Emerging respiratory infections threatening public health in the Asia-Pacific region: A position paper of the Asian Pacific Society of Respirology.

In past decades, we have seen several epidemics of respiratory infections from newly emerging viruses, most of which originated in animals. These emerging infections, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and the pandemic influenza A(H1N1) and avian influenza (AI) viruses, have seriously threatened global health and the economy. In particular, MERS-CoV and AI A(H7N9) are still causing infections in several areas, and some clustering of cases of A(H5N1) and A(H7N9) may imply future possible pandemics. Additionally, given the inappropriate use of antibiotics and international travel, the spread of carbapenem-resistant Gram-negative bacteria is also a significant concern. These infections with epidemic or pandemic potential present a persistent threat to public health and a huge burden on healthcare services in the Asia-Pacific region. Therefore, to enable efficient infection prevention and control, more effective international surveillance and collaboration systems, in the context of the 'One Health' approach, are necessary.

INTRODUCTION

Emerging infectious diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), pandemic influenza A(H1N1) 2009 (influenza A(H1N1)pdm09) and avian influenza (AI) pose a threat to global health. Bird and swine influenza viruses continuously obtain new gene segments through reassortment with human strains. Moreover, infections by multidrug‐resistant Gram‐negative bacteria are also increasing worldwide. Hence, action is needed to curtail the dissemination of these organisms. For this position paper, members of the Asian Pacific Society of Respirology (APSR) Respiratory Infections Assembly selected respiratory pathogens that are most likely to pose significant threats to humans, particularly in the Asia‐Pacific region. The members reviewed epidemiological features of the pathogens and put together a consensus opinion. The recommendations presented here are, in essence, expert opinion based on case reports or serious outbreaks that may not represent a high level of evidence.

PANDEMIC AND SEASONAL INFLUENZA

Unlike seasonal influenza, pandemic influenza virus is a new virus that has not circulated in humans before, and to which humans have little or no immunity. Hence, the virus can cause significant illness or death and, when it acquires the ability of human‐to‐human transmission, could easily spread globally.

Four pandemics (Spanish flu in 1918, Asian flu in 1957, Hong Kong flu in 1968 and pandemic influenza A(H1N1) in 2009) have occurred since the early 20th century. Although the most recent pandemic due to A(H1N1)pdm09 was not as severe as the Spanish flu, the rate of patients requiring intensive care unit (ICU) admission was much higher than that due to seasonal influenza.1 However, the disease severity and impact on public health of an influenza strain can be determined by various factors, including the characteristics of circulating viruses (e.g. transmissibility), the time in the season, vaccine strains being used and the vaccination rate of the population. The World Health Organization (WHO) reported that the predominant influenza viruses in Asia, Europe, America and Africa were A(H1N1)pdm09 and influenza B during the 2015–2016 season.2 In East Asia, the predominant circulating virus was A(H1N1)pdm09 in the first half of the season, followed by influenza B virus in the second half of the season.2

Although vaccination is the most effective way to prevent influenza infections, the current vaccination rates vary and are suboptimal in many countries (21–78% in the elderly).3 Furthermore, considering the variable and moderate effectiveness of current vaccines, rapid development of efficacious vaccines with long‐lasting and cross‐protective immunity or broad‐spectrum neutralizing antibody will be needed.4

Antiviral treatment (e.g. 75 mg oseltamivir twice daily (bd) for 5 days in adults) should be started as soon as possible after illness onset, ideally within 48 h of symptom onset, for hospitalized patients or those with severe disease or at higher risk of influenza complications

For post‐exposure prevention, antiviral agents (e.g. 75 mg oseltamivir once daily for >7 days in adults) are recommended

Annual seasonal influenza vaccines (trivalent or quadrivalent vaccines) are recommended for the high‐risk group, which includes pregnant women, children aged 6–59 months, the elderly, individuals with specific chronic medical conditions and healthcare workers

Considering the suboptimal vaccination rates, strategies for improving the vaccination rates, including free vaccination programme provided by government or non‐profit organization, should be encouraged

New approaches for the development of universal influenza vaccines or broad‐spectrum neutralizing antibody should be investigated

