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General clinical symptoms of the Fuyang HFMD outbreak included rash, fever, general malaise, cough, vomiting and neurologic complications (such as encephalitis, aseptic meningitis, or acute flaccid paralysis). The analysis of the clinical characteristics of 15 out of 22 fatal cases showed that these cases had an acute onset of fever, sore throat, and myalgia (influenza-like illness) without catarrhal syndrome, but the rash was rare. The conditions of most of cases subsequently deteriorated, in which the patients developed tachypnea, cyanosis, and some presented seizures with white or pink foaming at the mouth (Table 1). Most hospitalized cases were initially diagnosed as severe pneumonia, some patients died within 1-5 days after onset.
The mild HFMD outpatients were defined as patients with fever and vesicular lesions on their palms, feet and mouth. Severe cases usually presented with neurologic complications, which were defined as having two of following clinical manifestations: brainstem encephalitis or aseptic meningitis; continuous high fever (temperature of at least 38°C); weakness, vomiting, irritability, myoclonus and acute flaccid paralysis; pulmonary edema or hemorrhage, heart and lung failure. Encephalitis, aseptic meningitis, pulmonary edema, pulmonary hemorrhage, acute flaccid paralysis, myocarditis were characterized by the same definition as described previously.
Paramyxoviridae is a large and diverse family whose members have been isolated from many species of avian, terrestrial, and aquatic animal species around the world. Paramyxoviruses are pleomorphic, enveloped, cytoplasmic viruses that have a non-segmented, negative-sense RNA genome. The family is divided into two subfamilies, Paramyxovirinae and Pneumovirinae, based on their structure, genome organization, and sequence relatedness. The subfamily Paramyxovirinae contains five genera: Respirovirus, Rubulavirus, Morbillivirus, Henipavirus, and Avulavirus, while the subfamily Pneumovirinae contains two genera, Pneumovirus and Metapneumovirus. All paramyxoviruses that have been isolated to date from avian species can be segregated into two genera based on the taxonomic criteria mentioned above: genus Avulavirus, whose members are called the avian paramyxoviruses (APMV), and genus Metapneumovirus, whose members are called avian metapneumoviruses. The APMV of genus Avulavirus are separated into nine serotypes (APMV-1 through -9) based on Hemagglutination Inhibition (HI) and Neuraminidase Inhibition (NI) assays. Various strains of APMV-1, which is also called Newcastle disease virus (NDV), have been analyzed in detail by biochemical analysis, genome sequencing, and pathogenesis studies, and important molecular determinants of virulence have been identified. As a first step in characterizing the other APMV serotypes, complete genome sequences of one or more representative strains of APMV serotypes 2 to 9 were recently determined, expanding our knowledge about these viruses.
APMV-1 comprises all strains of NDV and is the best characterized serotype because of the severity of disease caused by virulent NDV strains in chickens. NDV strains vary greatly in their pathogenicity to chickens and are grouped into three pathotypes: highly virulent (velogenic) strains, which cause severe respiratory and neurological disease in chickens; moderately virulent (mesogenic) strains, which cause mild disease; and non-pathogenic (lentogenic) strains, which cause inapparent infections. In contrast, very little is known about the comparative disease potential of APMV-2 to APMV-9 in domestic and wild birds. APMV-2 strains have been isolated from chickens, turkeys and wild birds across the globe. APMV-2 infections in turkeys have been found to cause mild respiratory disease, decreases in egg production, and infertility. APMV-3 strains have been isolated from wild and domestic birds. APMV-3 infections have been associated with encephalitis and high mortality in caged birds. APMV-4 strains have been isolated from chickens, ducks and geese. Experimental infection of chickens with APMV-4 resulted in mild interstitial pneumonia and catarrhal tracheitis. APMV-5 strains have only been isolated from budgerigars (Melopsittacus undulatus) and cause depression, dyspnoea, diarrhea, torticollis, and acute fatal enteritis in immature budgerigars, leading to very high mortality. APMV-6 was first isolated from a domestic duck and was found to cause mild respiratory disease and drop in egg production in turkeys, but was avirulent in chickens. APMV-7 was first isolated from a hunter-killed dove and has also been isolated from a natural outbreak of respiratory disease in turkeys. APMV-7 infection in turkeys caused respiratory disease, mild multifocal nodular lymphocytic airsacculitis, and decreased egg production. APMV-8 was isolated from a goose and a feral pintail duck. APMV-9 strains have been isolated from ducks around the world. APMV types -2, -3, and -7 have been associated with mild respiratory disease and egg production problems in domestic chickens. There are no reports of isolation of APMV-5, -8 and -9 from poultry. But recent serosurveillance of commercial poultry farms in USA indicated the possible prevalence of all APMV serotypes excluding APMV-5 in chickens.
APMV-1 (NDV) is known to replicate in non-avian species including humans, although its only natural hosts are birds. APMV-1 infections in non-avian species are usually asymptomatic or mild. Clinical signs in human infections commonly involve conjunctivitis, which usually is transient and self-limiting. Presently, APMV-1 is being evaluated as a vaccine vector against human pathogens. When administered to the respiratory tract of non-human primates, NDV is highly restricted in replication, but foreign antigens expressed by recombinant NDV vectors are moderately to highly immunogenic. One of the major advantages of this approach is that most humans do not have pre-existing immunity to APMV-1. Pre-existing immunity is a potential drawback to using vectors derived from common human pathogens, and also can be a concern for any vector if two or more doses are necessary to elicit protective immunity. Therefore, we are investigating APMV types 2 to 9, which are antigenically distinct from APMV-1, as alternative human vaccine vectors. Also, some of these additional APMV types likely will have differences in replication, attenuation, and immunogenicity compared to APMV-1 that may be advantageous. However, the replication and pathogenicity of APMV-2 to -9 in non-avian species has not been studied. As a first step, we have evaluated the replication and pathogenicity of APMV-2 to -9 in hamsters. In this study, groups of hamsters were infected with a prototype strain of each APMV serotype by the intranasal route and monitored for virus replication, clinical symptoms, histopathology, and seroconversion. Our results showed that each of the APMV serotypes replicated in hamsters without causing adverse clinical signs of illness, although histopathologic evidence of disease was observed in some cases, and also induced high neutralizing antibody titers.
