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

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.

In order to evaluate the NV potential of the rVSV filovirus GP vectors cynomolgus macaques were inoculated by IT inoculation with 1×107 PFU of either rVSV-ZEBOV-GP (n = 7, Fig. 1A), rVSV-MARV-GP (n = 7, Fig. 1A), rVSV-wt (n = 3, Fig. 1A), or vehicle control (n = 4). Each animal received two inoculations, one per hemisphere, with the left hemisphere receiving the experimental inoculation and the right hemisphere receiving the vehicle control. Animals were then observed for neurologic signs of disease. Clinically, two macaques from the rVSV-wt control group (67-01 and 56-09) developed progressive neurological signs including ataxia, proprioceptive deficits, and tremors, and were euthanized at either day 5 or 6 post inoculation (Table 1). One of the rVSV-wt animals (362-09) did not show any discernable neurological signs. No neurological deficits were observed in any of the macaques in the vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP groups. Hematology and serum biochemistry were also monitored for each animal with no changes being observed in any animal, when compared to a prebleed for each animal, over the course of the study (data not shown).

The order Mononegavirales comprises the non-segmented, negative sense, single-stranded RNA viruses in the family Filoviridae along with the families Rhabdoviridae, Paramyxoviridae, and Bornaviridae. The family Filoviridae contains two genera, Ebolavirus (EBOV) and Marburgvirus (MARV),. Infection with EBOV or MARV causes severe and often fatal hemorrhagic fever (HF) with case fatality rates ranging from 23–90% depending on the strain and/or species. The Ebolavirus genus is diverse and consists of four species: Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Reston ebolavirus (REBOV). A putative fifth species, Bundibugyo ebolavirus (BEBOV) was discovered during an outbreak in Uganda during 2007. Together, the Ebolavirus genus has accounted for at least 22 outbreaks dating back to 1976 with18 of these occurring within the last 20 years. The Marburgvirus genus has one species, Lake Victoria marburgvirus, that has been responsible for at least nine outbreaks since 1967 with five of these occurring in the last decade. The increased frequency of EBOV and MARV outbreaks along with the fact that these viruses are potential agents of bioterrorism has increased public health concern regarding filoviruses. Presently, there are no licensed vaccines or postexposure treatments available for human use; however, there are at least six different vaccine candidates that have shown the potential to protect nonhuman primates (NHP) from lethal EBOV and/or MARV infection,,,,,,,,,,,,,,,.

The filoviruses contain an RNA genome, approximately 19 Kb in length, which encodes seven proteins that are arranged from 3′ to 5′: nucleoprotein (NP); virion protein (VP)35; VP40; glycoprotein (GP); VP30; VP24; and the polymerase protein (L). The EBOV species express two extra nonstructural proteins from the GP gene referred to as soluble (s)GP and small soluble (ss)GP. Vaccine studies that have shown protection in animals from filovirus infections have primarily employed the GP protein as the immunogen with a few studies also using VP40 and/or NP,,,,,,,,,,,,,,,.

Vesicular stomatitis virus (VSV), a member of the family Rhabdoviridae, is composed of a genome of approximately 11 Kb which encodes five proteins that are arranged from 3′ to 5′: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the large catalytic subunit (L) of the RNA-dependent RNA polymerase. Over the last decade the use of recombinant (r)VSVs as vaccine candidates has been studied due to the ability to insert and express foreign genes in the simple genome, the ability to propagate the virus to high titers in most mammalian cell lines, the lack of recombination or insertion into the host cell genome, the extremely low percentage of VSV seropositivity in the general population of Central America,, and the minimal pathogenicity of VSV in humans. rVSV vectors have been developed as vaccine candidates against many important human pathogens such as influenza virus, human immunodeficiency virus (HIV),,, measles virus,, respiratory syncytial virus, papillomavirus,, severe acute respiratory syndrome coronavirus, and HF viruses such as Lassa, EBOV, and MARV.

