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

The application of NGS to the unbiased mass sequencing and bioinformatic analysis of total nucleic acids extracted from biological samples obtained from a wide range of sources has led to an explosive increase in the number of complete or near-complete viral genomes. For example, a recent study using NGS to sequence the transcriptomes of arthropods representing 70 species from four classes (Insecta, Arachnida, Chilopoda, and Malacostraca) identified 112 novel viruses, many of which are represented by complete or near-complete genomes. The novel viruses encompass the entire taxonomic diversity of previously known families and/or genera of (-) ssRNA viruses and include divergent viruses with entirely novel and unusual genome architecture. Similarly, sequence analysis of the transcriptomes of animals of more than 220 species sampled across nine metazoan phyla (Arthropoda, Annelida, Sipuncula, Mollusca, Nematoda, Platyhelminthes, Cnidaria, and Echinodermata), as well as chordates of the subphylum Tunicata (salps and sea squirts), resulted in the discovery of 1445 RNA viruses, mostly represented by complete or near-complete genomes. Based on phylogenetic analysis of RNA polymerase (RdRp) domain sequences, the novel viruses included clades representing many established families of plant and animal RNA viruses, as well as at least five clades that are so divergent that they are considered as likely new virus families or orders. Also, the sequencing of transcriptomes of gut, liver, and lung or gill tissue of fish, reptiles, amphibians, and birds identified 214 novel vertebrate-associated viruses, representing every family or genus of RNA virus associated with vertebrate infection, including those containing important human pathogens (orthomyxoviruses, arenaviruses, and filoviruses). These and other similar studies have heralded a new era in virology, revealing new dimensions in viral biodiversity and providing largely unexpected insights into the deep evolutionary history of viruses. However, only a minor subset of newly discovered viruses has been subject to full phenotypic characterization which can provide critical and fundamental insights into their biology and virus-host interactions, ultimately transforming our understanding of the evolutionary forces that shape the virosphere and disease emergence. Realistically, as important as these discoveries are to the advancement of science, very few of the viruses will ever cause human disease or influence the global economy.

This mass sequencing approach, which has been called viral metagenomics, can also be applied in a more targeted way to identify viruses in clinical cases of diseases of unknown etiology or to survey for potentially novel zoonotic viruses that may represent a significant risk of transmission to humans. Indeed, NGS is being used increasingly in conjunction with real-time PCR as a front-line tool in medical and veterinary settings for rapid detection and identification of exotic or unknown emerging viruses. For example, in 2009, an outbreak of acute hemorrhagic fever occurred in Mangala, Democratic Republic of Congo (DRC), involving three human cases, two of which were fatal. As no positive diagnosis was obtained using real-time PCR for known viral hemorrhagic fevers in Africa, NGS was conducted on acute phase serum collected from the surviving patient, revealing the near-complete sequence of a novel rhabdovirus, Bas-Congo virus (BASV; species Bas Congo tibrovirus). Although the disease was attributed by the investigators to the novel virus, no isolate was obtained and there was no evidence of neutralising antibodies in 43 serum samples from undiagnosed hemorrhagic fever cases or 50 random serum donors from the DRC. Subsequently, NGS of blood collected from healthy individuals from Nigeria identified two related viruses, Ekpoma virus 1 (EKV-1; species Ekpoma 1 tibrovirus) and Ekpoma virus 2 (EKV-2; species Ekpoma 2 tibrovirus), and a serological survey indicated that antibodies to these or similar viruses occur commonly in healthy humans in Nigeria. However, once again, neither virus was isolated. Interestingly, several other tibroviruses had previously been isolated from healthy cattle or biting midges (Culicoides spp.) in Australia and Florida. None have been associated with either disease in livestock or the infection of humans. These and other studies raise important issues regarding the significance of NGS data, even when providing complete or near-complete viral genome sequences, when investigating disease etiology. Most viruses can cause asymptomatic infections and many newly discovered viruses may be benign in their natural host. Therefore, in the absence of a virus isolate which can be used for experimental studies, establishing a causal association with disease based only on detection of the viral genome should be approached cautiously.

