Epidemic Viruses
Influenza is responsible for an average 36,000 deaths annually in the United States,
with more than 90% of these occurring in the elderly population.[7] There have been four pandemics over the past 100 years due to antigenic shift. The
Spanish influenza pandemic of 1918–1919 was the first and was the most severe of these
and responsible for an estimated 40 million deaths.[8] The 1918 pandemic virus shared properties with swine H1N1 viruses[8]
[9] and is likely to have originated from an avian influenza virus that underwent adaptive
mutations to gain the ability to transfer to humans. Later pandemics include those
of 1957 (H2N2), 1968 (H3N2), and 2009 (H1N1).[10]
[11]
The ability of viruses to jump species barrier and cause severe human infections is
not limited to influenza virus as shown in [Table 1] which highlights recent emergent respiratory viral pathogens, their potential source,
and transmission. In the Guangdong Province in the southern area of China in 2002,
a novel coronavirus (SARS-CoV) was reported causing severe viral pneumonia, i.e.,
SARS.[12]
[13] The intermediate host of SARS-CoV was thought initially to be the masked palm civet
cat, but subsequently evidence shifted to the Chinese horseshoe bat.[14] This zoonotic virus became a global threat due to an infected physician traveling
to Hong Kong in February 2003.[12] It spread rapidly worldwide with 8,273 cases and 774 deaths in 1 year in more than
30 countries[15]
[16] before it was contained 6 months later.
Table 1
Recent emergent respiratory viruses, sources, and transmission patterns
|
Date
|
Infection
|
Region
|
Potential source
|
Transmission
|
|
1997
|
H5N1[89]
|
Hong Kong
|
Poultry environment
|
Contact with infected poultry, close contact human to human
|
|
1999
|
H9N2[90]
|
Hong Kong
|
Poultry (quail)
|
Direct infection from live poultry
|
|
2003
|
SARS-CoV[14]
|
Hong Kong
|
Bats
|
Human to human, sporadic
|
|
2004
|
H7N7[91]
|
The Netherlands
|
Dutch poultry farms
|
Direct infection from live poultry
|
|
2005
|
H3N2[92]
|
Canada
|
Pig, pig farms, turkeys, and swine farm worker
|
Contact with infected pigs, limited nonsustainable human-to-human spread
|
|
2009
|
H1N1[93]
|
Mexico
|
Not clear, virus most similar to influenza viruses found in pigs
|
Human to human
|
|
2012
|
MERS-CoV[7]
|
Saudi Arabia
|
Camels, bats, camel farms, human patients
|
Close contact human to human, sporadic
|
|
2013
|
H7N9[36]
|
China
|
Poultry environment (bird markets, poultry farms), human patients
|
Direct contact with live poultry, close limited human-to-human spread
|
Nearly 10 years later, in June 2012 in Saudi Arabia, the index case of a new coronavirus,
Middle East respiratory syndrome (MERS-Cov), causing severe viral pneumonia emerged.
A few days later, the same virus was detected in a Qatari patient receiving intensive
care in a London hospital, highlighting the role of air travel in early spread of
disease, as was the case in SARS in 2002. Since its discovery in 2012, MERS-CoV has
reached 26 countries affecting approximately 1,300 people, including a dozen children,
and claiming nearly 500 lives.[17] Most MERS-CoV cases (>85%) reported thus far have a history of residence in, or
travel to, the Middle East, predominantly confined to six countries: Saudi Arabia,
United Arab Emirates, Qatar, Jordan, Oman, and Kuwait, although travel-related cases
have been identified in Tunisia, the United Kingdom, France, Germany, and Italy. The
zoonotic vector and reservoir of MERS-CoV are dromedary camels, with bats as another
possible vector for transmission to humans.[18]
Surveillance
With our current level of medical knowledge and the existing global political and
economic situation, we cannot realistically hope to prevent new pathogens from emerging,
as is demonstrated by the emergence of a second highly pathogenic coronavirus within
a decade, MERS-CoV. The best opportunities to prevent global spread of a new pathogen
are rapid and early identification systems to allow control measures to be put in
place to prevent its spread.
