Exposure to airborne pathogens is a common denominator of all human life. With the improvement of research methods for studying airborne pathogens has come evidence indicating that microorganisms (e.g., viruses, bacteria, and fungal spores) from an infectious source may disperse over very great distances by air currents and ultimately be inhaled, ingested, or come into contact with individuals who have had no contact with the infectious source [2–5]. Airborne pathogens present a unique challenge in infectious disease and infection control, for a small percentage of infectious individuals appear to be responsible for disseminating the majority of infectious particles. This paper begins by reviewing the crucial elements of aerobiology and physics that allow infectious particles to be transmitted via airborne and droplet means. Building on the basics of aerobiology, we then explore the common origins of droplet and airborne infections, as these are factors critical to understanding the epidemiology of diverse airborne pathogens. We then discuss several environmental considerations that influence the airborne transmission of disease, for these greatly impact particular environments in which airborne pathogens are commonly believed to be problematic. Finally, we discuss airborne pathogens in the context of several specific examples: healthcare facilities, office buildings, and travel and leisure settings (e.g., commercial airplanes, cruise ships, and hotels).

In the following, we will compare the number of people infected and the total

cost of treatment in both cases to illustrate the impact of government

intervention. As we cannot obtain a specific analytical solution using the

calculation process mentioned above, the research process will obtain the

results through the numerical simulation process. Assuming the total number of

people to be Nt=1, that is, regardless of the new birth and death of the

population, St,It,Rt indicate the number of susceptible people, infected people,

and patients cured. Furthermore, we assume the number of effective contact.

Following is the numerical simulation of the number of infected persons in

different parameters, including 3 cases: high cost (α=10,μ=0), low cost (α=5,μ=0), and full subsidy (α=5,μ=5). Through comparative analysis of high-cost and low-cost

treatment, the impact of treatment cost on the evolution of infectious diseases

was obtained. The impact of government intervention on the evolution of

infectious diseases was captured by comparing the results between no subsidy and

full subsidy. (Due to limitations, this article only considers these 3

situations. Readers can use other parameters to practice numerical simulation,

such as partial subsidy case, but the basic rules and main conclusions will not

change.) The simulation results are shown in Figure 4; for more details on the

numerical simulation, please see the appendix.

From Figure 4, 2 important conclusions

can be drawn: first, the treatment cost of infectious diseases has a critical

influence on the evolution of infectious disease. Specifically, under the

condition of high cost and no government intervention (α=10,μ=0), even after 10 000 periods of time evolution, the proportion

of infected people still exceeds 50%, and the highest number of infected people

is close to 80%. At low cost, even without government intervention

(α=5,μ=0), the number of infected people will decrease rapidly over

time, but the maximum number of infected people will exceed 77%, and it will

take a very long period of time (1774 periods) to control the disease. In other

words, infectious will fall to zero or everyone is cured after 1774 periods.

Second, government intervention has an important impact on the evolution of

infectious diseases. If the government implements full subsidy for infectious

disease (without considering the impact of data costs under full subsidy), the

number of infected people will drop rapidly and will fall to zero in the eighth

period. Infectious diseases can be effectively controlled in a short period of

time.

In 2008–2017, morbidity of Class B infectious diseases showed a significant downward trend, from 185.34/100,000 in 2008 to 54.36/100,000 in 2017 (χ2trend = 11,093.22, p < 0.05), with an annual morbidity of 90.39/100,000; morbidity of Class C infectious diseases showed a fluctuating upward trend, from 1352.97/100,000 in 2008 to 2549.03/100,000 in 2017 (χ2trend = 97,595.69, p < 0.05), with an average annual morbidity rate of 2412.47/100,000 (Table 1).

The top 5 reported Class B infectious diseases were dysentery, scarlet fever, measles, Influenza A (H1N1) and syphilis. The morbidity of measles, dysentery and syphilis showed a decline (measles: χ2trend = 10,156.59, p < 0.05; dysentery: χ2trend = 6301.75, p < 0.05; syphilis: χ2trend = 3376.99, p < 0.05); and that of scarlet fever was on the rise in recent years (χ2trend = 4185.20, p < 0.05). Influenza A (H1N1) was classified as a Class B infectious disease in 2009; 5805 cases of influenza A (H1N1) were reported in 2009, ranking first among Class B infectious diseases reported in the same year. This disease showed a decline in 2010 (χ2 = 5126.04, p < 0.05), and the number of cases reported was between 3 and 259 in 2010–2013. Since 1 January 2014, it was removed from Class B to Class C under the management of existing influenza (Figure 1).

The top 5 reported Class C infectious diseases were hand-foot-and-mouth disease (HFMD), other infectious diarrheal diseases, mumps, influenza and acute hemorrhagic conjunctivitis, among which the morbidity of HFMD, other infectious diarrheal diseases, and influenza were on the rise, while the morbidity of acute hemorrhagic conjunctivitis and mumps were decreasing year by year. In 2010, 11,789 cases of acute hemorrhagic conjunctivitis were reported, and thereafter the number of cases reported decreased rapidly (Figure 2).

The origins of infections resulting from droplet and airborne transmission are at the intersection of the clinical manifestation of disease, the site of infection, the presence of a pathogen, and the type of pathogen. Thus, when investigating the origins of droplet and airborne infections, there are several well-known primary sources of infectious particles (see Table 1): vomiting, toilet flushing (i.e., toilet water aerosolization), sneezing, coughing, and talking. Moreover, toilet bowls, the water in them, and toilet seats may harbor infectious particles after the initial flush, making additional aerosolization of infectious particles possible with additional flushes for as long as 30 minutes after the initial flush. Particle desiccation, discussed above, is important in this context. A single sneeze, for example, generates as many as 40,000 large droplet particles; most will desiccate immediately into small, infectious droplet nuclei, with 80% of the particles being smaller than 100 μm.

The transmission of infectious diseases via airborne or droplet routes may also depend on the frequency of the initiating activity. For example, while a single sneeze may produce more total infectious particles than a cough [11, 28, 65, 66], Couch et al. reported that coughing is more frequent than sneezing during infection with Coxsackievirus A. This finding suggests that coughing is a more likely method of airborne transmission for this disease than sneezing. As coughing is also a common symptom of influenza infection [68, 69], it may also contribute to the airborne transmission of this pathogen.

Finally, infectious individuals are not always the immediate source of airborne infectious particles. Many people spend considerable time in office buildings, for example, and as a result become exposed to airborne pathogens that originate from nonhuman sources (e.g., molds, toxins produced by molds, pollen, pet dander, and pest droppings) [70–77]. The health effects associated with naturally occurring indoor biological air pollutants include disease, toxicoses, and hypersensitivity (i.e., allergic) diseases [70–77]. In addition, exposure to indoor biological air pollutants has been associated with “sick building syndrome,”a set of nonspecific symptoms that may includeupper-respiratory symptoms, headaches, fatigue, and rash and“appear to be linked to time spent in a building, but no specific illness or cause can be identified.”.

During the period of 2008–2017, a total of 32 types and 1,994,740 cases of notifiable diseases in children aged 0–14 years, including 266 deaths, were reported in Zhejiang Province, with an annual average morbidity rate of 2502.87/100,000 and an annual average mortality rate of 0.33/100,000. There were no cases and deaths involving plague, cholera, infectious atypical pneumonia, human infection with avian influenza, polio, anthrax, diphtheria and filariasis. No Class A infectious diseases were reported. Twenty-two types and 72,041 cases of Class B infectious diseases were reported, including 138 deaths; 10 types and 1,922,699 cases of Class C infectious diseases were reported, including 128 deaths.