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.
Small ruminants particularly sheep and goats contribute significantly to the economy of farmers in Mediterranean as well as African and Southeast Asian countries. These small ruminants are valuable assets because of their significant contribution to meat, milk, and wool production, and potential to replicate and grow rapidly. The great Indian leader and freedom fighter M. K. Gandhi “father of the nation” designated goats as “poor man's cow,” emphasizing the importance of small ruminants in poor countries. In India, sheep and goats play a vital role in the economy of poor, deprived, backward classes, and landless labours. To make this small ruminant based economy viable and sustainable, development of techniques for early and accurate diagnosis holds prime importance. Respiratory diseases of small ruminants are multifactorial and there are multiple etiological agents responsible for the respiratory disease complex. Out of them, bacterial diseases have drawn attention due to variable clinical manifestations, severity of diseases, and reemergence of strains resistant to a number of chemotherapeutic agents. However, sheep and goat suffer from numerous viral diseases, namely, foot-and-mouth disease, bluetongue disease, maedi-visna, orf, Tick-borne encephalomyelitis, peste des petits ruminants, sheep pox, and goat pox, as well as bacterial diseases, namely, blackleg, foot rot, caprine pleuropneumonia, contagious bovine pleuropneumonia, Pasteurellosis, mycoplasmosis, streptococcal infections, chlamydiosis, haemophilosis, Johne's disease, listeriosis, and fleece rot [3–10].
The respiratory diseases represent 5.6 per cent of all these diseases in small ruminants. Small ruminants are especially sensitive to respiratory infections, namely, viruses, bacteria, and fungi, mostly as a result of deficient management practices that make these animals more susceptible to infectious agents. The tendency of these animals to huddle and group rearing practices further predispose small ruminants to infectious and contagious diseases [6, 9]. In both sheep and goat flocks, respiratory diseases may be encountered affecting individuals or groups, resulting in poor live weight gain and high rate of mortality. This causes considerable financial losses to shepherds and goat keepers in the form of decreased meat, milk, and wool production along with reduced number of offspring. Adverse weather conditions leading to stress often contribute to onset and progression of such diseases. The condition becomes adverse when bacterial as well as viral infections are combined particularly under adverse weather conditions. Moreover, under stress, immunocompromised, pregnant, lactating, and older animals easily fall prey to respiratory habitats, namely, Streptococcus pneumoniae, Mannheimia haemolytica, Bordetella parapertussis, Mycoplasma species, Arcanobacterium pyogenes, and Pasteurella species [2, 4, 7–9, 12, 13]. Such infections pose a major obstacle to the intensive rearing of sheep and goat and diseases like PPR, bluetongue, and ovine pulmonary adenomatosis (Jaagsiekte) adversely affect international trade [2, 9, 10, 13], ultimately hampering the economy.
In May 2013, a devastating outbreak of epidemic diarrhea in young piglets commenced in swine farms of the United States, causing immense economic concerns. The mortality can reach up to 100% in piglets less than 10 days of age, with a recorded loss of at least 8 million neonatal pigs since 2013 (1, 2). Enteric viruses, such as swine enteric coronaviruses (SECoVs), porcine epidemic diarrhea virus (PEDV), and porcine deltacoronavirus (PDCoV), were isolated from these outbreaks (3, 4) and characterized (5). However, despite intensive biosecurity measures adopted to prevent the spread of SECoV in many farms and the use of two U.S. Department of Agriculture (USDA) conditionally licensed vaccines against PEDV, the outbreaks continue and have now spread to many other countries, including Mexico, Peru, Dominican Republic, Canada, Columbia, and Ecuador in the Americas (6) and Ukraine (7). Repeated outbreaks have also been reported on the same farms that were previously infected with PEDV. In June 2014, the USDA issued a federal order to report, monitor, and control swine enteric coronavirus disease (SECD) (8). In our efforts to understand the seemingly uncontrollable porcine epidemic diarrhea outbreaks, we discovered a novel mammalian orthoreovirus type 3 (MRV3) in feces of pigs from these outbreaks and ring-dried swine blood meal (RDSB). We have also reproduced severe diarrhea and acute gastroenteritis in neonatal pigs experimentally infected with purified MRV3 strains.
The family Reoviridae comprises 15 genera of double-stranded RNA (dsRNA) viruses (9). Orthoreoviruses with 10 discrete RNA segments have been isolated from a wide variety of animal species, including bats, civet cats, birds, reptiles, pigs, and humans (10, 11). Most orthoreoviruses are recognized to cause respiratory infections, gastroenteritis, hepatitis, myocarditis, and central nervous system disease in humans, animals, and birds (11); orthoreovirus genomes are prone to genetic reassortment and intragenic rearrangement (11, 12). The exchange of RNA segments between viruses could lead to molecular diversity and evolution of viruses with increased virulence and host range (13, 14). MRV serotypes 1 to 3 were associated with enteritis, pneumonia, or encephalitis in swine around the world, including China and South Korea (15–18). The zoonotic potential of MRV3 has been reported recently (19–21). However, porcine orthoreovirus infection of pigs was unknown previously in the United States.