AVIAN INFLUENZA

A(H7N9) virus

A human case of A(H7N9) infection was first reported in March 2013 in China. There have been five epidemics of A(H7N9) since the virus was first discovered; China is currently experiencing the fifth.5, 6, 7 As of 25 July 2018, a total of 1625 human infections have been reported since 2013 and the mortality rate is 38.3% (Table 1).5, 7, 10 To date, although no human or animal infections by A(H7N9) have been detected at a poultry farm, the majority of infected patients had a link to infected live poultry or contaminated environments such as live poultry markets.25

Table 1

Comparisons of clinical and epidemiological features among AI infections in humans

	A(H5N1)8, 9	A(H7N9)6, 10, 11, 12	A(H5N6)13, 14, 15	A(H9N2)16, 17, 18	A(H10N8)19, 20	A(H3N2)v21, 22, 23
Pathogenicity	HPAI	LPAI/HPAI	HPAI	LPAI	LPAI	N/A
First human case	Hong Kong in 1997	China in 2013	China in 2014	Hong Kong in 1999	China in 2013	United States in 2011
Regions with human cases	China, Laos, Cambodia, Thailand, Vietnam, Indonesia, Pakistan, Azerbaijan, Bangladesh, Turkey, Nigeria and Egypt	China, Taiwan, Malaysia and Hong Kong	China	Hong Kong, China, Bangladesh, serological evidence in Asia, Africa and Middle East	China	United States
Total number of human cases (years)	903 cases (1997–2015)	1625 cases (2013–2018)2	17 cases (2014–2016)	28 cases (1999–2016)	3 cases (2013–2014)	405 cases (2011–2017)
Median ages (years)	19 (5–32)	61 (46–73)	35 (26–45) in recent 9 cases reported by WHO	Mostly children	73, 56, 75	7 (range, 3 months–74 years) <18 years in 92%
Onset of illness to hospitalization (days)	4 (2–6)	4 (3–6)	3 (1–7) in recent 9 cases	N/A	3, 7, 2	4 (1–16) in illness duration
Clinical characteristics	Less URT symptoms Admission rate: 90.3% Advanced life supports: 63%	ARDS: 57.8% MV: 61.5%	Usually severe infections	Mild or asymptomatic illness	Bilateral severe pneumonia in all cases	Mild illness
Mortality rate	53.3%	38.3%	58.8%	0%	66.6%	1/405
Epidemiological features	67.2% between December and April Recent epidemic in Egypt (2014)	Five epidemics Currently the largest epidemic	Sporadic infections	Sporadic infections	Sporadic infections	Sporadic infections A large epidemic in 2012 (n = 306)
Risk factors	Exposure to sick and dead poultry, and live poultry market	Exposure to live poultry (81.6%)	Exposure to dead poultry and live poultry	Exposure to live poultry and poultry farm	Exposure to live poultry market	Exposure to pigs

Thirty‐two cases with HPAI A(H7N9) were recently reported.24

A(H3N2)v, A(H3N2) variant; AI, avian influenza; ARDS, acute respiratory distress syndrome; HPAI, highly pathogenic AI; LPAI, low pathogenic AI; MV, mechanical ventilation; N/A, not applicable; URT, upper respiratory tract; WHO, World Health Organization.

Li et al. reported that 81.6% of patients had a history of exposure to live animals, including chickens and ducks (hospitalization rate: 98.6%, pneumonia or respiratory failure rate: 91.2%).11 In particular, they found four family clusters and suggested the possibility of human‐to‐human transmission. However, while most human cases were caused by the low pathogenic AI A(H7N9), new cases of highly pathogenic A(H7N9) virus infection have also been confirmed since 2017.10, 24

A(H5N1) virus

Influenza A(H5N1) viruses are endemic among poultry in parts of Asia, Africa and the Middle East. Human cases of A(H5N1) were first detected in Hong Kong in 1997.26 After a 6‐year absence, human cases with confirmed influenza A(H5N1) virus infection re‐emerged in 2003 in Southeast Asia. Since then, the highly pathogenic influenza haemagglutinin (H5) has evolved into many phylogenetically distinct clades and subclades,27 and the infection has spread from East Asia to West Asia and Africa, with a high incidence in Egypt since November 2014.26 Vietnam has seen a total of 123 cases and 61 deaths since 2004, when the strain was first found there, through to 2012.28

