The AACR Virtual Meeting: COVID-19 and Cancer opened Monday with a keynote address from the nation’s leading infectious disease expert, Anthony Fauci, MD, the director of the National Institutes of Allergy and Infectious Diseases. Well known for several decades in the realm of infectious diseases, Fauci has now become a household name in the United States due to his contributions in the response to the COVID-19 pandemic.
“Dr. Fauci is a renaissance man amongst physician-scientists,” said David Tuveson, MD, PhD, FAACR, program committee chair of the meeting and President-Elect of the AACR, in his introduction to Fauci’s presentation, adding that Fauci has devoted his entire 52-year career at the National Institutes of Health (NIH) to the understanding, prevention, and eradication of infectious diseases and autoimmune diseases. Fauci’s many career accomplishments include pivotal research discoveries, working with AIDS activists to introduce combination therapy for HIV patients, advising six successive United States presidents, and leading multiple national and international efforts against disease outbreaks, such as Ebola, tuberculosis, and now COVID-19. Fauci is a member of the President’s Task Force against COVID-19.
“His combination of scholarship, leadership, a tireless work ethic, and attention to detail have established Dr. Fauci as a beacon of knowledge and truth in our battle against COVID-19,” added Tuveson.
Fauci’s opening keynote address touched on several topics relating to the pandemic, laying a foundation for the sessions to come.
A HISTORICAL PERSPECTIVE ON CORONAVIRUS PANDEMICS
Fauci began his talk with an overview of two previous pandemics: the severe acute respiratory syndrome (SARS) pandemic of 2002 and the Middle East respiratory virus (MERS) pandemic of 2012. Like the current COVID-19 pandemic, these pandemics were also caused by coronaviruses. Fauci explained that for many years, coronaviruses had been predominantly known for causing the common cold and that it was not until 2002—with the start of the SARS pandemic—that the potential for these viruses to cause pandemics became apparent.
SARS was first observed in November 2002 in the Guangdong province of China after the causative virus—SARS-CoV-1—was transmitted from a bat to a civet cat and finally to a human. SARS began to spread throughout the world after an infected individual traveled to Hong Kong and transmitted the virus to 19 other people who were staying at the same hotel. The pandemic lasted from November 2002 to July 2003; during this time, over 8,000 individuals were infected, and close to 800 people died from the disease. Fauci noted that SARS-CoV-1 was only moderately transmissible; therefore, measures such as wearing masks, physical distancing, and quarantine resolved the pandemic relatively quickly. “In essence, the outbreak was controlled purely by public health measures, without any drugs and without any vaccines,” he stated.
In 2012, the MERS pandemic began after the MERS coronavirus was transmitted from a bat to a camel and then to a human in Saudi Arabia. Since the onset of the pandemic, MERS has been diagnosed in more than 2,500 people and has caused 866 deaths, for an approximately 35 percent fatality rate. While the spread of MERS has slowed substantially, it continues to be observed to this day.
NO END IN SIGHT: THE COVID-19 PANDEMIC
Like the viruses that caused SARS and MERS, SARS-CoV-2, the virus that causes COVID-19, likely emerged from an animal host. Since COVID-19 was first observed in December 2019, over 13 million cases have been confirmed, over half a million people have died, and there is “essentially no end in sight,” Fauci summarized.
CLINICAL MANIFESTATION OF COVID-19
“The thing that I’ve been most impressed with [about SARS-CoV-2]—of all the viruses that I’ve been dealing with over the last several decades—is the extraordinarily wide spectrum of disease,” Fauci noted. He explained that the disease can range from asymptomatic (in approximately 20 to 45 percent of cases) to severe, although the majority of cases tend to be mild or moderate. Severe illness can manifest as acute respiratory distress syndrome, hyperinflammation, cardiac or kidney injury, neurologic disorders, stroke, and/or pulmonary embolism. In some children, COVID-19 may manifest as multisystem inflammatory syndrome, a condition in which multiple organs become inflamed.
It has been observed that older adults and individuals with certain underlying conditions are at greater risk of developing severe disease. Underlying conditions that are known to increase the risk of severe illness include obesity, type 2 diabetes, renal disease, sickle cell disease, serious heart conditions, and being immunocompromised. Other factors, such as pregnancy, asthma, hypertension, type 1 diabetes, HIV infection, and smoking, may increase the risk, but the evidence is not clear at this point. Furthermore, hospitalization rates are highest for individuals of certain races/ethnicities, including American Indian/Alaska Native, Black, and Hispanic/Latino.
IMPACT OF COVID-19 ON CANCER
The COVID-19 pandemic has also impacted other areas of medicine, including cancer. Fauci explained that the closures caused by the pandemic have led to disruptions in both cancer care and research, which may have long-term effects. He cited a recent editorial from National Cancer Institute Director Ned Sharpless, MD, that projected 10,000 additional deaths from breast and colorectal cancer over the next decade due to reductions in routine screenings for these cancers.
