Emerging Infectious Diseases: MERS-COV, Avian Influenza Remind Us of the Ongoing Challenge

Emerging infectious diseases comprise a substantial fraction of all consequential human infections. They have caused the deadliest pandemics in recorded human history, including the Black Death pandemic (bubonic/pneumonic plague; 25 million to 40 million deaths) in the 14th century, the 1918 influenza pandemic (50 million deaths), and the HIV/AIDS pandemic (35 million deaths so far).

By Kelly M. Pyrek

Emerging infectious diseases comprise a substantial fraction of all consequential human infections. They have caused the deadliest pandemics in recorded human history, including the Black Death pandemic (bubonic/pneumonic plague; 25 million to 40 million deaths) in the 14th century, the 1918 influenza pandemic (50 million deaths), and the HIV/AIDS pandemic (35 million deaths so far).

In an article published in PLOS Pathogens in July 2013, "Emerging Infectious Diseases: Threats to Human Health and Global Stability," experts David M. Morens and Anthony S. Fauci allude to mankind's evolving relationship with microorganisms and that "The inevitable, but unpredictable, appearance of new infectious diseases has been recognized for millennia, well before the discovery of causative infectious agents. Today, however, despite extraordinary advances in development of countermeasures (diagnostics, therapeutics, and vaccines), the ease of world travel and increased global interdependence have added layers of complexity to containing these infectious diseases that affect not only the health but the economic stability of societies. HIV/AIDS, severe acute respiratory syndrome (SARS), and the most recent 2009 pandemic H1N1 influenza are only a few of many examples of emerging infectious diseases in the modern world; each of these diseases has caused global societal and economic impact related to unexpected illnesses and deaths, as well as interference with travel, business, and many normal life activities. Other emerging infections are less catastrophic than these examples; however, they nonetheless may take a significant human toll as well as cause public fear, economic loss, and other adverse outcomes."

Infectious Diseases: Unique Foes
Fauci and Morens (2012) acknowledge the uniqueness of infectious diseases, noting, "Paramount among these characteristics is their unpredictability and their potential for explosive global effect, as exemplified by the bubonic/pneumonic plague pandemic in the 14th century, the 1918 influenza pandemic, and the current pandemic of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS), among others. Infectious diseases are usually acute and unambiguous in their nature. The onset of an infectious illness, unlike the onset of many other types of disease, in an otherwise healthy host can be abrupt and unmistakable. Moreover, in the absence of therapy, acute infectious diseases often pose an all-or-nothing situation, with the host either quickly dying or recovering spontaneously, and usually relatively promptly, often with lifelong immunity to the specific infecting pathogen. Not only are some infectious diseases transmissible to others, a unique characteristic among human diseases, but their transmission mechanisms are relatively few (including inoculation and airborne and waterborne transmission), well understood, and comparatively easy to study, both experimentally and in the field. In addition, such transmission is generally amenable to medical and public health interventions. Unlike many chronic and lifestyle-associated diseases resulting from multiple, interacting risk cofactors, most infectious diseases are caused by a single agent, the identification of which typically points the way not only to general disease-control measures (e.g., sanitation, chemical disinfection, handwashing or vector control) but also to specific medical measures (e.g., vaccination or antimicrobial treatment).

The characteristics of infectious diseases that set them apart from other human diseases include:
- Potential for unpredictable and explosive global impact
- Frequent acquisition by host of durable immunity against re-infection after recovery
- Transmissibility
-Potential for becoming preventable
-Potential for eradication
- Evolutionary advantage over human host because of replicative and mutational capacities of pathogens that render them highly adaptable
- Close dependence on the nature and complexity of human behavior
-Frequent derivation from or co-evolution in other animal species
- Possibility of treatment for having multiplying effects on preventing infection in contacts and the community, and on microbial and animalo ecosystems