Overall, 903 cases of A(H5N1) virus were reported between 1997 and 2015, and most cases occurred between December and April.8 The rate of hospitalization was 90.3% and the case fatality rate was 53.5%. Eighty percent of cases were aged under 30 years8 and upper respiratory tract symptoms were less prominent in human H5N1 cases, as compared to seasonal influenza.27 Compared to influenza A(H1N1)pdm09 virus, few clustering cases were reported and evidence for human‐to‐human transmission is still insufficient for A(H5N1) viruses.29, 30

Other AI viruses

The first reported human case of A(H6N1) infection was a young woman with influenza‐like illness in Taiwan in 2013.31 The virus had a characteristic G228S substitution in the haemagglutinin protein, which might increase its affinity for the human α2‐6 linked sialic acid receptor and, therefore, increase the potential for human‐to‐human transmission.31

The A(H5N6) virus is a new reassortant strain that contains gene segments from A(H5N1) and A(H5N2). The first human A(H5N6) infection was reported in a 5‐year‐old girl who had visited a live poultry market in China in 2014.13 Influenza A(H5N6) outbreaks in birds and poultry have been reported in Vietnam and mainland China since 2014. To date, 16 human infections and six deaths due to A(H5N6) have occurred in mainland China.14

Regarding A(H10N8) infection, three human cases have been confirmed in Jiangxi Province in China since December 2013.19, 20 All three cases had severe bilateral pneumonia and two died. Surveillance at the suspected live poultry markets showed an increased prevalence of A(H10N8) viruses. Notably, this virus contains genes from A(H9N2) and was frequently co‐infected with A(H9N2). This implies that novel reassortants could emerge.

Since 1990, influenza A(H9N2) has circulated among domestic poultry in Asian countries and has now globally expanded.32 So far, human infections have mainly been reported in Hong Kong and mainland China.33, 34 Although A(H9N2) infection results in mild disease or asymptomatic illness, the emergence of this virus is worrisome because it could potentially transfer its genes to another strain. Recent analyses of A(H7N9) and A(H10N8) viruses suggest that they have acquired gene segments from influenza A(H9N2) virus.35, 36

AI is a notifiable disease listed by the OIE (World Organization for Animal Health). The early detection of outbreaks, followed by a prompt response, is the first step. Monitoring and controlling AI virus at its poultry source is also crucial.

Individuals who are engaged in activities in close contact with infected poultry or wild animals should wear appropriate personal protective equipment (PPE) and be monitored for 7 days after their last contact

Although the optimal dose and duration of antiviral agents are uncertain, we recommend oseltamivir (75 mg bd for 5 days in adults) for the treatment of patients with influenza A(H5N1) infection; however, higher doses are also considerations in severe cases

Adults who have been in close contact with confirmed or highly suspicious cases should commence a course of prophylactic oseltamivir (75 mg/day) for 7–10 days

Poultry workers in affected countries by AI should also receive seasonal influenza vaccines

To reduce AI, source control measures, such as the regular closure of live poultry markets or prevention of the overnight storage of live poultry in markets, are recommended

In case of outbreaks, destruction of infected poultry as well as poultry that have been in contact with infected birds is recommended

Poultry vaccination at farm level also needs to be considered for infection control

HUMAN CORONAVIRUS

SARS‐coronavirus (CoV) caused an outbreak that began in China in 2002 and eventually led to 8422 infections and 916 deaths in 37 countries.37 No SARS cases have been reported since 2004.37 However, in September 2012, a novel CoV infection (i.e. MERS‐CoV) was reported in Saudi Arabia and a large number of people died from severe respiratory illness and acute kidney injury (i.e. 40~60%).38 In 2015, a large outbreak began in South Korea with a single case and eventually reached 186 cases through household and nosocomial transmission.39 As of September 2017, the WHO has reported 2103 cases of MERS‐CoV and 733 deaths.40, 41