ADVANCES IN TREATMENT AND PREVENTION
For the final portion of his presentation, Fauci summarized some of the latest advances in treating and preventing COVID-19. He explained that two investigational therapeutics, remdesivir and dexamethasone, showed efficacy in patients with COVID-19 in recent clinical trials. The phase III clinical trial for remdesivir, an anti-viral that has been shown to inhibit the SARS and MERS coronaviruses, was the first randomized placebo-controlled study for COVID-19. The trial included 1,063 patients from 10 countries and found that hospitalized patients who were treated with remdesivir had a 32 percent faster recovery time, which Fauci described as a “modest but definite decrease in time to recovery.”
The RECOVERY trial examined the effect of dexamethasone, an anti-inflammatory agent, on patients with COVID-19. The trial included 6,425 patients in the United Kingdom, who were randomized to receive either dexamethasone in addition to standard care or to receive standard care alone. Dexamethasone was found to reduce mortality by 35 percent in patients who were ventilated and by 20 percent in those who were receiving oxygen. However, there was no benefit for patients who did not require any respiratory support, and results suggested that dexamethasone may have even had a negative effect for some of these patients. Fauci explained that the differing results between patients with early and advanced disease were consistent with the known pathogenesis of COVID-19. “Early on, you want to block the virus, but you want to keep the inflammatory and immunological response intact,” he said. “Later in the disease, when it becomes more advanced, you don’t have that much viral activity perhaps, but you certainly have a lot of aberrant inflammatory response [that] you want to damp down.”
Treatment guidelines continue to evolve as research provides new insight into the disease. To aid clinicians, the NIH has generated a live document of COVID-19 treatment guidelines. The page is updated regularly as guidelines shift in response to new advances.
Another key facet to addressing the COVID-19 pandemic is prevention through public health measures and vaccination. The NIH is supporting the testing of multiple vaccine candidates, including those that utilize DNA or RNA, viral vectors, or protein subunits as the vaccine platform. The NIH has tried to standardize the evaluation of these vaccine candidates with common protocols, data and safety monitoring boards, and primary and secondary endpoints. At the moment, the vaccine candidate produced by Moderna, which uses an mRNA platform, is the farthest along in the process and will be initiating a phase III clinical trial at the end of this month. Fauci noted that data from the phase I trial of this vaccine candidate demonstrated that even a moderate dose induced robust immune activity that was at the same or higher level as would be seen with convalescent serum.
For now, preventive measures such as washing hands, wearing a mask, and social distancing are important to slow the spread of COVID-19. “The bottom-line common denominator is physical distancing,” stressed Fauci, adding that this can be accomplished through stay-at-home orders, school and business closures, bans on public gatherings, aggressive case identification and isolation, and contact tracing and quarantine.
LOOKING BEYOND COVID-19
While COVID-19 has shaken much of the world, it is not the first pandemic to do so, and it will likely not be the last. As Fauci concluded his address, he emphasized the importance of being prepared for future emerging diseases. “We’ve always had emerging infectious diseases. We have them now, and we will continue to have them in the future. Just as emerging infections provide for us a perpetual challenge, we need to be perpetually prepared.”
- Abstract Emerging and re-emerging infectious diseases, and their determinants, have recently attracted substantial scientific and popular attention. HIV/AIDS, severe acute respiratory syndrome, H5N1 avian influenza, and many other emerging diseases have either proved fatal or caused international alarm. Common and interactive co-determinants of disease emergence, including population growth, travel, and environmental disruption, have been increasingly documented and studied. Are emerging infections a new phenomenon related to modern life, or do more basic determinants, transcending time, place, and human progress, govern disease generation? By examining a number of historically notable epidemics, we suggest that emerging diseases, similar in their novelty, impact, and elicitation of control responses, have occurred throughout recorded history. Fundamental determinants, typically acting in concert, seem to underlie their emergence, and infections such as these are likely to continue to remain challenges to human survival.
“Not a single year passes without [which]…we can tell the world: here is a new disease!”
Rudolf Virchow, 18671
Infectious diseases are responsible for 15 million (26%) of 57 million annual deaths in a global population of 6·2 billion,2 a proportion that could rise substantially as chronic diseases continue to be reclassified as infectious—eg, cervical cancer (human papillomavirus), Kaposi’s sarcoma (human herpesvirus 8), and Helicobacter pylori ulcers, among others.