In 1952, the World Health Organization (WHO) established a global network of influenza
surveillance; this is now called the WHO Global Influenza Surveillance and Response
System (GISRS) and the network includes 142 National Influenza Centres (NICs) in 112
WHO member states, 6 WHO Collaborating Centres, and 4 WHO essential regulatory laboratories.[19] GISRS provides real-time virus monitoring and sharing, to rapidly identify and respond
to influenza outbreaks including those with pandemic potential. The laboratory-confirmed
surveillance information is available real time publicly through FluNet, the web-based
database and reporting system since 1996.[20] GISRS provides recommendations on the composition of seasonal influenza virus vaccines
biannually and on development of vaccines for zoonotic influenza viruses. This network
also provides a global mechanism for maintaining an up-to-date inventory of candidate
vaccine viruses and potency reagents for seasonal and zoonotic influenza. The majority
of NICs are in Europe and the United States, so there is an absence of information
about influenza transmission and the burden of disease is the tropics and the subtropics.
The WHO surveillance strategies determine the start and end of the influenza season
and characterize the types and subtypes of circulating strains as well as detecting
the emergence of novel viruses. It assists with selection of future vaccine strains
and monitors for the emergence of viral resistance. Since the reemergence in 2004
of the highly pathogenic influenza A H5N1, GISRS also has a role in the identification
of novel influenza or other viruses causing Severe Acute Respiratory Infection (SARI,
defined as a fever of at least 37.8 or self-reported fever, and either a cough or
a sort throat, and hospital admission)[21] and in the identification of a potentially new pandemic pathogen.
The importance of early identification of a pathogen with pandemic potential in increasing
the capability for effective control measures is self-evident. For early warning systems
to work, specific triggers are needed for immediate reporting of possible occurrence
of a single or multiple cases that might be the first indicators of the emergence
of a novel respiratory virus. To assist with this and as part of the global public
health response after the SARS epidemic, the WHO established the international health
regulations in 2005[22] (see below). These internationally binding regulations require all countries to
report all cases of human influenza cause by new viral subtypes to the WHO.[23]
Other important signal events in early recognition of respiratory viral infections
with a pandemic potential are SARI or pneumonia in health care workers that indicates
the development of human-to-human transmission (as occurred in the SARS epidemic)
and clusters of SARIs in social or occupational connected individuals. Other surveillance
triggers are a shift in age distribution, increase in mortality, or increase in number
of cases.[24]
[25]
Containment and Limiting Initial Spread
With effective surveillance, pathogens are identified early, but the mitigating actions
to contain and limit spread are a scientific and political challenge. Following the
global threat of an infected physician traveling from China to Hong Kong in February
2003,[12] Chinese authorities received international criticism for not revealing the extent
of the epidemic earlier, prior to SARS spreading internationally, when it could have
potentially been contained.[26] The delay in the Chinese communicating the extent of the epidemic to the international
community was a combination of political considerations as well as significant deficiencies
in the structure of its public health service that severely limited its ability to
recognize and track potential epidemics.[27]
[28]
The SARS pandemic highlighted that few countries possessed the necessary surveillance
and response capacities to rapidly detect and control emerging infectious diseases.[29] The deficiencies of the 1969 International Health Regulations (IHR) at the global
level had been acknowledged, and attempts to revise them were ongoing before 2003,
but the SARS outbreak added new urgency and momentum for change. These were updated
in close consultation with WHO member states, international organizations, and other
relevant partners, and were adopted by the 58th World Health Assembly on May 23, 2005
and the adoption began from June 15, 2007. Global acceptance of the 2005 IHR[30] has improved international vigilance and collaboration and should provide the framework
for cooperation between countries so that effective public health actions can be initiated.
