The COVID-19 pandemic, caused by SARS-CoV-2, has entered its fourth year and still is apparently waxing and waning. At the time of writing of this article, approximately 681 million reported cases of COVID-19 had been recorded, although the actual number may be much higher due to home testing and relaxed protocols around the world.¹ Many questions remain unanswered about the virus, and we are now experiencing another problem—postacute sequelae of SARS-CoV-2 infection (PASC), also referred to as post–COVID-19 condition (PCC) or post-COVID syndrome.

PASC is defined as a multisystemic disorder comprising chronic condition symptoms that follow a SARS-CoV-2 infection. O’Mahoney et al² published a meta-analysis of 194 studies totaling 735,006 participants, with 5 studies conducted in participants younger than 18 years.

The time to follow-up ranged from more than 28 days to 387 days, with 122 studies reporting data on hospitalized patients, 18 reporting on nonhospitalized patients, and 54 on hospitalized and nonhospitalized combined. O’Mahoney and colleagues concluded that 45% of survivors of COVID19, regardless of hospitalization status, were experiencing a range of unresolved PASC symptoms at about 4 months.²

The unknowns about PASC pose a serious challenge in accurately assessing the collateral damage on morbidity or other aspects of our lives, in the short term and the long term. There is evidence of SARS-CoV-2 having the potential to affect every tissue of the body and triggering chronic inflammation and its consequences. Stein et al³ detected evidence of the virus in virtually every tissue in postmortem analysis.

The Role of Inflammation and Autoimmunity

Immune dysregulation has occurred in individuals with PASC, who had mild acute COVID-19; they have been found to have T-cell alterations, reduced CD4+ and CD8+ effector memory cell numbers, and elevated PD-1 expression on central memory cells.^4,5 Findings from other studies have shown highly activated innate immune cells and elevated expression of type I and type III interferons (IFN-β and IFN-λ1) persisting for at least 8 months.⁶ Data from other studies have indicated elevated levels of IL-1β and IL-6, tumor necrosis factor, and IP-10.^7,8 High levels of autoantibodies have been found in some patients with COVID-19, including autoantibodies that target the tissue and immunomodulatory proteins (cytokines, chemokines, complement components, and cell surface proteins).⁹

PASC and Patients With Cancer

High mortality rates in patients with COVID-19 and cancer have been reported in a recently published analysis.¹⁰ In addition, delayed or missed cancer screenings,¹¹ a higher risk of morbidity and mortality,¹² and COVID-19–associated cardiac and other tissue complications can interfere with cancer treatment.¹³ Moreover, COVID-19 induced systemic inflammatory response may also affect cancer recurrence.¹⁴ Mental stress and the impact of isolation can lead to additional inflammation and perhaps oncogenic drivers.¹⁵

Whether COVID-19 increases the risk of cancer in those without previous history of malignancies has not yet been studied. Cancer progression, recurrence, and metastasis depend on the complex interaction between the tumor and the host inflammatory response. Extreme proinflammatory cytokine release (cytokine storm) and multiorgan failure are hallmarks of severe COVID-19.

Chronic low-grade inflammation in PCC may facilitate cancer progression and recurrence, besides impaired T-cell response; tissue damage; and elevated levels of cytokines, growth factors, and chemokines in the plasma of patients in the acute phase of COVID-19. There remains the possibility of the integration of SARS-CoV-2 into the host genome, which may cause cancer.¹⁶ These mechanisms have also been shown to be implicated in both tumorigenesis and metastasis. The link between inflammation and cancer and tumorigenesis has already been established beyond doubt.

Francescangeli et al¹⁷ have proposed the hypothesis that PASC-associated inflammation may generate a microenvironment favorable to tumor cell proliferation and particularly to the reawakening of dormant cancer cells. These cells may represent minimal residual disease, often surviving treatment of primary tumors and populating premetastatic niches in the lungs and other organs, retaining the potential for metastatic outgrowth.

Their reawakening may be promoted by several events associated with PASC, including activation of neutrophils and monocytes/macrophages, lymphopenia, and an uncontrolled production of proinflammatory cytokines.¹⁸ Among proinflammatory factors produced during COVID-19 infection, neutrophil extracellular traps (NETs) released by activated neutrophils have been specifically shown to activate premetastatic cancer cells disseminated in the lungs, suggesting they may be involved in this process.¹⁹ In data from confirmed prospective studies, tumor relapse may support the exploratory use of specific anti-inflammatory and antimetastatic therapies in patients with COVID-19 and an active or previous cancer.¹⁹

The hypothesis that severe COVID-19 may create a microenvironment conducive to oncogenesis stems from studies on protein- protein interactions during COVID-19 infection, whose data revealed that common cancer pathways were targeted by SARS-CoV-2, including those involved in cell cycle progression, metabolism, and epigenetics.²⁰ Although the first large studies in this field focused on the susceptibility to and mortality from COVID-19 in patients with cancer, new studies are investigating anticancer therapies or interventions.²¹ For example, patients with severe COVID-19 often present with concomitant clinical conditions predisposing them to cancer recurrence that may complicate the evaluation of individual risk factors.

An observational study has been launched to capture COVID-19 antiviral response in a pan-tumor immune monitoring trial.²² Investigators are assessing PASC in patients with cancer, including the impact on cancer outcomes, to determine potential effects of COVID-19 on cancer recurrence. If data from future studies confirm a link between severe COVID-19 and tumor recurrence, this finding may be used to schedule personalized treatments and follow-up programs for patients with both conditions. For example, prolonged anti-inflammatory therapies may be evaluated for patients with cancer who experienced SARS-CoV-2 infection.

Altogether, the observations presented in this perspective suggest a possible link between COVID-19, inflammation, and immune-mediated tumor reawakening that, if confirmed by future study evidence, may have important implications for the treatment and long-term management of patients with cancer.

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