In recent years, the terms “emerging” (ie, newly recognised) and “re-emerging” (previously recognised) infectious diseases have entered the vocabulary of medical science.3, 4, 5 These infections also include “deliberately emerging diseases”—eg, bioterrorism.5 Concern about emerging infections has grown following the appearance of new diseases, such as HIV/AIDS, and the re-emergence of others, such as dengue, and from appreciation of the complex determinants of their emergence—eg, microbial adaptation to new hosts (HIV infection, severe acute respiratory syndrome [SARS]), population immunity pressures (influenza A), travel (acute haemorrhagic conjunctivitis), animal migration and movement (West Nile virus infection, H5N1 avian influenza), microbial escape from antibiotic pressures (multidrug-resistant and extensively drug-resistant tuberculosis), mechanical dispersal (Legionnaires’ disease), and others (panel , figure 1 ).3, 4, 5, 6, 7
Factors involved in infectious disease emergence4–6
Panel: Often differing for newly emerging, re-emerging, and deliberately emerging diseases, these selected factors include genetic, biological, social, political, and economic determinants
- International trade and commerce
- Human demographics and behaviour
- Human susceptibility to infection
- Poverty and social inequality
- War and famine
- Breakdown of public-health measures
- Technology and industry
- Changing ecosystems
- Climate and weather
- Intent to harm
- Lack of political will
- Microbial adaptation and change
- Economic development and land use
Emerging infections have for millennia threatened the survival of human societies who share ecosystems with rapidly evolving microbial organisms and their non-human hosts, vectors, and reservoirs. Man’s struggle against emerging infections has been a fundamental determinant of the existence and evolution of the human species. The possibility that individual and population resistance to emerging pandemic diseases results from gene selection by previous emerging diseases underscores the complex nature of the human–microbial interaction.87
The ten historical emerging epidemics/epizootics examined here were selected non-systematically from among many newly emerging and re-emerging diseases recorded over several millennia. We attempted to provide examples that were not only well documented but also reflective of the range and complexity of individual and interacting risk determinants. Although these examples cannot be considered representative of all of the many hundreds of historically documented emerging diseases, inclusion of those widely considered among the most important, such as the Black Death, Spanish influenza, and AIDS, serves to highlight determinants relevant at least to emerging diseases with pronounced impact on human beings.
Comparison of historical determinants of emergence and those associated with modern emerging diseases suggests that they are largely the same.5 Prominent among these are determinants reflecting human mobility such as demographics/behaviour and trade/commerce, host susceptibility factors, and poverty/social inequality (panel and table).5 For example, although separated by millennia, the spread along trade routes of newly emerging diseases in ancient Greece (the Plague of Athens), in medieval Europe (the Black Death), and across the African continent (AIDS), are similar in their dependence on human modes and patterns of movement. Other less universal determinants of historical emergence have nonetheless appeared repeatedly in association with varying other cofactors—eg, the role of technology and industry in the re-emergence of diseases such as dengue and chikungunya, spread by the Aedes aegypti mosquito, which oviposits preferentially in modern products such as discarded tyres and tin cans.
If there is anything new in disease emergence today, it seems to be less in the nature of specific determinants of emergence than in the greater complexity of modern existence, which in turn leads to increased opportunities for convergence of interactive risk determinants and greater speeds with which emergence can occur and escape control measures. As long ago as 1918, in the era before commercial air travel, the second wave of the influenza pandemic appeared in different regions of the world almost simultaneously. In 2008, air travel can bring a new disease from any major city to any other in a day (figure 3 ), while complex trade and distribution systems can spread even a non-contagious infectious disease quickly beyond the reach of local public-health containment, as exemplified by a US national ice cream-associated epidemic of salmonella in 199488 and a spinach-associated epidemic of Escherichia coli O157:H7 in 2006.89 Moreover, recent recognition of the role of weather/climate, climate cycles (eg, the El Niño southern oscillation), and global warming in the emergence of diseases such as dengue and malaria suggests that risk determinant complexities and interactions may increase.6
Figure 3. Average travel time between England and Australia, 1925–2000
Although this article has emphasised emerging pandemic diseases, emerging diseases with more limited (non-pandemic) spread, such as hantavirus pulmonary syndrome and Lyme disease, have also presented substantial public-health challenges. In other cases, disease emergence may occur so insidiously that recognition is difficult (eg, tuberculosis during the Renaissance [14–17th centuries]). In recent times we have seen an extraordinary growth in re-emergence of infectious diseases, a phenomenon that apparently began in the Age of Discovery (15–18th centuries), when microbes came into contact with new human populations, and which is still accelerating as population growth and travel provide better avenues of escape for microbes entrenched in complex localised ecosystems (eg, geographic extension of arboviral diseases such as dengue, Japanese encephalitis, West Nile virus, and chikungunya infections).
Well-understood determinants of modern disease emergence, typically acting in concert, have been associated throughout recorded history with the emergence of major diseases. These determinants have been similar in their explosiveness, impact, and elicitation of public-health control responses. Whether the nature and pattern of these determinants are changing or will change in the future remains speculative. That most of the historical emerging diseases we examined were associated with unique patterns of common determinants suggests to us that an increasingly complex modern world will probably provide increasing opportunities for disease emergence. For centuries a fundamental challenge to the existence and well-being of societies—as reflected by scientific attention, as well as in art, religion, and culture—emerging infections remain among the principal challenges to human survival.