In parallel to the WHO IHR 2005, international and national planning has improved
with the recognition of Global Surveillance Systems and epidemic intelligence systems
such as the Global Public Intelligence Network and ProMed.[31] ProMed mail was the forum used by a Saudi Arabian physician on September 20, 2012,
to report the isolation of a novel coronavirus from a patient with pneumonia[32] (subsequently identified as MERS-CoV). New monitoring and information initiatives
have been established to provide important insights into laboratory-confirmed cases
and clinical manifestations of disease, such as the Early Alert and Response System
established by the Global Health Security Initiative member states[33] and the Connecting Organizations for Regional Disease Surveillance.[34] The increased use and availability of social media has further driven transparency
or informally increased awareness where there is a lack of collaboration.
Since 2003, international and national authorities have recognized the importance
of more effective animal health surveillance. Limited resources in most countries
have resulted in investments in surveillance capacity predominantly in those countries
affected by major outbreaks, such as the case with an outbreak of influenza A H5N1
virus infection in Thailand, China, Vietnam, and Indonesia.[35] The response to the H7N9 infection by the Chinese authorities in 2013 demonstrates
the substantial improvements made in international surveillance compared with the
SARS outbreak in 2002. On March 31, 2013, China notified the WHO of the first recorded
human infections with avian H7N9 virus. The poultry markets were rapidly identified
as a major source of transmission of H7N9 to humans and were quickly closed down in
the affected areas. The health authorities collaborated with the WHO in risk assessments
and communication, with heightened surveillance in humans and poultry and prompt reporting
of new cases. As a result, the infection was contained to China with 139 cases (82%
had a history of exposure to live animals, including chickens) and 34% death rate.[36]
The Global Health Security Agenda[37] launched in the United States in 2014 is a program to link the U.S. government,
other nations, international organizations, and public and private stakeholders. This
initiative aims to overcome barriers to sharing information, samples, protocols, and
to develop a more integrated global laboratory for diagnostic and vaccine development,
as well as addressing specific capacity-building activity to further progress the
community of trust within the global public health system.
The International Severe Acute Respiratory and Emerging Infection Consortium[38] (ISARIC) was launched in December 2011 and is a global initiative aiming to ensure
that clinical researchers have the protocols and data-sharing processes needed to
facilitate a rapid response to emerging diseases that may turn into epidemics or pandemics.
The consortium brings together over 70 networks and individuals involved in research
related to the outbreaks of diseases such as H5N1, H1N1, and SARS. It is working to
discover how severe acute respiratory diseases develop and progress in patients, and
identify the most efficient treatments and the best way to prevent further transmission.
Although there have been substantial improvements in worldwide preparedness for emerging
infections and potential pandemics, establishing trust and overcoming tensions generated
by political differences remain a challenge.[39] An example of this occurred following the H1N1 pandemic in 2009, when the Council
of Europe highlighted potential conflicts of interest of individual members of the
WHO emergency pandemic committee (membership of which was secret) linking them to
industry. Shortfalls and delay in the H1N1 vaccine distribution in low- and middle-income
countries also added to the controversy around the 2009 H1N1 response.[39]
[40]
Containment at International Borders
As more than 700 airlines transport over 2.5 billion travelers between 4,000 airports
each year, local infectious disease outbreaks have the opportunity to transform quickly
into international epidemics. As an epidemic emerges and the threat is recognized,
the vast majority of public health authorities and governments across the world will
be trying to prevent infection of their own population employing the strategies of
quarantine and screening at points of entry into the country. Neither of these ineffectual
strategies is recommended by the WHO,[41] and it is generally accepted that exit screening is a more effective intervention
although there is often less political motivation for this approach.
Exit Screening
Exit screening appears to be more effective than entry screening, perhaps primarily
related to the reduced numbers of infected passengers on board the aircraft and therefore
decreased transmission.[41]
[42] The screening method used determines the effectiveness and resource implications
of exit screening for the detection of infectious cases. As with any screening measure,
the impossibility of detecting asymptomatic cases or people who are incubating the
infection limits its implementation,[41]
[43] particularly with influenza, where cases are infectious during incubation and when
asymptomatic.[44]
Although SARS did spread to 28 countries,[45] it is likely that exit screening with quarantine helped to contain the epidemic.[41] On this background, exit screening was recommended by the WHO during the H1N1 2009
pandemic,[46] while entry screening was not recommended. Arguments for the choice of exit screening
over entry screening included the possible impact on passengers' behaviors by discouraging
ill passengers from traveling abroad, the decreased risk of global transmission due
to the reduced numbers of travelers, and being most effective in containing a disease
at the source.[6]
[41]
[46] Arguments against exit screening include passenger concerns about the cost of accessing
affordable health care in the country of departure if they are not allowed to leave,[47] resulting in failure to disclose possible infections.