Emerging infectious diseases under this category were subcategorized into 1a, 1b and 1c. Subcategory 1a covers known pathogens that occur in new ecological niches/geographical areas. A few past examples belonging to this subcategory are the introduction and spread of West Nile virus in North America; chikungunya virus of the Central/East Africa genotype in Reunion Island, the Indian subcontinent and South East Asia; and dengue virus of different serotypes in the Pacific Islands and Central and South America.18,19,20,21,22,23 Factors that contributed to the occurrence of emerging infectious diseases in this subcategory include population growth; urbanization; environmental and anthropogenic driven ecological changes; increased volume and speed of international travel and commerce with rapid, massive movement of people, animals and commodities; and deterioration of public health infrastructure. Subcategory 1b includes known and unknown infectious agents that occur in new host ‘niches'. Infectious microbes/agents placed under this subcategory are better known as ‘opportunistic' pathogens that normally do not cause disease in immunocompetent human hosts but that can lead to serious diseases in immunocompromised individuals. The increased susceptibility of human hosts to infectious agents is largely due to the HIV/acquired immune deficiency syndrome pandemic, and to a lesser extent, due to immunosuppression resulting from cancer chemotherapy, anti-rejection treatments in transplant recipients, and drugs and monoclonal antibodies that are used to treat autoimmune and immune-mediated disorders. A notable example is the increased incidence of progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system that is caused by the polyomavirus ‘JC' following the increased use of immunomodulatory therapies for anti-rejection regimens and for the treatment of autoimmune diseases.24,25,26 Subcategory 1c includes known and unknown infectious agents causing infections associated with iatrogenic modalities. Some examples of emerging infections under this subcategory include therapeutic epidural injection of steroids that are contaminated with Exserhilum rostratum and infectious agents transmitted from donor to recipients through organ transplantation, such as rabies virus, West Nile virus, Dandenong virus or Acanthamoeba.27,28,29,30,31

Before introduction of the immunization program, mumps had occurred mostly in elementary school-aged population, but since the program was introduced, those incidence in patients aged 15 years or more has tended to increase in all years. In the beginning of 1960, 5,000 or more cases of mumps were reported and then gradually decreased thereafter, and to less than 1,000 cases in the middle of the 1990s. However, it started to increase thereafter and 5,000 or more cases have been reported for in the past 5 years (Fig. 3)5,11). This phenomenon not only might result from an actual increase of incidence, but also from increased reporting through the consolidated report system.

According to data collected in 2008, mumps occurred year-round, but occurred mostly in April through September (71.0%), and occurred more frequently in men than in women6). For the past decade, the total number of reported cases was 31,238 and patients aged <10 years and 10 to 19 years accounted for 34.4% (10,754 cases) and 59.7% (18,656 cases), respectively5).

Ten to twenty thousand cases of measles were reported every year, but since the measles vaccine was introduced in 1965, the incidence had continuously decreased, except for an epidemic at an interval of 4 to 6 years. An average of 4,000 to 6,000 cases was reported yearly by the beginning of the 1980s, but with continuation of the immunization program, the incidence decreased to 1,000 to 2,000 cases per year after 1985. There was a nationwide epidemic event during 1993 to 1994. Compared to the period between 1989 and 1990, during the above mentioned period, the epidemic occurred more often in those aged 6 years or more, and thus in 1994, the Korean Pediatric Society temporarily recommended that those aged 6 years should be revaccinated with the measles, mumps, and rubella (MMR) vaccine, in addition to vaccination at the recommended age of 15 months. Since 1997, the government has reduced the time of primary MMR vaccination to 12 to 15 months and adjusted the immunization schedule for revaccination in those aged 4 to 6 years5,6,10).

From the latter half of 2000 to the first half of 2001, a large epidemic event occurred with about 56,000 cases reported, and the incidence has greatly decreased since in May 2001, the measles catch-up immunization program was executed in all school-aged populations10). Except 194 cases in 2007 and 114 in 2010, just 10 to 30 cases were reported every year (Fig. 3)5).

According to reports in 2007 and 2010, patients aged <10 years and 10 to 19 years accounted for 88.7% and 3.1%, and 14.9% and 82.5%, respectively. The age difference between two outbreaks might be dependent upon the age of the first case as the source of infection5).

From 2008 to 2017, China achieved impressive reductions in the burden from infectious diseases in children and adolescents aged 6 to 22 years. This complements the reduction in mortality from infectious diseases in under 5s—a longstanding focus of the Millennium Development Goals, and will contribute to reductions in the overall burden from infectious diseases in China.16

60 However, China’s rapid success poses challenges for policy makers as priorities for infectious disease control continue to evolve. Beyond maintaining the gains, the priorities for the coming decade include reducing regional inequalities; scaling-up vaccination for mumps, seasonal influenza, and hepatitis B; preventing further escalation of HIV/AIDS and other sexually transmitted diseases; and redoubling efforts around persisting diseases, including tuberculosis, rabies, and scarlet fever. Different responses will be needed by region and by age across childhood and adolescence, while the newer emerging disease epidemics will require rapid and targeted responses. Seasonal variation in respiratory infections and in gastrointestinal and enterovirus diseases reflect the high vulnerability of children and adolescents. A comprehensive national surveillance system remains an integral part of infectious disease control in these age groups to maintain the gains of recent decades and respond effectively to new epidemics.

Incidence of infectious diseases differed by age (fig 5). For quarantinable diseases, haemorrhagic fever was the leading disease in each age group in each year. Among 11 vaccine preventable diseases, mumps dominated in children aged less than 13 years in 2017, but was surpassed by hepatitis B and seasonal influenza in those older than 13 years. Within gastrointestinal and enterovirus diseases, the leading disease was hand, foot, and mouth disease in children aged less than 11 years, but infectious diarrhoea was the most common infection in those older than 12 years. For vectorborne diseases, Japanese encephalitis was the leading diagnosis in children aged less than 10 years. Before 2011, malaria was most common in those older than 11 years, whereas dengue became most common from 2011 onwards. For zoonotic infections, brucellosis was the most common infection in each age group, apart from an outbreak of influenza A H1N1 from 2009 to 2013. For bacterial infections, scarlet fever predominated in children aged 6 to 11 years, whereas tuberculosis was the leading disease in adolescents older than 11 years. Sexually transmitted diseases and bloodborne infections, gonorrhoea, syphilis, and hepatitis C were the most common diseases in all ages, whereas HIV/AIDS increased from 2011, particularly in those older than 18 years.

A noticeable association was observed between age and some infectious diseases. The most common infections in early childhood included vaccine preventable diseases and gastrointestinal and enterovirus diseases. Those that largely affected older adolescents included sexually transmitted diseases and bloodborne infections, whereas other infections such as zoonoses had a U-shaped age distribution. In terms of sex differences, one of the noticeable features of almost all the infections, except for pertussis, Kala-azar, and dengue in a particular year, was that many more cases and a higher incidence was observed in males than females during the 10 years (P<0.05), particularly for gonorrhoea, HIV/AIDS, and hepatitis C among those older than 14 years (see supplementary figs S7 and S8).