The availability of a rapidly expanding number of novel viral genomes identified by metagenomic studies has also presented challenges for virus taxonomy—a system for classification of viruses that is administered by the International Committee on Taxonomy of Viruses (ICTV). Should viruses detected only by their nucleotide sequence be classified and assigned to species and other higher taxa (genus, family order, etc.) alongside viruses for which we have a viable isolate? The ICTV (then the International Committee on Nomenclature of Viruses) was established in 1966 at the ninth International Congress for Microbiology in Moscow, publishing its first report in 1971. It operates under the auspices of the International Union of Microbiological Societies (IUMS), with the authority to develop, refine, and maintain a universal virus taxonomy. Historically, the description and classification of a new virus by the ICTV required significant information, such as host range, serology, replication cycles, and structure, aspects that could be determined from the study of isolates. On the other hand, sequences alone provide a trove of information, including evolutionary relationships (e.g., phylogeny), genome organization (e.g., the number of genes and their order), presence or absence of distinctive motifs (e.g., protein cleavage sites, terminal sequences, internal ribosome entry sites), as well as genome composition (e.g., codon usage, GC content), which of course could be used to inform classification into species. These concerns framed the contents of a workshop of experts and members of the ICTV, resulting in a seminal consensus statement in which viruses identified only from metagenomic data are considered to be bona fide viruses and thus candidates for taxonomic assignment. The expanding diversity of the known virosphere also presented challenges. A recent analysis of metagenomes of 3042 geographically and ecologically diverse samples led to the discovery of 125,842 new partial dsDNA viral genomes encoding more than 2.79 million proteins, 75% of which had no sequence similarity to proteins from known virus isolates. Other metagenomic studies have revealed similar diversity in ssDNA and RNA viruses, particularly in marine ecosystems. This has led ICTV to consider a far broader framework for taxonomic assignment of viruses, recently approving the establishment of a taxonomic hierarchy that includes 15 ranks (realm, subrealm, kingdom, subkingdom, phylum, subphylum, class, subclass, order, suborder, family, subfamily, genus, subgenus, and species), thus expanding the range even beyond those currently available for other organisms. The sheer volume of new virus genomes identified by metagenomic studies has also led to the development of new bioinformatic tools, that are increasingly being applied for automated virus classification of viruses, based almost exclusively on nucleotide sequence data.

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.

Bluetongue disease history is scarred with incidents of contamination of biological samples. In 1992, modified live vaccines against canine distemper, canine adenovirus type 2, canine parainfluenza, and canine parvovirus, reconstituted with a killed canine coronavirus vaccine, led to abortions in several bitches. A virus could be isolated and was eventually identified as BTV serotype 11. More recently, a case of BTV11 contamination was reported by ANSES (Agence nationale de sécurité sanitaire

de l’alimentation, de l’environnement et du travail, Maison-Alfort, France), in the context of an experimental infection of goats with BTV8. It appeared to be very closely related to the BTV11 isolated in Belgium. We discussed a BTV15 contamination in a recent study. This particular inoculum has been previously involved in two other experimental infections. Eschbaumer et al. used BTV1 culture supernatant that was then passaged once on VERO cells before being injected in calves and sheep. That inoculum has been subsequently used by Dal Pozzo et al., with the exact same outcome, namely discovery of the BTV15 contamination. BTV inoculums were not only contaminated with BTV heterologous serotypes: Rasmussen et al. reported the use of a BTV2 inoculum contaminated with Border Disease Virus in sheep.

So far, literature does not report experimental infections with a SBV inoculum that was contaminated by another virus belonging to the same or a different family. Broadly speaking contamination routes are most likely related to i) laboratory contamination during sample preparation or ii) natural multiple infection of the original donor animal. Given the potential dramatic consequences of such contamination incidents, inocula should be tested for major pathogens affecting the host species used in challenge experiments but also for a set of BTV serotypes considered to be the most at risk. Despite the transient circulation of BTV6, BTV11, and BTV14 of vaccine origin in Europe, the BTV11 contamination here above mentioned happened to be similar to BTV11 reference strain. Hence, the contamination of the inoculum is far from being necessarily related to an ongoing viral circulation even though it might remain silent because of the lack of clinical consequences. Thus, to rule out any potential BTV contamination all known BTV serotypes should be tested for. Such a recommendation would inevitably increase the constraints and costs of quality control of inocula prior to their use in experimental infections. Extensive screening could however be considered on a case-by-case basis.

When it comes to arboviruses the choice of the route of inoculation can be driven by two main considerations:(1)The need for a route that best mimics the behaviour of the vector in field conditions. Usually haematophagous arthropods are either telmophagous or solenophagous; depending on the vector species the route might be intradermal (ID), subcutaneous (SC), or intravenous (IV). In experimental infections the inoculated viral load and volume are usually higher than the ones inoculated through naturally occurring feeding given the size of the arthropods and the size of their mouthparts. Another drawback already mentioned is the lack of vector saliva components, which can modify the structure and infectivity of Reoviridae and Peribunyaviridae viral particles.(2)The need for a route that will ensure the virus to reach the blood stream. Quite obviously this is the intravenous route. Since vector saliva components can enhance the infectivity of arboviruses there is a risk that the inoculation of the virus alone or at a distal site from the vector feeding site could result in a failed infection. Therefore, the option to bypass the skin for reaching the bloodstream may be relevant.

Several authors including us used mixed routes to overcome the respective disadvantages of each approach (Table 1;). In a study of our group, we compared intranasal, intradermal and subcutaneous routes for experimental infections of ewes with SBV. Intradermal is an interesting yet underused route: indeed most haematophagous arthropods do not pass the skin and their mouthparts only allow them to feed intradermally. Most of the cellular and fluid exchanges between the skin and the blood do occur in the dermis. In addition, there are some evidences suggesting that intradermal inoculation can be more appropriate to reproduces many aspects of natural infection, including clinical disease, viral and immune responses. The intradermic route was demonstrated to better mimic natural early stages of the infection, directly influencing the severity of the disease. BTV-induced immunosuppression is linked to the infection and disruption of follicular dendritic cells, which is mostly possible through intradermic inoculation.