Fever during neutropenia is a frequent problem in patients with hematological malignancies and is the most common cause of non-malignant morbidity and mortality in this patient group. An infectious etiology is identified in only 30 to 60 percent of the febrile neutropenic episodes. Despite this diagnostic gap, most studies and guidelines merely presume bacterial and fungal microorganisms as the cause of neutropenic fever, but do not extensively look at possible viral etiologies. Since respiratory viruses are known to be the most common cause of fever in the general population and the clinical presentation of a viral infection is often not specific in neutropenic patients, diagnostic screening for respiratory viruses seems rational in patients presenting with neutropenic fever. In children, there is growing evidence that neutropenic fever is frequently associated with respiratory viral infections. Moreover, in stem cell transplantation (SCT) patients, viruses are recognized to frequently cause post-transplant fever.
Over the last decade molecular techniques, such as polymerase chain reaction (PCR), have revolutionized the diagnosis of viral infections. PCR has enabled rapid and highly sensitive detection of a large number of respiratory viruses, including those that cannot, or are difficult, to culture, such as human Bocavirus (hBoV) and human metapneumovirus (HMPV). In patients with hematological malignancies, PCR has shown to be far more sensitive than viral culture, but these studies have not looked into viral prevalence during neutropenic fever.
This study was performed to look at the role of respiratory viruses in neutropenic fever in adults with a hematological malignancy and assess the usefulness of screening for respiratory viruses before the onset of neutropenia.
For many years, FCoVs have been classified into different biotypes on the basis of their pathobiology. Avirulent strains, which usually induce mild or subclinical symptoms, are referred to as feline enteric coronavirus (FECV). Virulent strains cause feline infectious peritonitis and are called feline infectious peritonitis viruses (FIPV). Until 2005, CCoVs were considered to be mild enteropathogens. In 2005, a virulent variant causing systemic disease in pups and mortality was first recognized in Italy. This virulent biotype has been named canine pantropic coronavirus in reference to its systemic distribution in internal organs [39, 40]. Interestingly, ferret coronaviruses are also classified according to their virulence. The ferret enteric coronavirus (FRECV), which is widely distributed, causes an enteric disease called epizootic catarrhal enteritis, whose overall mortality rate is low. By contrast, the highly pathogenic ferret systemic coronavirus (FRSCV) induces FIP-like disease [42, 43].
Both feline genotypes may be responsible for mild enteric or FIP diseases. FIP remains a rare event, and only a minority of FCoV-infected cats (up to 10%) develop the illness [24, 44]. Two forms of FIP are recognized: the wet/effusive form with accumulation of a characteristic viscous yellow fluid in body cavities and the dry/noneffusive form with pyogranulomatous lesions affecting several organs. Both forms are progressive and ultimately fatal. FIP is often observed in young cats [47, 48]. In ferrets infected with FRSCV, the gross lesions resemble those described in cats with the dry form of FIP. Again, histologic lesions are characterized by severe pyogranulomas commonly observed in the mesentery and the peritoneal surface.
Both canine genotypes have been associated with enteric CCoV. By contrast, pantropic CCoVs identified so far all belong to the CCoV-IIa genetic cluster. Enteric CCoV infection does not prevent subsequent infection with the pantropic variant. Dogs seropositive for enteric CCoVs are still susceptible to pantropic viruses, but the clinical signs are moderate by comparison with those in seronegative dogs, probably owing to partial cross-protection induced by antibodies against enteric CCoV. During infection with the enteric CCoV, the virus remains restricted to the gastrointestinal tract. Conversely, the highly virulent pantropic CCoV is detected at high titres in lungs, spleen, liver, kidney, and brain. Clinical signs consist of fever, lethargy, haemorrhagic diarrhoea, severe lymphopenia, and neurological signs followed by death [39, 49]. The prevalence of the canine pantropic coronavirus is yet unknown, and further epidemiological studies are required to determine its distribution in dog populations. A pantropic strain (CB/05) has been successfully isolated from the lungs of a dead pup. CB/05 has subsequently been used to reproduce the disease experimentally, thereby improving understanding of this new illness. Infection with the CB/05 strain has demonstrated that disease outcome depends on the age at infection. Puppies over 6 months old may recover, whereas younger puppies (2-3 months) develop the most severe symptoms. Lymphopenia is one of the main features of pantropic CCoV infection under natural and experimental infections. While a transient reduction in T and B cell populations is observed during the first week after infection, the CD4+ T cell population remains depleted for 30 days postinfection, which could cause dysfunction of the immune system and favour opportunistic infections.
Acute respiratory tract infection (ARTI) is one of the most common illnesses of childhood. ARTIs range from common cold, a mild self-limiting catarrhal syndrome to life threatening lower respiratory tract infection. Viruses account for most ARTIs and associated respiratory diseases [1, 2]. The most frequently reported viruses in newborns and children under 5 years with ARTI are respiratory syncytial virus (RSV), parainfluenza virus types 1, 2, 3, adenovirus, influenza virus types A, B, corona virus, Coxsackievirus, other enteroviruses, human boca virus and human metapneumovirus (hMPV).
The hMPV, is the first member of a new genus Metapneumovirus of the Paramyxoviridae family that infects humans [2, 3]. The RSV belongs to a separate genus within the Paramyxoviridae family. hMPV was first isolated in 2001 in the Netherlands. hMPV has been recently identified in nasopharyngeal aspirates (NPA) of children and adults with ARTI in various parts of the world [2, 5–8]. In temperate zones, hMPV infections peak in late winter and spring months but slightly later to the RSV peak in most studies. We do not know the prevalence of hMPV in tropical countries and it might be due to lack of diagnostic facilities to detect respiratory viruses in these countries.