As Fauci and Morens (2012) explain further, "Infectious diseases are closely dependent on the nature and complexity of human behavior, since they directly reflect who we are, what we do, and how we live and interact with other people, animals, and the environment. Infectious diseases are acquired specifically and directly as a result of our behaviors and lifestyles, from social gatherings, to travel and transportation, to sexual activity, to occupational exposures, to sports and recreational activities, to what we eat and drink, to our pets, to the environment even to the way we care for the ill in healthcare environments. Moreover, microbial colonizing infections that lead to long-term carriage without disease (e.g., within the endogenous human microbiome) may influence the development of infections with exogenous microbes and also have an effect on general immunologic and physiologic homeostasis, including effects on nutritional status. Human microbiomes seem to reflect, and may even have helped to drive, human evolution. In this struggle, infectious diseases are intimately and uniquely related to us through our immune systems. The human immune system, including the primitive innate system and the specific adaptive system, has evolved from both invertebrate and vertebrate organisms, developing sophisticated defense mechanisms to protect the host from microbes. In effect, the human immune system evolved as a response to the challenge of invading pathogens. Thus, it is not by accident that the fields of microbiology and immunology arose and developed in close association long before they came to be considered distinct disciplines."
Disease Emergence and Re-emergence
 The impact of infectious disease on morbidity and mortality is not insignificant. Of an estimated 58.8 million annual deaths worldwide, approximately 15 million (25.5 percent) are believed by experts to be caused by infectious diseases. The following is an example of the annual cause-specific mortality estimates from the World Health Organization (WHO):
- Respiratory infections: 4.3 million deaths
- Diarrheal diseases: 2.5 million deaths
- HIV/AIDS: 1.8 million deaths
-Tuberculosis: 1.3 million deaths
- Malaria: 0.8 million deaths
- Meningitis: 0.3 million deaths
- Pertussis: 0.2 million deaths
- Measles: 0.2 million deaths
- Hepatitis B: 0.1 million deaths
- Other infectious diseases: 1.2 million deaths

As Fauci and Morens (2012) observe, "Because infectious pathogens are evolutionarily dynamic, the list of diseases they cause is ever-changing and continually growing. Since newly emerging infectious agents do not arise spontaneously, they must recently have come from somewhere else, usually from animal infections, as occurred with HIV infection, influenza, and the severe acute respiratory syndrome. This interspecies transmission underscores the importance of interdigitating the study of human and animal diseases and recognizing the central role that microbial reservoirs, including those in animals, vectors, and the environment, play in human infectious diseases. Preexisting or established infectious diseases also may reemerge in different forms, as in extensively drug-resistant tuberculosis, or in different locations, as in West Nile virus infection in the United States, to cause new epidemics. Indeed, many human infectious diseases seem to have patterns of evolution, sometimes played out over thousands of years, in which they first emerge and cause epidemics or pandemics, become unstably adapted to human populations, undergo periodic resurgences, and eventually become endemic with the potential for future outbreaks.

Let's take a look at some of the infectious diseases that have emerged and/or re-emerged in the last year or so.

Coronaviruses are a large family of viruses that cause illness in humans and animals. In people, coronaviruses can cause illnesses ranging in severity from the common cold to Severe Acute Respiratory Syndrome (SARS). The novel coronavirus, first detected in April 2012, is a new virus that has not been seen in humans before. In most cases, it has caused severe disease. Death has occurred in about half of cases. This new coronavirus is now known as Middle East respiratory syndrome coronavirus (MERS-CoV). It was named by the Coronavirus Study Group of the International Committee on Taxonomy of Viruses in May 2013.

According to the World Health Organization (WHO), nine countries have now reported cases of human infection with MERS-CoV. Cases have been reported in France, Germany, Italy Jordan, Qatar, Saudi Arabia, Tunisia, the United Arab Emirates, and the United Kingdom. All cases have had some connection (whether direct or indirect) with the Middle East. In France, Italy, Tunisia and the United Kingdom, limited local transmission has occurred in people who had not been to the Middle East but who had been in close contact with laboratory-confirmed or probable cases.