Despite the implementation of exit screening, throughout March and April 2009, international
air travelers departing from Mexico were unknowingly transporting the H1N1 virus to
cities around the world. In Australia, for example, just 20 days after quarantine
measures were enacted for H1N1, public health authorities conceded defeat in the face
of widespread infection in the general population.[48] The difference in effectiveness of control measures in containing SARS and H1N1
are due to the differences in the infectivity of the viruses and the speed of onset
of infectivity after initial exposure. The fact that SARS continued to be viewed as
a serious mortality threat whereas H1N1 rapidly became regarded as a predominantly
non lethal disease may also have reduced public compliance with public health measures
for the latter.[49]
[50]
Unfortunately, many countries are more focused on preventing new cases of infection
from entering their borders rather than preventing established cases from leaving.
As this is the more commonly adopted approach, the WHO suggests that entry screening
should be considered in passengers arriving from countries where there are concerns
about the presence or thoroughness of exit screening.[41]
Entry Screening
There is substantial evidence confirming that entry screening at international borders
for controlling influenza and other epidemics is ineffective.[41]
[51] Infrared thermography (IRT) involves the quantification of emitted radiation to
measure temperature and provides a quick noninvasive means to measure body temperature.[52] It was implemented as a border control strategy during the SARS epidemic with the
advantages of its ability to screen mass numbers of individuals and reduce close contacts
with infected individuals. Unfortunately, no cases were detected for over 35 million
travelers screened.[53] There was a similar story with H1N1 where IRT was found to be both ineffective and
inaccurate.[54] IRT may be influenced by several confounding factors including age and outdoor temperature,
and in addition, results from studies looking at IRT as a tool to detect fever tend
to have small positive predictive values due to the small prevalence of febrile passengers.[25]
The use of quarantine and entry screening at international borders is costly and in
some countries its use has created considerable debate about the legality and ethical
basis for this approach.[55]
[56]
[57]
[58] The IHR 2005 specifically addresses issues of human rights related to quarantine
and travel restrictions,[22] stating travelers' dignity and fundamental freedoms should be respected as well
as minimizing any discomfort or distress and providing food, accommodation, and interpreter
services. A review of experiences from the H1N1 pandemic revealed that compliance
with these sections was far from universal.[59] The cost and time taken for additional screening measures are also predicably not
popular with airlines.[60]
Air Travel
A controversial area with viral epidemics is the extent to which air travel itself
is responsible for infecting passengers. Modern high-efficiency particulate air filters
in aircraft recirculate air within very localized cabin areas,[60] in theory containing most of the risk to within two rows of the infective individual.
Of course, pathogens vary in their innate infectivity; however, even for a highly
contagious virus like H1N1, there is considerable debate. Modeling from Wagner et
al based around a single individual infected by H1N1 suggested that in long-haul flights
from 7 to 17 people may be infected during the flight.[61] Analysis of a group of students suffering inflight exposure to H1N1 found the risk
to be approximately 3.5% for those seated within two rows of the index case.[42] It is not safe, however, to assume that there is no risk beyond the two-row limit,
with one case of SARS leading to infection of 22 of 120 passengers and crew dispersed
throughout the aircraft.[62]
In an ideal world, passengers should be responsible and not travel when symptomatic,
which, combined with effective exit screening, should significantly reduce the risk
to fellow passengers. However in practice, many people fly while actively infected
with respiratory tract infections and airlines seldom refuse to allow them to board,
possibly due to the many practical and potentially legal issues that would ensue,
over complex issues such as who has responsibility for their care, who pays for additional
accommodation, canceled flights, medical expenses, etc. Again the extent to which
airlines and airline crew are prepared to act to prevent passengers with active respiratory
tract infections from boarding is likely to be highly influenced by the level of threat
they perceive the circulating epidemic poses to them. In the event of a highly lethal
infection, we can expect substantial reductions in airline traffic including possible
complete prohibition of travel between countries. In the event of infections of less
perceived threat, such as with H1N1, there was virtually no limitation placed on air
travel.