The clinical syndrome in the children infected with hMPV ranges from mild respiratory disease to severe bronchiolitis and pneumonia. The children with severe disease require hospitalization. Co-infection with RSV and hMPV causes severe disease compared to RSV or hMPV mono-infections [11, 12]. The risk factors for acquisition of viral ARTI is being studied in depth but the details of the viral co-infection have not being fully explored. Conversely, the prevalence of hMPV infection in Sri Lanka was not known and there are no published reports on the presence of hMPV in the country. Here we report a case series of hMPV infection in children less than 5 years of age in Sri Lanka.
Enteritis is a main problem in poultry, associated to considerable direct and indirect economic losses. Several enteric viruses have been identified in commercial flocks of turkeys worldwide. Enteric diseases may be occur in all age groups, nevertheless, they are predominantly affect young birds in the three first weeks of age, where infections appear more severe (Nuñez and Piantino Ferreira, 2013; Mettifogo et al., 2014). Enteric viruses increase susceptibility of affected birds to secondary infections and others immunosuppressive diseases.
Several viruses are incriminated in the enteric diseases in commercial turkeys. Interaction between them is very complex, including many other management, feeding, and infectious factors. Because of the various etiologies, clinical signs are in general nonspecific, including diarrhea, increased mortality, and poor performances. Gross pathology showed gastrointestinal lesions, associated to liver, pancreatic, and lymphoid damage. These symptoms and lesions are considered to be the main enteric syndrome that is why laboratory investigations consist on the use of essential tool to confirm etiological agents (Alavarez et al., 2014; Mettifogo et al., 2014).
In turkeys, the most important enteric viral diseases are represented by hemorrhagic enteritis (HE), runting stunting syndrome (RSS) and PEMS (Table 1).
HE is an acute disease of turkeys caused by Siadenovirus (group II Aviadenovirus), immunosuppressive virus, which infect essentially animals at 4 weeks of age and older. Depression, bloody droppings, heterogeneity of the flock, and increased mortality characterize this disease. In field outbreaks, mortality varied from 0.1% to 60% (Gross and Moore, 1967). Virus replication occurs essentially in spleen, considered to be the major site (Saunders et al., 1993; Pierson and Fitzgerald, 2013). However, Enzyme Linked Immunosorbent Assay (ELISA), Immunofluorescent (IF), and Polymerase Chain Reaction (PCR) are used to confirm the presence of infected cells in many other tissues, such as intestine, bursa of Fabricius, caecal tonsils, thymus, liver, kidney, leukocytes, and lungs (Silim and Thorsen, 1981; Fasina and Fabricant, 1982; Fitzgerald et al., 1992; Trampel et al., 1992; Hussain et al., 1993; Suresh and Sharma, 1996). Primarily viral replication occurs in B cells and macrophages. Other cells target are represented by adherent mononuclear macrophages and non-adherent mononuclear cells (van den Hurk, 1990) bearing IgM (Suresh and Sharma, 1995; 1996).
Virulent HEV strains are capable to induce apoptosis in spleen cells, due to the induction of interleukine-6 (IL-6) secretion in the spleen (Rautenschlein et al., 2000b). Activation of macrophages leads to cytokines (IL-6, interferon type I and II, and TNF) production. Immunosuppressive is the consequence of the nitric acid production, stimulated by the interferon-II (IFN-II) (Dhama et al., 2017). Transient immunosuppression has been reported during clinical phase of the disease, with considerable depletion of IgM-bearing B cells (Rautenschlein et al., 2000b).
Vaccination failures are observed in infected turkeys. A significant decrease in hemagglutination inhibition antibody titers is detected in turkeys infected with virulent HEV. Moreover, depression in phytohemagglutinin (PHA) is also described in inoculated birds (Nagaraja et al., 1985).
Secondary bacterial infections may extend the course of illness and increase mortality for an additional 2–4 weeks (Dhama et al., 2017). Increased predisposition to enteropathogenic Escherichia coli infection (Larsen et al., 1985; van den Hurk et al., 1994; Giovanardi et al., 2014) and clostridial dermatitis (Thachil and Nagaraja, 2013) has been well documented.
Resistance of the virus outside, poor hygiene conditions, and short down time between flocks, contribute to the persistence of the HE (Pierson and Fitzgerald, 2013).
Due to hemorrhage, carcasses appear pale. Gross pathology showed hemorrhagic intestinal mucosa, with the presence of natural coagulated blood. Spleen is characteristically enlarged, marbled, and friable. In dead birds, spleen may be smaller and pale because of blood loss and subsequent splenic contraction (Gross, 1967; Carlson et al., 1974; Fujiwara et al., 1975; Itakura and Carlson, 1975). Histological findings are more apparent in lymphoreticular and gastrointestinal systems. Hyperplasia of the white pulp, lymphoid necrosis and intranuclear inclusion body within lymphoreticular body cells are the most described microscopic modifications (Saunders et al., 1993).
Histopathological changes are more evident in the duodenum, where congestion, hemorrhage, and hetetrophils infiltration and epithelium villus degeneration, consist the major observations. Less severe lesions cans be also find in the gizzard, the proventiculus, the caeca tonsils and the bursa of Fabricius (Saunders et al., 1993; Pierson and Fitzgerald, 2013). Intranuclear inclusions have been detected in many tissues, such as liver, pancreas, bone marrow, renal tubular epithelium, and lung (Gross, 1967; Carlson et al., 1974; Fujiwara et al., 1975; Itakura and Carlson, 1975; Meteyer et al., 1992; Trampel et al., 1992; Hussain et al., 1993).
