DOI: 10.31038/CST.2020525

Abstract

The success of an antiviral drug depends on its potency to neutralize the virus in vitro and its ability after administration in vivo to reach the anatomic compartments that fuel viral dissemination in the body. For instance, remdesivir, a potent SARS-CoV-2 antiviral drug based on studies in vitro, if administered orally would be poorly effective because low drug levels would reach the lungs due to its high first pass destruction in the liver. This is the reason remdesivir can only be administered intravenously, a requirement that clearly limits its use as a prophylactic agent for COVID-19, although novel formulations for its easier administration are under development. Whether an antiviral prophylaxis could further control or even stop the COVID-19 epidemic in synergy with other non-pharmacological based mitigation strategies is today unknown. Since the mid-1960s, pharmacologists have investigated the use of lipid-based nanoparticles for efficient delivery of antivirals to tissues, for example by transforming the route of administration from intravenous to oral, subcutaneous or aerosol administrations. These novel encapsulation strategies have also the potential to maintain high levels of the antiviral drugs in tissues, with reduced dose frequency compared to the non-encapsulated drug. Several lipid-based nanoparticles are today approved by the US Food and Drug Administration or being tested in clinical studies with favorable toxicity profiles.

Nonhuman primate models of coronavirus infection offer unique platforms to accelerate the search for SARS-CoV-2 antiviral prophylaxis.Paradigms, to corroborate this claim, are borrowed from nonhuman primate research studies, some of which had a profound impact on global public health in the specific setting of the AIDS pandemic. Sharing information from nonhuman primate research programs, invoking principles of scientific transparency and bioethics similar to those universally agreed for human studies, would also likely significantly help our collective fight (as the human species) against this public health emergency.

What Makes an Antiviral Potent Against SARS-CoV-2?

Remdesivir, a nucleoside analogue specific for the RNA-dependent RNA polymerase of several coronaviruses, is a potent SARS-CoV-2 antiviral drug based on studies in vitro. Its half maximal effective concentration (EC50) leans consistently towards the lowest estimates when screened, using the same assay, with other antivirals tested against several coronaviruses [1-4] hence, a relatively lower concentration of the drug is needed to cut similar levels of viral replication in vitro, compared to other antiviral drugs less successfully repurposed, so far, as medical countermeasures against COVID-19. These include the HIV-1 protease inhibitor lopinavir/ritonavir (Kaletra) and the immunosuppressive and anti-parasitic drug hydroxychloroquine [5,6].

The success of an antiviral drug in fighting a virus depends, however, not only on how potent the drug is in inhibiting the virus in vitro but also on how well the drug penetrates the anatomic compartments in which the virus mostly replicates in vivo; the lungs for COVID-19. If administered orally, for instance, remdesivir would be ineffective because low drug levels would reach the lungs due to its high first pass destruction in the liver, resulting in poor oral bioavailability. This is the reason remdesivir can only be administered intravenously to exert its viral inhibitory function, a requirement that clearly limits its use as a prophylactic agent or as a test-and-treat pharmacologic-based mitigation strategy for COVID-19.

Delivering Potent Antivirals Straight to the Lungs, without Calling a Nurse

What can be done to transform the route of administration of an antiviral or to enhance its concentration into the lungs? Since the mid-1960s, pharmacologists have investigated the use of lipid-based nanoparticles for efficient delivery of antivirals and other drugs, for example by transforming the route of administration from intravenous to oral, subcutaneous or aerosol administrations [7,8], with potentially useful ramifications in the pharmacoeconomics of developing countries [9]. These novel encapsulation strategies are capable of maintaining high levels of the antiviral drugs in tissues, with reduced dose frequency. For instance, Kaletra in its oral formulation requires daily administration due to its rapid clearance, but data produced from nonhuman primates have demonstrated that the equivalent mass of one pill of Kaletra formulated as a lipid-nanoparticle for subcutaneous administration achieves approximately 10-fold higher concentrations in lymph nodes for about one week [10]. Similarly, the lipid-nanoparticle encapsulation of tenofovir, a nucleotide analogue used to treat HIV and hepatitis B infection that has some structural and functional similarities with remdesivir, has also been shown to enhance tissue concentrations and prolong retention of its active phosphorylated moieties in nonhuman primate studies [11]. The opportunity offered by nanoparticle technologies, not only to simplify the administration of a candidate antiviral drug, but also to enhance its concentrations in tissues, is relevant in the search for SARS-CoV-2 antiviral prophylaxes, especially given the limited data we have today for the penetration in the lungs or in the upper airways of most anti-SARS-CoV-2 repurposed antivirals [12], including lopinavir/ritonavir [13] and nelfinavir (another HIV-1 protease-inhibitor with a favorable EC50 against coronaviruses [14]). It is well known that lipophilic drugs preferentially penetrate the lungs and, in fact, this formed the rationale for encapsulating certain hydrophilic drugs in liposomes to promote delivery to the pulmonary compartment [15,16]. One example is amphotericin, an antifungal drug encapsulated in nanocochleates (soy-bean organic-based lipid particles) which can be formulated as an oral drink. Pharmacodynamic animal studies have advanced to phase-II clinical trials, in which patients are being administered the oral nanocochleate antifungal formulation, which appears to offer an overall effective oral formulation associated with low toxicity after prolonged (more than one year) continuous treatment [17]. Several lipid-based nanoparticles are today approved by the US Food and Drug Administration or being tested in clinical studies with favorable toxicity profiles [18]. Indeed these nanocarriers, by affecting the biodistribution in the body of the encapsulated antiviral compound, can substantially modify toxicological properties of the formulated drug. Of note, subcutaneous and aerosol formulations of remdesivir are now under development [19].

Consistent with the ranking by in vitro potency (the EC50), clinical trials in which these drugs have been administered to COVID-19 patients have thus far shown clear evidence of therapeutic potential only for remdesivir(intravenous formulation) [5,6]. Pharmacodynamic correlates of poor clinical responses could guide efforts in the search for an optimal prophylaxis. For instance, the antiviral drug Kaletra (available in pills) has been administered to COVID-19 patients with the same dose used to treat HIV-1 infected patients; however, its potency in vitro against SARS-CoV-2 is known to be significantly weaker than against HIV-1 [20].

