All current commercial human and animal vaccines used for lyssavirus prophylaxis were developed for the prevention of genotype 1 rabies virus arthritis under breast bone purchase medrol 4mg otc. Poor crossprotection against the divergent viruses is supported by cases of Lagos bat and Mokola virus infection in rabies-vaccinated cats and dogs mild arthritis in the knee buy medrol 16mg with amex. Prevention of bat lyssavirus spill-over in humans is based on the management of any bat bite (penetration of the skin by teeth) or non-bite exposure arthritis in dogs metacam medrol 16mg on line, defined as contamination of open wounds arthritis in the knee natural remedies generic medrol 16 mg without prescription, abrasions (including scratches) or mucous membranes with saliva or other potentially infectious material rheumatoid arthritis education cheap 16mg medrol with mastercard. Pre-exposure prophylaxis reduces the risk to individuals where medical attention or rabies biologics are unavailable arthritis in dogs and baby aspirin buy medrol 4 mg fast delivery, or when post-exposure vaccination is delayed or not sought after unapparent exposure arthritis in back of leg buy 16 mg medrol otc. Pathogenesis and clinical presentation Virus introduced through the skin or mucous membranes may undergo replication in local tissues arthritis with dogs proven 4mg medrol, or enter the nerve process directly and ascend to the nerve cell bodies of ganglia, the spinal cord or brain stem. Spread to the salivary glands and excretion in saliva enables further transmission. The location of viral sequestration and the factors responsible for the delayed progression of long incubation periods are unknown. The precise mechanisms producing nervous system dysfunction and death are complex. Disruption of cellular functions, loss of homeostasis and inflammation usually culminate in multi-system organ failure and death. Classically, clinical rabies in humans and dogs is described as "furious" (encephalitic) or "dumb" (paralytic). However, the clinical presentations of all genotypes of lyssavirus in all species span a broad spectrum of signs reflecting abnormal function of the central, peripheral and autonomic nervous systems. Clinical signs in bats reflect alterations in behaviour and motor function and rapidly progress to death within hours or days. In Microchiroptera and flying foxes, signs include unusual aggression or tolerance of people, fighting with other bats, being active and away from roosts and camps during the day, biting and vocalizing, and being grounded and unable to fly (Barrett, 2004; Constantine, 2009). A minority of cases (19 of 74, 19 percent) showed signs of overt aggression, including flying out of trees in unprovoked attacks, and repeated attempts to bite (Barrett, 2004). As natural infections in bats are rarely observed, and testing for lyssavirus is usually postmortem, diagnosis of lyssavirus in bats is biased towards cases with fatal outcomes. The full scope of the natural history of lyssavirus infection in bats is probably not known. Diagnostics Definitive diagnosis of lyssavirus infection is based on viral isolation or detection of viral antigens, antibodies or viral genome. Lyssavirus identification to the level of specific variants requires antigenic typing with a panel of monoclonal antibodies, or molecular characterization. Detection of lyssavirus antibodies indicates current infection, past exposure or rabies vaccination. Primary identification of a lyssavirus infection is typically made by direct examination of brain impressions and demonstration of viral inclusions (antigens). Electron microscopy may be used to determine a morphologic identification of lyssaviruses by examination of the virion ultrastructure in cell cultures or tissues. Appropriate samples Definitive diagnosis of lyssavirus infection requires examination of fresh or 10 percentbuffered formalin-fixed tissues. Tests are available for formalin-fixed tissues, but fixed samples are not recommended for primary diagnosis unless fresh brain tissues are unavailable owing to longer tissue processing and testing times. Serum and cerebrospinal fluid may be tested for the presence of anti-lyssavirus antibodies, indicating an immune response to current or prior infection. All unfixed samples should be shipped on dry ice (or icepacks for same-day delivery) to the diagnostic laboratory, by the most expedient method. Haemolysis of red cells compromises the test reliability of serum samples and can be minimized if whole blood is centrifuged and serum separated prior to transport. Whole blood should not be shipped in the same container as samples on dry ice, because there is a risk of freezing and haemolysis, regardless of packing insulation. Formalin-fixed tissues should remain in the fixative for a minimum of 24 to 48 hours at room temperature. Thereafter, formalin-fixed brain tissues should be stored in 70-percent ethanol at room temperature for long-term storage, and never frozen. Paraffin-blocked tissues and tissue sections (slides) should be stored at ambient temperatures and not frozen. Available tests A range of tests for lyssavirus provide different degrees of specificity for the particular genotype or variant. For routine primary lyssavirus diagnosis, antigen detection tests, such as the direct fluorescent antibody test, are highly sensitive and broadly reactive, and are less expensive and less time-consuming than other methods. Viral protein detection: Lyssavirus diagnosis is most efficiently based on the detection of abundant intracellular collections of viral proteins (antigen) that form viral inclusions. Direct 94 Investigating the role of bats in emerging zoonoses detection methods can be used to detect viral antigens and histopathological changes and to observe virion morphology. All virus antigen tests require thorough tissue sampling (including complete crosssectioning of the brain stem and cerebellum) to ensure that samples include adequate quantities of viral product. These methods provide rapid diagnosis within minutes or hours without the need for amplification as required for genome or live virus detection: 1. This test is easy to perform, highly specific and approximately 100 percent sensitive for most genotypes, and can be completed within three to four hours. The conjugates may be hyper-immune polyclonal or monoclonal antibodies directed against one or more highly conserved rabies or variant-specific epitopes. Morphologically fluoresceinlabelled intracellular inclusions occur as fluorescent large or small (oval or round) inclusions, dust-like particles or strands. Advantages of this procedure include the rapidity of the test protocol (one hour for completion), the fixation of brain touch impression slides in formalin (inactivating rabies virus), and the minimal equipment requirements (ambient incubation temperatures, standard light microscope). Antigenic typing in indirect fluorescent antibody tests is an inexpensive, rapid and easily performed method of determining virus variants in a few hours. Tests are performed on acetone-fixed brain impression slides or virus-infected cell culture slides. Amplification of virus by inoculating cell cultures or animals may be required if the primary test material