Experts do not yet know how people become infected with this virus, but investigations are underway to determine the source of the virus, the types of exposure that lead to infection, the mode of transmission, and the clinical pattern and course of disease. MERS-CoV has recently been found to be genetically related to a virus identified in bats from Southern Africa. But there is no definitive evidence that MERS-CoV originates in bats. On 11 November, the Ministry of Health of Saudi Arabia announced that MERS-CoV had been detected in a camel linked to a human case in Saudi Arabia. This finding is consistent with previously published reports of MERS-CoV reactive antibodies in camels, and adds another important piece of information to our understanding of MERS-CoV ecology. However, this finding does not necessarily implicate camels directly in the chain of transmission to humans. The critical question that remains about this virus is the route by which humans are infected, and the way in which they are exposed. Most patients who have tested positive for MERS-CoV had neither a human source of infection nor direct exposure to animals, including camels. It is still unclear whether camels, even if infected with MERS-CoV, play a role in transmission to humans. Further genetic sequencing and epidemiologic data are needed to understand the role, if any, of camels in the transmission of MERS CoV to humans.

The WHO has now seen multiple clusters of cases in which human-to-human transmission has occurred. These clusters have been observed in healthcare facilities, among family members and between co-workers. However, the mechanism by which transmission occurred in all of these cases, whether respiratory (e.g. coughing, sneezing) or direct physical contact with the patient or contamination of the environment by the patient, is unknown. Thus far, no sustained community transmission has been observed. Transmission has occurred in healthcare facilities, including spread from patients to healthcare providers. WHO recommends that healthcare workers consistently apply appropriate infection prevention and control measures (see the WHO's updated guidance at: http://www.who.int/csr/disease/coronavirus_infections/IPCnCoVguidance_06May13.pdf)

Since the emergence of MERS-CoV, WHO has been working under the International Health Regulations to gather scientific evidence to better understand this virus and provide information to its member states. For this purpose, WHO convened the first international meeting on MERS-CoV in Cairo in January 2013. On mid-June 2013, WHO convened a second meeting in Cairo to discuss advances in scientific research and the international response to MERS-CoV. In early July 2013, WHO announced it would convene an Emergency Committee under the International Health Regulations to offer advice to the WHO's director-general on public health measures that should be taken. WHO is also working with affected countries and international partners to coordinate the global health response, including the provision of updated information on the situation, guidance to health authorities and technical health agencies on interim surveillance recommendations, laboratory testing of cases, infection control and clinical management.
As preventive measures have become more effective and efficient, history has shown that certain infectious diseases, particularly those with a broad global health impact and for which there is no nonhuman host or major reservoir, can be eliminated, according to Fauci and Morens (2012). Such diseases include poliomyelitis, which has been eliminated in the Western Hemisphere, and smallpox, which has been eliminated globally.

Some other infectious diseases also are making headlines.

As of mid-November 2013, 13 cases of wild poliovirus type 1 (WPV1) have been confirmed in the Syrian Arab Republic. Genetic sequencing indicates that the isolated viruses are most closely linked to virus detected in environmental samples in Egypt in December 2012 (which in turn had been linked to wild poliovirus circulating in Pakistan). Closely related wild poliovirus strains have also been detected in environmental samples in Israel, West Bank and Gaza Strip since February 2013. Wild poliovirus had not been detected in the Syrian Arab Republic since 1999.

A comprehensive outbreak response continues to be implemented across the region. In late October 2013, an already-planned large-scale supplementary immunization activity was launched in the Syrian Arab Republic to vaccinate 1.6 million children against polio, measles, mumps and rubella, in both government-controlled and contested areas. Implementation of a supplementary immunization campaign in Deir Al Zour province commenced promptly when the first hot acute flaccid paralysis (AFP) cases were reported. Larger-scale outbreak response across the Syrian Arab Republic and neighboring countries will continue for at least six to eight  months depending on the area and based on the evolving situation. Given the current situation in the Syrian Arab Republic, frequent population movements across the region and the immunization level in key areas, the risk of further international spread of wild poliovirus type 1 across the region is considered to be high. A surveillance alert has been issued for the region to actively search for additional potential cases.