The rVSV filovirus GP vaccine platform, where the VSV glycoprotein (G) is replaced with filovirus GP, has shown promise as both a single-injection preventive vaccine,,,,, and a postexposure treatment against EBOV and/or MARV challenge in NHPs, . Initial studies showed that a single intramuscular (i.m.) vaccination of cynomolgus macaques with a rVSV vector expressing the ZEBOV GP or MARV GP induced strong humoral and/or cellular immune responses and elicited complete protection against a high dose (1000 plaque forming unit [PFU]) i.m. challenge of homologous ZEBOV or MARV given 28 days later. The efficacy of these vaccines to protect by i.m. vaccination against homologous high dose (1000 PFU) aerosol challenge was also tested. Importantly, homologous aerosol challenge with either ZEBOV or MARV 28 days after vaccination resulted in complete protection of the macaques. In addition to vaccinating via the i.m. route, the ability of the rVSV-ZEBOV-GP vaccine to protect cynomolgus macaques by intranasal and oral routes was also studied. Vaccination by these different routes resulted in complete protection against homologous challenge and elicited robust ZEBOV GP-specific humoral responses and T-cell responses that were induced after vaccination and also 6 months after ZEBOV challenge. More recently, we showed that a single injection of a blended vaccine consisting of equal parts of rVSV-ZEBOV-GP, rVSV-SEBOV-GP, and rVSV-MARV-GP completely protected NHPs against lethal challenge with either ZEBOV, SEBOV, CIEBOV, or MARV.

While the rVSV filovirus GP vectors have proven robust as preventive vaccines, these vectors have also shown utility as postexposure treatments with the rVSV-MARV-GP vector protecting 100%, 83%, and 33% of rhesus macaques challenged with MARV and treated 30 minutes, 24 hours, and 48 hours postexposure, respectively,. Treatment of macaques 30 minutes after challenge with a rVSV-SEBOV GP vector protected all animals against a lethal SEBOV challenge while treatment of macaques 30 minutes after challenge with the rVSV-ZEBOV GP vector protected 50% of the animals against a homologous ZEBOV challenge.

To date, the rVSV filovirus GP vectors have been used in over 80 NHPs with no signs of toxicity as a result of vaccination,,,,,. In addition, the rVSV-ZEBOV-GP vector was recently used as a treatment less than 48 hours after a possible, accidental ZEBOV exposure to a laboratory worker in Germany. While the efficacy of the treatment was not conclusive, the treated individual experienced mild fever, myalgia, and headache 12 hours after injection. Although these data suggest that the vectors are innocuous, the use of the rVSV filovirus GP vectors as vaccines and/or postexposure treatments in humans requires further safety testing. This is important considering that the vaccine is replication-competent and there is potential for VSV neurovirulence (NV), as has been reported in rodents,,,,,,,, macaques, cattle, sheep, and horses. Regardless of the potential for rVSV vector NV, replication-competent vaccines that are to be used in humans are generally subjected to NV testing. Typically, NV is evaluated by direct inoculation of the vaccine into the central nervous system (CNS) of a NHP. These NV tests have been developed for measles virus,, mumps virus,, yellow fever virus,, and poliovirus,. Most recently rVSV HIV vaccine variants have been tested for NV by intrathalamic (IT) inoculation with promising results.

In the current study, we evaluated the NV potential of the rVSV-ZEBOV-GP and the rVSV-MARV-GP vectors in cynomolgus macaques. The NV tests were modeled on previous examinations of the yellow fever virus vaccine and rVSV HIV vector variants where cynomolgus macaques were given an IT inoculation with 107 PFU of the vaccine and closely monitored over the course of 21 days.

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).

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].

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).