contains low levels of antigen. Lyssavirus antigen will appear as large or small (oval or round) inclusions or dust-like particles in the colour of the selected chromagen within the cytoplasm of infected neurons against a light-blue background of the haemotoxylin-stained tissue. Although of historical importance, these older diagnostic methods lack both the specificity and the sensitivity of modern antigenic or genomic tests. Direct observation of virions by electron microscopy allows the examination of virus ultrastructure, shape and size (Gosztonyi, 1994). This technique provides supportive evidence of a rhabdovirus infection, but is less sensitive, not specific for the lyssavirus genus, genotype or variant, and too costly and time-consuming for routine diagnosis. Sequencing and phylogenetic analysis provide a very high degree of resolution of the virus variant. These tests are most useful when the likely genotypes and variants are known and limited, so that a small panel of primers and probes can detect all anticipated variants, as is the case in Australia. The future incorporation of real-time techniques that detect all lyssaviruses, including the most divergent Mokola, Lagos bat, West Caucasian and Shimoni viruses, will allow for more rapid diagnosis, less risk of cross-contamination, and test automation. Classical methods include in vivo isolation in animals (usually intra-cerebral inoculation of suckling mice) and in vitro virus isolation in cell cultures. The identification of virus amplified by in vivo inoculation and cell cultures should be confirmed by antigenic or molecular methods. For most routine diagnostic needs, inoculation of cell cultures, such as mouse neuroblastoma cells, provides the same sensitivity as animal inoculation, but with quicker results and without the ethical issues or maintenance involved in the use of laboratory animals. Propagation, amplification and quantification of virus and antibodies with cell cultures are also used to produce vaccines, determine the safety of vaccine lots, and study the pathogenesis of rabies virus in particular cells. Antibody detection: Genotype 1 rabies virus neutralization tests are the standard tests for detecting antibodies to the rabies G protein, particularly for determining if rabies vaccination has produced adequate titres of rabies virus-neutralizing antibody. These tests are also used to detect cross-reactive immune responses to other lyssaviruses. A lack of validated serological tests for other bat lyssavirus genotypes hampers the sensitivity and interpretation of serological surveys of bats outside the Americas (Barrett, 2004; Freuling et al. The endpoint antibody titre is the last dilution demonstrating specific fluorescence. Significant zoonotic diseases identified in bats 97 Test limitations Test limitations arise from issues related to sample selection and storage, test performance quality, test sensitivity and specificity, delay before a diagnosis can be made, and the expertise, infrastructure and equipment required to perform the test reliably (Fooks et al. The validity of different laboratory diagnostic tests depends on appropriate storage for the sample and test type. Test performance quality can be assured through quality control, laboratory accreditation and staff proficiency programmes. There is need to identify which tests can provide reliable results in the required time from the available samples, staff and equipment. Diagnostic sensitivity and specificity can be enhanced by testing in parallel or series, usually by using broadly reactive antibody conjugates. Nucleotide sequence analysis, rather than antigenic typing, may be required to differentiate some variants in rabid bats. These reagents cross-react very well with most genotypes, including Australian and European bat lyssaviruses, but the ability of a particular product to detect the more divergent lyssaviruses should be confirmed. The ability of reagents to detect novel bat lyssavirus will need to be established as further genotypes are discovered. Test interpretation the limitations, accuracy, specificity and sensitivity of each diagnostic test should be understood before interpreting test results. Samples that produce weak, non-specific reactions or unusual or inconclusive results should be confirmed by alternative testing methods or submission to a reference laboratory. Diagnosis to the level of virus variant is very useful in a range of circumstances, including when determining the virus variants in human cases with unclear or unknown virus exposure 98 Investigating the role of bats in emerging zoonoses histories; discovering the emergence of new viruses; monitoring the epidemiologic spread or re-emergence of virus in defined geographical areas; detecting spill-over or host-switching of variants from the predominant host species to another species; and monitoring the success of rabies vaccination programmes. The N protein gene has been the one most frequently utilized in molecular epidemiology studies. Older studies focused their analyses on short sequences of fewer than 400 nucleotides. Improving technologies have expanded the focus from single gene sequences to whole viral genomes. Genbank now holds thousands of N gene sequences (complete and partial) for comparisons, and lyssavirus researchers are focusing on the G, P and L genes. These data may assist in understanding specific gene functions in host species, viral pathogenesis, replication and virion formation. Serology is useful for studying population levels of exposures and infection dynamics. Interpretation of bat lyssavirus serology is complicated by its reliance on detecting crossreactions in rabies virus tests, and the use of modified genotype-specific assays that have not been standardized or validated. Post-exposure serology in a clinically normal subject is of no value for predicting whether or not clinical disease will develop for risk evaluations. Conclusions Species-specific lyssavirus variants should be presumed to be present in all bat species globally. Enhanced surveillance and applied research are needed for a better understanding of the epidemiology, disease ecology, pathogenesis and immunobiology of lyssaviruses in bats. New biologics are needed for the development of a pan-lyssavirus vaccine and prophylactic control. Evidence of two lyssavirus phylogroups with distinct pathogenicity and immunogenicity. Brisbane, Australia, Brisbane School of Veterinary Science, University of Queensland. Public veterinary medicine: public health rabies surveillance in the United States during 2009. A comparison of two serological methods for detecting the immune response after rabies vaccination in dogs and cats being exported to rabies-free areas. Rabies human diploid cell vaccine elicits cross-neutralising and cross-protecting immune responses against European and Australian bat lyssaviruses. Susceptibility of sheep to European bat lyssavirus type-1 and -2 infection: A clinical pathogenesis study. Phylogeography, population dynamics, and molecular evolution of European bat lyssaviruses. Emerging technologies for the detection of rabies virus: challenges and hopes in the 21st century. Experimental infection of serotine bats (Eptesicus serotinus) with European bat lyssavirus type 1a. An emerging disease causes regional population collapse of a common North American bat species. Reproduction of lyssaviruses: Ultrastructural composition of lyssavirus and functional aspects of pathogenesis. Use of a single anti-nucleocapsid monoclonal antibody to detect rabies antigen in formalinfixed, paraffin-embedded tissues. Evolutionary timescale of rabies virus adaptation to North American bats inferred from the substitution rate of the nucleoprotein gene. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: Recommendations of the Advisory Committee on Immunization Practices. Rabies transmitted by vampire bats to humans: An emerging zoonotic disease in Latin America Host phylogeny constrains cross-species emergence and establishment of rabies virus in bats. Rabies in red foxes (Vulpes vulpes) experimentally infected with European bat lyssavirus type 1. A comparative study of the fluorescent antibody test for rabies diagnosis in fresh and formalin-fixed brain tissue specimens. However, although it was acknowledged that the human outbreak likely originated from contact with infected market animals, it was not clear that these species were the natural reservoir of the virus. CoVs (order Nidovirales, family Coronaviridae) cause a range of disease syndromes, including respiratory and gastroenteric disease in humans, and respiratory, gastroenteric, neurological and hepatic disease in animals, often with significant public health and economic consequences (Fraenkel-Conrat, Kimball and Levy, 1988; Lai and Cavanagh, 1997). CoVs have historically been divided into three groups (groups 1, 2 and 3) based on their antigenic and genotypic characteristics (Lai and Cavanagh, 1997). Knowledge of the origin of emerging agents and an understanding of the factors associated with emergence are fundamental to managing the risk of subsequent spill-overs and associated disease outbreaks. Wildlife markets are complex and dynamic places, with a random mix of farmed and wild-caught wildlife housed, sold and slaughtered side-by-side. This model was a useful tool not only for conceptualizing the likely complexity of the system, but also for identifying possible transmission control points. For example, regulation (or elimination) of the trade in wild-caught wildlife might control transmission to market and farm populations, and thus to humans; elimination of infection in the farmed wildlife population and ongoing monitoring might control transmission within this group, and thus to wildlife markets and humans. Thus, a necessary extension of understanding the ecology of the reservoir is an understanding of the trade and the social and cultural context of wildlife consumption. It is known that a wholesale and retail structure for the wildlife trade exists in southern China, with multiple wholesalers providing multiple retailers at the city level. The wildlife trade is driven by a complex mix of economic, social and cultural factors. The demand for and consumption of wildlife in southern China have increased in recent years, purportedly owing to improved economic conditions. Increases in legal and illegal wildlife trade have paralleled this growth in demand, with animals reportedly channelled from many and various locations in Southeast Asia. Different species and dishes are favoured for a range of social, business and health reasons. People believed that eating the animal (known colloquially as the "fruit fox" or "flower fox" because of its dietary preferences) provided the same health benefits as eating fruit. In the markets, wild-caught civets still attract a price premium, because people believe they are more health-giving (and taste better) than their grain-fed farmed counterparts. At the time of writing, 109 species of bats, representing 11 families and 44 genera, have been surveyed for CoVs (Table 5. CoVs were detected in 36 species, and anti-CoV antibodies in a further seven species (Tables 5. Miniopteridae Miniopterus africanus inflatus magnater minor natalensis pusillus schreibersii Molossidae Chaerephon pumilus sp. Molossus Mops major condylurus midas Otomops Tadarida Mormoopidae Mormoops Pteronotus Noctilionidae Nycteridae Noctilio Nycteris martinsseni brasiliensis sp. Coronavirus nomenclature: host species/country of origin/laboratory identification/year collected. Significant zoonotic diseases identified in bats 111 Group 1 bat coronaviruses Multiple authors (Poon et al. Group 1 bat CoVs have nucleotide sequence similarity (of 54 to 75 percent) to non-bat group 1 CoVs. They are highly divergent and related to CoVs previously identified from domestic animals (Figure 5.
The virus was soon characterized as a quadruple reassortant virus of the H1N1 subtype arthritis care medication best 4 mg medrol, with gene segments from swine and avian influenza viruses climacteric arthritis symptoms definition buy discount medrol 16 mg on-line. Although illness caused by the nascent pandemic virus was generally mild to moderate arthritis in dogs legs treatment generic 16 mg medrol mastercard, severe illness was observed in individuals with underlying conditions such as obesity and diabetes how to prevent arthritis in fingers naturally buy generic medrol 16 mg line, in pregnant women rheumatoid arthritis diet blog buy 4mg medrol overnight delivery, and-surprisingly-in older children and young adults arthritis in young horses neck generic 4 mg medrol amex. Resistance to adamantanes was conferred by a mutation in the M2 gene of the 2009 H1N1 viruses arthritis pain big toe order medrol 16 mg free shipping. An immediate response to the emergence of the 2009 H1N1 virus was the production of a vaccine rheumatoid arthritis red eyes discount medrol 16 mg. Vaccine manufacturers in the Northern Hemisphere had recently finished distribution of the trivalent vaccine for the 2008 to 2009 winter influenza season when the pandemic H1N1 virus emerged. As a result of these delays, vaccine was not distributed until the peak of infections had passed. Human clinical testing of the monovalent inactivated H1N1 vaccine revealed a high titer antibody response to vaccination in most age groups tested, providing more evidence of preexisting immunity to the pandemic H1N1 virus. However, recent estimates of global mortality from this pandemic are reported to be approximately 10- to 15-fold higher. The first influenza pandemic of the 21st century was the first influenza pandemic to occur in the molecular biology era. Although delays occurred in vaccine production and deployment, the novel virus was rapidly identified and characterized. Key questions about this virus remain, including the precise point of origin of the virus and the reason for the severity of disease in pregnant women infected with this virus. These questions and other features of the virus are the subjects of intensive study. Fortunately, the morbidity and mortality from the 2009 influenza pandemic were not on the scale of the 1918, 1957 or 1968 pandemics. In 2011, and particularly in the summer of 2012, a number of cases of human infection with quadruple reassortant swine H3N2 viruses were reported. Influenza viruses that circulate in swine are referred to as "variant" viruses when isolated in humans, so that the human cases are considered to be infections