In September 2013, the WHO issued an alert about the high risk of further international spread of WPV1 from Israel. The risk assessment reflects evidence of increasing geographic extent of WPV1 circulation in Israel over a prolonged period of time. Recently, WPV1 has also been isolated from sewage samples collected by the Palestinian Authority, both in West Bank and the Gaza Strip. No cases of paralytic polio have been reported by Israel or the Palestinian Authority.

Health authorities of Israel and the Palestinian Authority have taken steps to respond to the threat posed by WPV1 circulation by strengthening surveillance for acute flaccid paralysis and increasing the frequency of environmental sample collection. A supplementary immunization activity with bivalent oral polio vaccine (bOPV) was conducted in Israel in early August, targeting children up to 9 years of age to rapidly interrupt WPV1 circulation. As of now, 60 percent of the 1.38 million children targeted in Israel have been vaccinated. Health authorities of the Palestinian Authority also conducted two supplementary immunization activities with trivalent OPV in the Gaza Strip and in West Bank.

The WHO says it is important that all polio-free countries, in particular those with frequent travel and contacts with poliovirus-affected countries and areas, strengthen surveillance for cases of acute flaccid paralysis in order to rapidly detect any new virus importations and to facilitate a rapid response. Three countries remain endemic for indigenous transmission of wild poliovirus virus: Afghanistan, Nigeria and Pakistan. Additionally, in 2013, the Horn of Africa has been affected by an outbreak of wild poliovirus type 1.

Zoonotic Diseases and Evolving Threats
Morens and Fauci (2013) note that 60 percent to 80 percent of new human infections likely originated in animals, disproportionately rodents and bats, as shown by the examples of hantavirus pulmonary syndrome, Lassa fever, and Nipah virus encephalitis. Most other emerging/reemerging diseases result from human-adapted infectious agents that genetically acquire heightened transmission and/or pathogenic characteristics. Examples of such diseases include multidrug-resistant and extensively drug-resistant (MDR and XDR) tuberculosis, toxin-producing Staphylococcus aureus causing toxic shock syndrome, and pandemic influenza.

As Morens and Fauci (2013) explain, "Two major categories of emerging infectionsnewly emerging and reemerging infectious diseasescan be defined, respectively, as diseases that are recognized in the human host for the first time; and diseases that historically have infected humans, but continue to appear in new locations or in drug-resistant forms, or that reappear after apparent control or elimination.

Emerging/reemerging infections may exhibit successive stages of emergence. These stages include adaptation to a new host, an epidemic/pathogenic stage, an endemic stage, and a fully adapted stage in which the organism may become nonpathogenic and potentially even beneficial to the new host (e.g., the human gut microbiome) or stably integrated into the host genome (e.g., as endogenous retroviruses). Although these successive stages characterize the evolution of certain microbial agents more than others, they nevertheless can provide a useful framework for understanding many of the dynamic relationships between microorganisms, human hosts, and the environment. It is also worth noting that the dynamic and complicated nature of many emerging infections often leaves distinctions between emerging and reemerging infections open to question, leading various experts to classify them differently. For example, we describe as reemerging new or more severe diseases associated with acquisition of new genes by an existing microbe, e.g., antibiotic resistance genes, even when mutations cause entirely new diseases with unique clinical epidemiologic features. Similarly, we refer to SARS as an emerging disease a decade after it disappeared, and apply the same term to the related Middle East Respiratory Syndrome coronavirus which appeared in Saudi Arabia in late 2012."