However, to perform an actual intradermal inoculation the volume to be injected has to be limited, the dermis being mostly composed of a dense network of collagen fibres. Therefore, it is required to multiply inoculation sites to reach desired total inoculum volume and infectious titre. To realize the inoculation itself, the most practical tools are Dermojet® (Akra Dermojet) or special syringes for intradermal injections (used to perform bovine tuberculosis skin tests for example). These devices allow usually volumes between 0.1 and 0.4 mL, thus the need for multiple injections to reach the common 1–4 mL inoculation volume used in ruminant infectious challenges experiments (Table 1). Moreover, with both systems the inoculum has to be transferred from its original vial to a small tank of the dermojet or to a special cartridge to be used with the intradermal syringe. This extra step increases the number of handlings, which should be limited especially in the case of BSL3 pathogens.

We investigated the intranasal route to test whether or not a potential direct SBV contamination between sheep could be achieved. Regarding BTV several authors reported unexpected and inconclusive direct horizontal transmission with different serotypes (BTV8, BTV1, and BTV26 at least).

Several authors reported a direct link between the inoculated viral doses and the onset of clinical signs and viraemia, i.e., the higher the dose the sooner the clinical signs and viral RNA detection. In another study, we evaluated four 10-fold dilutions of a SBV infectious serum inoculum in ewes. The undiluted original inoculum had a titre of 2 × 103 TCID50/mL. It appears there is a critical dose to be inoculated for reproducing field-like virological and immunological parameters, and once this threshold is reached, there is no dose-dependent effect anymore. In the successfully infected animals, no statistical differences between the different inoculation doses were found in the duration or quantity of viral RNA circulating in blood, nor in the amount of viral RNA present in virus positive lymphoid organs. Likewise Di Gialleonardo et al. compared three groups of cattle inoculated with 100-fold dilutions of BTV8; no significant differences in viraemia kinetics could be found.

Inoculation by the bite of Culicoides was reported to be more efficient than intradermal inoculation, especially by delaying the early immune response of the host despite a generally lower inoculated viral dose when compared to needle inoculation. Several mechanisms were hypothesized to explain this apparently enhanced infectivity in Culicoides transmitted BTV:(1)The Culicoides saliva contains proteases able to cleave VP2, leading to the formation of infectious subviral particles (ISVP) displaying higher infectivity in KC cells and Culicoides;(2)The ratio of infectious BTV particles versus defective virions produced within Culicoides might be higher when compared with cell culture grown BTV; and(3)Pharmacological agents contained in Culicoides saliva might affect the host’s immune response by anti-proliferative effects on leucocytes or a reduced INF alpha/beta expression, as demonstrated with vesicular stomatitis virus and mosquito saliva.

Nonetheless, the use of Culicoides to perform experimental challenges remains highly limited by practical constraints: to date besides C. nubeculosus, C. riethi, and C. sonorensis no other Culicoides species were successfully establish as lab-adapted colonies, the alternative being insects caught in the wild. In addition, prior to the infectious challenge on the ruminant host, the infection of Culicoides is particularly tricky given the size of the insect and the exact amount of virus delivered to each ruminant cannot be known.

Altogether, the subcutaneous route seems to represent the best compromise for BTV and SBV. The dose itself has to be sufficient but there is no gain in using massive viral load.

West Nile virus is maintained in nature in an enzootic (“rural” or “sylvatic”) cycle between its natural reservoirs, wild birds, and ornithophilic mosquitoes acting as vectors. WNV is a generalist pathogen, as exemplified by the fact that in North America the virus has been found infecting 284 different species of birds and 59 species of mosquitoes, although of these not more than 10 have a relevant role as vectors (Hayes et al., 2005a). This wide host and vector ranges probably facilitate the colonization of vast areas (Kramer et al., 2008). Primary enzootic vectors are most often mosquitoes belonging to the genus Culex, but the virus can be transmitted by mosquitoes of other genera (e.g., Aedes sp.) Transovarial transmission of the virus has been shown to occur in at least some Culex species (Mishra and Mourya , 2001), and this may provide an overwintering mechanism in very cold climates. However, it is not clear whether transovarial transmission takes place as effectively as to allow overwintering. The virus has been repeatedly isolated from ticks, and transmission through tick bites has been shown experimentally (Abbassy et al., 1993; Hutcheson et al., 2005; Formosinho and Santos-Silva, 2006). This has led to the postulation of a role for ticks in overwintering, though this issue needs further studies to be ascertained. WNV can also be transmitted in the absence of vector, using different routes. Firstly, there is experimental evidence of direct transmission in poultry (geese; Banet-Noach et al., 2003). Secondly, carrion birds found infected during periods of absence of vector suggests oral transmission, likely through feeding on contaminated carrion (Garmendia et al., 2000; Dawson et al., 2007). In humans, WNV transmission routes such as intrauterine, lactogenic, and iatrogenic (through transfusions and transplants), are well documented (Hayes et al., 2005b). Occupational exposure of laboratory workers handling contaminated samples has also led to some cases of disease, mostly through cuts or punctures with contaminated material (Hayes et al., 2005b; Venter et al., 2010).