Many other fowl adenoviruses (FAV) are considered as immunosuppressive agent in turkey. Adenovirus responsible of inclusion body hepatitis (IBH) can induce atrophy of the bursa, the thymus and the spleen, that occurs following challenges involving serotypes 1, 4, and 8 (Singh et al., 2006; Schonewille et al., 2008).
Virulent strains show affinity to lymphocytes and consequently cause impairment of the humoral and cellular responses. Effects on immune system are more severe when associated to aflatoxins (Shivachandra et al., 2003). Several FAV strains are capable of increasing the susceptibility of the bids to E. coli infections (Rosenberger et al., 1985). Vaccination failures again ND and avian influenza (subtype H9) is reported in animals inoculated by FAV serotype 4 (Niu et al., 2017).
What was the diagnosis of the febrile illness, based on the information provided by the gospels of Mark, Matthew and Luke? It seems that the woman suffered an acute febrile illness with high fever and was sick enough to be bed-ridden. Luke did not quantify the fever as the Fahrenheit temperature scale was not invented until 1724. No other symptom or chronic illness was described in the three gospels. Possible etiology of her "acute febrile illness" is some sort of infection or inflammation. The Bible describes that when Jesus touched the woman, the fever retreated instantaneously. This implies that the disease was probably not a severe acute bacterial infection (such as septicemia) or subacute endocarditis that would not resolved instantaneously. It was probably not an autoimmune disease such as systemic lupus erythematousus with multiple organ system involvement, as the Bible does not mention any skin rash or other organ system involvement. The instantaneous cure also makes an underlying malignant etiology unlikely. It seems that an acute self-limiting infectious illness is a possible diagnosis. The brief duration, high fever, and abrupt cessation of fever makes influenza disease probable. Shortly following her recovery, presumbly within minutes, it is described that the woman began to serve Jesus and the disciples, thus making influenza illness highly probable. Most miserably sick patients recover without sequlae when the high fevers subside following influenza-like illness.
The next question is whether the virus is influenza, avian flu, parainfluenza, or other respiratory viruses such as adenovirus or even SARS-CoV (Severe Acute Respiratory Syndrome-associated Coronavirus). Adenovirus and SARS-CoV are usually associated with pulmonitis, and the pulmonary symptoms may not resolve promptly. It is unable to tell if the woman has been in contact with poultry or swine and contracted avian or swine influenza. The Bible does not describe if any members of the family including Andrew and Simon developed febrile illness, before or subsequent to her febrile illness. The characteristic features of seasonal influenza include abrupt onset of fever, chills, non-productive cough, myalgias, headache, nasal congestion, sore throat, and fatigue. The diagnosis is mainly clinical. Seasonal influenza would be less likely if no members of the family were affected. Avian influenza and other respiratory viruses may cause isolated infection without efficient human-to-human transmission. In any case, influenza-like illness due to a respiratroy virus would explain her symptomatology and clincial course. Other possibilities include drug fever and poisoning (such as atropine). Naturally-occurring plants containing the belladonna alkaloid atropine could have been consumed but the Bible does not describe unusual food or medicine intake by the woman and her family. The other side effects of anticholinergic agent were absent. The woman would recover spontaneously when the effect of the offending substance wore off.
One final consideration that one might have is whether the illness was inflicted by a demon or devil. The Bible always tells if an illness is caused by a demon or devil (Matthew 9:18-25, 12:22, 9:32-33; Mark 1:23-26, 5:1-15, 9:17-29; Luke 4:33-35, 8:27-35, 9:38-43, 11:14). The victims often had what sounded like a convulsion when the demon was cast out. In our index case, demonic influence is not stated, and the woman had no apparent convulsion or residual symptomatology.
The Bible has many examples of descriptions of medical diseases. For instance, the first pediatric case of mouth-to-mouth cardiopulmonary resuscitation is vividly described in the Old Testament when the prophet Elisha pressed upon an apparently dead child and breathed into him seven times, and the child was revived (Kings 4:34-35).
Influenza and respiratory viral infections have been documented throughout human history. The current 2009 flu pandemic is a global outbreak of a new strain of H1N1 influenza virus, often referred to colloquially as "swine flu" which began in the state of Veracruz, Mexico in April 2009 and the virus continued to spread globally. The World Health Organization (WHO) and US Centers for Disease Control (CDC) in June escalated the global alert level to phase 6 and declared the outbreak to be a global pandemic since the 1968 Hong Kong flu.
The Bible descrbies the case of a woman with high fever cured by our Lord Jesus Christ. According to Mark 1:29 to 33 and Matthew 8:14-15, the mother-in-law of Simon Peter "lay sick" with a febrile illness. When Jesus took her by the hand and lifted her up, the fever immediately left. The lady began to serve the household and probably prepared a meal. The case is also described in the gospel by Luke (Luke 4:38-39), who was a physician in his days and he specifically mentioned that the fever was high.
Influenza and other acute respiratory infections (ARIs) are the most common human diseases and are nearly 70% of all infectious diseases. Up to 90% of the population suffer from one of these infections at least once a year. The current epidemic process is characterized by simultaneous circulation of different types of influenza viruses and annual outbreaks respiratory viruses during the winter and spring seasons; however, parainfluenza viruses—for example—are prevalent throughout the year.
ARIs are caused by viral or bacterial pathogens and can result in hospitalization and death, particularly among young children, older adults, and other high-risk groups. Viruses are the leading causes of acute respiratory disease throughout the world. The most common viral etiologic agents of ARIs are respiratory syncytial virus (RSV), human metapneumovirus (MPV), influenza A and B viruses, parainfluenza viruses (PIV 1-2-3) and adenoviruses (AdV), human rhinoviruses (RV), human coronaviruses (CoV), enteroviruses (EnV), and human bocavirus (BoV). In addition, human polyomaviruses (KI, WU) have been detected in patients with respiratory infections. Although ARIs have traditionally been thought to be caused by single viruses, an increasing number of reports have reported respiratory diseases occurring as dual or multiple virus infections. There are suggestions that respiratory viral co-infections affect disease severity with some studies suggesting that dual and multiple infections increase the severity of respiratory disease, while dual or multiple infections may actually be protective.
