, this is a totally different matter for CLL patients who never received treatment before and have 'COVID-Induced Lymphocytosis'. A case series reports beneficial effect of BTK inhibitors in 6 patients receiving ibrutinib for Waldenstrom Macroglobulinemia who were diagnosed with COVID-19 (12). Five of the patients only had mild symptoms and did not require hospitalization. One patient's ibrutinib was on hold during their admission and subsequently the patient developed dyspnea and oxygen desaturation. It was later resumed followed by a dose escalation. The patient's oxygen saturation then improved, and the patient recovered from acute COVID-19. The authors suggest that BTKi can be protective against COVID-19 induced lung injury due to their role in reduction of proinflammatory cytokines in lung tissues. Another study also found similar beneficial effect in patients who continued BTKi during hospitalization for COVID-19 (13) . Currently two phase two clinical trials are investigating possible beneficial effect of BTKi (acalabrutinib and zanubrutinib) in COVID-19 (ClinicalTrials.gov Identifier: NCT04346199, NCT04382586). Considering a large population of CLL patients under observation, it would not be surprising to see more similar cases in the future. If above mentioned trials had promising results one may consider initiating a BTKi in a patient with 'Covid-induced lymphocytosis/hyperlymphocytosis'.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Cancer Facts & Figures 2020

Clinical and laboratory predictors of in-hospital mortality in patients with COVID-19: a cohort study in Wuhan, China

Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19

Tocilizumab for Treatment of Severe COVID-19 Patients: Preliminary Results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

Covid-19 infection in therapy-naive patients with B-cell chronic lymphocytic leukemia

CLL and COVID-19 at the Hospital Clinic of Barcelona: an interim report

Genomic aberrations and survival in chronic lymphocytic leukemia

Management of CLL patients early in the COVID-19 pandemic: An international survey of CLL experts

Protective role of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID-19