Most of emerging viruses that are continuously detected belong to the RNA viruses and are often zoonotic in nature with epidemic or epizootic potential in case of transmission to livestock or humans [1–3]. Interestingly, approximately 50% of the highly pathogenic diseases caused by these agents affect the central nervous system [4–6]. Emerging viruses and also viruses highly pathogenic for animal species often arise from animal reservoirs, namely bats, rodents and insectivores. Thus, reliable animal models for the in vivo analysis of host-pathogen interactions in respective reservoir species and the mechanisms that drive crossing of species barriers are urgently needed. This could also allow characterization of transmission routes and maintenance in reservoir populations of these viruses. The order Mononegavirales comprises non segmented negative stranded RNA viruses with a considerable number of highly pathogenic viruses which reside inconspicuously in natural reservoirs, e.g. lyssaviruses, paramyxoviruses and henipaviruses in bats. In case of transmission to susceptible animals or humans they cause fatal disease [7, 8]. Borna disease virus-1 (BoDV-1) also belongs to the order Mononegavirales and was classified within an own and currently growing family named Bornaviridae. A new classification of this family with subdivision into 5 species has been proposed with the classical Borna disease virus-1 as part of the species Mammalian 1 bornavirus. Recently, a variegated squirrel-derived bornavirus (VSBV-1) was found in association with the death of three people indicating the zoonotic potential for this newly discovered bornavirus. Comparably to other reservoir-bound viruses of the order Mononegavirales, BoDV-1 infection can lead to a lethal neurological disorder in accidental hosts such as horses and sheep due to a severe immune mediated non purulent meningoencephalitis. The strictly endemic course of Borna disease with seasonal appearance in spring and early summer, the varying incidence between years with peaks every three to five years as well as the highly conserved viral genome pointed to a natural reservoir for BoDV-1 already for a long time. However, many studies in wild rodents did not reveal any signs of BoDV-1 infection in these species. First evidence of natural BoDV-1 infection in small mammals was provided by the detection of BoDV-1 antigen and RNA in bicolored white-toothed shrews (Crocidura leucodon) originating from an endemic area in Switzerland [14, 15]. This was substantiated by a study based on a geographic information system analysis which connects the prevalence of Borna disease and the distribution of C. leucodon. Recently, similar occurrence of BoDV-1 infection in C. leucodon in endemic areas in Bavaria and in Saxony-Anhalt [17, 18] further underlines the role of this shrew species as BoDV-1 reservoir. Overlapping feature of all BoDV-1-infected shrews—regardless of their endemic origin—is the widespread virus distribution not only in the central nervous system (CNS) but also in peripheral organs capable of shedding virus in secretions and excretions [15, 17, 18]. Experimental BoDV-1 infection of neonatal immune incompetent rats leads to a quite comparable mode of virus distribution. In these animals, persistent infection is achieved by immune tolerance. Obvious neurological signs are lacking but behavioural deficiencies have been noted. In contrast, adult Lewis rats exhibit a severe neurological biphasic disease due to a non purulent meningoencephalitis closely resembling the accidental host situation. Certain mice strains develop a fatal neurological disease only after intracerebral infection of newborns [20, 21]. Thus, outcome of experimental BoDV-1 infection in rodents such as mice and rats depend on the species and even the particular strain and, the age at time point of infection. The latter is most likely explainable by the status of the immune system. This leads to significant differences in virus-host interactions resulting in variable clinical outcome and fatality of disease, reaction pattern of the immune system, virus distribution and shedding.

Whether natural BoDV-1 infection of C. leucodon may fit to any of the known experimental courses or even run a different and so far unknown way of infection remains unknown. Thus, clinical outcome, routes of virus shedding including demonstration of infectivity was characterized in BoDV-1-infected C. leucodon. This contributes to understand not only BoDV-1 pathogenesis but also serve as in vivo model for the analysis of general mechanisms of viral co-existence of reservoir-bound neurotropic viruses in physiologically normal appearing hosts.

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).

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).

Reservoir-bound RNA viruses reside typically inconspicuously in animal reservoirs such as bats, rodents and insectivores. However, transmission routes, host-pathogen interactions necessary for viral maintenance in the respective animal population and factors needed to cross the species barrier are still rudimentarily known. Thus, reliable animal models are urgently needed. The order Mononegavirales comprises many viruses with high zoonotic and pathogenic properties, e.g. filoviruses, henipaviruses, paramyxoviruses and lyssaviruses which reside in bat reservoirs [7, 31]. In their biological behaviour, bornaviruses, as known from the mammalian Borna disease virus-1 (BoDV-1), are unique [10, 32], but in several aspects pretty comparable to other neurotropic Mononegavirales. The recently found zoonotic variegated squirrel 1 Bornavirus (VSBV-1) clearly differs in its homology to the classical mammalian BoDV-1 but provides evidence for its zoonotic capacities. As the current knowledge is sparse, it is not known if VSBV-1 share features with BoDV-1 behaviour. However, detection of VSBV-1 in several organs including CNS and peripheral organs like lung and kidney of the squirrel also indicate a widespread virus distribution comparable to the BoDV-1 infected bicolored white-toothed shrew.

Typically shrews rear up to four litters from March to September and winter resource shortage is the most important source for mortality. Trapping took place during summer and autumn, therefore caught shrews were likely born in the same year and the age at time of trapping could be estimated between 1 to 6 months. As most of the offspring settles locally kinship between the individuals and joint rearing cannot be excluded.