Lessons Learned from the History of HIV-Prophylaxis Research

A successful antiviral prevention strategy is Truvada-PrEP for HIV, a combination of two nucleo(t)side analogues, that is lighter than the combination therapies (Highly Active Anti-Retroviral Therapy, HAART) used to treat HIV-1 infected patients, with important toxicological implications. Of note, dosing and administration strategies to conceive Truvada-PrEP (tenofovir+emtricitabine) were generated primarily from two monkey studies that produced, through invasive experimental designs not implementable in humans, precious data on the minimal drug levels needed in tissues to achieve protection from viral challenges [21,22]. These molecules attack the polymerase of HIV (or of lentiviruses that possess replication capacity in monkeys similar to HIV in humans, e.g. the simian-human immunodeficiency virus, SIV/SHIV) with a mechanism similar to the one adopted by remdesivir to attack the polymerase of several coronaviruses (including SARS-CoV-2), i.e. as chain terminators by mimicking the structure of a natural nucleoside [23].

Those studies demonstrated that the administration of two pills of Truvada (two hours prior to viral exposure) followed by two consecutive pills at 24 and 48 hours post-exposure provided sufficient drug levels in the rectal mucosa tissue to cut most viral transmissions. That prophylactic regimen (later called “On-Demand”) achieved in monkeys a protection similar to that achieved through daily drug administrations. This data prompted randomized clinical trials of “On-Demand-PrEP” prophylaxis, which confirmed an efficacy similar to the one estimated with the heavier “Daily-PrEP” regimen [24] and which later received endorsement in revised HIV treatment and prevention recommendations issued by the International Antiviral Society–USA [25]. Hence the former are two examples of nonhuman primate studies that have had a profound impact on public health worldwide.

Similarly, two decades earlier, the simian-human immunodeficiency virus (SIV/SHIV)-monkey model had been used to generate the HIV Post-Exposure Prophylaxis (PEP) guidelines we are using today for both occupational and non-occupational exposure to HIV, by demonstrating the effectiveness of a cocktail of HIV drugs (a combination of antiretrovirals similar to the one administered to HIV-1 infected patients, for four consecutive weeks), in preventing viral transmission if administered within 72 hours (but the sooner the better) from viral exposure [26,27]. The length of this window of opportunity for HIV PEP was identified, again, through nonhuman primate studies, in which lentiviruses replicate with dissemination capacity and antiviral drugs distribute in tissues with kinetics, much more similar to humans than any other animal model in our hands. In general, although animal models (including nonhuman primates) are known to be poor predictors (for obvious reasons) of the efficacy of specific HIV vaccines in humans [28], the monkey models proved to be valuable resources, during the past decades, in predicting the efficacy of antiviral HIV strategies not only as prophylaxis but also in the therapeutic arena.

The lessons learned from HIV and Truvada-PrEP studies include the following: 1) an antiviral may show a weak therapeutic effect, especially if administered late in the course of the viral induced disease, yet can effectively cut most viral transmissions if administered prophylactically. This observation holds true also for COVID-19. For instance, a recent study in a coronavirus rodent model showed that another nucleoside analogue with in vitro inhibitory activity similar to remdesivir can efficiently reduce viral replication in the lungs yet may fail to prevent disease progression if administered too late [29]; and 2) the higher the drug concentration in the anatomic compartments that fuel viral dissemination in the body, the higher the efficacy of the pharmacologic prevention strategy aimed at promptly eradicating the virus from the body [30]. The latter observation built the rationale for encapsulating HIV drugs in lipid-nanoparticles in research programs developed in the past decades [31], with the dual objective of simplifying (by reducing dosing frequency) and optimizing (by enhancing drug tissue levels) the delivery of antiretroviral drugs for both HIV-1 prevention and treatment, through proof-of-concept studies in nonhuman primate models of AIDS; an important experimental step for its effective translation into human studies.

The same experimental designs can be efficiently conceived to develop medical countermeasures to COVID-19 through the SARS-CoV-2 rhesus macaque model [32], which induces a respiratory disease milder than in COVID-19 patients, but that replicates at similar levels in the lungs [33,34]. In general, although non-invasive in vivo imaging technologies have also been used to study the biodistribution of antiviral drugs (including in the upper and lower respiratory tracts of humans [35,36]), our understanding of how an antiviral prophylaxis strategy succeeds or fails in protecting people from SARS-CoV-2 infection would inherently advance (as it did for HIV prophylaxis), by designing viral challenge experiments and producing measurements directly in tissues using these animal models. Sharing information from nonhuman primate research programs on what antiviral strategies are being tested on these animal models for COVID-19 throughout the world, invoking principles of scientific transparency and bioethics similar to those universally agreed for human studies (e.g. by registering studies in public databases) [37], would also likely significantly help our collective fight (as the human species) against this public health emergency [38].

These studies could also, in principle, be efficiently designed using other nonhuman-primate coronavirus animal models [39], especially if the antiviral target is the polymerase gene, given its high level of sequence conservation through evolution [29]. To date, remdesivir is the only antiviral drug tested in nonhuman primate models of SARS-CoV-2 with published observations [39,40]. Macaques infected with either the MERS-CoV [39] or the SARS-CoV-2 [40] rapidly cleared the virus following intravenous administration of remdesivir compared to untreated controls, consistent with the successful therapeutic effect of remdesivir observed in COVID-19 patients [6]. Data from both monkey studies also predict that remdesivir could prevent SARS-CoV-2 infection in humans, if used prophylactically. Prophylactic remdesivir (intravenous) treatment had been also successfully tested in nonhuman primates models of Ebola virus [41] and Nipah virus infection [42], two RNA viruses with an RNA-dependent RNA polymerase also highly sensitive to its inhibitory activity [43]. Indeed, both the cynomolgus [44] and the rhesus macaque models [45] of SARS-CoV-2 infection are being interrogated in these weeks to test the prophylactic efficacy of hydroxychloroquine.

These studies have been run in laboratories with the highest levels of biological safety (biosafety level-3 [39,40,44,45] and biosafety level-4 [41,42]) due to the high risk these pathogens pose to research personnel, which are very expensive to build and maintain, hence not readily available in most countries [46]. The modification of an antiviral, e.g. through lipid nanoparticle technology, as anticipated above, requires preliminary testing in vitro as well as in animal models. Specifically, there is need to demonstrate that the lipid structure does not impair the inhibitory activity of the encapsulated antiviral (e.g. does not increase its EC50 against the challenge virus). In healthy uninfected animals, biodistribution studies are subsequently needed to demonstrate that the encapsulated antiviral is capable of reaching the tissues in which the virus is expected to mostly replicate in vivo, and, in the case of a nucleoside analogue (like remdesivir), that its active phosphorylated moieties are produced at sufficient concentrations in those tissues. These preliminary pharmacokinetic studies will inform on the optimal dose of the encapsulated antiviral under scrutiny and on how frequently it will need to be administered in the pharmacodynamic studies. The latter studies can demonstrate the feasibility of the modified antiviral drug to exert its inhibitory activity in an infected host, hence an important step for the translation of the nanoparticle approach to human studies.