Seasonal variation was observed in most infectious diseases in 2017 (see supplementary fig S9). Among the quarantinable diseases, the incidence of haemorrhagic fever peaked in winter. Similarly, among the vaccine preventable diseases, consistent peaks occurred in winter (December) for seasonal influenza, whereas the incidence of rubella and measles peaked in spring (March). Almost all the gastrointestinal and enterovirus diseases, most vectorborne diseases, and zoonotic infections, as well as hepatitis C in sexually transmitted diseases and bloodborne infections had consistent peaks in summer and leading into autumn.

Finally, in the case of free treatment, patients’ willingness to treat reaches

the highest, and the number of people healed per unit time is also the highest,

which is the ideal state. In other words, if μ−α=0, then it has γ=1.

Under the condition that the government provides certain compensation

(μ≠0, µ ≫0μ≫0), if the treatment cost is greater than the government

compensation, both high treatment cost and low government compensation will lead

to a decrease in people’s willingness to treat. And the number of people cured

within a unit of time will decrease correspondingly, which means when

−α+μ→∞,γ→0. If the government compensation and treatment costs are equal,

which is equal to free treatment, people’s willingness to treat will also reach

the maximum, and this is also an ideal condition. Or −α+μ=0 leads to γ=1.

It is unrealistic for the government to compensate more than the treatment cost

(μ≥α). Low willingness to spend money on the treatment of

infectious diseases leads to quick spreading of them and thus affects the

society sustainability. The government compensates people to control the

disease, but compensation for the government supply will only be enough for

people to treat infectious diseases. After all, more compensates means higher

expenditures for the government. Therefore, government compensations must be no

more than the treatment expenditures, or μ≤α. To be consistent with the real policy of Chinese government,

this article assumes that if μ−α=0, then γ=1. Under this condition, the evolution number of the 3 groups is

shown in Figure 3.

Figure 3 shows that the

number of infected people drops rapidly and will reach zero in the eighth

period. Besides, according to Figure 3, we learn that only 5.59 people need treatment under full

government subsidy, much less than that under no government intervention. But

the total cost of treatment is related to unit person treatment cost, which is

55.88 at high cost and 27.94 at low cost. (These exact numbers themselves have

no meaning; they are only used to show the gap between different conditions.)

Figure 3 shows that

when the cost of treatment is high, the expenditures of implementing the full

compensation mechanism are also high.

disease events

Specific subtypes of influenza A viruses that circulate in birds can infect humans. Influenza infections of avian origin occur through both direct and indirect exposure to infected animals, whether alive or dead. One important unique feature of influenza viruses is their ability to cause both annual epidemics (seasonal influenza) and, from time to time, more serious pandemics (93). Each emerging strain has the potential to become seasonal.

Birds are a natural reservoir for influenza viruses, and A virus subtypes H5, H7 and H9 have all led to outbreaks in human populations (94). In recent years, the most significant outbreaks have been related to H5N1 and H7N9. Although a limited number of human cases infected with influenza A(H5N1) has been reported, the high case fatality and its potential ability to adapt to human hosts have raised concern at the global level (95). More recently, in the spring of 2013, 145 people in China were infected by the avian influenza strain A(H7N9), leading to 45 deaths (96). The virus was detected in poultry but also in the environment. The closure of live poultry markets in April 2013 did lead to a dramatic drop in the number of cases (97) although sporadic cases have been reported through the end of 2013.7

A broad combination of factors can trigger and sometimes amplify avian influenza outbreaks (98, 99). Ecological and environmental factors play a key role. Population density of both human and animals – as well as the proximity between them – are known risk factors for avian influenza infections in humans. Live bird markets and human consumption patterns of poultry and other avian species are also known to contribute to the risk of both influenza emergence as well as infection (100). Seasonality is another influencing factor, although different hypotheses exist as to why winter seasons are traditionally driving influenza transmission (101). Bird migratory patterns, particularly where migratory birds might interact with livestock poultry, create potential pathways for introduction of the virus into new regions. Air travel can quickly lead to the rapid global spread of influenza (3). Meanwhile, the level of available public health measures, from molecular surveillance to rapid vaccine production, are important determinants of the impact that any given influenza outbreak might have (102). Significantly, different avian influenza strains have different characteristics, further challenging the public health response. For example, influenza A(H5N1) is highly pathogenic in birds, leading to natural sentinel surveillance systems, while influenza A(H7N) may circulate among healthy birds, thereby remaining undetected (103).

The global and sectoral interdependencies related to influenza have been well documented. A widespread pandemic could quickly disrupt activities in many sectors, including trade (including potential trade bans) (104), transportation, healthcare delivery, critical infrastructure, and so on. School closures and workplace absenteeism are oft-cited control measures that might also have substantial impact on society. Numerous economic estimates indicate that the direct costs (use of healthcare services) and indirect costs (productivity losses) related to seasonal influenza can amount to billions of dollars globally (105). An economic scenario analysis of pandemic influenza in the United Kingdom indicated potential costs of 0.5–1% of GDP in low fatality scenario and 3.3–4.3% in a high fatality scenario (106).

The financing, provision, and quality of healthcare systems; the availability of vaccines, antivirals, and antibiotics medicines, and appropriate compliance to treatment protocols are all important determinants of infectious disease transmission. Although the correlation between healthcare system financing and efficacy is not perfect, recent budget cuts to healthcare are an important consideration when anticipating infectious disease risk. In part related to the global economic crisis, it has been reported that many high-income governments have introduced policies to lower spending through cutting the prices of medical products and, for example, through budget restrictions and wage cuts in hospitals (54). There are many indirect and direct pathways through which budget cuts could affect disease transmission; to provide just one example, it has been estimated that 20–30% of healthcare-associated infections are preventable with intensive hygiene and control programmes2 – should investments in this area diminish, then healthcare-acquired infections could become an even more problematic issue. There are currently roughly 4.1 million healthcare-associated infections each year in the EU alone.3

A broader issue related to healthcare provision is population mobility for both healthcare professionals and patients who might increasingly seek work or healthcare in other countries – the provision of cross-border healthcare and the mitigation of cross-border health threats will necessitate collaboration across borders (55, 56) and solutions for the brain-drain of medical personnel from resource-poor countries (57). Also related to the healthcare provision and practice is the over-prescription or overuse of antibiotics. In combination with a lag in pharmaceutical innovation, rapid transmission, and poor infection control measures, this has driven resistance of organisms such as methicillin-resistant Staphylococcus aureus, or extended-spectrum beta-lactamases, and carbapenemase-producing gram-negatives such as Klebsiella pneumoniae carbapenemase (KPC) (58). Antimicrobial resistance is currently one of the major health risks facing society (59).

Food production systems remain a persistent source for human infectious diseases. Attempts are underway to estimate the global burden of food-borne disease (60), which is likely substantial. Many factors in food production affect human health. A vast range of familiar human pathogens can be acquired through the consumption of animal products and other disease drivers, such as global travel, further provoke this (61). In addition to farmed animals, the hunting and slaughtering of wild animals has led to the emergence of more exotic pathogens: SARS originated in wildlife markets and restaurants in southern China (62) and HIV and Ebola have both been linked to the hunting or slaughtering of primates and other wild animals (33, 63, 64). The density and health of livestock, meanwhile, have been linked to disease in humans (65, 66). Although inconclusive, there is some evidence to suggest that livestock production may lead to increased antibiotic resistance in human pathogens. There are certainly many pathways by which drug resistant pathogens could transmit from livestock to humans, including environmental contamination by excreted veterinary antibiotics (33, 67, 68).

