Does COVID‐19‐related cachexia mimic cancer‐related cachexia? Examining mechanisms, clinical biomarkers, and potential targets for clinical management

Cancer cachexia (CC) is a multi‐factorial, pathological disorder of striated muscle (skeletal and cardiac) and adipose tissue, characterized by the cardinal features of loss of skeletal muscle tissue or sarcopenia, with or without loss of adipose tissue, and often accompanied by anorexia, anaemia, asthenia, increased metabolism, altered immune function, decreased functional status, and decreased quality of life. ¹ , ² , ³ Overall, cancer cachexia may afflict 50–80% and cause up to 20% of deaths of cancer patients, with highest prevalence noted in pancreatic and gastric cancers. ³ , ⁴ , ⁵ , ⁶ More recently, guidelines to define each of the four stages of CC have been proposed. ⁵ , ⁶ CC begins initially in a pre‐cachectic stage involving unplanned weight loss followed by a more severe, irreversible and progressive loss of both muscle and fat, in addition to complications involving compromises in metabolic and immune processes, ultimately resulting in death. ⁷ , ⁸ Despite the clinical significance and decades of research to prevent progression of early stages of CC to the irreversible refractory stages, there is currently no defined standard of care to effectively mount a defence to the multi‐factorial disorders associated with CC. CC is a critical problem in clinical oncology. ¹ , ² , ⁹

Globally, there have been 44 002 003 confirmed cases of COVID‐19, including 1 167 988 deaths, reported to the World Health Organization (WHO). ¹⁰ To date, there have been 8 683 298 confirmed cases of COVID‐19 with 225 073 deaths in the USA. ¹⁰ Preclinical and clinical studies consistently report a significant elevation in proinflammatory cytokines in COVID‐19, ⁹ , ¹¹ , ¹² , ¹³ especially in stages of COVID‐19 disease accompanied by acute respiratory distress resulting from ‘cytokine storm’. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Related to the significant increase in proinflammatory cytokines, symptoms, like those observed in cancer patients with cachexia, have also been observed in conjunction with COVID‐19. ⁹ , ¹³ Symptoms, similar to those observed in CC including sarcopenia, anorexia, unplanned weight loss, fatigue and functional loss, have been observed to be accelerated in patient populations at all stages of patients diagnosed with COVID‐19. ¹¹ , ¹² , ¹³ However, the data regarding the prevalence and prognosis of COVID‐10‐related cachexia accounting for age, stage at presentation, and other co‐morbidities have not been comprehensively evaluated. Additionally, with factors such as anorexia, age at presentation, immobility due to mechanical ventilation or oxygen supplementation, preexisting nutritional deficiencies and decreased physical activity due to isolation, fatigue, hypoxemia, sarcopenia, and weight loss has been observed to be accelerated in patient populations with COVID‐19. ¹¹ , ¹² , ¹³ It is unknown if COVID‐19‐related sarcopenia and cachexia persists post recovery and if it is reversible. A recent report of results of a preclinical study has shown that suppression of host inflammatory response in early stages of COVID‐19 with interventions can reverse cachexia and increase survival. ¹² Based on this early and evolving observations, it can be hypothesized that if early COVID‐19‐related cachexia mimics early stages of cancer‐related cachexia, cachexia in these patient populations can be targeted early and potentially reversed, thus reducing mortality in these patient populations. In addition, cancer patients presenting with COVID‐19 may be at exceptional risk of sarcopenia and cachexia. The goal of the current editorial is to compare the mechanisms and clinical biomarkers and discus the potential targets for clinical management of this phenomena in both COVID‐19 and cancer‐related sarcopenia and cachexia. Our understanding of these mechanisms may potentially identify targets and inform management of early stages of both cancer‐related and COVID‐19‐related cancer cachexia.

In addition to the diagnosis of cancer, CC is characterized by unplanned weight loss including loss of both skeletal and visceral muscles and fat stores, manifesting in the cardinal features of emaciation, anorexia, hypo albuminuria, myalgia, weakness affecting functional status, hypo albuminuria, significant increase in proinflammatory cytokines, dysfunction of the metabolic processes, and compromised quality of life. ¹ , ³ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ Similarly, coronavirus disease (COVID‐19) is characterized by a pneumonic process of varying degree depending on the stage at diagnosis, significant increase in proinflammatory cytokines (cytokine storm), ¹⁴ anorexia, dysgeusia, anosmia, unplanned weight loss, sarcopenia, myalgia, hypo albuminuria, increased C‐reactive proteins, ferratin and proinflammatory cytokines‐TNF‐alpha, Il‐1 and Il‐6, ¹⁴ , ¹⁵ , ²⁷ which are symptoms similar to cancer cachexia. Inflammatory organ injury has been reported in severe cases. ¹⁶ Although not evaluated and characterized in this patient population to date, the prevalence of sarcopenia and cachexia has been reported in this population at all stages with COVID‐19, underscoring the need to understand the pathogenesis of COVID‐19‐related cachexia based on the similarities to CC. Data from both experimental and clinical studies have demonstrated that CC is mediated or modulated by an interplay of a highly complex and multiple biologic pathways. Angiotensin I and angiotensin II levels (Ang II) are increased in patients with CC, ¹⁷ leading to elevated levels of proinflammatory cytokines such as TNFα, IL‐1, and IL‐6. ¹⁷ , ¹⁸ , ²⁶ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ Being produced by both tumour and host, these pro‐inflammatory cytokines have frequently been suggested as possible mediators in cachexia. ³² , ³³ It has been hypothesized that the cytokines that are important in the initiation of the acute phase response (APR) contribute to the genesis of CC. ²⁶ , ³¹ Significant increases in TNF‐α have been observed specifically in cachectic patients. ³² TNF‐α has been demonstrated to produce direct catabolism of skeletal muscle, increases in protein degradation in conjunction with depression of protein synthesis and catabolism of adipose tissue leading to induction of muscle atrophy. Studies have shown that these changes in protein degradation occurs via the ubiquitin‐proteasome pathway, with the formation of reactive oxygen species leading to activation of NF‐κB. ³⁴ , ³⁵ NF‐κB, a critical regulator protein degradation and skeletal muscle proteasome expression, has been shown to be up‐regulated in CC. ⁸ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² This up‐regulation of NF‐κB has been shown to increase the rate of myosin heavy chain and telethonin degradation, compromising sarcomere integrity. ⁴³ Sarcopenia in CC is the thus a result of imbalance between protein synthesis and degradation. ⁴⁴