During trapping, infection status of the individuals was unknown. Previous studies showed different infection prevalence of shrews that also differed between the trapping sites in the study. Hilbe et al found only infected shrews (100%), Puorger et al. detected 2/6 infected shrews (33%), Bourg et al. showed 1/1 infected shrews (100%) at one site und 1/19 infected shrews (5%) at the other site whereas Dürrwald et al. found an amount of 9/17 infected shrews (53%) at one site with a variance between the years from 25% to 100%. These differences can be due to the small number of animals in the respective population or represent the natural variation within the shrew population between sites and years. Since examination of larger cohorts has not been carried out so far, the percentage of naturally infected shrews among the trapped animals could not be predicted in detail. Six naturally infected shrews out of eleven shrews implies a percentage of 55% of infected shrews with variations between the sites and years from 50% (site A, year 2013 3/6, year 2014 1/2) to 66% (site B, year 2014 2/3). As all non-infected animals did not show any shedding during the whole observation period, transmission of the virus in the husbandry could be successfully prevented in captivity.

Current data from living shrews provide reliable evidence that natural BoDV-1-infection in these animals is indeed clinically inconspicuous over a long time period as already previously assumed [15, 18] despite persistent infection with shedding of infectious virus via various sites. During the observation period of up to 600 days, only two naturally infected animals were lost due to an intestinal invagination in one case and hepatitis/pneumonia in the other case which did not seem to be directly related to BoDV-1 infection. In the bronchial epithelium of the animal suffering from hepatitis/pneumonia only few cells harboured BoDV-1 nucleoprotein, BoDV-1 mRNA and genomic RNA without associated distribution to the pneumonia and in the liver only genomic RNA was detected in very few cells.

Interestingly, shedding of viral RNA was continuously present.As shrews were naturally infected before trapping, the time between the infection and first virus release remain unknown. However, low ct-values were found in samples taken at time points at least more than 4 to 8 weeks after infection and at time points at least more than 200 days after infection. This indicates a persistent BoDV-1 infection as known from other animals [11, 13] with long lasting and continuous virus release. There was certain variability in the amount of viral RNA, sites of shedding, between individual animals and for the time points of sampling. Some of these variations can be due to variations in sample size, as gathering of samples had to be performed non-invasive on non-anaesthesized animals. However, several shrews exhibited lowest ct-values in saliva and lacrimal fluid regardless of time point of sampling. Whether this might have a role for virus transmission, e.g. combating, needs to be further investigated.

The simultaneous presence of viral antigen, viral mRNA and genomic RNA in CNS and peripheral tissues points to many sites of viral replication thereby enhancing probability of successful virus transmission to other animals. Horizontal transmission of BoDV-1 in shrews might be either achieved via direct contact with secretions or excretions or even via contaminated environment. Since shrews are known to behave territorially, infection by infected saliva during combating for a habitat might also occur. Vertical transmission of BoDV-1 in shrews cannot be excluded as viral antigen has been detected in the uterus. However, the route of entry in the reservoir still remains unknown. Offspring might already be infected early by their mothers due to the various sites of viral shedding even from the skin. The underlying viral mechanisms of maintenance in the reservoir are still incompletely understood but might include adjusted viral life cycle possibly with attenuated pathogenicity, differences in viral entry and circumvention of the antiviral host immune system [4, 34, 35]. The latter could be achieved best in specific situations of the host immune system. Infection of animals in an immune-incompetent stage can lead to persistent, immune-tolerant virus infections, often associated with shedding of high doses of infectious virus and without any severe clinical signs and notable inflammatory lesions. To date it remains unknown whether disseminated BoDV-1 infection of shrews is only possible when infected in an immune incompetent state as known for rats. However, the clinical inconspicuous course could point to an immune tolerant infection and a highly adapted viral-host interaction. Neonatally BoDV-1 infected rats display no neurological signs but increased motor activity, learning deficits and subtle changes in social behaviour and memory [36, 37]. Moreover, experimental BoDV-1 infection of the prosimian tree shrew (Tupaia glis) leads to a persistent infection and transient mild encephalitis, resulting in a disorder characterized primarily by hyperactivity and pronounced disturbances in social and breeding behavior rather than neurological signs. In the neonatally BoDV-1 infected rat the behavioral changes were attributed to lesions in the hippocampus and cerebellum and in the tree shrew to alterations of the limbic system. Whether naturally BoDV-1 infected shrews also display subtle deficits in learning, memory and/or social behavior, especially mating, needs to be addressed in further behavioral and breeding experiments. As known so far, C. leucodon did not exhibit any morphological changes in cerebellum, hippocampus or elsewhere in the brain as noted for the neonatally infected rat. However, any behavioral changes might contribute to higher contact frequency or increased aggressive and territorial behavior thereby facilitating viral transmission and maintenance in the reservoir.