Examples of past emerging infectious diseases under this category are antimicrobial resistant microorganisms (e.g., Mycobacterium tuberculosis, Plasmodium falciparum, Staphylococcus aureus) and pandemic influenza due to a new subtype or strain of influenza A virus (e.g., influenza virus A/California/04/2009(H1N1)).9,32,33,34,35 Factors that contribute to the emergence of these novel phenotype pathogens are the abuse of antimicrobial drugs, ecological and host-driven microbial mixing, microbial mutations, genetic drift or re-assortment and environmental selection. Accidental or potentially intentional release of laboratory manipulated strains resulting in epidemics is included in this category.

Although lower respiratory infections, including pneumonia, are one of the main causes of death worldwide, real-time surveillance systems and situational awareness are generally lacking.

In the year after the SARS outbreak in 2003, NHFPC developed a surveillance system for unexplained pneumonia to facilitate timely detection of airborne pathogens that form a severe threat to public health. Therefore, all Chinese health care facilities are required to report any patient who has a clinical diagnosis of pneumonia with an unknown causative pathogen and whose illness meets the following five criteria (2007 modified definition): (1) fever ≥38 °C; (2) radiologic characteristics consistent with pneumonia; (3) normal or reduced leukocyte count or low lymphocyte count in early clinical stage; (4) no improvement or worsening of the patient’s condition after first-line antibiotic treatment for 3–5 days; and (5) the pneumonia etiology cannot be attributed to an alternative laboratory or clinical diagnosis (clinicians are granted flexibility to determine how to interpret this criterion and specific tests are not specified) [22, 23]. Once the case is registered in NIDRIS, the data are further analysed in CIDARS as a type 1 disease, for which a fixed-threshold method (of 1 case) is applied. A real-time SMS is followed by a field investigation, whereby case samples are tested to rule out avian influenza, SARS and Middle East respiratory syndrome coronavirus (MERS-CoV). Although physicians are required to report unexplained pneumonia cases, considerable under-reporting occurs. The aim of this surveillance system is not to detect each unexplained pneumonia case but to focus on clusters that could indicate an (unknown) emerging infectious disease outbreak.

Unexplained pneumonia is not a notifiable condition in the Netherlands as it is in China. However, according to the Public Health Act (2008), each physician should notify a case or an unusual number of cases with an (unknown) infectious disease that forms a severe threat to public health. An example is the Q fever outbreak (2007); the unusual number of atypical pneumonia cases early in the outbreak were not detected by routine surveillance systems but by astute general practitioners (GPs). Both Dutch legislation and the Chinese pneumonia surveillance system aim for early notification of (unknown) emerging infectious disease outbreaks. However, in both countries, criteria for notification are not well defined and a considerable degree of under-ascertainment and under-reporting is likely. In the Netherlands, structural syndromic pneumonia surveillance is carried out using data extracted from electronic patient files maintained by sentinel GP practices, representing 7% of the Dutch population. Moreover, sentinel registration of pneumonia cases in nursing homes takes place. A separate virologic laboratory surveillance system provides information on circulating respiratory viruses. Since 2015, a pilot study has been carried out for hospitalized severe acute respiratory infections (SARI) patients. As it includes only two of 133 hospitals in the country at present, the obtained data is not yet reliable to provide early warning of infectious pneumonia outbreaks. Currently, no set threshold exists for unusual occurrence of pneumonia. Expert opinion determines which signals are discussed by the NEWC.

Canine morbillivirus (canine distemper virus, CDV) causes canine distemper (CD) in a wide range of mammalian hosts, and may produce systemic, respiratory, cutaneous, bone, and/or neurological manifestations in these animals1,2. CDV produces immunosuppression3 in susceptible hosts by targeting cells that express the signalling activation molecule (SLAM)4, which frequently results in opportunistic infectious diseases caused by agents such as Bordetella bronchiseptica5,6, Candida sp.7, Clostridium piliforme8, Toxoplasma gondii9–11, Dirofilaria immitis11, Mycoplasma cynos12, and Talaromyces marneffei13. Although the occurrence of CD is significantly reduced in domestic dog populations in developed countries due to the use of vaccination14, the disease is endemic and a major cause of canine mortality in urban populations of Brazil15,16, where an estimated 147.5–160.3 million USD is spent annually due to the therapy of the systemic effects of CDV15.

CDV has been diagnosed concomitantly with traditional viral infectious disease agents such as canine parvovirus-2 (CPV-2)17,18, canid alphaherpesvirus-118,19, canine adenovirus-1 and -2 (CAdV-1)20, and (CAdV-2)18,21 in dogs. Moreover, recently CDV has been identified in dogs simultaneously with emerging viral infectious agents including Canine kobuvirus22, Canine pneumovirus23, and Canine respiratory coronavirus6,23. Additionally, studies have detected canine infectious disease agents due to the amplification of nucleic acids in symptomatic6,23–25 and asymptomatic19 dogs by molecular assays. Alternatively studies have combined the pattern of organ disease observed by histopathology with electron microscopy20, immunohistochemistry (IHC)8,12,21,22,25,26 and/or the molecular identification8,10,12,18,22,27 of infectious disease agents of dogs.

Previous studies by our group8,10,18 and others12,21,26,27 have demonstrated the concomitant participation of several infectious disease agents in the development of diseases in dogs, principally puppies. It is proposed that puppies are probably more frequently coinfected by several infections disease agents than has been previously reported, particularly if there is the simultaneous involvement of CDV, and coinfections may result in the death of the affected dog due to multiple organ failure10. The objectives of this retrospective study were to evaluate the frequency of concomitant traditional infectious disease agents in the development of infectious diseases in puppies, correlate the presence of these pathogens with histopathologic patterns, and review specific aspects of the pathogenesis involving these infectious disease agents.

Hepatitis B is found in virtually every region of the globe. Of the more than 2 billion people who are or have been infected, 350 to 400 million are carriers of the chronic disease; the remainder undergo spontaneous recovery and production of protective antibodies. Nearly 100% of infected infants (that is, those born to HBV-infected mothers) become chronically infected. The risk of developing a chronic infection decreases with age.

At least 30% of those with chronic HBV infection experience significant morbidity or mortality, including cirrhosis and hepatocellular carcinoma. Most people do not know they are infected until they present with symptoms of advanced liver disease, which means that infected individuals can spread the infection unknowingly, sometimes for many years. Although oral antiviral therapies are effective at stopping HBV replication, they do not cure the disease. Therefore, therapy is usually lifelong. Treatment is also complicated by the development of drug resistance and side effects. A vaccine against HBV is safe and effective in 90 to 95% of people; however, the individuals who are most at risk of becoming infected are often those with limited access to the vaccine, such as marginalized populations or people living in resource-limited countries.

There is substantial evidence that an individual's likelihood of recovering from an acute HBV infection or developing severe sequelae from infection is influenced, in part, by genes [39–45]. Candidate gene and genome-wide association studies have identified variants associated with HBV-related disease progression or hepatocellular carcinoma in various populations [46–52]. Treatment response to interferon (IFN)-α has been associated in some, but not all, studies with IFNλ3 polymorphisms. Finally, specific gene variants (HLA and non-HLA alleles) have been associated with vaccine response and non-response [54–57].