Recent research has indicated that complete closure of air travel may not be needed
and that alternative strategies such as closure of high transmission risk routes may
be more cost-effective and much less disruptive to air travelers.[63] Whether such an approach is truly practical when the primary driver of behavior
is likely to be the public (and therefore political) perception of risk remains to
be seen.
Established Epidemics: National and Local Control
As demonstrated in recent epidemics, by far the most likely scenario in any new epidemic
is that it will not be contained and all countries will need to combat it based on
the resources they have available. The key to controlling spread at this stage is
rapid and accurate diagnosis, then limiting the spread from that individual through
both nonpharmacological and pharmacological means, until a vaccine becomes available.
Some measures to each emerging threat are generic, and others will be tailored to
the characteristics of each pathogen.
As with surveillance, the sharing of diagnostic and clinical information across the
global health community is crucial. One of the aims of the 2005 IHR was to collate
and disseminate clinical data on the emerging epidemic as fast and widely as possible.
For example, an early and clear understanding of the severity of illness that is likely
to be seen, including mortality, is essential for accurate public health planning.[32]
[64] Clinical manifestations to aid rapid diagnosis and response to antiviral treatment
need to be shared promptly. With SARS it became apparent early on that the health
care setting and especially procedures such as nebulisation and intubation were associated
with extremely high risks of disseminating infection,[12] leading to significant alterations in clinical approach. Early information with
respect to MERS has shown that the transmission of MERS-CoV among family contacts
remains relatively low but that the infection causes a spectrum of disease from asymptomatic
to severe and that, compared with SARS, MERS-CoV appears to kill more people (40 vs.
10%) more quickly and is especially more severe in those with preexisting medical
conditions.[17]
Summary
The SARS epidemic highlighted the weaknesses in national and global capabilities to
detect and respond to emerging infectious diseases. As such, it had a transformative
effect on global laboratory and surveillance networks and accelerated the revision
of the WHO IHR. Global surveillance and response capacity for public health threats
have been strengthened with coordination of the sharing of diagnostic and clinical
information across the Global Health Community. This framework is support by the revised
International Health Agreement that endorses international vigilance and collaboration.
Despite the SARS and MERS outbreak, influenza remains the respiratory viral pathogen
with the most significant global impact. Via the coordinating functions of the WHO,
the infrastructure is in place for real-time, web-based virus monitoring and sharing
to quickly identify potential pandemic strains. This framework also provides a global
network for early identification of zoonotic influenza with heightened surveillance
in humans and poultry and prompt reporting of new cases as occurred with H7N9 in 2013.
It seems unlikely that we can prevent new pathogens from arising, as has been shown
recently with MERS-CoV, so enhanced syndromic surveillance to provide rapid and early
identification to prevent spread is critical. Once a pandemic is suspected, exit screening
offers the most effective solution for containment within a country although the political
incentives are low. Experience from previous pandemics has taught us that health care
institutions are major foci of disease transmission and all institutions need to have
the facility to isolate infected patients as well as have maximal protection for staff.
There is no doubt that personal protective measures such as handwashing and avoidance
behaviors are effective, and the general public also needs to act responsibly by staying
at home when unwell and not traveling when potentially infective. Mechanisms for early
international communication around clinical features such as infectivity, disease
course, and treatment responsiveness are becoming more robust, with trust improving
between countries.
Recent history has shown that further respiratory epidemics not only are likely to
happen, but also will occur with increasing frequency. No single measure will be effective
in stopping the mortality, morbidity, and cost from future epidemics. Respiratory
physicians need to be aware of the potential roles they will need to play from advocacy
to influence public policy, control of spread of infection within their clinical environment,
and patient-specific management.