The most obvious example of an emerging infectious disease is HIV/AIDS, which likely emerged a century ago after multiple independent events in which the virus jumped from one primate host to another (chimpanzees to humans) and subsequently, as a result of a complex array of social and demographic factors, spread readily within the human population. AIDS was not recognized until 1981 after its initial detection among certain risk groups, such as men who have sex with men, recipients of blood products, and injection drug users. It was soon apparent, however, that the disease was not restricted to these groups, and indeed, the bulk of HIV infections globally has resulted from heterosexual transmission that has been heavily weighted within the developing world.
 According to Morens and Fauci (2013), other examples of disease emergences include "SARS, which emerged from bats and spread into humans first by person-to-person transmission in confined spaces, then within hospitals, and finally by human movement between international air hubs. Nipah virus also emerged from bats and caused an epizootic in herds of intensively bred pigs, which in turn served as the animal reservoir from which the virus was passed on to humans. The 2009 H1N1 pandemic influenza virus emerged from pigs as well, but only after complex exchanges of human, swine, and avian influenza genes. H5N1 influenza emerged from wild birds to cause epizootics that amplified virus transmission in domestic poultry, precipitating dead-end viral transmission to poultry-exposed humans."

Other emerging infections maintain the attention of clinicians worldwide. As Morens and Fauci (2013), explain, "Emergences of disease caused by community- and hospital-acquired Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA) have been driven by increased and/or inappropriate use of antibiotics, and some hospital-acquired organisms such as MRSA have now moved into community transmission. The global emergence of plasmid-spread NDM-1 (New Delhi -lactamase) Gram-negative pan-resistant organisms, linked to global antibiotic use and inadequate antibiotic stewardship, medical tourism, economic globalization, and other aspects of modern life, has prompted calls for development of international control mechanisms that are applicable to a number of emerging bacterial diseases in the developing and developed world. Drug resistance mutations have also caused the re-emergences of certain pathogens such as multidrug-resistant and extensively drug-resistant tuberculosis, drug-resistant malaria, and numerous bacterial diseases such as vancomycin-resistant enterococci."

Ever since the 2009-2010 H1N1 influenza pandemic, the world has been watching mutating influenza viruses very closely. In early 2013 a new H7N9 avian influenza virus became epizootic in Eastern China, causing infections and fatalities in humans. An outbreak of human infections with H7N9 virus was first reported in China by the WHO on April 1, 2013. The virus was detected in poultry in China as well. Most human infections are believed to have occurred after exposure to infected poultry or contaminated environments. According to the WHO, as of late October 2013, there have been 137 cases and 45 deaths. According to the Centers for Disease Control and Prevention (CDC), while some mild illnesses in human H7N9 cases have been seen, most patients have had severe respiratory illness, about one-third leading to death. Close contacts of confirmed H7N9 patients have been followed to determine whether any human-to-human spread of H7N9 has occurred. No evidence of sustained person-to-person spread of H7N9 has been found, though some evidence points to limited person-to-person spread in rare circumstances. Limited person to person spread of bird flu is thought to have occurred rarely in the past, most notably with avian influenza A (H5N1), and so would not be surprising with H7N9. No cases of H7N9 outside of China have been reported, and the new H7N9 virus has not been detected in people or birds in the United States. Its pandemic potential, if any, remains to be determined. Whether or not such outbreaks become more widespread, they nonetheless attract global attention and require significant international effort to monitor and contain. The WHO and the CDC emphasize that microbial advantages can be met and overcome only by aggressive vigilance, ongoing dedicated research, and rapid development and deployment of such countermeasures as surveillance tools, diagnostics, drugs, and vaccines.