The Coronovirus‐2 spike protein uses angiostensin converter enzyme 2 (ACE2) receptor, that are ubiquitously present in all cells, known to bind to cells resulting in fusion of the viral envelope to fuse with cell membrane, permitting the viral genetic material to enter the cells, contributing to cellular damage at the organ level. ⁴⁵ Additionally, ACE2 is present in ample quantities in the epithelia of the human lung, small intestine, arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied, providing the first clues in our understanding of the pervasive pathogenesis of the main SARS disease. ⁴⁶ ACE2 is present in muscle tissue which may explain in part the effect of the virus in sarcopenia. Angiotensin I and angiotensin II levels i (Ang II) have been shown to increase protein breakdown, lower muscle regeneration, and increase apoptosis in muscle tissue. ⁴⁷ , ⁴⁸ Similar to patients with CC, Ang II are increased in patients with COVID‐19 ¹⁷ and act as an inflammatory mediator leading to elevated levels of proinflammatory cytokines such as TNF‐α, Il‐1, I1–6, ¹⁴ , ¹⁵ through a variety of mechanisms including increasing reactive oxygen species and NF‐κB. ⁴⁹ Thus, there are several similarities in the pathogenesis of both CC and COVID‐related cachexia.

Patients with a diagnosis of cancer and COVID‐19 are at exceptional risk for sarcopenia and cachexia. Advanced cachexia is refractory and has a high mortality rate. Cachexia and sarcopenia continue to impact mortality in cancer and potentially in COVID‐19. In patients with early stage disease, sarcopenia and cachexia may impact function, prognosis, and quality of life in patients with cancer and COVID‐19. Several studies, including our own, suggest that maintenance of lean body mass including myofibrillar proteins are difficult to achieve in CC, unless we have a clear understanding of the underlying aetiology that can be targeted and reversed/corrected. ¹ , ² , ²⁶ , ³¹ , ⁵⁰ , ⁵¹ Research to understand the pathogenesis, incidence, course, and prognosis of various stages of presentation of disease for both CC and COVID‐19‐related cachexia and strategies to mitigate the immune response and deliver improved outcomes is much needed. Our current knowledge and evolving evidence from the fields of oncology and COVID‐19 may inform management of cachexia in both diseases. The use of dexamethasone in patients diagnosed with COVID‐19 and receiving either mechanical ventilation or oxygen alone demonstrated a lower 28‐day mortality compared with those patients who did not receive any form of respiratory support. ¹⁶ Early evidence including preclinical studies have shown promise with IL‐1, IL‐6 receptor antagonists to treat COVID‐related increase in proinflammatory cytokines. It can be hypothesized that multimodal approaches in early stages of this disease may offer promise and can include (i) early identification of reversible (Stage I) stage of sarcopenia and cachexia, (ii) therapeutic agents to lower viral load (COVID‐19)/appropriate treatment to reduce tumour burden (cancer), (iii) timely evaluation of intervention with targeted agents to reduce proinflammatory cytokine levels (dexamethasone, IL‐1, IL‐6 receptor antagonists), ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ (iv) addition of appetite stimulants to treat anorexia (v) in combination with a nutritionally enriched diets with high quality proteins, antioxidant/anti‐inflammatory foods, ¹ , ³ and (vi) incorporating proactive respiratory and physical rehabilitation interventions to improve pulmonary status and muscle mass towards preventing sarcopenia and improving physical function. Effectiveness and safety of these approaches can be evaluated using established as well as recently identified novel biomarkers relevant to the mechanistic pathways. Finding from these studies promise to inform management of CC, COVID‐19‐related cancer cachexia as well as cachexia in cancer patients with COVID‐19.

Kumar N. B. (2021) Does COVID‐19‐related cachexia mimic cancer‐related cachexia? Examining mechanisms, clinical biomarkers, and potential targets for clinical management, Journal of Cachexia, Sarcopenia and Muscle, 12, 519–522, 10.1002/jcsm.12681