The human PIV type 3 (PIV3) is common human respiratory tract pathogen, which causes ARI, pneumonia, and bronchiolitis. PIV3 is known to be an important community-acquired pneumonia pathogen in transplant recipients and immunosuppressed patients, is also an important pathogen in immunocompetent adults. In normal adult hosts, the clinical presentation of PIV 3 pneumonia may clinically closely mimic H1N1 pneumonia.
Currently, there are no approved vaccines for the prevention of most respiratory viral infections despite continual efforts in this field. Medications cover almost all possible responses to the infectious process and often do not show the desired results, and the idea of fast elimination of a viral agent from the cells of infected body is still a topical issue. The emergence of drug-resistant influenza variants has led to a decline in the efficacy such drugs as oseltamivir (Tamiflu), amantadine (Symmetrel), and rimantadine (Flumadine). Therefore, new therapeutics against respiratory viral infections with novel mechanisms of action and against new targets are urgently required. Moreover, co-infection with influenza and other respiratory viruses decreases the efficiency of some aforementioned drugs.
It is established that oligoribonucleotides-D-mannitol (ORNs-D-M) complexes (total yeast RNA modified with D-mannitol) possess an antiviral, anti-inflammatory, and immunomodulatory effects. These complexes were registered under the commercial name ‘Nuclex’ in Ukraine. This medicine effects influenza virus surface antigens, depresses virus activity, and increases interferon production during infection of influenza virus A/Fort Monmouth/1/1947-mouse adapted (H1N1) (FM147) in vitro. ORNs-D-M as an antiviral drug proved to be effective in fighting with many infectious diseases. It was not previously used by patients who suffered from influenza or other ARIs. This study was performed to determine an antiviral efficiency of ORNs-D-M drug against different strains of the influenza viruses and PIV3 and the clinical efficiency of ORNs-D-M in patients with ARI of various etiologies.
Nasopharyngeal cultures, polymerase chain reaction (PCR) testing and serologic studies are available to confirm an infection with Bordetella pertussis, the causative organism.11 However, these tests offer varying levels of sensitivity and may not be obtainable in a timely fashion to confirm cases in the acute setting. Furthermore, other laboratory studies, such as a complete blood count (CBC), may be helpful in distinguishing causes for cough, but only in certain age groups (see “Differential Diagnosis” section). Imaging studies also provide limited information, as patients often do not demonstrate significant findings on chest radiograph. However, chest imaging may be helpful in assessing for superinfection.
Every year, emerging and re-emerging viruses, such as Ebola virus (EBOV), Marburg virus (MARV), and Rift Valley fever virus (RVFV), surface from natural reservoirs and kill people. In addition, influenza A virus (FLUAV), human immunodeficiency (HIV-1), herpes simplex (HSV), and other viruses regularly infect human population and represent substantial public health and economic burden. The World Health Organization (WHO) and the United Nations (UN) have called for better control of viral diseases (https://www.who.int/blueprint/priority-diseases/en/; https://sustainabledevelopment.un.org/). Developing novel virus-specific vaccines and antiviral drugs can be time-consuming and costly. In order to overcome these time and cost issues, academic institutions and pharmaceutical companies have focused on the repositioning of existing antivirals from one viral disease to another, considering that many viruses utilize the same host factors and pathways to replicate inside a cell.
Broad-spectrum antiviral agents (BSAAs) are small-molecules that inhibit a wide range of human viruses. We have recently reviewed approved, investigational and experimental antiviral compounds and identified 108 BSAAs, whose pharmacokinetics (PK) and toxicity had been studied in clinical trials. We tested 40 of these BSAAs against human metapneumovirus (HMPV), hepatitis C virus (HCV), cytomegalovirus (CMV), and hepatitis B virus (HBV). We demonstrated novel antiviral effects of azacytidine, itraconazole, lopinavir, nitazoxanide, and oritavancin against HMPV, as well as cidofovir, dibucaine, azithromycin, gefitinib, minocycline, oritavancin, and pirlindole against HCV. We also tested 55 BSAAs, including these 40, against FLUAV, RVFV, echovirus 1 (EV1), ZIKV, CHIKV, RRV, HIV-1 and HSV-1. We identified novel activities for dalbavancin against EV1, ezetimibe against HIV-1 and ZIKV, and azacytidine, cyclosporine, minocycline, oritavancin and ritonavir against RVFV.
Here, we evaluated the efficacy of 43 BSAAs, which do not overlap with 55 agents we tested before. We identified novel in vitro activities of obatoclax and emetine against HSV-2, EV1, HMPV and RVFV. Moreover, we demonstrated novel antiviral effects of emetine against FLUAV, niclosamide against HSV-2, brequinar against HIV-1, and homoharringtonine against EV1 in vitro.
Severe and sometimes fatal pertussis-related complications can occur in certain groups. These include infants <12 months of age, particularly those
Diagnostic results are shown in Table 2. Before the start of chemotherapy (phase A), viral nucleic acids were detected in 14% (10/71) of patients. In 13% (6/46) of neutropenic patients without fever (group B) and in 19% (8/42) of those with fever (phase C) a respiratory virus was detected by PCR. The distribution of viral species found in the different groups is described in Table 2. RV was the most frequently detected virus followed by hBoV and hCoV. InfA & B and PIV 2 & 4 were not present in any of the tested samples. No substantial differences in the distribution of specific viral species were observed between groups. Viral positivity did not show any seasonal pattern for any of the groups. Patients with respiratory symptoms were not associated with a higher prevalence of respiratory viruses compared to asymptomatic patients. (resp. 2/10 [20%] vs. 6/32 [19%]).