Birds are the natural reservoirs of WNV. Once infected, they are able to replicate the virus in sufficient quantity to enable its transmission to a blood-sucking mosquito. This is not the case of mammals, in general poorly effective as hosts for the virus (Blitvich, 2008). Nevertheless, mammals can be susceptible to the disease to varying degrees. Birds maintain the virus in a rural cycle. In some instances a spillover from this cycle occurs which enables the establishment of a urban cycle, producing outbreaks, sometimes of epidemic character, especially in equines and humans, but also affecting susceptible birds.

West Nile virus is endemic in large parts of Africa, Australia, and India, and more recently (as discussed below) arrived to North America, where since then became endemic. In Europe, North Africa, and the Middle East the virus has produced occasional outbreaks in areas close to river basins and large wetlands where the presence of vectors (mosquitoes) and reservoirs (birds) provide the optimal conditions for the maintenance of the viral cycle. Short distance spread of the virus to neighboring territories occurs most likely by birds (not necessarily migratory) acting as carriers. The virus can occasionally be spread to long distances by wild bird migrations (Malkinson et al., 2002), although this is not likely a frequent event (Sotelo et al., 2011b), neither it explains all transcontinental translocations of the virus, and significantly, it does not explain the arrival of WNV to North America. Long distance geographic dispersal of WNV by migrating birds is a hypothesis based mainly on circumstantial evidence, such as the discovery of an infected flock of storks in Israel in summer 1998 on their migration back to Africa from central Europe (Malkinson et al., 2002). This hypothesis is supported by molecular phylogenetic studies between isolates from recent outbreaks in Europe and isolates from central Africa, suggesting that birds that migrate between continents may act carrying the virus (Charrel et al., 2003). However, although translocation of WNV (and also other flaviviruses alike, for instance Usutu virus) by bird migration is likely to occur, its frequency does not seem to be as high as to explain every WNV outbreak found in Europe. On the contrary, recent phylogenetic evidence supports that all WNV strains isolated in the western Mediterranean area since 1996 are a monophyletic group arising from a single common ancestor, a strain which could have arrived to this area in 1996 or even earlier, and since then it has been maintained in endemic circulation, evolving and spreading throughout the area (Sotelo et al., 2011b). Finally, one must not assume that the flow of WNV between Europe and Africa operates only in one direction (i.e., from Africa to Europe). The example previously mentioned on migrating storks (Malkinson et al., 2002) as well as specific studies on bird migrations and risk of introduction of pathogens (Jourdain et al., 2007) show that WNV can be translocated from Europe to Africa.

The Food and Agriculture Organization of the United Nations has recently estimated that the world equid population exceeds 110 million (FAOSTAT 2017). Working equids (horses, ponies, donkeys, and mules) remain essential to ensure the livelihood of poor communities around the world. In many developed countries, the equine industry has a significant economical weight, with around 7 million horses in Europe alone. The close relationship between humans and equids, and the fact that the athlete horse is the terrestrial mammal that travels the most worldwide after humans, are important elements to consider in the transmission of pathogens and diseases, amongst equids and to other species. The potential effect of climate change on vector ecology and vector-borne diseases is also of concern for both human and animal health.

With this Special Issue, which assembles a collection of communications, research articles, and reviews, we intend to explore our understanding of a panel of equine viruses, looking at their pathogenicity, their importance in terms of welfare and potential association with diseases, their economic importance and impact on performance, and how their identification can be helped by new technologies and methods. Beyond their potential risk to other species, including humans, equine viruses may also represent an interesting model for reproducing virus infection in the host species.

