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NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)

increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis

Another indirect route of SARS-CoV-2-induced NET production is platelet activation

When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis

In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.

SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors

Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause

NETosis and NETs are increasingly recognized as causes of vascular injury

SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation

NET formation may be caused by activated platelets rather than SARS-CoV-2 itself

NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.

early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses

NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease

NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation

“cytokine storm”

SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19

NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response

patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]

COVID-19 NETs may act as potential inducers for autoimmune responses

have weakened adaptive immunity as well as a high level of inflammation

tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised

NETs have also been shown to enhance macrophage pyroptosis in sepsis

facilitating an immunosuppressive microenvironment

persistent immunosuppression may result in bacterial co-infection or secondary infection

can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes

NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection

Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness

NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells

decreased E-cadherin (an epithelial marker) expression

COVID-19 also has a long-term influence on tumor progression

Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19

patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis

awaken cancer cells

NETs have been shown to change the tumor microenvironment

enhance tumor progression and metastasis

vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response

vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS

vitamin C may also inhibit NETosis and NET production in COVID-19

Metformin

Vitamin C

bone marrow suppression

cardiomyopathy

irreversible retinal toxicity

hypoglycaemia

daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature

chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks

long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness

both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds

CQ and HCQ can effectively increase the efficacy of various anti-cancer drugs

CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces

This study recommends an adjuvant HCQ dose of 600 mg, twice daily.

HCQ addition was shown to produce metabolic stress in the tumours

HCQ (400 mg/day)

important effects of CQ and HCQ on the tumour microenvironment

The main and most studied anti-cancer effect of CQ and HCQ is the inhibition of autophagy

the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis

TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA

HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells

In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks

CQ or HCQ would be considered for use in combination with immunomodulation anti-cancer therapies

Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy

Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.

daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD

HCQ is often administered twice daily to limit plasma fluctuations and toxicity