While alternative animal models could possibly serve the pharmacodynamic study objectives, the nonhuman primate model is likely the best model to accelerate this area of research. To my knowledge, coronaviruses less pathogenic to humans [47] but still sensitive to the inhibitory activity of remdesivir [48] (and possibly to other antiviral drugs [29]) have not been tested in nonhuman primates, although serologic studies suggest that these viruses may be able to replicate well in these hosts [49]. Indeed, a 229E coronavirus experimental infection study in normal volunteers failed to demonstrate efficacy of a nucleoside analogue for prophylaxis, as previously shown in rodent models, possibly due to the differential tissue pharmacokinetics of the specific drug under scrutiny in the two evolutionarily distant hosts [50].

In other words, “non-perfect” nonhuman primate models (i.e. those in which the SARS-CoV-2 or an older cousin does not cause disease yet replicates in tissues at levels similar to humans) can still generate useful data to screen prophylactic antiviral strategies, including, for instance, lipid nanoparticle formulations of “non-perfect” antiviral drugs (i.e. a putative antiviral drug failing to demonstrate a robust therapeutic effect in patients with advanced COVID-19 or if suboptimal drug levels in the lungs are confirmed from preclinical or post-mortem studies). Had we not discovered the rhesus-macaque model of HIV infection (in which the simian immunodeficiency virus [SIV] causes a disease similar to AIDS), we likely still would have generated pharmacodynamic data using the natural hosts of SIV infection (in which SIV does not cause disease, but still replicates in the body at levels similar to HIV in humans or SIV in the non-natural nonhuman-primate hosts [51]) equally useful for their inference to HIV-(post- and pre-exposure) prophylaxis (PEP and PrEP, respectively) in humans.

Had We the Equivalent of Truvada-Prep for SARS-CoV-2, How Would We Use it to Mitigate COVID-19?

Pharmacologic-based mitigation strategies to curb epidemics have been postulated [52], but their efficacy in synergy with social distancing and face mask wearing mitigation strategies (with or without digital contact-tracing technology [53]) for an epidemic with a doubling-time and dynamic features similar to COVID-19 [54,55] is today unknown. Consensus is growing among modelers, however, that mitigation strategies interventions (which primarily act on reducing the same variable of the viral transmission dynamic models adopted in their studies, i.e. the infectivity rate) work best in keeping the number of new cases at bay (or could even stop the epidemic [53]), if administered when the pool of infected people is small, i.e. during the early steps of a viral outbreak or when the R-naught (average number of people that one infected person will pass the virus to) has been sufficiently reduced, for instance following a period of effective lock-down [53,55]. The larger the initial pool of infected people, the more aggressive the interventions aimed to promptly control an epidemic may need to be (including voluntary centralized quarantine) [56].

Efforts in this area of mathematical modeling research are critically needed to serve this and any future viral outbreak. For bioethical reasons, similarly to what happened for PEP studies in the 1990s, once the effectiveness of the first available COVID-19 prophylaxes is demonstrated, it will be difficult to estimate the relative contribution of each mitigation strategy to the curve of new cases in a given region. Epidemiological models of COVID-19 for instance predict that a 50% reduction in within-population contact rates can already have a dramatic effect in slowing the course of the epidemic [54]. Massive data sharing among countries, which will likely adopt different combinations of those strategies at different times, will be of utmost importance to produce that knowledge.

The role of an antiviral prophylaxis goes beyond its ability to substantially impact the curve of cases. The high likelihood of SARS-CoV-2 transmission among individuals living in households with infected people [57] offers an important context in which a safe antiviral drug is highly desired to protect, first of all, those at high risk of severe disease, such as the elderly with chronic health conditions, as well as those at high risk of contracting the virus through occupational exposure. This would enhance the quality of life not only for uninfected adults living in the same household but also for the COVID-19 patients who could go through the quarantine period with less fear of infecting those who gravitate around their lives; a peace of mind that carries priceless benefits to patient welfare, somewhat similar (within the limitations of the proposed parallelism) to those experienced by HIV serodiscordant couples with the advent of Truvada-PrEP.

Acknowledgements

The author thanks Katelyn W. Le, from Frederick National Laboratory for Cancer Research/Leidos Biomedical Research, for providing medical writing editorial support during the preparation of this paper.