Morbidity of notifiable infectious diseases in China, represented by estimated numbers of new cases, declined substantially (>90%) from 22,000 cases per million in 1975 to a nadir level of 1,800 cases per million in 1995 (Figure 1a). Since then, the rate of new infectious disease cases gradually reverted and maintained an upward trend. In 2008, the estimated rate of infectious diseases among the general Chinese population reached over 3000 cases per million population. The composition of diagnosed diseases cases also changed substantially, in 1975, the three most reported diseases were gastrointestinal diseases (41.9%), vector-borne diseases (30.8%) and vaccine-preventable diseases (21.1%), corresponding to a total of 93.8% of all diagnosed cases (Figure 1a). Additionally, these three types of diseases account for 35.5, 21.7 and 18.4 million reported cases respectively during the period 1975–1979 (Table 1). In contrast, in 1995, although gastrointestinal diseases remained the dominating disease type (41.6%), the proportion of all cases that were due to viral hepatitis quickly rose to 35.7%. Sexually transmitted diseases re-emerged, and together with HIV, consisted of a substantial 6.3% of all reported cases. In 2008, the three most frequently reported disease types included viral hepatitis (38.3%), bacterial infections (33.3%) and STIs and HIV (9.8%), which account for 5.4, 4.8 and 1.4 million diagnosed cases respectively during the period 2005–2008 (Table 1).

Rapid declines in infectious diseases mortality and its similar saddle pattern were also observed in the past 35 years. The overall mortality rate in China decreased from 66 cases per million in 1975 to 5 cases per million in 1995, then it gradually reverted to 10 cases per million in 2008 (Figure 1b). Vaccine-preventable diseases, bacterial infections and gastrointestinal diseases were the greatest causes of death, accounting for 30.0%, 24.0% and 19.5% of reported infectious diseases death cases among Chinese population in 1975 (Figure 1b). However, the rank of composition shifted to zoonoses (22%), viral hepatitis (17.3%) and quarantinable diseases (15.3%) in 1995. Since then, the proportion of deaths caused by STIs and HIV, and bacterial infections rapidly increased. By 2008, STIs and HIV (39.5%) has become the mostly deadly infectious disease, followed by bacterial infections (24.7%) and zoonoses (20.0%). During the period 2005–2008, these three types of diseases have led to approximately 12,500, 13,300 and 11,400 deaths in China, respectively (Table 1).

Case fatality rate measures the percentage of deaths among people who contracted a disease. During 1975–2008, the disease type with the highest fatality rate is zoonoses, consistently causing 5–15% of deaths among the infected population. Following that, quarantinable diseases killed 1.4–5.6% of its infected population during the same period. In comparison, fatality rates in vaccine-preventable (0.112% during 2005–2008), gastrointestinal diseases (0.036%), bacterial infections (0.277%) and viral hepatitis (0.086%) show clear decreasing trends in China, corresponding to 3.5, 3.6, 12.4 and 2.4 folders reduction in comparison with the period 1975–1979, respectively. However, fatality of STIs and HIV increased to 0.894% during 2005–2008, doubling the level in 1985–1989 (Table 1).

In China, if a notifiable infectious disease is clinically diagnosed and/or laboratory confirmed according to the unified national diagnostic criteria issued by the NHFPC, cases must be reported to the national China CDC, which collects and analyses the acquired data. The health care provider enters the case information using a standard form into the Notifiable Infectious Diseases Reporting Information System (NIDRIS), a web-based system that enables all healthcare institutions to report cases of notifiable infectious diseases. Approximately 5 million infectious disease cases are reported annually (≈ 385 cases per 100,000 citizens per year). Each China CDC level can analyse its own data in NIDRIS and data from subordinate levels within its own administrative boundaries.

In the Netherlands, if a notifiable infectious disease is suspected and/or laboratory tests confirms it, the case must be reported both by the attending physician and the laboratory to the regional PHS. The case information is collected and entered by the PHS into Osiris, a web-based database that transmits the data to RIVM for further analyses. In 2014, 13,863 notifiable disease cases were reported via Osiris to RIVM (≈ 815 cases per 100,000 citizen per year).

Acute viral infections such as influenza also have profound impacts on global health. In contrast to the yearly epidemics caused by seasonal influenza, a pandemic can occur when a new virus emerges in a naive population and is readily transmitted from person to person. The US Centers for Disease Control (CDC) estimates that the H1N1 2009 pandemic resulted in 41 to 84 million infections, 183,000 to 378,000 hospitalizations, and nearly 285,000 deaths worldwide. Although the morbidity and mortality of that pandemic were lower than feared, public health professionals continuously monitor for the emergence of more virulent strains.

As an airborne infection, influenza is transmitted easily and quickly, and its effects can be acute, although there is wide variability in response to infection. Much of the heterogeneity in the severity of seasonal influenza infections has been attributed to the degree of acquired immunity in the population affected, patient co-morbidities and the virulence of the strain. Also, influenza epidemics and pandemics are often caused by the introduction of novel viruses for which most people have limited acquired immunity. The emergence of new strains, and the lack of cross-protection by existing vaccines, does not leave much time for vaccine development. In pandemics, including the H1N1 2009 influenza pandemic, healthy young individuals with no co-morbidities have comprised a significant proportion of fatal and severe cases. These pandemics have provided an opportunity to evaluate the host innate immune response among populations without underlying background immunity.

Research has identified genetic factors associated with severity of illness due to influenza [63–65] and death from severe influenza. Genetic information about immune response to influenza could inform vaccine development and distribution, and disease treatment strategies. Several candidate gene studies suggest that variations in HLA class 1 and other genes contribute to differences in antibody response to influenza vaccines. Ongoing experience with vaccine use has provided opportunities to learn about the potential role of genetics in vaccine safety and efficacy.

The results from these findings have demonstrated that most puppies (80%; 12/15) submitted for routine autopsy were infected by two or more infectious disease pathogens. These results are similar to those described in other studies that examined one5,8,10,13,17,20,21,35 or more dogs7,18,19,24,25, to identify infectious disease pathogens by using several diagnostic methods. The location (cytoplasmic or nuclear) for the labelling of the antigens for all infectious disease pathogens observed during this study is consistent with previous studies26,36. During this investigation, 60% (9/15) of the puppies demonstrated triple or quadruple infectious diseases; similar results were described in a population of German Spitz puppies18, while a 45-day-old puppy was infected by five pathogens10, and triple viral infections were diagnosed in dogs from Mexico by IHC26. These findings suggest that concomitant infectious diseases in dogs, principally in puppies, as observed in this and other studies8,10,12,21,22,26 may be more frequent than previously described, and can result in sudden death, as occurred in all puppies from this study, probably due to multiple organs failure10. Although this study was focused on the identification of traditional infectious disease pathogens of dogs, it cannot be ignored that the possibility exists of the occurrence of additional infections associated with emerging19,37 infectious disease agents.

Nevertheless, this is one of the few studies that have associated traditional infectious disease pathogens of dogs with their respective histopathologic patterns and the intralesional identification by IHC; this strategy was used to identify several infectious disease pathogens in puppies8,11,26,38. This methodology has the advantage of confirming the participation of infectious disease agents in the development of disease processes, since tissue antigens are easily observed within histological sections39. Alternatively, other investigations have used several methods to associate the participation of pathogens with disease in dogs, including the exclusive identification of characteristic histopathologic findings5,7, histopathology with electron microscopy20, genotyping35, and with the IHC identification of associated pathogens21,26,38, or histopathology with molecular testing10,12, and in situ hybridization, ISH12,27. Moreover, these investigations have identified the presence of infectious disease pathogens using molecular techniques in symptomatic9,23,24, or asymptomatic19 dogs. Although there are advantages and disadvantages with the utilization of diagnostic IHC40, this method is recommended for the identification of intralesional antigens of infectious disease agents in Formalin-fixed paraffin embedded (FFPE) tissue sections36,39,41, and has been used extensively in veterinary medicine39. Additionally, immunohistochemistry, ISH, and electron microscopy, unlike molecular identification methods, clearly demonstrates the active participation of the infectious disease agent in the development of the disease process, while the molecular identification of disease pathogens does not necessarily imply that the identified pathogen is the cause of the associated disease process42.