Most recently, scientists reported in November 2013 on human infection with avian influenza A H6N1 virus. As Wei, et al. (2013) explain, "Avian influenza A H6N1 virus is one of the most common viruses isolated from wild and domestic avian species, but human infection with this virus has not been previously reported." In a report in The Lancet, the researchers conveyed the clinical presentation, contact, and environmental investigations of a patient infected with this virus, and assessed the origin and genetic characteristics of the isolated virus: A 20-year-old woman with an influenza-like illness presented to a hospital with shortness of breath in May, 2013. An unsubtyped influenza A virus was isolated from her throat-swab specimen and was transferred to the Taiwan Centres for Disease Control (CDC) for identification. The medical records were reviewed to assess the clinical presentation. We did a contact and environmental investigation and collected clinical specimens from the case and symptomatic contacts to test for influenza virus. The genomic sequences of the isolated virus were determined and characterized.
Wei, et al. (2013) reported further that the unsubtyped influenza A virus was identified as the H6N1 subtype, based on sequences of the genes encoding hemagglutinin and neuraminidase, but the source of infection was not established. Sequence analyses showed that this human isolate was highly homologous to chicken H6N1 viruses in Taiwan and had been generated through interclade re-assortment. As Wei, et al. (2013) note, "This is the first report of human infection with a wild avian influenza A H6N1 virus. A unique clade of H6N1 viruses with a G228S substitution of hemagglutinin have circulated persistently in poultry in Taiwan. These viruses continue to evolve and accumulate changes, increasing the potential risk of human-to-human transmission. Our report highlights the continuous need for preparedness for a pandemic of unpredictable and complex avian influenza."

Fauci and Morens (2012) say that although antimicrobial resistance is a significant threat for the future, it is important to note the progress made in fighting infectious diseases: "Almost all the major advances in understanding and controlling infectious diseases have occurred during the past two centuries, and momentous successes continue to accrue. These breakthroughs in the prevention, treatment, control, elimination, and potential eradication of infectious diseases are among the most important advances in the history of medicine. Nevertheless, because of the evolutionary capacity of infectious pathogens to adapt to new ecologic niches created by human endeavor, as well as to pressures directed at their elimination, we will always confront new or reemerging infectious threats. Our successes in meeting these threats have come not just from isolated scientific triumphs but also from broad approaches that complement the battle against infectious diseases on many different fronts, including constant surveillance of the microbial landscape, clinical and public health efforts, and efficient translation of new discoveries into disease-control applications. These efforts are driven by the necessity of expecting the unexpected and being prepared to respond when the unexpected occurs. It is a battle that has been well fought for more than two centuries but that will almost certainly still be raging, in now-unimagined forms, two centuries from now. The challenges are truly perpetual. Our response to these challenges must be perpetual as well."

In an essay a year after writing those words, Morens and Fauci (2013) add, "We have many tools in our armamentarium, including preparedness plans and stockpiles of drugs and vaccines. But each new disease brings unique challenges, forcing us to continually adapt to ever-shifting threats. The battle against emerging infectious diseases is a continual process; winning does not mean stamping out every last disease, but rather getting out ahead of the next one."



Fauci AS and David M. Morens DM. The Perpetual Challenge of Infectious Diseases. N Engl J Med 2012; 366:454-461Feb. 2, 2012. doi: 10.1056/NEJMra1108296.

Morens DM, Fauci AS (2013) Emerging Infectious Diseases: Threats to Human Health and Global Stability. PLoS Pathog 9(7): e1003467. 2013. doi:10.1371/journal.ppat.1003467.

Morens DM, Fauci AS (2012) Emerging infectious diseases in 2012: 20 years after the Institute of Medicine report. MBio 3: e0049412 doi: 10.1128/mBio.00494-12.

Morens DM, Folkers GK, Fauci AS (2008) Emerging infections: a perpetual challenge. Lancet Infect Dis 8: 710719. doi: 10.1016/S1473-3099(08)70256-1.

Wei S-H, Yang J-R, et al. Human infection with avian influenza A H6N1 virus: an epidemiological analysis. The Lancet Respiratory Medicine, Early Online Publication, Nov. 14, 2013.

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