Dennis et al. contributed a review on African Horse Sickness (AHS). This disease, caused by the orbivirus AHS virus (AHSV), induces a very high mortality rate that can exceed 95% in its most severe form. This disease mostly occurs in southern African countries, but its transmission by Culicoides biting midges is of great concern in the current context of global warming and its consequence on displacement of vector populations. In the absence of treatment, prevention is essential, and Dennis et al. also provide a comprehensive review of the different vaccine strategies and technologies available and in current development against AHSV. While live attenuated and inactivated AHSV vaccines have played a role to reduce the impact and occurrence of AHS in affected areas, the number of AHSV serotypes in circulation and their lack of DIVA markers (differentiating infected from vaccinated animals) is a drawback that leads to the development of a new generation of vaccines, such as poxvirus-vectored or reverse genetics vaccines. Lecollinet et al. reviewed major viruses inducing encephalitis in equids and their growing importance as a threat to the European horse population. Amongst them, equid herpesviruses (EHVs) are some of the most frequently isolated equine viruses worldwide. The equine herpesvirus type 1 (EHV-1) is of particular interest to the equine industry because of the different forms of disease it can induce, from a mild respiratory infection to abortion, neonatal death, and myeloencephalopathy (EHM). A communication from Preziuso et al. and an article from Sutton et al. specifically focused on EHV-1 strain characterization in order to better understand EHV circulation in Italy and France. Different approaches were compared, from the single-nucleotide point (SNP) mutation in ORF30 (historically associated with abortive or neuro-pathogenic strains), to other ORF gene sequences and the newly described multilocus strain typing methods (MLST;). The MLST method is an interesting new approach for EHV-1 and a potential epidemiological tool that could provide an alternative until the development of more accessible EHV whole-genome sequencing methods. EHV-1 strain characterization by Sutton et al. allowed to conclude that the surge of EHV-1 outbreaks reported in France in 2018 was not linked to the introduction and/or circulation of a new EHV-1 strain in the French horse population. The origin of this crisis could be linked to a shortage of EHV vaccine and a subsequent reduced rate of EHV vaccination in the preceding years. Lecollinet et al. also reviewed less frequently isolated encephalitis viruses, which may be zoonotic, such as rabies virus, borna disease virus, and West Nile virus (WNV). In the case of WNV, both horses and humans are highly susceptible to viral infection through infected mosquitoes. Unprecedented circulations of WNV have been observed in several European countries in the last decade, with a potential role of climatic and environmental conditions. Both species are considered as dead-end hosts. However, the horse could be used as a sentinel species to monitor and control vector-borne virus activity. Other enzootic flaviviruses were also reviewed, such as Tick-Borne Encephalitis virus (TBEV) and Louping Ill virus (LIV). In Europe, vaccination is only available against some of these pathogens (i.e., EHV-1 and 4, Rabies virus, and WNV), which highlights the importance of surveillance. Taking into account that most of these viruses will induce similar clinical signs of disease, the development of discriminative diagnostic tools is also of increasing importance. Finally, the review presents some other vector-borne (mosquitoes or midges) equine encephalitis viruses, not currently circulating in Europe, from the Flaviridae family (i.e., the Japanese encephalitis virus (JEV), Saint Louis encephalitis virus (SLEV), and Murray Valley encephalitis virus (MVEV)) or the alphaviruses from the Togaviridae family (i.e., eastern, western, and Venezuelan equine encephalitis viruses; EEEV, WEEV, and VEEV, respectively). In relation to VEEV, Rusnak et al. presented systematic approaches for strain selection and propagation of virus and challenge material for the development and approval of a VEEV vaccine under the FDA Animal Rule and the different animal models available (rodents and non-human primates).

Altan et al. have used metagenomics to identify viruses in horses with neurological and respiratory diseases. The equine hepacivirus (EqHV) was detected in the plasma from several neurological cases. This virus, which was first reported in horses in 2012, was further investigated by Badenhorst et al., with a specific focus on its circulation in Austria and the potential role of mosquitoes in its transmission. The prevalence of EqHV in the Austrian horse population studies reached 45% (based on serological evidence), with around 4% of samples positive for EqHV RNA. No EqHV RNA was found in mosquitoes collected across Austria, raising questions about its methods of transmission. Some aspects of this particular question of EqHV transmission were treated by Pronost et al., who presented evidence to support a potential in utero transmission of EqHV from the mare to the foal, based on three positive clinical cases amongst 394 dead foals screened for the presence of EqHV RNA (prevalence of 0.76%). Altan et al. also detected two copiparvoviruses, the equine parvovirus-hepatitis (EqPV-H) and a new one named Eqcopivirus by the authors, with no specific and/or statistical association with disease. Equine parvovirus-hepatitis was also the subject of the article from Meister et al., which reported an EqPV-H infection occurrence in a quarter of the actively breeding Thoroughbred horse population from northern and western Germany. EqPV-H prevalence reached 7% and 35% (EqPV-H DNA positive detection and seroconversion, respectively). This study concerned mostly Thoroughbred brood mares, which represented 97% of the analyzed cohort. Concerning Thoroughbred stallions, Li et al. identified a new equine papillomavirus (EcPV9) in the semen from an Australian Thoroughbred stallion suffering from a genital wart. The clinical significance of this new equine papillomavirus remained to be determined and will require further investigation. A similar question was raised by Nemoto et al., who reported the first detection of equine coronavirus (ECoV) in Irish equids suffering from diarrhea. At five occasions, ECoV RNA was detected in feces from more than 400 equids with enteric diseases. However, the association with disease remains to be substantiated. While ECoV prevalence in Irish equids was 1.2% when measured by rRT-PCR in feces samples, evidence of ECoV infection was significantly higher when measured by serology in 984 serum samples from Dutch horses, 100 serums from Icelandic horses, and 27 paired serum samples from an ECoV outbreak in the USA. Zhao et al. developed and validated an S1-protein-based ELISA for this purpose. Seroprevalence ranged from 26% in young horses to nearly 83% in adults. The authors highlighted the potential use of this ELISA as a diagnostic test to confirm ECoV outbreaks, as a complement to feces samples analysis by qRT-PCR. The study from Back et al. shed some light on the potential role of equine rhinitis A virus (ERAV) infection in poor performance. This longitudinal study, which involved 30 Thoroughbred racehorses, significantly associated seroconversion to ERAV and subsequent failure to attend races. However, similarly to EqPV-H and ECoV infections previously reported in this Special Issue, a direct association of ERAV infection with clinical signs of disease could not be confirmed in this study.