All puppies investigated during this study contained CDV RNA as detected by RT-PCR, while antigens of CDV were observed in multiple tissues of most puppies. These findings demonstrated the disseminated tropism of CDV for epithelia and its capacity to induce clinical disease with associated histopathologic alterations in multiple tissues. The concomitant infections identified in most puppies can be attributed to the immunodepressive effects of this virus3,4, associated with the immature immunological system of these puppies, which facilitated the development of simultaneous infections in the same puppy. The immunodepressive effects associated with infections induced by CDV is associated with the selective destruction or impairment of cells that express the signalling lymphocyte activation molecule (SLAM, CD150) due to tropism for lymphoid tissues4. Moreover, experimental studies have demonstrated that in cases of fatal CDV-induced infections, as occurred during this study, there are reduced gene expressions of interferon gamma (IFN-γ) and interleukin-4 (IL-4)43. Collectively, reduced expression of cytokines (IFN-γ and IL-4) and downregulation of CD150 cells may be the key to understand the immunodepressive effects of CDV.

Antigens of CDV were identified within the epithelial cells of the lungs in all puppies with a histopathologic diagnosis of interstitial pneumonia, while in some of these cases there was the concomitant positive immunolabelling of antigens of CAdV-1 and -2; similar findings were described7,21,26. These results suggest that these two viral agents are also associated with interstitial pneumonia in dogs, and not only with CIRD2,34. Most cases of white matter demyelination of the cerebellum during this investigation contained CDV-positive astrocytes; similar findings were described11,38, indicating that these puppies were in the initial phase of neurological distemper in progression to develop canine distemper encephalitis, CDE2,3,44. These findings indicate that demyelination continues to be an important histopathologic lesion of neurological distemper2,3,15, with the cerebellum being the tissue of choice for the histopathologic diagnosis of CDE in immature dogs, since this neuroanatomical location is frequently affected in CDE2,44.

Positive immunolabelling for antigens of CAdV-1 were observed predominantly in hepatocytes and Kupffer cells of puppies with a histopathologic diagnosis of necrohaemorrhagic hepatitis and to a lesser extent in cases of interstitial pneumonia; similar findings have been described in ICH10,45–48. Additionally, gallbladder oedema was observed during the autopsy of several of these puppies during this investigation, as well as in other studies20,45,46. Moreover, the “blue eye” phenomenon and gallbladder oedema observed in one puppy are considered as typical clinical findings associated with CAdV-130,33,49,50. Intriguingly, positive immunolabelling to CAdV-1 was observed within hepatocytes and/or Kupffer cells but not at the oedematous epithelium of the gallbladder in any of these cases, while there was positive immunoreactivity to CDV at the oedematous gallbladder in one of these puppies. These findings might suggest that gallbladder oedema in ICH is not a direct viral-induced lesion but may be associated with CAdV-1 related haemodynamic alterations that are characteristic of this disease30,49, resulting in oedema to the gallbladder but without IHC evidence of this viral pathogen. However, the absence of positive IHC detection of CAdV-1 antigens in these cases can also be related to the clearance of the virus from the gallbladder and be time dependent, since infected dogs develops effective antibody response resulting in virus clearance from the liver seven days post-infection30. The authors have not located any manuscript that described this association, so these results are unique and add to the understanding of this important disease of dogs. In addition, the positive labelling of CDV at the oedematous epithelium of the gallbladder may simply represent the widespread tropism of this virus for epithelia and not directly related to the development of oedema at this or any other location.

This is one of the few investigations that have evaluated the histopathologic and immunohistochemical features of the “blue eye” phenomenon of ICH in modern diagnostic veterinary pathology, and adds to the excellent experimental studies that described the histopathologic features of the ocular disease in the 1960s31,32 with emphasis in Afghan hounds51, experimental confirmation of the type III hypersensitivity lesions52, and a review of this unique lesion50. This ocular lesion is traditionally considered and accepted as a type III hypersensitivity reaction of CAdV-130–32,50,53, and occurs in 20% of recovered puppies after 2–3 weeks of being infected31,32,53. However, in the case herein descried (puppy #15) as well as the eye from a previous study10, there was oedema of the corneal stroma with disruption of the anterior corneal epithelium and the Descemet’s membrane; these lesions were previously described in experimentally induced CAdV-1 infection puppies in which where there were accumulations of neutrophils, mononuclear inflammatory cells31,32,51, and fibrinous exudation31,32, frequently resulting in uveitis and interstitial keratitis31,32. However, in the cases herein described, moderate inflammatory reactions were restricted to the conjunctiva of puppy #15 and not observed in any anatomical region of the eye of a puppy from a previous study10. Alternatively, degenerative alterations to the corneal epithelium were not described in the experimentally induced ocular disease31,32,52. Furthermore, the post-infection period of the occurrence of corneal oedema in ICH seems to coincide with the initial manifestations of hepatocelular necrosis30,49. However, in puppy #15 with the “blue eye” phenomena, hepatocellular swelling (hydropic degeneration) and not hepatocellular necrosis was the predominant histopathologic pattern with positive immunoreactivity observed only within epithelial cells of bile ducts. While in puppy #16, there was necrohaemorrhagic hepatitis associated with intranuclear inclusion bodies characteristic of CAdV-1, with the hepatic disease being further aggravated due to the concomitant presence of intralesional cysts of T. gondii10. Additionally, the hepatocellular alteration as observed in puppy #15 is frequently described in ICH49, and may be associated with reduction in levels of blood glucose33. Consequently, it is proposed that CAdV-1 should be considered as a possible cause of hepatocellular degenerative lesions in puppies, principally those that have died after an acute onset of clinical manifestations.

Collectively, these findings may suggest that the histopathologic features of the ocular lesions associated with CAdV-1 seem to be predominantly degenerative in the spontaneous disease herein described and inflammatory in experimental-induced infections. Although the differences in histopathologic findings observed between the spontaneous ocular disease and the experimentally induced lesions32,52,54 are not fully known, we postulate that these differences might have occurred due to several factors. Firstly, they may be related to the routes of inoculation in the experimental studies; being subcutaneous and intravascular31,51 or intraocular32,52, as compared to the oronasal exposure in the natural disease. Secondly, the post-inoculation observation period of 2–3 weeks31 relative to the one week after initial manifestation of disease in the spontaneous disease can also contribute to these histopathologic differences. Furthermore, these time-based differences can be related to the pattern of histopathologic lesion observed in ICH. The hepatic pattern observed in puppy #15 was degenerative and not necrotic, and may probably represent an initial manifestation of hepatocellular injury induced by CAdV-1, since hepatocelular degeneration is commonly observed in ICH49, and antigens of CAdV-1 were identified in another puppy with this pattern of hepatic injury. Thirdly, the viral load used in the experimentally induced infectious studies might have been significantly elevated when compared to that of the spontaneous exposure of susceptible puppies to CAdV-1. Notwithstanding the above findings, two inflammatory phases of the CAdV-1 associated ocular disease were proposed50,52,55: the first is considered as a subclinical/clinical infection that is characterized principally by oedema with mononuclear accumulations and occurs at the anterior uvea, while the second is predominantly manifested by corneal oedema with histopathologic lesions indicative of type III hypersensitivity and results in keratouveitis. However, these phases are based on the results of experimental induced studies and not on the spontaneous occurrence of this unique ocular disease. Nevertheless, additional spontaneous cases of the “blue eye” phenomenon are required to efficiently characterize and understand the histopathologic findings of the ocular lesions in puppies naturally infected by CAdV-1.