References

1. Wang M, Cao R, Zhang L, Yang X, Liu J, et al. (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res30: 269-271. [crossref]
2. Martinez MA (2020) Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus. Antimicrob Agents Chemother64.
3. Liu J, Cao R, Xu M, Wang X, Zhang H, et al. (2020) Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov6: 16. [crossref]
4. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, et al. (2020) Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun11: 222. [crossref]
5. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB (2020) Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA[crossref]
6. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, et al. (2020) Remdesivir for the Treatment of Covid-19 – Preliminary Report. N Engl J Med. [crossref]
7. Milovanovic M, Arsenijevic A, Milovanovic J, Kanjevac T, Arsenijevic N (2017) In: Antimicrobial Nanoarchitectonics, A. M. Grumezescu (Eds.). (Elsevier, 2017) Pg No: 383-410.
8. Pandey R, Khuller GK (2004) Subcutaneous nanoparticle-based antitubercular chemotherapy in an experimental model. J Antimicrob Chemother54: 266-268. [crossref]
9. Salamanca-Buentello F, Persad DL, Court EB, Martin DK, Daar AS, et al. (2005) Nanotechnology and the developing world. PLoS Med2: e97. [crossref]
10. McConnachie LA, Kinman LM, Koehn J, Kraft JC, Lane S, et al. (2018) Long-Acting Profile of 4 Drugs in 1 Anti-HIV Nanosuspension in Nonhuman Primates for 5 Weeks After a Single Subcutaneous Injection. J Pharm Sci107: 1787-1790. [crossref]
11. Koehn J, Iwamoto JF, Kraft JC, McConnachie LA, Collier AC, et al. (2018) Extended cell and plasma drug levels after one dose of a three-in-one nanosuspension containing lopinavir, efavirenz, and tenofovir in nonhuman primates. Aids 32: N2463-2467. [crossref]
12. Arshad U, Pertinez H, Box H, Tatham L, Rajoli RKR, et al. (2020) Prioritization of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics. Clin Pharmacol Ther. [crossref]
13. Twigg HL, Schnizlein-Bick CT, Weiden M, Valentine F, Wheat J, et al. (2010) Measurement of antiretroviral drugs in the lungs of HIV-infected patients. HIV Ther4: 247-251. [crossref]
14. Yamamoto N, Yang R, Yoshinaka Y, Amari S, Nakano T, et al. (2004) HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus. Biochem Biophys Res Commun318: 719-725. [crossref]
15. Nanoformulations for the Therapy of Pulmonary Infections (2017) In: Nanostructures for Antimicrobial Therapy, Sagar Dhoble, Vinod Ghodake, Manasi Chogale, Vandana Patravale (eds.). Elsevier, 457-480.
16. Pea F, Viale P (2006) The antimicrobial therapy puzzle: could pharmacokinetic-pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis42: 1764-1771. [crossref]
17. Aigner M, Lass-Florl C (2020) Encochleated Amphotericin B: Is the Oral Availability of Amphotericin B Finally Reached? J Fungi(Basel)6: 66. [crossref]
18. Bulbake U, Doppalapudi S, Kommineni N, Khan W (2017) Liposomal Formulations in Clinical Use: An Updated Review. Pharmaceutics 9: 12. [crossref]
19. https://www.reuters.com/article/us-health-coronavirus-gilead-sciences/gileads-next-step-on-coronavirus-inhaled-remdesivir-other-easier-to-use-versions-idUSKBN2391FP
20. Cao B, Wang Y, Wen D, Liu W, Wang J, et al. (2020) A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382: 1787-1799. [crossref]
21. Garcia-Lerma JG, Otten RA,Qari SH,Jackson E,Mian-er Cong, et al. (2008) Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med5: e28. [crossref]
22. Garcia-Lerma JG, Mian-er Cong, Mitchell J, Youngpairoj AS, Zheng Q, et al. (2010) Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection. Sci Transl Med2: 14ra4. [crossref]
23. Deval J (2009) Antimicrobial strategies: inhibition of viral polymerases by 3′-hydroxyl nucleosides. Drugs 69: 151-166. [crossref]
24. Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, et al. (2015) On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. N Engl J Med373: 2237-2246. [crossref]
25. Saag MS, Benson CA, Gandhi RT, Hoy JF, Landovitz RJ, et al. (2018) Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2018 Recommendations of the International Antiviral Society-USA Panel. JAMA 320: 379-396. [crossref]
26. Tsai CC, Emau P, Follis KE, Beck TW, Benveniste RE, et al. (1998) Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment. J Virol72: 4265-4273. [crossref]
27. Black RJ (1997) Animal studies of prophylaxis. Am J Med102: 39-44. [crossref]
28. Herati RS, Wherry EJ (2018) What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Consideration of Strategies to Improve the Value of Animal Models. Cold Spring Harb Perspect Biol10: a031583. [crossref]
29. Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, et al. (2020) An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med12: eabb5883. [crossref]
30. Patterson KB, Prince HA, Kraft E, Jenkins AJ, Shaheen NJ, et al. (2011) Penetration of tenofovir and emtricitabine in mucosal tissues: implications for prevention of HIV-1 transmission. Science translational medicine 3: 112re114-112re114. [crossref]
31. Kraft JC, Freeling JP, Wang Z, Ho RJ (2014) Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J Pharm Sci103: 29-52. [crossref]
32. Munster VJ, Feldmann F, Williamson BN, Doremalen NV, Pérez-Pérez L, et al. (2020) Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature. [crossref]
33. Pan Y, Zhang D, Yang P, Poon LLM, Wang Q (2020) Viral load of SARS-CoV-2 in clinical samples. Lancet Infect Dis20: 411-412. [crossref]
34. Wichmann D, Sperhake JP, Lütgehetmann M, Steurer S, Edler C, et al. (2020) Autopsy Findings and Venous Thromboembolism in Patients With COVID-19. Ann Intern Med. [crossref]
35. Bergstrom M, Cass LM, Valind S, Westerberg G, Lundberg EL, et al. (1999) Deposition and disposition of [11C]zanamivir following administration as an intranasal spray. Evaluation with positron emission tomography. Clin Pharmacokinet1: 33-39. [crossref]
36. Dabisch PA, Xu Z, Boydston JA, Solomon J, Bohannon JK, et al. (2017) Quantification of regional aerosol deposition patterns as a function of aerodynamic particle size in rhesus macaques using PET/CT imaging. Inhal Toxicol29: 506-515. [crossref]
37. Zarin DA, Keselman A (2007) Registering a clinical trial in ClinicalTrials.gov. Chest 131: 909-912. [crossref]
38. Brouillette M (2017) To Treat Primates More Humanely: Transparency Scientists look to open-data initiatives to lessen the burden of research on our closest animal relatives. Sci Am316: 14. [crossref]
39. Wit ED, Feldmann F, Cronin J, Jordan R, Okumura A, et al. (2020) Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A117: 6771-6776. [crossref]
40. Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, et al. (2020) Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. [crossref]
41. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, et al. (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531: 381-385. [crossref]
42. Lo MK, Feldmann F, Gary JM, Jordan R, Bannister R, et al. (2019) Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge. Sci Transl Med11: eaau9242. [crossref]
43. Pardo J, Shukla AM, Chamarthi G, Gupte A (2020) The journey of remdesivir: from Ebola to COVID-19. Drugs Context9: 4-14. [crossref]
44. https://www.researchsquare.com/article/rs-27223/v1
45. https://www.biorxiv.org/content/10.1101/2020.06.10.145144v1
46. Peters A (2018) The global proliferation of high-containment biological laboratories: understanding the phenomenon and its implications. Rev Sci Tech37: 857-883. [crossref]
47. Bende M, Barrow I, Heptonstall J, Higgins PG, Al-Nakib W, et al. (1989) Changes in human nasal mucosa during experimental coronavirus common colds. Acta Otolaryngol107: 262-269. [crossref]
48. Parang K, El-Sayed NS, Kazeminy AJ, Tiwari RK (2020) Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs Against Human Coronavirus 229E (HCoV-229E). Molecules 107: 262-269. [crossref]
49. Dijkman R, Mulder HL, Rumping L, Kraaijvanger I, Deijs M, et al. (2009) Seroconversion to HCoV-NL63 in Rhesus Macaques. Viruses 1: 647-656. [crossref]
50. Higgins PG, Barrow GI, Tyrrell DAJ, Snell NJC, Jones K, et al. (1991) A study of the efficacy of the immunomodulatory compound 7-thia-8-oxoguanosine in coronavirus 229E infections in human volunteers. Antiviral Chemistry & Chemotherapy2: 61-63.
51. Gordon SN, Dunham RM, Engram JC, Estes J, Wang Z, et al. (2008) Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis. J Virol82: 3725-3735. [crossref]
52. Ferguson NM, Cummings DAT, Fraser C, Cajka JC, Cooley PC, et al. (2006) Strategies for mitigating an influenza pandemic. Nature 442: 448-452. [crossref]
53. Ferretti L, Wymant C, Kendall M, Zhao L, Nurtay A, et al. (2020) Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Science 368: eabb6936. [crossref]
54. Wu JT, Leung K, Leung GM (2020) Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet 395: 689-697. [crossref]
55. Hellewell J, Abbott S, Gimma A, Bosse NI, Jarvis CI, et al. (2020) Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts. Lancet Glob Health8: e488-e496. [crossref]
56. Pan A, Liu L, Wang C, Guo H, Hao X, et al. (2020) Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA323: 1-9. [crossref]
57. Li W, Zhang B, Lu J, Liu S, Chang Z, et al. (2020) The characteristics of household transmission of COVID-19. Clin Infect Dis. [crossref]

