Our study is the first to prospectively characterize longitudinal pattern of COVID19 infection among cancer patients on active anti-neoplastic treatment as well as healthcare providers at a tertiary cancer center. Once a national lockdown was announced in Israel on 15 March 2020, both cohorts experienced similar exposure levels, visiting only the cancer center, a secluded building within the main hospital campus (of 5300 employees). The study comprised a cohort of 164 consecutive patients who were treated during the last week of March 2020 who consented to the protocol and were followed until June 2020. The second cohort consisted of 107 healthcare providers who complied to enrolment into the study at the same time point. Our results indicate similar infection rate in both cohorts of about 2% asymptomatic cases in a longitudinal prospective study throughout a 2-month period with three points of serologic assessment. Out of 8500 cancer patients who had visited our cancer center between December 2019 to May 2020, no clinical symptomatic cases had been documented. Moreover, no symptomatic case had been reported among the 228 healthcare workers of the cancer center. It had been recently shown that there is a robust correlation between clinical severity of COVID19 infection and antibody titer since 2-week post-illness onset [13
], which may entail a similar correlation in asymptomatic cases and rapid decline of antibody titer. Though it had been demonstrated that seroconversion following SARS-CoV-2 infection occurs usually 11–14 days after the first symptoms [14
], there is no former evidence regarding dynamics in asymptomatic patients. To note, IgM and IgA levels that had been assessed in our study were undetectable at all three time points.
Several recent studies have addressed symptomatic COVID19 incidence among cancer patients. Dai et al. performed a multicenter study including 105 cancer patients and 536 age-matched non-cancer patients that were diagnosed with symptomatic COVID19 in China and indicated that cancer patients displayed more severe outcomes compared with non-cancer COVID19 patients. Risk factors for COVID19 severity were metastatic, hematological, and lung cancer. There was no difference between patients who were under active treatment or were not, and hence the authors concluded that cancer history may confer high risk to develop severe COVID19 disease [15
]. In another study of 218 cancer patients with COVID19 in New York, increased mortality was significantly associated with older age, multiple comorbidities, need for intensive care unit support, and elevated levels of d
-dimer and lactate dehydrogenase in multivariate analysis. Age-adjusted case fatality rates in patients with cancer compared with noncancer patients indicated a significant increase in case fatality for patients with cancer [16
]. Analysis of comorbidities demonstrated increased risk of dying from COVID19 in patients with cancer with concomitant heart disease and chronic lung disease. Nevertheless, Lee et al. reported clinical outcomes of a larger cohort of 800 cancer patients with symptomatic COVID19 in the United Kingdom and indicated a lower mortality rate compared with the American study. Moreover, the only high-risk factors that were significantly correlated with COVID19 severity were patient age and cardiovascular comorbidities [6
]. Therefore, current evidence is inconclusive and the potential role of cancer or anti-neoplastic treatments in COVID19 course remains to be elucidated. Evolving data regarding the immune profile in SARS-CoV2 infection shed light on a unique mechanism of action. Acute SARS-CoV2 infection results in broad changes in circulating immune cell populations—it induces local immune response within the lungs, recruiting macrophages and monocytes, cytokine release, and prime adaptive T and B cell immune responses. Due to increased secretion of the pro-inflammatory cytokine and chemokine T helper 1 (TH1), cell-polarized response is triggered and T lymphocytes, but not neutrophils, are attracted from the blood into the infected site [17
]. A recent study described pathological findings in severe COVID19 and demonstrated the aberrant immune cell infiltrates found in the lung, resulting in lymphopenia and the increased neutrophil–lymphocyte ratio seen in the majority patients with SARS-CoV-2 infection [10
]. It had been shown that the counts of peripheral CD4 and CD8 T cells were substantially reduced in COVID19-symptomatic patients, while their status was hyperactivated [17
]. However, studies present heterogenous data regarding the immune response to SARS-CoV-2. While many COVID19 patients displayed robust CD8 T cell and/or CD4 T cell activation and proliferation, there was a subgroup of patients that had no detectable response compared to controls. In their recent study, Mathew et al. showcased that strong T and B cell activation and proliferation observed in a subset of COVID19 patients was durable and that the relative clinical lymphopenia was preferential for CD8 T cells with a lesser effect on CD4 T cells and almost no impact on B cells [18
]. We have previously demonstrated in preclinical cancer models as well as in cancer patients that in response to anti-cancer therapy, the host mediates pro-tumorigenic and pro-metastatic activities [19
]. These cellular host effects are accompanied by acute elevations of cytokines and growth factors generated by the host in response to the therapy. However, such effects are transient, and the host immediately reacts to the treatment by inducing counteractive activities by means of immunosuppression and anti-inflammatory cellular and molecular mechanisms, which in turn shift the immune states towards regeneration [19
]. Overall, these phenomena indicate that cancer patients undergo immunological alterations towards anti-inflammation state due to anti-cancer treatments.
Due to the altered immune milieu, we sought to evaluate COVID19 dynamics throughout the pandemic among cancer patients. We performed immune profiling of the SARS-CoV-2 IgG+ subjects in our study compared with age-matched, co-morbidity matched SARS-CoV-2 IgG- subjects from both cohorts. For the cancer cohort, SARS-CoV-2 IgG- cases for immune profiling were selected upon the treatments of the positive cases. Limited by a small sample size of positive cases, our results imply a differential immune profile for the cancer patients compared with healthy subjects.
SARS-CoV-2 IgG+ non-cancer subjects exhibited major changes when compared with cancer patients, who displayed relatively modest changes, when we compared patients who were positive or negative to COVID19 infection. Interestingly, in the myeloid lineage, the reduction in myeloid cells in the healthcare workers was substantially reduced (over 90% reduction in SARS-CoV-2 IgG+ group), whereas in SARS-CoV-2 IgG+ cancer patients, reduction was moderate (approximately 50%) compared with matched SARS-CoV-2 IgG-. As myeloid cells and especially myeloid-derived suppressor cells (MDSCs) are key players in reducing cytotoxic immune cell activation [21
], this may imply reduction of cytokine secretion in cancer patients when compared to the overall population.
Limited by the very small sample size, our preliminary results indicate that cancer may exhibit differential host response to SARS-CoV2 infection. Along with the very low incidence of COVID19 in our cohort in a longitudinal serologic study, as well as no documentation of any clinical symptomatic COVID19 case in a larger cohort of 8500 patients who were actively observed in the last 6 months in our center, our study indicates that the immunological perspective of cancer treatments on the risk for COVID19 infection should be further explored. Another limitation of the study is the lack of symptomatic COVID19 cases (of hospitalized non-cancer patients) as positive controls, as such individuals were not amenable to be enrolled into the study.
Delineating prospective COVID19 infection trends and patterns in a larger cohort of cancer patients who are on active anti-cancer treatment will lend credence to tailor future healthcare policy in the current unpredictable COVID19 era.