with the H3N2v virus. From July to September 2012, 306 cases of human infection with H3N2v influenza viruses were reported. Almost all cases have documented histories of swine exposure, and the majority of cases were associated with at- tendance at state fairs. However, some cases have suggested the presence of limited person-to-person transmission. Influenza viruses in swine do not appear to be subjected to the same immunologic pressure that leads to antigenic drift in human influenza viruses. Once introduced into swine populations, influenza viruses therefore tend to be antigenically stable. The H3N2v viruses isolated from humans are phylogenetically most closely related to human influenza viruses from the mid 1990s. Several studies have assessed the degree of baseline population immunity to H3N2v viruses by measuring antibody against these viruses using serum samples from different age groups. These studies have also suggested that children younger than 10 would be largely susceptible to infection based on lack of preexisting antibody. The viruses are prevalent in domestic swine and have a demonstrated ability to infect humans. They possess genotypes that have features that potentially enable human transmission, and some cases of human-to-human transmission have been observed. Previous swine origin viruses have already caused pandemics, and influenza viruses of the H3 subtype are clearly capable of causing widespread human disease. Although the pattern of baseline antibody possibly suggests that the impact of an H3N2v pandemic would be focused on young children, the majority of adults would also be predicted to be susceptible. Thus, development of effective vaccines for H3N2v candidate viruses is a high priority. Human Infections With Avian Influenza Viruses Wild aquatic birds are the major reservoirs of all subtypes of influenza A virus that have been isolated, and the viruses do not cause symptomatic infections in these species. Specifically, seroprevalence levels of 2% to 7% for H5 viruses alone were reported,180 and the seropositivity of human sera for H7, H10, and H11 viruses was estimated to be as high as 38%, 17%, and 15%, respectively. Human Infections With Highly Pathogenic H5N1 Avian Influenza Viruses the first reported cases of H5N1 influenza infections in humans occurred in 1997 in Hong Kong. Phylogenetic analysis of the H5N1 Hong Kong isolate revealed no 662 evidence of genetic reassortment with recent human influenza A viruses. No clear epidemiological link was established between the infected child and infected poultry. However, outbreaks of influenza occurred in poultry on farms in Hong Kong between late March and early May 1997, and two viruses from one of these outbreaks were identified as H5N1 influenza viruses. The cases, which were not geographically related or confined to a specific age group, occurred in children and adults with ages ranging from 1 to 60 years. In 7 of the 18 cases, histories of possible exposure to poultry existed, where the patients had either bought chickens before they became ill or had worked in proximity to chicken stalls near their homes. With one exception, patients younger than age 13 recovered from their illness whereas older patients had more severe disease that resulted in death in five cases. An epidemiological study of the human H5N1 cases in Hong Kong in 1997 suggested that the viruses were transmitted directly from birds to humans, and serological evidence of human-to-human transmission was limited. However, the actual sequence of reassortment events cannot be definitively determined from the small number of viruses available for analysis from preceding years. Reintroduction of poultry to the Hong Kong Special Administrative Region began in February 1998. At this time, new practices were introduced for the live bird markets in Hong Kong. Waterfowl (eg, ducks and geese) are now sold at separate markets from chickens; ducks and geese are now slaughtered at the markets; and markets have a monthly rest day when they close for thorough cleaning, the remaining birds are culled, and restocked with fresh imported poultry. Multiple genotypes and several clades of H5N1 influenza viruses have been identified. Cases occurred in eight contiguous provinces of eastern China and in the two municipalities of Beijing and Shanghai, and a single case was reported in Taiwan. In the majority of the laboratory-confirmed cases of H7N9 in China and in the case reported in Taiwan, illness was severe. Radiologic findings were consistent with pneumonia, with diffuse opacities and consolidation. Gao et al194 reported the clinical features of an additional 111 laboratory confirmed cases in China. Ninety-seven percent of these patients had findings consistent with pneumonia upon admission to the hospital, 77% were admitted to the intensive care unit, and 27% of patients died. The median age of patients was 61 years; 68% were male and 61% had at least one underlying medical condition-most commonly, coronary heart disease, hypertension, diabetes, or chronic obstructive pulmonary disease. It has been suggested that many mild cases may have occurred but were not reported. In addition, infection of avian species with H7N9 isolates did not result in disease, although virus was shed and the birds developed antibodies. These observations underscore the challenge for surveillance of these viruses in avian populations, since they do not cause overt disease. However, H7N9 virus was isolated from only a small percentage of samples taken from birds and the environment all across China. In both cases, the infections were thought to have been acquired in the neighboring city of Shenzhen Bats are thought to be possible reservoirs of filoviruses, including Ebola virus and Lloviu virus, a novel filovirus205,206 since viral nucleic acid sequences have been identified in a variety of bat species. Additionally, Marburg virus has been isolated from Egyptian fruit bats (Rousettus aegyptiacus). Virus was not isolated, but nucleic acid sequences were derived from rectal swab samples, and from liver, intestine, and kidney tissue samples. The sequences were identified as originating from a highly divergent influenza virus. The novel virus was designated as belonging to a new subtype of influenza A viruses, H17N10. The solution of the N10 crystal structure determined that, although it shares general structural features with the other influenza A Emerging Infectious Diseases and Future Threats Figure 25-11. Diagram showing the likely genetic evolution of the H7N9 virus that emerged in China in 2013. The eight genes of the H7N9 virus are closely related avian influenza viruses found in domestic ducks, wild birds, and domestic poultry in Asia. The virus likely emerged from "reassortment," a process in which two or more influenza viruses coinfect a single host and exchange genes. This process can result in the creation of a new influenza virus, and it is likely that multiple reassortment events led to the creation of the H7N9 virus. These events may have occurred in habitats shared by wild and domestic birds and/or in live bird/poultry markets, where different species of birds are bought and sold for food. The sequences were most closely related to the H17N10 influenza sequences