DOI: 10.31038/CST.2020524

Review Article

Stress of Working in Oncology

Oncology is a medicine area of high psychic investment. Working with cancer patients is a source of human and professional satisfaction but can involve high emotional costs [1,2]. High levels of burnout and compassion fatigue are reported by about 32% of oncologists [3,4] this percentage rises to 70% among people under 40 years [5]. High levels are also found among nursing staff with marked levels of emotional exhaustion [6]. Repeated exposure to suffering and loss, to the side effects and/or the failure of treatments to the end of life stages, to feeling overwhelmed by work, are among the causes of chronic distress that medical staff accumulate in clinical practice. Care of cancer can result  in emotional distress and exhaustion, loss of empathy, and demotivation from work [7]. Of no less importance is the “difficult” communications that are estimated at around 20,000 in the career of an oncologist [8].

Prevalence of COVID-19 and Risk of Infection

It is well known in the history of infectious diseases that health workers are those who pay a high cost. On the one hand testifies to the tendency of healthcare personnel to take risks for patient care, on the other highlights how often they are confronted with epidemics without adequate safety systems [9]. COVID-19 has been the most catastrophic pandemic after the 1918 H1N1, known as the “Spanish flu”. The Italian data of April 23, 2020, by the Istituto Superiore di Sanità (ISS) [10], show that 11% of the symptomatic infected people are health workers, with a median age of 48 (vs 62 years, total case median age), 69% women, with a lethality rate of 0.4%. The increased exposure of health personnel is also confirmed by the data of the Italian National Institute for Accident Insurance at Work  (INAIL)  [10]. The Health and Social Care sector (hospitals, nursing and rest homes, etc.) reports 72.8% of cases. Of the 28,381 SARS-CoV-2 occupational infections reported between the end of February and April 21, 2020, 71.1% are women. The median age of 48, 45.7% are health technicians (nurses, physiotherapists), 18.9% socio-health workers, 14.2% doctors, 6.2% social workers, 4.6% unqualified staff related to health services and education. The territorial analysis shows a distribution of complaints of 52.8% in the North-West (Lombardy 35.1%), 26.0% in the North-East (Emilia Romagna 10.1%), 12.7% in the Centre (Tuscany 5.5%), 6.0% in the South (Puglia 2.6%), 2.5% in the Islands (Sardinia 1.3%). The monitoring also detects 98 reports of accidents with a fatal outcome following COVID-19 (about 40% of the total deaths at work reported to INAIL in the period under review), median age 59 years, 79.6% are men. The territorial analysis shows a distribution with 54.1% of deaths in the North-West (Lombardy 36.7%), 13.3% in the North-East (Emilia Romagna 9.2%), 10.2% in the Centre (Marche 4.1%), 20.4% in the South (Campania 9.2%) and 2.0% in the Islands (Sicily 2.0%). The category of health technicians (nurses, physiotherapists) is the most affected (15%), followed by doctors, social and health workers, and social workers (all three professional categories, 13%).

The data on the place of exposure of the contagion (sample n = 5000) in the period 1-23 April 2020, show as most at risk the Healthcare Residences (RSAs), then the Communities for Invalids and Retirement Homes (44.1%), family (24.7%), hospitals and clinics (10.8%), workplace (4.2%) [11]. The Italian data are consistent with the Chinese and North American ones which identify a category at risk of contracting COVID-19 in healthcare personnel, with percentages of 3.8% of the total cases in China and 19.0% in the USA. A higher prevalence of women, younger individuals, and a lower lethality, probably due to the higher number of swabs carried out, are the characteristics that differentiate health workers from the total sample of subjects who contracted the virus [12,13].

Challenges Posed by COVID-19 to Healthcare Workers in Oncology in the Phase of Strong Epidemic Spread

Our country and the National Health System (NHS) were not prepared for this pandemic unlike others like China and South Korea who had faced other flu epidemics such as SARS and MERS. Italy had never found itself having to implement such an impressive health response plan. In phase I, while many hospitals were transformed into intervention hospitals or HUBs for COVID-19, the staff who worked with cancer patients faced professional  and  personal  problems.  The scarcity of adequate Personal Protective Equipment (PPE), the uncertainty regarding the mode of transmission  of  the  virus  and the related protective behaviours, the consequences of the delay in recognizing some positive  patients,  the  responsibility  of  patients at risk for age and immune conditions, the first contagions among colleagues with consequent worry and workload, the fear of infecting their family members, the lack of swabs and reagents constituted the initial scenario. In an “unexplored terrain” where little was known about the virus and even less about possible therapies, the oncological health workers participated together with the others in the trauma and mourning, powerless witnesses of the surge of infections, the wave of deaths, the collapse of the Intensive care, patient transfers to other contexts.

Working in oncology they should have been used to considering death in the background, but this was “another” disease. The high rate of contagion among health professionals [14], the median 10 days from diagnosis to death, the lethality rate reported as preliminary data by the National Institute of Statistics-ISTAT [15] showed an increase in deaths equal to or greater than 20% compared to the average figure for the same period in the years 2015-2019, which made COVID-19 a different phenomenon. Health workers were personally touched by the fear of contagion, by the death of colleagues, patients, and loved ones, feeling exposed, mortal, and fragile [16,17]. “Am I part of the cure or am I part of the disease?” a doctor asks himself, stressing the conflict between a sense of responsibility for one’s job and that of one’s family [18]. The fear of “taking the virus home” is not unfounded if we think that 41% of COVID-19 cases in Wuhan resulted from hospital- related transmission [19] and that Italian data show how the exposure to the virus occurred in 24.7% of cases in the family environment. [10] A fear that can trigger primitive reactions of social stigma in an insidious way. This explains the paradox described in other epidemics whereby what are called “heroes” for the value attributed to their work [20] may be feared by some as potential “greasers” capable of bringing the virus into their condominiums or homes [21].