Finally, Fatima et al. investigated the antiviral activity of the equine interferon-mediated host factors myxovirus (Mx) protein (eqMx1) against a range of influenza A viruses (IAVs). The authors highlight the potential protective role of eqMx1, which primarily targets the virus nucleoprotein (NP), against the transmission of new IAVs in horses (i.e., eqMx1 could only inhibit the polymerase activity of IAVs of avian and human origin but remained inactive against the equine IAVs tested). Introduction of a new IAV in the equine population is considered a rare event. In 1989, an equine influenza epizootic was reported in the Jilin and Heilongjiang provinces of northeastern China, with up to 20% mortality, which is quite high when compared with conventional equine influenza outbreaks. The IAV strain representative of this outbreak (i.e., A/equine/Jilin/1/1989) was closely related to an avian H3N8 IAV. The authors show that the IAV strain A/equine/Jilin/1/1989 bears two adaptive NP mutations that confer resistance to eqMx1. To date, equine influenza virus remains one of the most important respiratory pathogens of horses worldwide, with a potential damaging impact on the equine industry, as clearly illustrated in 2007 in Australia and in 2019 in Europe.

We hope this Special Issue helps to highlight the diversity of equine viruses and their importance, in terms of welfare and/or economic impact, to equids and humans.

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).

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).

West Nile virus is the etiological agent of an emerging zoonotic disease whose impact on animal and public health is considerable, being the most widespread arbovirus in the world today (reviewed in Hayes et al., 2005a; Kramer et al., 2008; Brault, 2009). A percentage of WNV infections result in severe encephalitis, and it is a communicable disease both for human and animal health. WNV taxonomically belongs to the family Flaviviridae, genus Flavivirus. Virions are spherical in shape, about 50 nm in diameter, and consist of a lipid bilayer that surrounds a nucleocapsid that in turn encloses the genome, a unique single-stranded RNA molecule, which encodes a polyprotein that is processed to give the 10 viral proteins. Of them, three (C, E, and M) form part of the structure of the virion, and the rest (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5) are so-called “non-structural” and play important roles in the intracellular processes of replication, morphogenesis, and virus assembly. Inserted into the lipid bilayer are two proteins, E (from “envelope”) and M (“matrix”), which participate in important biological properties of the virus, such as its host range, tissue tropism, replication, assembly, and stimulation of cellular and humoral immune responses. E protein contains the major antigenic determinants of the virus.

As far as we know, there are no serotypes of WNV, but two main genetic variants or lineages can be distinguished, namely lineages 1 and 2. While the former is widely distributed in Europe, Africa, America, Asia, and Oceania, the second is found mostly restricted to Africa and Madagascar, although it has recently been introduced in Central and Eastern Europe (Bakonyi et al., 2006; Platonov et al., 2008) and has further extended to southern Europe (Bagnarelli et al., 2011; Papa et al., 2011). In addition, other viral variants closely related phylogenetically to WNV have been described, which are different from lineages 1 and 2, and have been proposed as additional WNV lineages. One of them, known as “Rabensburg virus,” isolated form mosquitoes in the Czech Republic in 1997, shows low pathogenicity in mice (Bakonyi et al., 2005). Similarly, other viruses closely related to WNV have been isolated in India (Bondre et al., 2007), Russia (Lvov et al., 2004) Malaysia (Scherret et al., 2001), and Spain (Vazquez et al., 2010). All these viruses have been proposed to represent different genetic lineages of WNV. Except for the Indian variant, which has been involved in outbreaks of encephalitis in humans, the rest are of unknown relevance for animal and human health.

West Nile fever/encephalitis is a disease transmitted mainly by mosquitoes, while wild birds are its natural reservoir. WNV is capable of infecting a wide range of bird species. Nevertheless, birds were considered less susceptible to the disease until the recent epidemic of WNV in North America, affecting many species of birds lethally, made to re-examine this concept (Komar et al., 2003). Occasionally it may affect poultry species, mainly geese and ostriches. Other domestic birds like chickens and pigeons, are susceptible to infection but do not get sick, and are often used as sentinels for disease surveillance. In addition to birds, WNV can also affect a wide range of vertebrates species, including amphibians, reptiles, and mammals, and it is particularly pathogenic in humans and horses, which act epidemiologically as “dead end hosts,” that is, they are susceptible to infection but do not transmit the virus (McLean et al., 2002; Kramer et al., 2008).

The first case of WNF was described in Uganda (West Nile district, hence the name of the virus) in a feverish woman, from whose blood the virus was first isolated in 1937 (Smithburn et al., 1940). It was considered a mild disease, endemic in parts of Africa (an “African fever”). However, since around 1950s, the occurrence of disease outbreaks with neurological disease, lethal in some cases, caused by WNV, especially in the Middle East and North Africa, made necessary to rethink this concept. In humans, the majority of WNV infections are asymptomatic, about 20% may develop mild symptoms such as headache, fever, and muscle pain, and less than 1% develop more severe disease, characterized by neurological symptoms, including encephalitis, meningitis, flaccid paralysis, and occasionally severe muscle weakness (Hayes et al., 2005b). Advanced age is considered a risk factor for developing severe WNV infection or death. The mortality rate calculated for the recent epidemic of the disease in the U.S. is 1 in every 24 human cases diagnosed (Kramer et al., 2008).