Characteristics of the shrew population correspond well to the epidemiologic pattern of Borna disease. The distribution of C. leucodon in Bavaria and the prevalence of Borna disease seem to be connected. The yearly varying peaks of Borna disease in accidental hosts and the decline of Borna disease within the last decades could be related to population dynamics of the shrews between the years and the restriction of habitats indirectly caused by modern agriculture. Inbreeding and low dispersal distance of the offspring correlates with the limited distribution of BoDV-1 within endemic territories.

Moreover, the continuous secretion and excretion of infectious BoDV-1 and the detection of viral RNA in the lair substantiates the hypothesis that “infectious dust” is responsible for BoDV-1 transmission to accidental hosts through the intranasal route as known for hantavirus infections. In this scenario, the BoDV-1 infection of horses and sheep might rather represent an accidental occasion. To date it still remains to be solved whether and which factors are responsible for successful crossing the species barrier. Amount of infectious virus, virulence, immune status and age of reservoir and accidental host as well as their genetic makeup might function as essential co-factors.

Taken together, shedding of BoDV-1 in the bicolored white-toothed shrew is achieved via various routes which enable successful viral maintenance in the reservoir population and even fatal transmission to susceptible accidental hosts such as horses and sheep. Moreover, these animals serve as suitable model to investigate host and pathogen factors that enable persistent viral co-existence in apparently healthy carriers.

Assume the number of population to be N in this group, including susceptibles, infected, and healers,

which are denoted as S, I, and R, respectively. The average effective contact (transferable) with

other people for a person in a unit time is β; the number of people who are cured within the unit time is

γ; the treatment cost is α; and the government compensation is µμ. In reality, the number of patients or the number of people

participating in the treatment depends on the treatment cost. To encourage infected

patients to take treatment promptly, the government should provide moderate

compensation. Furthermore, suppose γ=e−α+μ in this study and obviously γ∈(0,1]. As the cost of treatment increases, the number of people

participating in treatment decreases, but government financial compensation can

effectively promote the participation of infected patients in treatment. According

to the model proposed by Kermack et al in 1927, and based on China’s successful

experience in dealing with SARS, this article establishes the compensation model for

important infectious diseases as follows:

(1)dSdt=−βISN,

(2)dIdt=βISN−e−α+μI,

(3)dRdt=e−α+μI.

Functions (1) to (3) meet the constraint S(t)+I(t)+R(t)=N. Compared with the traditional infectious disease models, this

model analyzes treatment costs and the impact of government interventions on

infectious diseases. Different from the traditional infectious disease models, the

above model considers the impact of government intervention on infectious diseases.

According to function (3), we know that government intervention will significantly

increase the population of the cured individuals, thereby reducing the spread speed

among the infected population.

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.

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.

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.

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.

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.

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).

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.

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.

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.

Transmission of infectious disease through contact among individuals increases the risk of outbreaks with epidemic potential. However, understanding how diseases spread over networks of contacts remains a challenge. In particular, outbreaks of potentially devastating infections, such as SARS (2003), Ebola (2014–2015), and Zika (2015–2016), have shown that the dynamics behind the spread of disease has become more complex, limiting our ability to predict and control epidemics. In this regard, patterns of disease transmission should be used to design specific public health strategies to enhance sustainable capacity while building activities to improve government responses to infectious diseases. Therefore, an analysis of disease dynamics based on the contact patterns can be used to build practical guidance while framing disease prevention and management strategies.

The interpersonal contact patterns of disease transmissions have often been discussed in a network context while modelling epidemics1–4. Most potential disease contact takes place in localized communities among individuals occupying a local geographic space around the diseased. If such contacts are repeated within a given period, certain patterns of links will arise. These link patterns can be represented as networks, which show the spread of an infection among individuals. Thus, certain disease dynamics represented in a contact network can be characterised by topologies.