Due to the risk of moral  injury,  that  particular  phenomenon that occurs when you know that “you should do something but you cannot do it” with a consequent sense of guilt, betrayal, and anger [22] is likely that oncological health workers have not been as exposed as the colleagues who worked in the front line or in the triage forced  for lack of oxygen, fans or beds to give priority to some categories  of patients and not to others. However, more nuanced feelings of “moral disorientation” have emerged related to both the fact that “the questions of Medical Oncology for  the  correct  approach  in the management of COVID-19 are multiple and unresolved”, [23] and to the “transgression”  of evidence-based reference paradigms,  in the absence of consolidated scientific evidence on the effects of COVID-19 on patients and cancer therapies, and the “distraction effect “consequent to the NHS focus on the pandemic [24-26]. In any case, the oncologist had to face the daily task of “balancing the value of cancer treatment with competing risks during a time of declining resources” with ethical and logistical challenges to clinical standards and humanism [23].

Impact of COVID-19 on the Mental Health of Operators and Family Members

We do not yet have prevalence data on peritraumatic distress from COVID in cancer healthcare professionals although data on a general population sample show that a third of people experienced symptoms of mild/moderate and severe peritraumatic distress [27].

That health workers can report mental health problems, personal and professional emotional pressure during epidemics and pandemics, even to a greater extent than that found in the general population, which is a phenomenon described in the literature on SARS, MERS and H1N1 and confirmed by recent studies on COVID-19. The prevalence of psychological and psychopathological disorders can vary according to the pandemic phase, with higher peaks in the initial periods [28] when the initial impact can cause a higher distress response. A single-center study on 5062 COVID hospital workers in Wuhan highlights distress (29.8%), depression (13.5%), and anxiety disorders (24.1%). The variables associated with psychic suffering were gender, years of seniority, the presence of chronic illness, and the history of mental disorders, having positive or suspicious family members, and evaluating the Hospital Institution as a tutelary and supportive [29]. Another study of 1257 health worker (60.8%, nurses and 39.2% doctors) in hospitals in China (60.5% in Wuhan and 39.5% outside Wuhan), of which 41.5% front line operators, reported depressive symptoms (50.4%), anxiety (44.6%), insomnia (34.0%) and distress (71.5%). Being nurses, women, working on the front line, in Wuhan Hospitals was associated with higher levels in all measured mental health dimensions. Healthcare professionals directly involved in the diagnosis and treatment of COVID-19 patients have a high risk of depressive symptoms, anxiety, insomnia, and distress [30].

An Italian study carried out between 27 and 31 March 2020 on 1379 health workers from 20 Italian regions, using an avalanche sampling technique, highlights symptoms of post-traumatic stress (49.4%), symptoms of severe depression (24.7%), anxiety (19.8%), insomnia (8.3%) and high distress (21.9%). Female gender and young age are risk factors for all study outcomes; having been personally exposed to the infection is a risk factor for depression, working in the front line is positively related to symptoms of post-traumatic stress, having a dead colleague, hospitalized or in quarantine was significantly associated with high levels of insomnia, depression and perceived stress, finally being nurses or social and health workers is a risk factor for severe insomnia [31].

Since being in hospital could favor the possibility of being infected it is legitimate to hypothesize the concern of family members considering the risks involved in the work of their relatives. Little has been studied in the psychological suffering of family members of health workers in epidemics. A recent survey [32] carried out from 10 to 20 February 2020 on 822 family members of health workers who worked in 5 hospitals in Ningbo, China, showed high levels of distress with  a prevalence of anxiety disorders (33.7%) and depressive symptoms (29.4 %). Significant differences were associated with characteristics of the health care professional’s work such as availability of adequate PPE, the number of hours worked, contacts with positive or suspect patients and personal characteristics of the family member, such as the number of hours focused on COVID. Parents and children, compared to their spouses, were at greater risk of distress. These data require attention for correct allocation of resources for dedicated interventions, as required by the Guidelines for interventions on the psychological crisis for the pneumonia epidemic due to new coronavirus infection. The Chinese National Health Commission treats family members of healthcare professionals as the 3rd priority group.

What Resources and What Interventions?

A first consideration regards the timeliness with which researchers from around the world reacted to the challenges posed by an unknown virus, the cause of a pandemic that has positioned itself in a few months among the main causes of death in different countries [33]. This reaction united the scientific community and witnessed the production and sharing of a large number of articles in peer-reviewed journals and sources such as bioRxiv and medRxiv, with a speed of publication unthinkable in normal times. Over 40,000 searches have been collected under the aegis of COVID-19 Open research Dataset (CORD-19) and uploaded to a site of the Allen Institute for Artificial Intelligence to allow data scientists and artificial intelligence experts to consult them [34]. Healthcare institutions in the USA [35] have set up a register of cancer patients for faster and wider sharing of data, as well as research groups and scientific associations from the oncology area in Italy.

All this has made it possible to identify new research paths and a better understanding of the phenomena in their evolution. And above all, it offers the knowledge bases to political and health authorities to develop and implement support actions for a category widely exposed to distress such as that of health workers. Peritraumatic distress is known to be associated with an increased likelihood of developing Post Traumatic Stress Disorder (DPTS) and other psychological symptoms in the years following natural disasters. A recent study highlighted that “to have received psychological support” was a variable associated with lower distress scores [27]. A first answer, at the level of available resources, is the psychoeducational material disclosed in the form of videos or informative material, produced by national and international Organizations and Agencies (e.g. CSTS, ISS, National Comprehensive Cancer Network – NCCN), which aims to support the well-being of healthcare professionals during the coronavirus epidemic or other epidemics [36,37].

In distress prevention programs one must not forget the importance of the role of the team leader and the type of leadership, of how they will be able to guide their collaborators in moments of uncertainty towards necessary changes, support them in the needs of reassurance, recognize their feelings of anxiety and condolence and encourage them in the development of group cohesion [38]. Cohesion is a powerful factor in the dynamics of a team, described as that particular “climate” that is perceived by observing a group at work, that “team spirit” characterized by a propensity for mutual support, even hard confrontation between members but always on a constructive and loyal group membership background. The “team spirit” is not easy to build from nothing in times of crisis and strong work pressure, therefore it would be desirable that the institutions in times of stability provided for the formation of leaders capable of proactively promoting a community of colleagues based on the value of the mutual support, particularly in critical areas such as oncology [39]. Other resources concern the activation by the health structures of remote psychological interventions dedicated to operators in the oncological area such as telephone helplines. The helplines operate with the first level of intervention which consists of accepting the motivation of the call and understanding its meaning. As a rule, a psychological triage follows to collect information in a short time on the nature and severity of the problem presented, on the resources available to deal with it. In some cases, a single contact that takes on counseling characteristics or a brief intervention on the crisis may be sufficient. However, in the presence of persistent symptoms, marked family difficulties, in work or in social life, with the risk of complications and/or suicide and/or evidence of major psychopathological disorders, a structured second- level intervention is carried out with a referral to a psychotherapist or psychiatrist [40,41].