Importantly, the SARS‐CoV and MERS‐CoV human outbreaks were epidemiologically similar in terms of healthcare‐associated infections (Table 2).45, 49 In China, 966 (18%) out of 5323 SARS cases were healthcare providers, and in the early days of the outbreak almost 90% of SARS patients were frontline healthcare providers.50 In the Korean MERS‐CoV outbreak, five ‘super‐spreaders’ spread MERS‐CoV to a large number of people in hospitals.45 About 20% of patients with SARS progressed to hypoxia and required mechanical ventilation, with a case fatality rate of 9.6%.51, 52 However, during the Korean MERS outbreak, pneumonia was detected in 80.8% (mechanical ventilation: 24.5%, extracorporeal membrane oxygenation: 7.1%).41

Table 2

Comparisons of clinical and epidemiological features between SARS‐CoV and MERS‐CoV infections in human

	SARS‐CoV37, 42, 43, 44	MERS‐CoV39, 40, 41, 45, 46, 47, 48
Genus	Beta‐CoV lineage B	Beta‐CoV lineage C
First human case	China in 2002	Saudi Arabia in 2012
Regions with human cases	China, Hong Kong, Singapore, Vietnam, United States and Canada	Saudi Arabia, United Kingdom, South Korea Arab Emirates, Qatar, Oman and Iran
Total number of human cases (years)	8422 cases (November 2002–July 2003) But, the last case was reported in May 2004	2182 (September 2012–February 2018)46 One recent case in Oman in November 2017
Median ages (years)	Less than or equal to 45 years	56 (14–94)
Incubation period (days)	4.6 (3.8–5.8)	5.2 (1.9–14.7)
Clinical characteristics	Invasive mechanical ventilation in 17%	Invasive mechanical ventilation in 37% (70% in another case series) Frequent acute kidney injury (~43%) Frequent vasopressor use Pneumonia in 80.8% (Korea)39
Mortality rate	9.6% (774/8098 cases)37 11.0% (916/8422 cases)44	39.0% in Saudi Arabia 20.4% in Korea39
Epidemiological features	Female predominance Nosocomial transmission Healthcare worker: 22% in China or >40% in Canada Mostly young people	Most cases from Arabian Peninsula Underlying co‐morbidities (96%) Human‐to‐human transmission (~50%) in Saudi Arabia Nosocomial transmission Healthcare worker: 21% in Korea A large outbreak in Korea (2015)
Risk factors	Employment in an occupation associated with an increased SARS‐CoV exposure Close contract of a person under investigation for SARS Travelling to areas experiencing an outbreak	Direct contact to dromedaries Travel to Middle East and North Africa

CoV, coronavirus; MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome.

MERS virus is stable in aerosol form, thus exacerbating the nosocomial spread of the virus during aerosol‐generating procedures. Hence, employment of strict infection control measures is needed to prevent nosocomial outbreaks.46, 53

The SARS‐CoV and MERS‐CoV human outbreaks are characterized by healthcare‐associated infections

All individuals who develop respiratory illness within 14 days after travelling to countries in the Arabian peninsula or who have had close contact with MERS cases should report to a healthcare provider for an evaluation and be on home isolation to prevent transmission

Healthcare personnel should adhere to the recommended infection prevention and control (IPC) measures, including standard, contact and airborne precautions

Healthcare personnel should be aware of the increased risk of nosocomial spread during aerosol‐generating procedures in MERS cases, thus they are recommended to use PPE during those procedures

MULTIDRUG‐RESISTANT GRAM‐NEGATIVE ORGANISMS

Carbapenem‐resistant Enterobacteriaceae (CRE), Acinetobacter baumannii (CRAB) and Pseudomonas aeruginosa (CRPA) are of significant concern worldwide.54, 55 In particular, CRE have also been found in the environment and community in India, Pakistan and Vietnam.56 Among many carbapenemases, Klebsiella pneumoniae carbapenemases (KPC) are the most common transmissible class A genes in Enterobacteriaceae, characterized by the clonal expansion of CC258 strains.54, 57 However, after the discovery of the New Delhi metallo‐β‐lactamase‐1 (NDM‐1) gene in 2008, there has been global concern for the rapid spread of NDM genes among countries and bacterial species; currently, NDM‐type genes predominate in India and Pakistan.55, 58 Notably, however, transmissible polymyxin‐resistance gene (mcr‐1) was also discovered, and cases infected by Enterobacteriaceae harbouring both carbapenemase and mcr‐1 genes have been reported.56, 59