Previous studies on super-spreaders have identified two major types of networks, small-world network5 and scale-free network6. In the small-world network, a small number of shortcuts are discovered either by randomly connecting the nodes or randomly rewiring the links. From the shortcuts, it can be inferred that the average node length between any two individuals is shortened, thereby making geographic distance a causal factor in epidemic outbreaks7. In the small-world network context, thus, it is important to control the super-spreading events to prevent completely new outbreaks8,9. In the scale-free network, on the other hand, the number of contacts per individual exhibits a power-law distribution of infection links. The variation in the connectivity distribution of the scale-free network is infinite, because it does not exhibit the threshold phenomenon. Hence, an outbreak can occur at any time10. It can be inferred from both networks that the average shortest path length and a small degree of separation are important factors in the epidemic network analysis11. Furthermore, the super-spreading characteristic of epidemics has been associated with the spatial proximity of neighbouring nodes in the network5,12. Localised transmission of the epidemic is facilitated by high clustering coefficients, because of the close spatial proximity in node connectivity and its influence on their relation. Thus, nodes with a high spatial proximity tend to intensify super-spreading events within clusters, making it easy for the disease to spread locally over the considered population or areas.

It is known that three factors can cause a disproportionately large number of secondary contacts during super-spreading events13: host factors (including physiological, behavioural, and immunological factors); viral factors (including virulence and co-infection factors); and environmental factors (including density, failure to recognise the disease, inter-hospital transfers, and airflow dynamics). Among these various factors, previous studies have focused specifically on the behaviour of the host and environmental factors in explaining the outbreak of SARS and MERS14,15. It has been established that certain behaviours of the hosts, such as doctor shopping (visiting multiple doctors and facilities), play a critical role in the spread of infectious disease, as multiple visits by the super-spreaders can lead to the contamination of several medical facilities. In addition to the behaviour of the infected individual, a high population density also correlates to a higher number of infections emanating from both the SARS and MERS hosts, because the probability of infection in such a setting tends to be high15. Given that the edges in the epidemic network represent physical proximity, a high level of clustering implies that infection occurs locally and spreads rapidly16.

The 2015 outbreak of the Middle East Respiratory Syndrome (MERS) in South Korea has been paid much attention as the outbreak was the first and biggest to occur outside Saudi Arabia, where the disease was identified in 2012. It has been known that the human-to-human transmission of MERS-coronavirus (CoV), which is a viral respiratory infection caused by a coronavirus, is relatively limited owing to its lower level of contagiousness. According to Centers for Disease Control and Prevention (CDC)17, MERS is thought to be transmitted through respiratory secretions. However, the particular way in which the virus spreads is not fully understood. During the MERS epidemic of 2015, 186 people across 16 healthcare facilities were infected, of whom 39 lost their lives. This biggest outbreak in a relatively short time began with an ‘index patient’, who had visited the Middle East and returned to Korea on May 4. The patient sought treatment for respiratory symptoms at several healthcare facilities and was later confirmed to have a MERS infection on May 20. By then, 31 people had come in contact with the patient, including family members, patients, visitors and hospital staff. In one instance of contact, a second patient was exposed to MERS while sharing an emergency room where the index patient sought care. The two patients became super-spreaders, assumed to generate many transmission events. Thus, they were likely to initiate infection among the susceptible population. Our expectation is that super-spreaders are more likely to hold certain structural advantages in facilitating continued transmission.

This study investigates the spread of infections over networks of contacts among individuals by exploring the 2015 MERS outbreak in Korea. We assume that the spread of a disease in a population depends on both the dynamics of the disease transmission and the structure of the contact networks over which they spread1,18–24. One perspective contends that the hosts who transmit the MERS infection are those who are highly central in the contact network. Thus, many neighbouring hosts form relational ties to others vulnerable to infection. Another perspective argues that if a host has already been infected and other hosts are not yet exposed, healthcare facilities play the pertinent role of delivering the infectious virus to other susceptible hosts. We analyze structural network properties of the epidemic transmission by examining both the relationship matrix of the infection tracing of infected individuals (from-whom-to-whom) and the bipartite transmission routes of infected individuals by healthcare facilities visited for treatment. In this study, we explore two research questions about the MERS outbreak in Korea: (a) How did the infectious disease become widespread through a network in a relatively short period of time?; and (b) How did a small fraction of individual hosts spread the MERS virus to a majority of the population?