previously reported by this group. The H18N11 influenza virus was not isolated, but viral sequences were identified in rectal swabs and intestines of the bats. In addition, the receptor-binding domain of the H18 glycoprotein is dramatically different. The N11 protein does not display glycan binding or enzymatic neuraminidase activity. Seroprevalence studies found that approximately 38% of the Guatemalan bats tested had detectable antibodies to H17,144 and 50% of bats tested had antibodies to either the recombinant H18 or N11. The significance of these findings for the potential for the emergence of novel influenza viruses that may infect humans, or for reassortment with other influenza viruses in nature remains to be determined. By January 2003, the disease had spread to Guangzhou, the capital of Guangdong province, and caused major outbreaks, primarily affecting healthcare workers. In February 2003, a physician from Guangdong spent a single day in a hotel in Hong Kong, during which time he transmitted the infection to 16 other guests. These individuals quickly spread the disease to Hong Kong, Singapore, Vietnam, and Toronto. Middle Eastern Respiratory Syndrome In June 2012, a 60-year-old man was admitted with a history of fever, cough, expectoration, and shortness of breath to a hospital in Jeddah, Saudi Arabia. Clinical isolates were initially tested and found negative for influenza, parainfluenza, enterovirus, and adenovirus. On September 23, 2012, the United Kingdom Health Protection Agency reported on the case of a 49-year-old man who had become sick while in Saudi Arabia in August 2012. That illness resolved, but he subsequently presented to a physician in Qatar with a cough, myalgia, and arthralgia on September 3, 2012. His condition deteriorated once in London, and he was placed on extracorporeal membrane oxygenation on September 20. In the first phase, four patients had onset of symptoms between March 21 and April 2. The patient with the earliest onset (a 25-year-old student) and a 40-year-old nurse who worked at the hospital died within 2 to 4 weeks of symptom onset. A second wave of disease followed with onset of symptoms between April 11 and April 26. This second Emerging Infectious Diseases and Future Threats wave consisted of seven healthcare workers from the hospital and two family members of patients from the first wave of disease. Three of the healthcare workers and the two family members had close contact with individuals in the first wave, raising the possibility of limited person-to-person transmission of the virus. The first patient is thought to have transmitted the virus to a patient in an adjacent room (in addition to his son), who then transmitted the virus to an additional seven patients (six in the dialysis unit and one in the intensive care unit). Further transmission of the virus was documented to an additional 10 patients, two healthcare workers, and three family members. History of travel from in or near the Arabian Peninsula within 14 days of illness onset for confirmed cases (N = 130) of Middle East respiratory syndrome coronavirus infection reported to the World Health Organization from 2012 to 2013. All cases have been directly or indirectly linked through travel to or residence in Saudi Arabia, Qatar, Jordan, and the United Arab Emirates. A secondary case from the second hospital went on to infect more than 80 additional people. During the recent outbreak in South Korea, secondary and tertiary transmission occurred from the index case who traveled to the Middle East. All other cases outside of the Middle East had recorded recent travel to the Middle East (Figure 25-12). Twenty-eight (60%) of the patients died, and the fatality rate increased with increasing age. The rapid identification of the receptor opens several avenues for generating antiviral therapeutics. The virus has been shown to be sensitive to type I interferon in vitro, with its replication limited by two to four orders of magnitude when cells are pretreated with interferon. The virus could then be transmitted to humans when they came into contact with infected civets in wild animal markets. One of the main concerns has centered on the Hajj, the annual event in which millions of Muslim pilgrims from around the world travel to Mecca in Saudi Arabia. The Saudi Arabian Ministry of Health recommended that persons older than 65, pregnant women, children younger than 12, or those with chronic diseases should postpone performing the Hajj in 2013. Many may have heeded those warnings, as participation in the 2013 Hajj was estimated at just less than 2 million pilgrims, down from 3. Diseases Caused by Emerging Paramyxoviruses Hendra Virus In 1994, a new member of the paramyxoviruses emerged for the first time in Brisbane, Australia, killing 14 race horses and a horse trainer. One year later, a farmer from Mackay (800 km north of Brisbane) died as a result of encephalitis caused by this novel virus. Genetic analysis of the virus showed it was distantly related to the morbilliviruses, which contain other members such as rinderpest, measles, and canine distemper viruses, and so the virus was initially named equine morbillivirus,241 but was later renamed Hendra virus after the Brisbane suburb where the outbreak occurred. Serologic evidence243 and later evidence of infection was found in several species of Australian flying foxes (ie, fruit bats of the genus Pteropus) (Figure 25-14), supporting epidemiological evidence that fruit bats are the natural reservoir for Hendra virus. Field, experimental, and molecular investigations indicate that Hendra virus is an endemic fruit bat virus that has probably co-evolved with its pteropid hosts. Four of these outbreaks have spread to humans as a result of direct contact with infected horses. Preliminary research on the new virus revealed that it had ultrastructural, antigenic, serologic, and molecular characteristics similar to Hendra virus. More than 70% of those infected have died and one-third of the survivors have permanent neurological deficits. Date palm sap is harvested in the winter in Bangladesh by shaving the bark from the sugar date palm tree and collecting the sap into open clay pots. Pteropus bats (see Figure 25-14) that shed Nipah virus in their saliva frequently visit the trees during sap collection and lick the sap as it is running into the pot, thereby contaminating the sap. Emerging Mosquitoborne Viruses: Dengue, West Nile, and Chikungunya Mosquitoborne viruses are members of the more general category of arthropodborne viruses or arboviruses. Human infection with arboviruses can be asymptomatic or can cause diseases ranging from a mild febrile illness to encephalitis or even severe hemorrhagic fever in some cases. Most arboviruses require a reservoir host such as a bird or small mammal while using a vector-usually a mosquito or tick-for transmission to another host. Flying foxes (Pteropus spp) are the natural reservoir of the Nipah and Hendra viruses, and possibly other emerging paramyxoviruses. Photos show the little red flying fox (Pteropus scapulatus) in flight (a) and roosting (b). Photographs: Courtesy of Raina Plowright, Department of Veterinary Medicine and Epidemiology, University of California, Davis, California. However, because