Further resources for healthcare professionals  are  represented by the defusing and debriefing interventions developed in the field  of emergency psychology, are used in psycho-oncology in highly stressful critical situations that suddenly impact on the usual routine of the work team, imply the perception of a threat on a physical and/or emotional level, upset the feeling of control and interfere with the usual coping skills of individuals. Defusing can be defined as an immediate psychological first aid technique, of “sharing and emotional reworking related to a traumatic event” [42]. The Debriefing intervention for Stress from Critical Accidents is a more structured intervention to be carried out in the 48/76 hours following a critical event, in any case no later than two months from it. If indicated, it can also be offered remotely [43].

Communication and Relationship Challenges in the Care of Cancer Patients

In phase I, with a strong epidemic spread, the members of the cancer team found themselves managing new relationship situations with patients and their families, following the abrupt reorganization of care. Clinical experience and scientific publications have proposed new topics that may constitute communication challenges: the management of patients’ feelings of anxiety, abandonment or ambivalence towards the Hospital, which is seen as a safe base but also as a reservoir of infection; the communication of positivity for COVID-19 to a metastatic patient hospitalized for cancer treatment or to a patient who has recently received a cancer diagnosis; the communication to the relatives of the transfer to the COVID-19 ward or of intensive care of their relative; being intermediaries of highly emotional communications, telephone or video calls at the patient’s bed; answering difficult questions and finally adapting to new ways of telematic assistance.

During a pandemic emergency, personal protective equipment and social distancing can modify, limit, and alter the use of non- verbal communication and require an “enhancement” of the role of verbal communication in the patient’s medical relationship to convey truthful information and reassurance on the reasons of the multiple changes in procedures, giving support in critical phases of the care path and in the absence of support from family members, answering difficult questions and, last but not least, of importance for having conversations on end-of-life issues (such as the discussion on the Advance Care Planning and Decisions about Do-Not-Resuscitate Order also in a proactive version adapted to COVID-19). The importance was stressed in addressing Advance Care Planning during COVID-19 and of prioritize discussions about goals of care at the onset of serious acute illness [44]. Not a simple task in a country like Italy where half of the patients with metastatic cancer are unaware of the prognosis [45] and where the Early Treatment Provisions (DAT) are rarely discussed in clinical practice [46].

It is known how communication skills can be perfected through Evidence-Based training and which are associated with less burnout in the care staff, with greater satisfaction with the care received and positively with other outcome measures in patients [47,48]. The psycho-oncologist can provide, in an emergency, healthcare professionals with targeted counseling on the psychological aspects of critical communication steps. Health workers with training in communication skills are facilitated and adapt the skills acquired to new communication challenges. Untrained operators  can benefit from toolkits with behavioral indication  of what   it would be better to say or do in difficult relationship situations of COVID-19 [49]. Taking care of  communication and  relationships  is not secondary for health workers because, when everything is over, the perception of having been important reference and support figures for other bewildered and frightened human beings will have a comforting and protective effect on one’s own and their mental health [50].

Abbreviations

COVID-19: Coronavirus Disease 2019

CSTS: Center for the Study of Traumatic Stress

DAT: Disposizioni Anticipate di Trattamento

INAIL: Istituto Nazionale Assicurazione Infortuni sul Lavoro

ISS: Istituto Superiore di Sanità

ISTAT: Istituto Nazionale di Statistica

NCCN: National Comprehensive Cancer Network

RSA: Residenza Sanitaria Assistenziale

SARS-CoV-2: Severe Acute Respiratory Syndrome – Coronavirus-2 or Coronavirus Disease 2019

SIPO: Società Italiana di Psico-Oncologia.

Keywords

COVID-19, Health workers, Psychological reactions, Health policy, Oncologists, Cancer, Crisis interventions