Looking at different sample types, nasal swabs had a positivity rate of 14% (16/117), compared to 6% (6/106) for throat swabs and 9% (14/148) for throat gurgles. The difference between nasal swabs and throat swabs was statistically significant (p < 0.05 chi square test). When multiple samples were taken, more than one sample was positive in 49% of the paired samples.
Longitudinal analyses of prospective samples showed that of the 10 viruses found before the start of chemotherapy only 2 were still present during neutropenia (one in a patient with, and another in a patient without, neutropenic fever). In both cases it concerned RV.
Coronaviruses are enveloped viruses with a large (27–32 kb) single-stranded, positive-sense RNA. The genome includes at least 6 open reading frames (ORFs) flanked by 5′ and 3′ untranslated regions. The viral RNA is packaged by the nucleocapsid protein (N), which are themselves enclosed in an envelope containing at least three virally-encoded membrane proteins: the spike (S) glycoprotein, transmembrane protein (M), and small membrane protein (E) [2, 3]. Some coronaviruses have an additional membrane glycoprotein, hemagglutinin esterase.
The trimeric S protein forms characteristic viral peplomers that are involved in virus attachment to cell receptors and in virus-cell fusion [5, 6]. The M protein, the most abundant structural component, is a type III glycoprotein consisting of a short amino-terminal ectodomain, a triple-spanning transmembrane domain, and a carboxyl-terminal inner domain. The E protein has been found to be important for viral envelope assembly.
Coronaviruses infect many animals species, including cats and dogs. Feline infectious peritonitis (FIP) was first recognized in 1963 at the Angell Memorial Animal Hospital in Boston by Holzworth. A few years later, Ward discovered that the etiologic agent of this disease was a virus of the family Coronaviridae, that is, the feline coronavirus (FCoV). The first observation of canine coronavirus (CCoV) infection was reported in 1971, when Binn and colleagues isolated a coronavirus (strain 1-71) from dogs with acute enteritis in a military canine unit in Germany. Since these discoveries, much knowledge has been gained as regarding the molecular biology and pathobiology of these viruses. This paper describes recent advances in knowledge of their genetic diversity, the determinants of pathogenesis, and their ability to cross the species barrier. Differences and similarities between these viruses have been highlighted. The paper focuses on feline and canine coronaviruses of the Alphacoronavirus genus, and leaves the canine respiratory coronavirus, which belongs to the Betacoronavirus genus, aside (see below).
In the control-GD group, four chicks showed signs of depression and tracheal and bronchiolar rales at 7 dpc. The mortality of the group control-GD was 30% during the 14-day observation period (Figure 3A). The main clinical manifestations in the dead chicks were kidney swelling, urate deposition on the kidneys, and heavy exudates of flaxen mucus on the bursa of Fabricius (Figure 3B). The mental status and appetite in the JS-GD group showed no obvious changes. The organs also exhibited no apparent pathological changes after challenge in the JS-GD group during the observation period.
Three-week-old SPF chickens challenged with the GD strain showed clinical signs of infection as early as 3 dpc, and these signs persisted until 10 dpc. The diseased chicks showed signs of coughing, sneezing, tracheal and bronchiolar rales, listlessness, huddling, and ruffled feathers. Four birds in the GD-inoculated group A died during the experiment, beginning at 5 dpc and peaking at 8 dpc, and the mortality rate reached 40% (Figure 1A). The birds in the control groups were alert and active during the experiment.
Deparaffinized sections of the virus-infected and uninfected control tissue (brain, lungs, nasal turbinates, small intestine, kidney, and spleen) were immunostained using polyclonal antisera against the N protein of the homologous APMV serotypes. Remarkably, animals infected with APMV-5 did not show any positive immunofluorescence in any of the tissues examined at 3 or 14 dpi. In animals infected with any of the other APMV serotypes, virus-specific antigens were detected on 3 dpi in the lungs and nasal turbinates (Figure 3). In the nasal turbinates, virus-positive immunofluorescence was noticed throughout the nasal epithelium lining the turbinate bone, and the harderian gland located near the eye showed complete diffuse fluorescence throughout the organ. In the lungs, the viral antigens were mostly localized in the epithelium surrounding the medium and small bronchi. Viral N antigens were not detected in any additional organs of infected hamsters at 3 dpi, and were not detected in any of the organs of infected hamsters at 14 dpi. The organs of uninfected control hamsters were also negative by immunohistochemistry assay.
Bluetongue (BT) is a non-contagious, arthropod-borne viral disease of domestic and wild ruminants, listed as a notifiable disease by the World Organization for Animal Health (OIE). The Bluetongue virus (BTV) is the prototype member of the Orbivirus genus within the Reoviridae family (1, 2).
BTV is a double-stranded (ds) RNA virus (3), its genome consists of ten segments (Seg-1 to Seg-10) of linear dsRNA coding 7 structural (VP1–VP7) and 5 non-structural (NS1, NS2, NS3/NS3a, NS4, and NS5) proteins (4) At present twenty-eighth distinct BTV serotypes have been officially recognized based on Seg-2 gene sequence (5, 6). Other putative novel BTV serotypes have also been described (7–11).