In horses (reviewed in Castillo-Olivares and Wood, 2004) neurological disease is manifested by approximately 10% of infections, and is mainly characterized by muscle weakness, ataxia, paresis, and paralysis of the limbs, as a result of nerve damage in the spinal cord. They may also suffer from fever and anorexia, tremors and muscle stiffness, facial nerve palsy, paresis of the tongue, and dysphagia, as a result of affection of the cranial nerves. A proportion of horses infected with WNV die spontaneously or is slaughtered to avoid excessive suffering. The mortality rate can vary between outbreaks. For example, in the outbreak in 2000 in the Camargue (France), 76 horses were affected, of which 21 died (Zeller and Schuffenecker, 2004). In 1996 in Morocco, a WNV outbreak affected 94 horses, of which 42 died (Zeller and Schuffenecker, 2004). Severe equine cases do not seem to predominate in older horses, as occurs in humans (Castillo-Olivares and Wood, 2004). Other mammals may also suffer from the disease. Rodents such as laboratory mice and hamsters are highly susceptible, so they can be used as experimental model of WNV encephalitis. Lemurs and certain types of squirrels appear to be the only mammals capable of maintaining the virus in local circulation (Rodhain et al., 1985; Root et al., 2006). WNV can also infect other mammals, including sheep, in which it causes abortions, but rarely encephalitis (Hubalek and Halouzka, 1999). WNV has been isolated from camels, cows, and dogs in enzootic foci (Hubalek and Halouzka, 1999). The virus has been shown to infect frogs (Rana ridibunda), which in turn are bitten by mosquitoes, so that the existence of an enzootic cycle in these amphibians is postulated, at least for some variants of the virus (Kostiukov et al., 1986). Outbreaks of severe WNF with high mortality have been reported in captive alligators and crocodiles, presumably transmitted through feeding of contaminated meat (Miller et al., 2003). It has been shown experimentally that WNV can infect asymptomatically pigs (Teehee et al., 2005) and dogs (Blackburn et al., 1989; Austgen et al., 2004). However, guinea pigs, rabbits, and adult rats are resistant to infection with WNV (McLean et al., 2002). Among non-human primates, rhesus and bonnet monkeys (but not Cynomolgus macaques and chimpanzees), inoculated with WNV develop fever, ataxia, prostration with occasional encephalitis and tremor in the limbs, paresis or paralysis. The infection can be fatal in these animals.

The virus is propagated in the reservoir hosts, resulting in a viremic phase that usually lasts no more than 5–7 days (Komar et al., 2003). The duration and level of viremia depends on the species infected (Komar et al., 2003). The detection of the virus or its genetic material in serum or cerebrospinal fluid in a laboratory test is a proof of diagnostic value (De Filette et al., 2012). The virus is evidenced by virological (virus isolation) or molecular (RT-PCR-conventional and real-time, NASBA) techniques. In epidemiological surveillance it is useful to detect the presence of WNV in mosquitoes, for which they are homogenized and analyzed using the same methods mentioned above (Trevejo and Eidson, 2008). Specific antibodies against the virus are detectable in blood few days after infection (Komar et al., 2003; De Filette et al., 2012). Antibody detection is performed by serological tests (enzyme immunoassay or ELISA, hemagglutination inhibition or HIT) which can be confirmed by more specific serological techniques (virus-neutralization test; Sotelo et al., 2011c). Serological diagnosis of acute infection should be done by detection of IgM antibodies in serum and/or cerebrospinal fluid using an immunocapture ELISA together with the detection of an increase in antibody titer in paired sera taken one in the acute phase and the other, at least 2 weeks later (Beaty et al., 1989).

The fight against this disease is not straightforward because there are no vaccines licensed for human use, and even though there are some available for veterinary use, they are efficacious to prevent disease symptoms and outcome at the individual level but do not prevent the spread of the infection, mainly due to the establishment of an enzootic cycle among wild birds and mosquitoes (Kramer et al., 2008; De Filette et al., 2012). Control methods are mainly based on prevention and early detection of virus spread through epidemiological surveillance and targeted application of insecticides and larvicides (Kramer et al., 2008).

Social and demographic contexts can significantly influence the transmission of infectious disease, while also creating increased vulnerabilities for some population subgroups. The elderly are at greater risk of many infectious diseases, and the ageing trend in many high-income countries could increase the challenges related to nosocomial (hospital-acquired) and nursing-home acquired infections. An additional challenge related to population ageing is that the share of employed workers in a country decreases. The combination of more people to care for and fewer tax-related revenues may challenge publicly financed public health and disease control programmes (7).

When persons from regions with high endemicity of a given disease move to ones with lower endemicity, new challenges for public health are created. In addition migrant communities can be highly vulnerable to certain infectious diseases. In the EU, for example, approximately 37% of HIV cases reported in 2011 were among people born abroad, and the equivalent number of cases for tuberculosis was 25% (40). Similarly, migrants suffer from a higher burden of chronic hepatitis B infections (41).