References

1. Poppito S, Tait GR (2014) Migliorare la formazione medica sulle dimensioni esistenziali del cancro avanzato In: Biondi M, Costantini A, Wise TN (eds.) Psiconcologia. Milano: Raffaelllo Cortina 219-52.
2. Shanafelt TD, Gradishar WJ, Kosty M, Satele D, Helen Chew, Leora Horn, et al. (2014) Burnout and career satisfaction among US oncologists. J Clin Oncol 32: 678-86. [crossref]
3. Kleiner S, Wallace JE (2017) Oncologist burnout and compassion fatigue: investigating time pressure at work as a predictor and the mediating role of work- family conflict. BMC Health Services Research 17: 639. [crossref]
4. Yates M, Samuel V (2019) Burnout in oncologists and associated factors: A systematic literature review and meta-analysis. Eur J Cancer Care 28: e13094 [crossref]
5. Banerjee S, Califano R, Corral J, de Azambuja E, L De Mattos-Arruda, et al. (2017) Professional burnout in European young oncologists: results of the European Society for Medical Oncology (ESMO) Young Oncologists Committee Burnout Survey. Ann Oncol 28: 1590-1596. [crossref]
6. Ortega-Campos E, Vargas-Román K, Velando-Soriano A, Suleiman-Martos N, Guillermo A Cañadas-de la Fuente, et al. (2020) Compassion Fatigue, Compassion Satisfaction, and Burnout in Oncology Nurses: A Systematic Review and Meta- Analysis. Sustainability 12: 72.
7. Biondi M, Costantini A, Grassi L (2009) Manuale pratico di Psico-oncologia. Roma: Il Pensiero Scientifico Editore 273-288.
8. Fallowfield L, Lipkin M, Hall A (1998) Teaching senior oncologist communication skills: results from phase 1 of a comprehensive longitudinal program in the United Kingdom. J Clin Oncol 16: 1961-1968. [crossref]
9. Jones DS (2020) History in a crisis-Lessons for COVID-19. N Engl J Med 382: 1681- 1683.
10. ISS Epicenter coronavirus extended report April 23, 2020 https://www.epicentro.iss. it/coronavirus/
11. INAIL (2020) I primi dati sulle denunce da Covid-19. Consulenza statistico attuariale. https://www.quotidianosanita.it/allegati/allegato1115237
12. Zunyou W, McGoonan JM (2020) Characteristic of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China. Summary of a report of 72.314 cases from the Chinese Center for Disease Control and prevention. JAMA 323: 1239-1242. [crossref]
13. CDCP – Characteristics of health care personnel with COVID-19 United States February 12- April 9 (2020) MMWR Morb Mortal Wkly Rep 69: 477-481. [crossref]
14. ISS Epicenter coronavirus extended report https://www.epicentro.iss.it/coronavirus/ pdf/rapporto-covid-19-22-2020.pdf
15. ISTAT Preliminary data National Institute of Statistics, March 01 – April 04, 2020. https://www.ilsole24ore.com/radiocor/nRC_17.04.2020_12.04_27018409
16. Pietrantonio F, Garassino M (2020) Caring for cancer patients with cancer during the COVID-19 outbreak in Italy. JAMA Oncol 10. [crossref]
17. Shah UA (2020) Cancer and Coronavirus Disease 2019 (COVID-19)- Facing the “C Words”. JAMA Oncology doi:10.1001/jamaoncol.2020.1848.
18. Rose C (2020) Am I part of the cure or am I part of the disease? Keeping coronavirus out when a doctor comes. N Engl J Med 382: 1684-1685. [crossref]
19. Wang D, Hu B, Chang H, Zhu F, Xing Liu, et al. (2020) Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323: 1061-1069. [crossref]
20. Bauchner H, Easley TJ (2020) Health care heroes of the covid-19 pandemic. JAMA. [crossref]
21. Wester M, Giesecke J (2019) Ebola and healthcare worker stigma. Scand J Public Health 47: 99-104. [crossref]
22. Greenberg N (2020) Managing mental health challenges faced by healthcare workers during covid-19 pandemic. BMJ 368:m1211. [crossref]
23. Trapani A, Marra A, Curigliano G (2020) The experience on COVID-19 and cancer from an oncology hub institution in Milan Lombardy Region EJC 132: 199-206. https://doi.org/10.1016/j.ejca.2020.04.017
24. Cortiula F, Pettke A, Bartoletti M, Puglisi F, Helleday T (2020) Managing COVID-19 in the oncology clinic and avoiding the distraction effect. Annals Oncol 31: 553-555. [crossref]
25. Lewis MA (2020) Between Scylla and Charybdis – Oncologic Decision Making in the time of Covid19. N Engl J Med 382: 2285-2287. [crossref]
26. Schrag D, Hersham DL, Bash E (2020) Oncology practice during the COVID-19 pandemic. JAMA 323: 2005-2006.
27. Costantini A, Mazzotti E (2020) Italian validation of COVID-19 Peritraumatic Distress Index and preliminary data in a sample of general population. Riv Psichiatr 55: 145-151. [crossref]
28. Lijung K, Yi L, Shaohua H, Chen M, Yang C, et al. (2020) The mental health of medical workers in Wuhan, China dealing with the 2019 novel coronavirus. Lancet Psychiatry 7: e14. [crossref]
29. Zhu Z, Xu S, Wang H, Liu Z, Jianhong Wu, et al. COVID-19 in Wuhan: Immediate Psychological Impact on 5062 Health Workers. Medrexiv. doi: https://doi.org/10.11 01/2020.02.20.20025338
30. Lai J, Ma S, Wang Y, Cai Z, Jianbo Hu, et al. (2020) Factors Associated with Mental Health Outcomes Among Health Care Workers Exposed to Coronavirus Disease 2019. JAMA Network Open 3: e203976. [crossref]
31. Rossi R, Socci V, Pacitti F, Di Lorenzo G, Antinisca Di Marco, et al. (2020) Mental health outcomes among frontline and second-line health care workers during the Coronavirus Disease 2019 (COVID-19) pandemic in Italy. JAMA Network Open 3: e2010185. [crossref]
32. Ying Y, King F, Zhu B, Yunxin Ji, Zhongze Lou, et al. (2019) Mental health status among family members of mental health care workers in Ningbo, China during the Coronavirus disease 2019 (COVID-19) outbreak: a cross-sectional study. Medrxiv.
33. Katz J, Sanger-Katz, Quealy K (2020) Could coronavirus cause as many deaths as cancer in the US? Putting estimates in context. New York Times.
34. COVID-19 Open Research Data set. https://www.semanticscholar.org/cord19
35. The COVID-19 and Cancer Consortium. Accessed April 27, 2020. https://ccc19.org/
36. Center for the Study of Traumatic Stress (CSTS). Sostenere il benessere del personale sanitario durante l’epidemia di coronavirus e di altre malattie infettive. https://www.cstsonline.org/assets/media/documents/CSTS_FS_ITL_Sustaining_Well_Being_ Healthcare_Personnel_during_Coronavirus.pdf
37. NCCN Self-Care and Stress Management During the COVID-19 Crisis: Toolkit for Oncology Health Care Professionals. https://www.nccn.org/covid-19/pdf/Distress-Management-Clinician-COVID-19.
38. CSTS – Grief Leadership During COVID-19 https://www.cstsonline.org/assets/ media/documents/CSTS_FS_Grief_Leadership_During_COVID19.pdf
39. Hlubocky FJ, Back AL, Shanafelt TD (2016) Addressing Burnout in Oncology: Why Cancer Care Clinicians Are At Risk, What Individuals Can Do, and How Organizations Can Respond. Am Soc Clin Oncol Educ Book 35: 271-279. [crossref]
40. SIPO-COVID-19 HELP LINE https://covid19.siponazionale.it.
41. ISS. COVID-19: gestione dello stress tra gli operatori sanitari https://www.epicentro. iss.it/coronavirus/sars-cov-2-gestione-stress-operatori
42. Meichenbaum D (1995) A clinical handbook/practical therapist manual for assessing and treating adults with post-traumatic stress disorder (PTSD). Institute Press.
43. Roberts AR, Yeager KR (2012) Gli interventi sulla crisi. Italia: Springer-Verlag.
44. Curtis JR, Kross EK, Stapleton RD (2020) The Importance of Addressing Advance Care Planning and Decisions About Do-Not-Resuscitate Orders During Novel Coronavirus 2019 (COVID-19). JAMA 323: 1771-1772. [crossref]
45. Costantini A, Grassi L, Picardi A, Brunetti S, Rosangela Caruso, et al. (2015) Awareness of cancer, satisfaction with care, emotional distress, and adjustment to illness: an Italian multicenter study. Psycho-Oncology 24: 1088-1096.
46. VIDAS (2019) Ricerca sulla percezione della popolazione italiana in merito al testamento biologico. https://www.vidas.it/biotestamento-una-ricerca-nazionale/
47. Baile W (2015) Giving bad news. The Oncologist 20: 852-853. [crossref]
48. Stovall MC (2015) Oncology communication skills training: bringing science to the art of delivering bad news. J Adv Pract Oncol 6: 162-166. [crossref]
49. Back A, Tulsky JA, Arnold RM (2020) Communication Skills in the age of COVID-19. Ann Intern Med 172: 759-760. [crossref]
50. Baile WF, Costantini A (2014) Comunicare con i pazienti oncologici e con i loro familiari. In: Biondi M, Costantini A, Wise TN (eds.). Psiconcologia. Milano: Raffaello Cortina 219-252.