Transmission between mammalian hosts and spread of the infection rely mostly on competent Culicoides species (12–14), so the presence of the disease is then strictly related to the distribution of competent vectors (2). Even though they don't seem to be epidemiologically important, vertical and horizontal transmissions have also been described (15–18). For BTV-26, BTV-27 v02 and, probably, BTV-X ITL2015 and BTV-28 transmission by direct contact has been demonstrated or hypothesized (6, 10, 19, 20).
Clinical signs of BT are more severe and most commonly observed in sheep or in white-tailed deer, often leading to animal fatality especially in naïve animals (1, 2). In cattle, BTV infection is usually asymptomatic, although symptoms were reported after infection with some strains (21–24).
As a RNA virus with a segmented genome, BTV can undergo reassortment which can occur when a cell is simultaneously infected with more than one BTV strain and involves the packaging, into a single virion, of full length of genomic segments of different ancestry. Reassortment in BTV is very flexible, and can involve any genome segment (25–27). However, the genome sequence of BTV isolates generally reflects their geographic origins (28–30).
Seg-2 and Seg-6 encoded the BTV outer capsid proteins VP2 and VP5. They represent the primary target for neutralizing antibodies generated during infection of the mammalian host (31–33). Their highly variable sequences are associated with virus serotype (particularly in VP2/segment) (34–36) and, within each serotype, with the geographic origin of the virus strain (28, 34–37).
Among BTV serotypes, Seg-2/VP2 sequences of BTV-3, BTV-16, and BTV-13 are closely related. All of them are included within the nucleotype B reflecting a serological relationship (3). BTV-3 strains can be subdivided into at least two main clusters. 1st cluster includes strains originated from Africa, Mediterranean Basin and North America (western topotypes, w); 2nd-includes strains originated from Japan, India, and Australia (eastern topotypes, e). The nucleotide (nt) identity between Western and Eastern topotype Seg-2 can be as small as 71.5% (7, 38–43).
Between 2016 and 2018, two novel BTV-3 western strains have been identified in two different geographical areas of Tunisia-one in the north-eastern part of the country (Peninsula of Cap Bon, prototype BTV-3 TUN2016) and the other in the South-East near by the border with Libya (prototype strain BTV-3 TUN2016/Zarzis). The BTV-3 TUN2016 spread in 2017 to Italy infecting a single 3-year-old female crossbred sheep belonging to a flock located in the municipality of Trapani, Sicily, which are 150 km distant from Peninsula of Cap Bon (7, 39, 40) and in 2018 in the Southern area of Sardinia causing numerous outbreaks (38). Clinical signs in infected sheep included depression, fever, nasal discharge, submandibular edema, and crusted discharge around the nostrils. Four animals died because of the severity of infection (38). In 2016, another BTV-3 strain closely related to TUN2016/Zarzis strain was detected in Egypt (38).
The present paper reports the results of the diagnostic activities on BTV conducted at Kimron Veterinary Institute between 2013 and 2018 and the evidence of BTV-3 circulation in Israel. Clinical signs of infected sheep, goats and cattle along with the genetic characterization and phylogenetic analysis of the BTV-3 strains are also described.
Gross pathological changes were observed mainly in the lungs of the infected animals that were necropsied at 4 dpi. One and two ferrets infected with the R11 and R61 viruses, respectively, presented with macroscopic lung lesions. The macroscopic lesions were characterised by heavy, firm, red and oedematous lungs. The animals in the control group did not exhibit any gross or histopathological changes.
The pulmonary histopathological scores are presented in Table 2. In general, the three lung lobes of any given animal were equally affected. No major differences in terms of histopathological scores were observed between the viral groups. Two animals infected with the R11 viral strain and two animals infected with R61 viral strain presented with severe lung lesions that were characterised by severe and diffuse alveolar damage. In general, the three lung lobes were equally affected, alveolar epithelial necrosis was observed, and the alveoli were distended and contained dense proteinaceous debris, desquamated cells, and high numbers of macrophages and neutrophils; in some cases, alveolar haemorrhage and hyaline membranes were also observed (Figure 1).
The remaining infected animals (two infected with the R11 virus and two infected with the R61 virus) presented with mild lung lesions that consisted of moderate to severe bronchial, bronchiolar and glandular necrosis with lymphoplasmacytic inflammation (Figure 1). The histopathological lesions observed at 7 dpi were similar to those described at 4 dpi but also included bronchiolar epithelial regeneration (data not shown).
The trachea and nasal turbinates were also microscopically examined. In general, the ferrets that presented with severe lung lesions also presented with necrotising rhinitis with mucous and tracheitis with a lymphoplasmacytic infiltration. The ferrets that presented with mild lesions also presented with lesions in the trachea and nasal turbinates that were characterised by a catarrhal rhinitis with mucous secretion and tracheal glandular necrosis (data not shown).
Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is known to be a benign disease that usually resolves spontaneously. It is a rare disease and was first reported in Japan in 1972 [1, 2]. KFD usually affects female patients under the age of 30 years and is characterized by regional lymphadenopathy with tenderness, predominantly in the cervical region, and is usually accompanied by mild fever and night sweats. It is of clinical importance because it is often misdiagnosed as tuberculosis, lymphoma, or systemic lupus erythematosus (SLE); therefore, the diagnosis should be confirmed by biopsy study. Diseases that generally accompany KFD are SLE, arthritis, mixed connective tissue disease, and similar conditions; however, comorbid testitis has not yet been reported. Neurological complications occur in about 11% of cases, as revealed by a review of 244 cases in which a minority of cases evolved to developing encephalitis. Brain magnetic resonance imaging (MRI) includes symmetrical hyperintense T2-weighted and FLAIR (fluid-attenuated inversion recovery) signals in the temporal lobes, pons, and periaqueductal gray matter [4–7]. This is the first report of KFD occurring with testitis and pathologically proven asymmetrical brain regions.