It is widely established that socially and economically disadvantaged groups suffer disproportionally from disease (42). This is applicable to infectious disease burdens in both high- and low-income settings (43, 44). Income inequalities are generally widening globally, and this appears to be have been exacerbated in many countries due to the global economic crisis (45). Rising unemployment and the prospect of public health budget cuts can increase the risk of infectious disease transmission (44, 46), with a prominent example being an outbreak of HIV among people who inject drugs (PWID) in Greece (see ‘Measles among Roma in Bulgaria and HIV among PWID in Greece: the impact of socioeconomic contexts’ section) (47, 48). In a similar fashion, it has been speculated that tuberculosis rates could rise in some countries in Central and Eastern Europe (49).

Social trends and behaviours can also play a significant role in infectious disease transmission. The most notable example would be vaccine hesitancy, the phenomenon through which vaccination coverage rates remain suboptimal due to the varying and complicated reasons that individuals may have for not getting vaccinated (50, 51). In some cases, this might be related to misconceptions about the safety or efficacy of vaccines (50, 52), whereas in others this may be related to religious or cultural beliefs (53).

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.

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.

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).

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.

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.

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.

The disease is caused by Corynebacterium pseudotuberculosis. There are two basic forms of caseous lymphadenitis, that is, internal form and external form. Most of the affected animals manifest both forms of the disease depending on the multiple factors that are age, physiological conditions, environmental factors, and managemental practices. There is obvious nodule formation under the skin as well as enlargement of peripheral lymph nodes in the external form. The affected lymph nodes along with the subcutaneous tissues are enlarged with thick as well as cheesy pus which may rupture outward spontaneously or during the process of shearing or dipping. The internal form of caseous lymphadenitis (CLA) is manifested by vague signs such as weight loss, poor productivity, and decrease in fertility [3, 148, 149]. For the detection of the causative agent, Corynebacterium pseudotuberculosis, in sheep and goats, a double antibody sandwich ELISA has been developed, which has been further modified for improving the sensitivity. The main objective of developing this test is to detect the presence of antibodies against the bacterial exotoxin. It has been found that six proteins with varying molecular mass ranging from 29 to 68 kilo Dalton (kDa) react with sera from both goats and sheep acquiring infection experimentally or naturally. For classification of the sera with inconclusive results, immunoblot analysis has been found to be valuable [100, 101]. Quantification of interferon gamma (IFN-γ) is essential for accurate diagnosis of the disease for which an ovine IFN-γ ELISA has been developed. The sensitivity of the assay is slightly more for sheep than in goats while the specificity of the assay is higher for goats than for sheep. It can thus be concluded that IFN-γ is a potential marker in order to determine the status of CLA infection in small ruminants. For the diagnosis of CLA, another novel strategy is the employment of PCR for identification of the bacteria isolated from abscesses. The PCR has been found to be both sensitive and specific in addition to its rapidity of detecting C. pseudotuberculosis from sheep that are naturally infected.

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.

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.

Depending upon the involvement of etiological agent, the infectious respiratory diseases of small ruminants can be categorized as follows [9, 14]:bacterial: Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, enzootic pneumonia, and caseous lymphadenitis,viral: PPR, parainfluenza, caprine arthritis encephalitis virus, and bluetongue,fungal: fungal pneumonia,parasitic: nasal myiasis and verminous pneumonia,others: enzootic nasal tumors and ovine pulmonary adenomatosis (Jaagsiekte).

Manytimes due to environmental stress, immunosuppression, and deficient managemental practices, secondary invaders more severely affect the diseased individuals; moreover, mixed infections with multiple aetiology are also common phenomena [5, 8, 13, 15].

These conditions involve respiratory tract as primary target and lesions remain confined to either upper or lower respiratory tract [7, 16]. Thus, these diseases can be grouped as follows [5, 8, 14, 17].Diseases of upper respiratory tract, namely, nasal myiasis and enzootic nasal tumors, mainly remain confined to sinus, nostrils, and nasal cavity. Various tumors like nasal polyps (adenopapillomas), squamous cell carcinomas, adenocarcinomas, lymphosarcomas, and adenomas are common in upper respiratory tracts of sheep and goats. However, the incidence rate is very low and only sporadic cases are reported.Diseases of lower respiratory tract, namely, PPR, parainfluenza, Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, caprine arthritis encephalitis virus, caseous lymphadenitis, verminous pneumonia, and many others which involve lungs and lesions, are observed in alveoli and bronchioles.

Depending upon the severity of the diseases and physical status of the infected animals, high morbidity and mortality can be recorded in animals of all age groups. These diseases alone or in combination with other associated conditions may have acute or chronic onset and are a significant cause of losses to the sheep industry [3, 10]. Thus, the respiratory diseases can also be classified on the basis of onset and duration of disease as mentioned below [3, 9, 14, 18]:acute: bluetongue, PPR, Pasteurellosis, and parainfluenza,chronic: mycoplasmosis, verminous pneumonia, nasal myiasis, and enzootic nasal tumors,progressive: Ovine progressive pneumonia, caprine arthritis encephalitis virus, caseous lymphadenitis, and pulmonary adenomatosis.

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.

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.