To prevent the dissemination of these organisms, infection control measures should be implemented in healthcare facilities.60 In addition, considering the indiscriminative use of antibiotics worldwide, strengthening the surveillance of antibiotic resistance and strict controls on antibiotic use (e.g. stewardship programme) should be emphasized.61, 62, 63, 64

Healthcare personnel should be alert to the spread of carbapenem‐resistant Gram‐negative bacteria, particularly in Asian countries

Infection control measures, such as hand hygiene, surveillance, isolation or cohorting of patients, contact precautions and environmental cleaning, should be employed in healthcare facilities

Strengthening the surveillance of antibiotic resistance and strict controls on antibiotic use are needed to tackle the increasing antibiotic resistance

HOW TO PREVENT THE TRANSMISSION OF INFECTIOUS DISEASES IN HEALTHCARE SETTINGS

In an era of emerging infectious diseases, multimodal IPC strategies are of great importance in healthcare settings in terms of the safety of patients and healthcare workers.65 In 2014, the WHO released revised guidelines for IPC of epidemic‐ and pandemic‐prone acute respiratory diseases in healthcare settings. We recommend that healthcare workers follow the guidelines to prevent transmission of infectious diseases.65

In healthcare settings, IPC measures including droplet precaution (e.g. wearing a surgical mask), contact precaution (e.g. hand washing or wearing gloves and gown) and airborne precaution (e.g. isolation room with negative pressure) should be implemented

We recommend the use of clinical triage for the early identification of patients with acute respiratory infections (ARI)

Isolation or cohorting of patients is recommended to prevent the transmission of ARI pathogens

We recommend the use of appropriate PPE when providing care to patients with ARI (e.g. masks, gloves, long‐sleeved gowns, and eye protections with goggles or facial shields)

We recommend the use of PPE and adequately ventilated single rooms when performing aerosol‐generating procedures

Vaccination of healthcare workers caring for patients at high risk of ARI is recommended

AIR TRAVEL

Most modern aircraft have air recirculation systems, using high‐efficiency particulate air (HEPA) filters for air quality, and research has shown that the risk of infectious disease transmission is low during flight.66, 67 However, the spread of SARS and A(H7N9) viruses indicated an important role for air travel in spreading respiratory pathogens among countries.5, 6, 68

If a passenger develops symptoms suggesting respiratory infection during flight, the passenger should be isolated, if possible, and wear a surgical face mask. The flight attendant should notify public health authorities at the destination airport via air traffic control, in accordance with the International Civil Aviation Procedures for Air Navigation Services‐Air Traffic Management (ICAO PANS‐ATM).69, 70, 71 For novel influenza virus with pandemic potential or AI virus, we can refer to the recommendations by the Centers for Disease Control and Prevention (CDC)70 or the guidelines by the European CDC.69

People who are acutely ill or have a fever should delay their travel until they have recovered

If a passenger develops symptoms suggesting respiratory infection during flight, the passenger should be isolated, if possible, and wear a surgical face mask. The flight attendant should notify public health authorities at the destination airport.

Passengers seated within a distance of two seats in all directions around the index case and close contacts (e.g. crew, travel companions and persons providing care) should be subject to contact investigation based on the situational risk assessment

‘ONE HEALTH’ APPROACH

Adopting the ‘One Health’ approach may lead to further improvement of global pandemic preparedness72, 73, 74 and enable a paradigm shift from detection and response to the prevention of emerging infections, resulting in better protection of animals and humans.75, 76, 77

For the ‘One Health’ approach, communication and collaboration between countries are of paramount importance

The first step should be building trust between countries and between communities

Academic or commercial barriers, which can hamper information sharing, should be removed

avian influenza

acute respiratory infection

Centers for Disease Control and Prevention

coronavirus

Carbapenem‐resistant Enterobacteriaceae

highly pathogenic AI

2009 pandemic influenza A(H1N1)

infection prevention and control

low pathogenic AI

Middle East respiratory syndrome

New Delhi metallo‐β‐lactamase

personal protective equipment

severe acute respiratory syndrome

World Health Organization