Proventricular dilatation disease (PDD) is considered by many to be the greatest threat to aviculture of psittacine birds (parrots). This disease has been documented in multiple continents in over 50 different species of psittacines as well as captive and free-ranging species in at least 5 other orders of birds. Most, if not all major psittacine collections throughout the world have experienced cases of PDD. It has been particularly devastating in countries like Canada and northern areas of the United States where parrots are housed primarily indoors. However, it is also problematic in warmer regions where birds are typically bred in outdoor aviaries. Moreover, captive breeding efforts for at least one psittacine which is thought to be extinct in the wild, the Spix's macaw (Cyanopsitta spixii), have been severely impacted by PDD.

PDD is an inflammatory disease of birds, first described in the 1970s as Macaw Wasting Disease during an outbreak among macaws (reviewed in). PDD primarily affects the autonomic nerves of the upper and middle digestive tract, including the esophagus, crop, proventriculus, ventriculus, and duodenum. Microscopically, the disease is recognized by the presence of lymphoplasmacytic infiltrates within myenteric ganglia and nerves. Similar infiltrates may also be present in the brain, spinal cord, peripheral nerves, conductive tissue of the heart, smooth and cardiac muscle, and adrenal glands. Non-suppurative leiomyositis and/or myocarditis may accompany the neural lesions. Clinically, PDD cases present with GI tract dysfunction (dysphagia, regurgitation, and passage of undigested food in feces), neurologic symptoms (e.g. ataxia, abnormal gait, proprioceptive defects), or both. Although the clinical course of the disease can vary, it is generally fatal in untreated animals.

The cause of PDD is unknown, but several studies have raised the possibility that PDD may be caused by a viral pathogen. Evidence for an infectious etiology stems from the initial outbreaks of Macaw Wasting Disease, and other subsequent outbreaks of PDD. Reports of pleomorphic virus-like particles of variable size (30–250 nm) observed in tissues of PDD affected birds led to the proposal that paramyxovirus (PMV) may cause the disease; however, serological data has shown that PDD affected birds lack detectable antibodies against PMV of serotypes 1–4, 6, and 7, as well as against avian herpes viruses, polyomavirus, and avian encephalitis virus. Similarly, a proposed role for equine encephalitis virus in PDD has been ruled out. Enveloped virus-like particles of approximately 80 nm in diameter derived from the feces of affected birds have been shown to produce cytopathic effect in monolayers of macaw embryonic cells, but to date no reports confirming these results or identifying this possible agent have been published. Likewise, adeno-like viruses, enteroviruses, coronaviruses and reoviruses have also been sporadically documented in tissues or excretions of affected birds yet in each case, follow-up evidence for reproducible isolation specifically from PDD cases or identification of these candidate agents has not been reported. Thus, the etiology of PDD has remained an open question.

To address this question, we have turned to a comprehensive, high throughput strategy to test for the presence of known or novel viruses in PDD affected birds. We employed the Virus chip, a DNA microarray containing representation of all viral taxonomy to interrogate 2 PDD case/control series independently collected on two different continents for the presence of viral pathogens. We report here the detection of a novel bornavirus signature in 62.5% of the PDD cases and none of the controls. These bornavirus-positive samples were confirmed by virus-specific PCR testing, and the complete genome sequence has been recovered by ultra-high throughput sequencing combined with conventional PCR-based cloning.

Bornaviruses are a family of negative strand RNA viruses whose prototype member is Borna Disease Virus (BDV), an agent of encephalitis whose natural reservoir is primarily horses and sheep. Although experimental transmission of BDV to many species (including chicks) has been described, there is little information on natural avian infection, and existing BDV isolates are remarkable for their relative sequence homogeneity. The agent reported here, which we designate avian bornavirus (ABV) is highly diverged from all previously identified members of the Bornaviridae family and represents the first full-length bornavirus genome cloned directly from avian tissue. Subsequent PCR screening for similar ABVs confirmed a detection rate of approximately 70% among PDD cases and none among the controls. Sequence analysis of a single complete genome and all of the additional partial sequences that we have recovered directly from the PDD case specimens suggests that the viruses detected in cases of PDD form a new, genetically diverse clade of the Bornaviridae.