Intralesional cysts that were immunoreactive to N. caninum but without positive immunolabelling for T. gondii were observed in multiple tissues of one puppy, indicating disseminated canine neosporosis56,57. In this case, the puppy did not demonstrate clinical manifestations suggestive of muscular disease; therefore, canine toxoplasmosis and not neosporosis was suspected, since T. gondii is frequently identified in dogs infected by CDV9,10. This puppy contained CDV RNA by RT-PCR, with additional positive immunolabelling for CDV, CAdV-2 and CPV-2, resulting in a quadruple infection; five infectious disease agents including T. gondii and CDV were diagnosed in puppy10. Moreover, coinfections of Leishmania chagasi, N. caninum, and T. gondii have been investigated in dogs, where it was suggested that the immunodepressive effects of L. chagasi might have influenced infections by N. caninum and T. gondii58. Therefore, one wonders if the known immunodepressive effects of CDV4 might have favoured the development of the protozoan infection in this puppy. This case represents one of the few documented reports of coinfections involving CDV and N. caninum in dogs. A clinical study demonstrated seropositivity to N. caninum in a dog with neurological manifestations and the simultaneous molecular identification of CDV nucleic acid9. Nevertheless, additional studies confirming concomitant infections involving these two infectious disease agents are required to efficiently evaluate this intriguing relationship.

Infections due to CAdV-2 are more frequently associated with CIRD2,34, while the occurrence of the spontaneous disease is rare in non-immunosuppressed dogs2. During this study, antigens of CAdV-2 were identified in the bronchiolar epithelium of puppies with interstitial pneumonia and CIRD, as well as in the liver of puppies with a histopathologic diagnosis of necrohaemorrhagic hepatitis and hepatocellular degeneration; similar findings were observed by ISH in puppies with interstitial pneumonia but without necrotizing bronchiolitis27 and by IHC in dogs with pneumonia26. However, we have not located a previous description of the intrahepatocellular localization and intestinal of CAdV-2 in dogs; disseminated infections involving the brain, lung, spleen and with ISH signals in Kupffer cells but not hepatocytes associated with CAdV-2 have been described in dogs with neurological manifestations27. These findings suggest that CAdV-2 can be associated with extra-pulmonary disease and that the occurrence of this pathogen should be investigated in multiple tissue of dogs. Additionally, the widespread identification of CAdV-2 in multiple organs and in several puppies can be associated with the immunosuppressive effects of CDV2, since all puppies were simultaneously infected by both pathogens.

The findings associated with infections due to CPV-2 in these puppies were similar to those described1,10,18,59 without any unusual pathologic or immunohistochemical observation, and suggest that CPV-2 should always be included in the differential diagnosis of puppies with a clinical history of haemorrhagic enteritis. Additionally, antigens of CDV, CAdV-2 and intralesional cysts of N. caninum were also identified concomitantly within the intestine in some of these puppies with haemorrhagic enteritis, suggesting that these infectious disease agents should also be included in the differential diagnoses of puppies with clinical histories of bloody diarrhoea. This is supported by the identification of antigens of CDV and not CPV-2 by IHC in the intestinal of with a puppy cryptal necrosis38, since CDV also produces enteric disease2,14.

During this study purebred dogs were overrepresented when compared to their mixed breed counterparts and may be a simple representation of the interest of their owners in determining the cause of death in these cases. However, when the head conformation of purebred dogs was analysed, brachycephalic breeds were more frequently affected relative to dolichocephalic dogs; similar findings were described in an epidemiological study of 250 dogs naturally infected by CDV16. Moreover, it was proposed that brachycephalic breeds are more predisposed to develop CD60, other neurological disorders, ocular and facial dysfunctions61 when compared to dolichocephalic dogs. Although the actual reason for this breed predisposition to develop diseases has not been fully elucidated, phenotypical head conformations of brachycephalic dogs was suggested as a possible reason due to differences in the orientation of the olfactory bulb in these specific breeds of dogs61. Additionally, dysfunctions to the olfactory bulb have been associated with the development of neurodegenerative diseases in humans due to the accumulations of pathologic proteins, α-synuclein, and neurofilament protein in the affected areas62. Consequently, it can be theorized that brachycephalic breeds of dogs are more likely to develop neurological disease, including CD, relative to their dolichocephalic counterparts, due to predisposed genetic confirmations at the olfactory bulb. Nevertheless, studies are needed to confirm the possible existence of histological differences at the olfactory bulb of brachycephalic and dolichocephalic breeds of dogs.

In conclusion, multiple infections by the viral agents herein described are common and more frequent than previously described and may result in the sudden death of puppies. Canine morbillivirus (CDV) continues to be one of the most important infectious disease agents of puppies and due to its immunosuppressive effects can facilitate the development of other infectious disease pathogens. The histopathologic pattern observed in the spontaneous cases of the “blue eye” phenomenon associated with infection by CAdV-1 in ICH was predominantly degenerative in nature. Antigens of CAdV-1 were not detected in association with gallbladder oedema in multiple animals from this study. Hepatocellular degeneration may be an initial degenerative phase of infections associated with CAdV-1, particularly in puppies that died suddenly. Interstitial pneumonia in dogs should be associated with multiple viral infectious disease pathogens, and several infectious disease pathogens must be included in the differential diagnosis during the investigation of the cause of death in puppies.

Genomics techniques, like PCR and high-throughput deep and whole-genome sequencing, that now greatly facilitate the discovery of EIDs (e.g., the etiologic agents of hantavirus pulmonary syndrome and Kaposi sarcoma) also reveal previously unimagined genomic diversity among microbes. This diversity includes complex and evolving viral quasispecies and microbes that have undergone considerable interbacterial horizontal gene transfer, creating new phenotypic properties of virulence and drug resistance.

Given these and other advances in science and technology, it is now possible to perceive, as Dawkins argued decades ago (15), that the evolution and natural selection of human diseases are not simply a struggle between microbes and hosts. Rather, it is fought out at a more basic level of gene-to-gene competition, pitting the genomes of microbes against those of their hosts (many of whose genomes contain genetic evidence of past microbial encounters). Dawkins contended that the visible evidence of genomic survival is an organism’s expressed phenotype, its “survival machine,” which is akin to a simple virus being protected by its external protein coat; however, Dawkins proposed that we should think of natural selection as operating at the level of the gene, not the organism it encodes.

This picture becomes more complex when we consider the human microbiome. Specifically, our gut flora represents a complex “external” organ system comprising at least three different “enterotypes” that have coevolved with us over millennia and appear to affect our health, including by preventing and modifying infection (16, 17). Indeed, fecal transplantation is now a novel treatment for Clostridium difficile colitis (a potentially fatal EID) (18). Infants who start life with or develop “reduced” flora (e.g., via pre- or postnatal antibiotics) may be at increased risk of IDs and EIDs. Variations in the microbiome may also affect the occurrence of certain chronic diseases, allergies, and malnutrition (19). In this newer view, humans are not just static victims of virulent microbes but hubs of gene flow in which pathogens not only “seek” to survive environmental barriers and natural and acquired immunity but also compete with other microbes on the playing field that we think of as “us.”