of various ecological or environmental changes (whether natural or manmade) that lead to changes in the mosquito vector distribution or genetic changes in the viruses themselves, some arboviruses may not always remain restricted to their previously known geographical regions. Classical dengue fever is an acute febrile illness that often occurs in children and is characterized by fever, severe headache and muscle aches, nausea, vomiting, and rash. Preexisting heterologous dengue antibody recognizes the infecting virus and forms an antigen-antibody complex, which is then bound to and internalized by immunoglobulin Fc receptors on macrophages. The principal urban vector, Aedes aegypti, is highly domesticated and is adapted to humans, preferring to feed on them and lay their eggs in artificial containers in and around houses. In the past 25 years, a marked global emergence of epidemic dengue has occurred, with more frequent and larger epidemics associated with more severe disease. Photograph: Courtesy of James Gathany, Centers for Disease Control and Prevention Public Health Image Library. In particular, unprecedented global population growth and associated unplanned and uncontrolled urbanization occurred, especially in the tropical developing countries. It is now one of the most widely distributed of all mosquitoborne arboviruses, and it is found in areas throughout Africa, Europe, Asia, and the Americas. Data represent counties reporting West Nile virus activity in humans (red) and nonhuman (eg, birds, mosquitoes, equines, and other mammals) (blue) in the United States. Data source: National Center for Infectious Diseases, Centers for Disease Control and Prevention. The infection manifested with a sudden onset of incapacitating joint pain and high fever, leading locals to call it chikungunya, meaning "that which bends up" in the local Makonde language. The disease also often led to development of a maculopapular rash, anorexia, and constipation. Most symptoms usually resolved within 7 to 10 days, but the arthralgia could last for months following the infection. In some patients, the joint pain was so severe months after infection that they were unable to change position without help. A viral agent was recovered from the serum of acutely ill patients by intracerebral inoculation into mice.
Mild recurrent anterior uveitis is usually self-limiting and symptomatically treated with local steroids and mydriatic agents under ophthalmic supervision arthritis medication horses generic 4 mg medrol. The inflammatory exudate arthritis diet coffee buy 4mg medrol overnight delivery, which can be seen by slit-lamp microscopy arthritis in dogs meds buy medrol 16mg with visa, may form small deposits on the back of the cornea (keratic precipitates arthritis symptoms in legs order medrol 16 mg on-line. The back of the inflamed iris may become stuck to the lens (posterior synechiae) arthritis pain base of thumb discount medrol 16 mg on line, producing an irregularly shaped pupil and increased pressure in the posterior chamber (secondary glaucoma) arthritis diet for dummies medrol 16 mg low price. This model has shown that cells in both chambers of the eye can suppress activation of bystander T cells and the production of inflammatory cytokines arthritis pain and associates medrol 16 mg discount. In the anterior segment and the aqueous humour arthritis in neck disability cheap medrol 4 mg, suppress activation of T cells is by cell-to cell contact with corneal endothelial cells and iris pigment epithelial cells, whereas in the posterior chamber, retinal pigment epithelial cells suppress the activation of T cells via soluble factors. She made an uneventful post-operative recovery but 2 weeks later developed a severe uveitis in the same eye. Two years after the operation, she still has to use topical steroids to suppress the uveitis. However, once uveitis has occurred, any inflammatory agent can trigger a recurrence. Sensitized Th1 and Th17 cells, as well as macrophages, play an effector role in ocular inflammation. Slight changes in vascular permeability in the eye, like those in the kidney, encourage the deposition of immune complexes or antigen and further activate macrophages. In contrast to acute anterior uveitis, chronic anterior uveitis is painless and presents with insidious loss of vision, due to a combination of raised intraocular pressure and cataract formation. This can occur without systemic disease but most notably occurs in children with juvenile idiopathic arthritis, particularly in those with early-onset disease involving a small number of joints and who have antinuclear antibodies (about 50% of children with this pattern of arthritis have uveitis). Ophthalmological screening of children with juvenile idiopathic arthritis is essential, as early detection and treatment can prevent blindness in this silent, insidiously progressive disease. This can occur as one of a group of idiopathic disorders confined to the eye, but more often occurs secondary to infection or systemic inflammatory disease. The inflammatory process is often centred on blood vessels, particularly when acute. It is appropriate to consider choroiditis, choroidoretinitis and retinal vasculitis under the same heading. However, similar ocular changes may be seen in infection, which should be excluded before immunosuppression is used. Granuloma formation occurs in several of these disorders and it seems likely that Th1-cellmediated hypersensitivity underlies their pathogenesis. This is not of any clinical consequence but is of interest in showing that the disease process in multiple sclerosis is not confined to the central nervous system. The suspicion of an associated systemic disorder depends on the pattern of the uveitis (bilateral, granulomatous site) and on a careful clinical history and examination. Although injection of sterile lens antigens into the eye has a minimal effect, any natural adjuvants present (such as bacterial antigens) potentiate the immune reaction. Animal experiments suggest that lensinduced uveitis is caused by local production of specific antibodies to denatured lens antigens, which cross-react with native uveal antigens. Antibodies to lens proteins are also found in the eye and circulation in human disease. The disease is usually confined to the traumatized eye, except in elderly patients when spontaneous leakage of lens protein may provoke a bilateral reaction. Sympathetic ophthalmia is a devastating bilateral, progressive granulomatous uveitis following penetration or perforation of one orbit. Uveitis in the non-traumatized eye is thought to be due to an autoimmune T-cell response to antigens liberated from the other eye. A choroiditis is the first sign, but granulomatous inflammation eventually involves the whole tract. Animal experiments suggest that a penetrating injury releases minute doses of retinal antigens into the subconjunctival space with drainage to the local lymph node where autosensitization occurs. Theoretically sympathetic ophthalmia could complicate any invasive surgical procedure on the eye. Organisms that enter through the airways may be killed by local defence mechanisms, persist in the lung with damaging consequences (such as granuloma or fibrosis) or invade the systemic circulation to cause septicaemia. Since all the blood from the right side of the heart passes through the pulmonary bed, the respiratory tract is also exposed to circulating organisms, immune complexes and toxic substances from distant sites. The respiratory tract can be crudely but usefully divided into two anatomical, functional and pathological compartments: the airways (from the nose to the terminal bronchiole) and the air spaces (or alveoli). The airways are protected from inhaled microorganisms and other potentially injurious particles by multiple mechanical factors, backed up by soluble antimicrobial proteins and rapid recruitment of neutrophils and other inflammatory cells. Access to the alveolar compartment is therefore usually limited to very small inhaled particles (<5 m diameter) (see. Particles and organisms gaining access to the alveoli encounter further protective mechanisms such as the surfactant proteins (which have a complement-like function) and alveolar macrophages. Alveolar macrophages are responsible for ingesting, killing and degrading foreign material, both living and dead. Although their action in removing organisms from the lower respiratory tract is crucial, their reaction to inert materials can sometimes cause pulmonary damage. Cigarette smoking increases the cell yield by fourto five-fold and the macrophages are filled with tars and silicates. Antigens are transported into the follicle where they can stimulate antigen-specific T- and B cells. Subsequently, IgA precursor B cells migrate into lymphatics and thence to the blood; bronchial IgA-bearing cells recirculate through both gut and lungs, so dispersing antigen-sensitive cells. There are also large numbers of less organized lymphocytes in the lung within the pulmonary vasculature, in the lung interstitium and in the bronchoalveolar space. Although relatively few lymphocytes are seen on routine sections, when calculated for the whole lung, lymphocyte numbers are similar to the circulating blood pool, i. The physiological reason for the presence of IgE cells in the lung is unknown; it may even be an evolutionary accident, since the respiratory tract is a foregut derivative and IgE has a role in expulsion of intestinal parasites. While its physiological function is unclear, IgE is implicated in immediate (type I) hypersensitivity mechanisms (see Chapter 4) responsible for allergic asthma and hay fever. We have considered respiratory diseases under four headings: infection, granulomatous disease, interstitial lung disease and vasculitis. Allergic diseases, which constitute the major immunological airways diseases, are considered in Chapter 4. Most respiratory tract infections reflect an interaction between virulent microorganisms and a relatively normal respiratory tract, whose protective mechanisms have been overcome either by the organism or by other injurious factors such as smoking or malnutrition. The respiratory tract is, however, also the most common site for infection to develop in immunodeficient subjects, and compromised immunity must Chapter 13: Chest Diseases / 247 Nasal filtering and humidification Table 13. These viruses usually replicate better in the cooler upper airways than at normal body temperature. Bacterial infection of the airways is less common and often occurs as a result of suppression of defence mechanisms by prior viral infection. The transient susceptibility of the airways to infection induced by some viral infections is only partially understood but includes physical factors such as inhibition of ciliary function and damage to the airway epithelium. The most striking example is influenza A, which can lead to devastating pneumonia, usually caused by Staphylococcus aureus, in debilitated patients. However, the most important causes of pneumonia in the immunocompetent host are bacterial (Table 13. While most of these deaths occur as a final event in debilitated patients, some previously healthy children Immune dysfunction and adults also die of pneumonia in spite of seemingly appropriate antibiotic therapy. Immunization against pneumococcal infections with polyvalent conjugate vaccines has significantly reduced the invasive disease in young children. However, pneumococcal disease remains a notable cause of mortality in the developing world and community-acquired pneumococcal pneumonia remains a problem in adults in the developed world despite pneumococcal polysaccharide immunisation. A recent Canadian study showed that the polysaccharide vaccine was not effective in patients with chronic obstructive airways disease who were 65 years of age or older, but it reduced the risk of acquiring pneumonia by 80% in younger patients. He had felt exhausted for 6 months, had lost 3 kg in weight and suffered 4 chest infections that responded to antibiotics. He was clinically anaemic but had no finger clubbing, lymphadenopathy or splenomegaly. Treatment with amoxycillin resulted in rapid clearing of the pneumonia but, in view of his high lymphocyte count and mild anaemia, he was started on chlorambucil to control the lymphoproliferation. He lacked detectable serum antibodies and failed to make IgG antibodies to pneumococci on immunization; furthermore, all three major classes of serum immunoglobulins were low. The abnormal mucosal environment in cystic fibrosis is a potent predisposing cause for infection, as is bronchial obstruction due to factors ranging from tumours to plugging by mucus. Recurrent bronchial inflammation from many causes, particularly when associated with obstruction, leads to the development of bronchiectasis: dilated, damaged bronchi which themselves predispose to further infection, thus amplifying and perpetuating the process. However, there are certain infections or patterns of infection that should always lead to the consideration of underlying immunodeficiency (Fig 13. Some of these infections (such as Pneumocystis pneumonia) are virtually always associated with underlying immunodeficiency, whereas chronic sinopulmonary infection is associated with antibody deficiency in only 5% of cases. Nevertheless, the highly treatable nature of many immunodeficiency states (particularly antibody deficiencies) makes investigation mandatory (see Chapter 3). The granulomatous diseases are a heterogeneous group of disorders with differing aetiologies, clinical presentations, histological characteristics and responses to therapy. Granulomas form in the presence of an antigen or foreign substance that cannot be easily broken down or eliminated; they can be regarded as a mechanism for containing and possibly destroying that antigen or foreign body, and may be reversible if antigen is destroyed only slowly. However granuloma formation is frequently associated with increased deposition of fibrous tissue. This fibrosis, which is irreversible, is often the most troublesome feature of granulomatous diseases. Active vitamin D plays an important role in stimulating macrophage differentiation within the granuloma. In some granulomatous disorders, sufficient active vitamin D is produced to cause hypercalcaemia. Crepitations were audible over the lung apices; there were no other physical signs. The chest X-ray showed bilateral upper- and middle-lobe shadowing but no hilar enlargement. The patient