Additional conceptual advances in EIDs include the realization that many chronic diseases have a direct or indirect infectious basis, e.g., cervical, hepatic, and gastric cancers; gastroduodenal ulcers; hemolytic-uremic syndrome; and possibly some types of tics and obsessive-compulsive disorders (6, 12). We also have become aware of the critical role of microbial coinfections in the pathogenesis of certain infectious diseases (e.g., HIV and numerous opportunistic infections; influenza and measles in association with secondary bacterial pneumonias) and of nutrition, e.g., the link between vitamin A and measles (20, 21).

The “one-health” concept, which emphasizes understanding and studying the unity of human and animal infectious diseases (22), reflects growing awareness that the majority of human EIDs, probably more than 60 per cent (11), are of animal origin (zoonotic), a realization that has implications not only for disease surveillance but also for understanding pathogenesis and controlling disease. For example, HIV/AIDS, influenza, Lyme disease, tuberculosis, measles, plague, smallpox, and possibly even leprosy are directly or primarily of animal origin. Viral host switching, in some cases associated with rapid and complicated microbial comutations (23), has become an important research topic (23, 24) for both newer EIDs, such as SARS, and reemerging ones, such as influenza. The processes by which animal-adapted microorganisms leave their hosts and adapt to new species, such as humans, are largely unknown and represent an important challenge in the study of EIDs.

Moreover, host-switching is not just a one-way street from other animals to humans. For example, Ebola virus, a devastating disease for humans, has decimated African gorilla populations; in the United States, suburban expansion associated with deforestation has driven raccoons into the suburbs, increasing rabies transmission to and from them; and a human strain of Staphylococcus aureus has adapted to chickens, spread globally, and developed new mutations enhancing avian virulence (25, 26). These examples remind us that ecosystem dynamism in which humans play a critical role is a key variable in EID occurrence and prevention (6, 12).

Currently, 39 infectious diseases are notifiable in China, classified as A, B or C according to their epidemic levels and potential population threats. Groups A and B (total 28 diseases) represent categories of diseases with high risk of outbreaks or that are likely to result in rapid spread once an outbreak occurs. Mortality and morbidity related to group A and B diseases are reported and published by the Chinese Ministry of Health on a monthly basis. Group C diseases are less infectious and, when outbreaks occur, are epidemiologically less severe. They are required to be reported only when outbreaks occur.

In this review, we searched published peer-reviewed research articles as well as online reports and grey literature from 1985 to 2010 relevant to disease surveillance in China in the following databases: PubMed, Chinese Scientific Journals Fulltext Database (CQVIP), China National Knowledge Infrastructure (CNKI) and Wanfang Data. Keywords used in the database search included [‘Chinese’ or ‘China’] and [‘Infectious diseases surveillance’ or ‘surveillance system’ or ‘infectious diseases monitoring’ or ‘infectious diseases information’ or the type of infectious disease or the name of individual infectious diseases]. We also searched governmental reports, reports of non-governmental organisations and other grey literature from online sources. We then collated data on notified cases and mortality related to these diseases, using the latest available information from the Ministry of Health. Notifiable infectious disease data, including morbidity and mortality rates, was summarised by Chinese Ministry of Health and published annually in Chinese Health Yearbook and online accessible through CNKI database. Notably, this dataset does not contain data on SARS and influenza A(H5N1) virus infection. Hence we did not include them in our statistical analysis, but describe them in the text.

The selected diseases were categorised into eight major types according to their diseases characteristics and origins. The morbidity and mortality for each disease type were calculated as the sum of the corresponding rates of individual diseases. The total number of diagnosed and death cases were estimated by multiplying morbidity and mortality rates by the overall Chinese population in the study years. Case fatality rate was defined as the percentage of persons diagnosed with the disease who die as a result of the illness during the calendar year, and was estimated by dividing mortality rate by morbidity rate of the diseases. Further, for each individual disease, we calculate the disease-specific mortality rates among the Chinese population in five-year intervals (1999–2003 and 2004–2008). For each disease, the mean annual increase or decrease during 1999–2008, with 95% confidence intervals, is estimated, based on linear regression of logarithmic values of the number of annual death cases.

It is now becoming accepted that disease eradication has a legitimate place in the armamentarium of responses to EIDs (6). Smallpox, a devastating reemerging disease for millennia, was eradicated in 1980, and the epizootic morbillivirus (measles-related) disease rinderpest was eradicated in 2011 (32, 33). With dracunculiasis and polio disease close to eradication, with measles on the path to eradication, and with significant strides in controlling such diseases as hepatitis B and even malaria and HIV infection being made, it is now possible to realistically consider eradication as an ultimate means of controlling certain EIDs.

Even though antibiotic resistance has accelerated alarmingly, new generations of antibiotics have kept pace (albeit, barely), and vaccines against some of the most important diseases have been developed or improved, such as those against Haemophilus influenzae type B, pneumococci, and cancer-causing human papillomavirus strains. The development of antivirals and antiviral combination therapies has led to a historic breakthrough in helping to control HIV/AIDS (12) and major strides in curing chronic hepatitis C virus infection. Future directions in research and drug development likely will include better antibacterial and antiviral combination therapies as well as the development and use of more narrow-spectrum drugs against infective agents, which are less likely to cause polymicrobial resistance.

In the 20 years since the IOM report on EIDs, remarkable progress has been made in understanding and controlling them. In 1992, HIV infection was considered a death sentence for most patients. In 2012, after the tragedy of more than 35 million AIDS deaths, persons treated early with combination antiretroviral therapy, although not “cured” of their viral infection, can expect to live normal life spans with only a low risk of transmitting infection to others. In 1992, at least a million children died annually of measles. In 2012, fewer than 100,000 are expected to die, and measles eradication based upon an already-available effective vaccine is a realistic near-term goal. In 1992, it was possible to enter villages in many developing countries to monitor poliovirus circulation by conducting childhood “lameness surveys.” In 2012, most lame individuals are adults whose children are largely free of the threat of polio and probably will live to see it eradicated (poliovirus type 2 has already been extinguished).

Despite extraordinary progress during the past 2 decades, infectious diseases still kill 15 million people each year (6), and new and deadly diseases continue to emerge and reemerge. The perpetual nature of the emergence of infectious diseases poses a continuing challenge, which is volatile and ever-changing. This challenge includes a need for constant surveillance and prompt, efficient diagnosis; a need to develop and deploy new vaccines and drugs to combat new diseases; and a need for ongoing research not only in developing countermeasures but also in understanding the basic biology of new organisms and our susceptibilities to them. The future is ever uncertain, because unimagined new diseases surely lie in wait, ready to emerge unexpectedly; however, our ability to detect and identify them, our armamentarium of treatment and prevention options, our capacity to undertake and maintain basic and applied research, and our commitment to eradicating certain EIDs have never been greater. We have made far-reaching advances in the past 20 years since the original IOM report, and scientists are guardedly optimistic that further breakthroughs lie ahead.

About 81,000 people received national support (120,000 won per person; about 100 USD) for immunoglobulin administration, antigen and antibody tests for hepatitis B to prevent vertical infection from infected mothers. The participation rate was 60% in 2002, 89% in 2003, 96% in 2004, 98% in 2005, and 98% in 2006.