was treated with isoniazid and rifampicin for 6 months, together with pyrazinamide for the first 2 months. He was allowed home on chemotherapy when his sputum became negative on direct smear. The impact of tuberculosis in Western Europe and North America is minimal by comparison, and has fallen considerably over the last 50 years, though this downward trend has stopped now. Other immunosuppressive factors should not be forgotten, particularly poor nutrition and the immunosuppressive effect of infections such as measles. Vitamin D deficiency (due to diet or lack of exposure to sunlight) may be an important cofactor, reflecting the role of this vitamin within granulomas. Mycobacterium tuberculosis is a slow-growing bacterium with an inert, waxy cell wall. In most individuals, activation of dendritic cells results in a brisk Th1-pattern immune response leading to local granuloma formation in an area of lung and the draining lymph node. This contains and effectively eliminates the organism, although the immune system alone may never be able to clear M. Once infection has occurred, the organism remains in a latent form if the host is untreated, even when disease does not develop. In a proportion of infected individuals, the T-cell response is less effective and the granulomatous response only partially contains the organism. An area of localized but progressive granulomatous inflammation develops which slowly enlarges and often cavitates due to a necrotic process called caseation, which is typical of tuberculous granulomas and which distorts surrounding structures by fibrosis. If the T-cell response is defective, or skewed towards a Th2 pattern, then the organism reproduces freely in macrophages, and disseminated disease may develop. A chest X-ray showed fine, diffuse radiological shadows, predominantly in the mid zones, and bilateral hilar lymphadenopathy. Since he had pulmonary infiltration on X-ray, he was treated with corticosteroids to good effect. This is associated with marked systemic ill-health, due to cytokine release from macrophages. Cytokine release is driven partly by the ineffective T-cell response and partly by the direct effect of the mycobacterial cell wall on dendritic cells. It is used to protect hospital personnel and tuberculosis contacts, though evidence for efficacy is controversial. This is useful in assessing prior immunity before immunization, and may also be a helpful diagnostic pointer in active disease. Treatment regimens Treatment regimens comprise a combination of several antimicrobial agents. These resistant organisms necessitate treatment with second-line agents and are associated with high mortality rates. Bilateral hilar lymphadenopathy alone is asymptomatic and may be a chance finding on chest X-ray. Most patients, however, have a more insidious disease; this form is about 10 times more prevalent in Afro-Caribbeans than in most other ethnic groups. The diagnosis of sarcoidosis depends on the clinical and radiological picture and the histology of any lesions that can be biopsied. Historically, the Kveim test was used to establish a diagnosis of sarcoidosis, but since this involves injection of biological material derived from splenic tissue of patients with sarcoidosis, the test is now abandoned. Curiously, the Mantoux test is nearly always negative in active sarcoidosis, even in subjects known to have a previously positive test, and then becomes positive again as the sarcoidosis goes into remission or is treated. Other laboratory tests are of little value in diagnosis or predicting disease evolution, although it is important to exclude hypercalcaemia due to uncontrolled vitamin D synthesis. Epithelioid and giant cells are found focally, and persistent lesions may become fibrotic and irreversible. The immunopathology of sarcoidosis is consistent with a Th1-cell response to an unknown, persistent, non-particulate antigen. There is often evidence of B-cell activation, with a polyclonal increase in immunoglobulin production. The similarities between sarcoid and tuberculosis have led to speculation that sarcoid is due to some form of mycobacterium, but no consistent evidence has been found to support an infective process yet. Inhalation of beryllium dust can produce lung disease (berylliosis), which is histologically identical to sarcoidosis. This amino acid lies within the antigen-binding groove and may affect binding of beryllium ions, possibly complexed with a self-peptide. There is no evidence that sarcoidosis is caused by beryllium exposure, but berylliosis does provide an instructive example of how a granulomatous disease can develop in response to a simple inert antigen, without invoking an infectious process. The prognosis of sarcoidosis depends on whether or not granulomas or fibrosis develop in vital organs. Those who present with acute disease have an excellent prognosis after treatment and 90% recover within 3 months, although the chest X-ray changes may take a further 3 months to resolve. Insidious-onset sarcoid can proceed to generalized sarcoidosis; those who present with exertional dyspnoea or non-productive cough often have a better prognosis than asymptomatic cases, because they receive treatment. Many patients improve spontaneously, but those with pulmonary infiltrates and evidence of granulomata in vital organs, such as the nervous system or lungs, should receive steroid therapy. Infliximab was initially helpful in pulmonary and extrapulmonary sarcoidosis but the trial was not successful overall and this drug was not approved for the treatment of sarcoidosis. It is likely that, as in other drug regimens, monoclonal antibodies against cytokines will need to be used in combination to be truly effective. Many of these disorders have a strong immunological contribution to their pathogenesis. Although this classification usually excludes specific infection, infection can both mimic and complicate interstitial Chapter 13: Chest Diseases / 253 lung disease, and should be considered part of the differential diagnosis. Almost all forms of interstitial lung disease can lead to a common endpoint, pulmonary fibrosis (see Table 13. Regardless of the initial cause, the pathogenesis of the fibrotic process may be similar in many disorders characterized by pulmonary fibrosis. Immunosuppressive and anti-inflammatory treatment is therefore effective in limiting progression of lung fibrosis. The assumption that chronic inflammation precedes fibrosis led to widespread use of immunosuppressive treatment in some forms of pulmonary fibrosis, usually with little or no clinical response. However, it is now clear that pulmonary fibrosis can develop and progress without any evidence of preceding chronic inflammation. Similar patterns of fibrosis without inflammation may be seen in other diseases in which there is strong evidence for an autoimmune pathogenesis, especially systemic sclerosis. Until such strategies are available, severe established pulmonary fibrosis can be treated only by lung transplantation. Bronchopulmonary eosinophilia is usually due to infection with Aspergillus fumigatus in asthmatic patients but the pneumonic type, which consists of pneumonia and a blood eosinophilia, has several causes. On examination, a few crepitations were audible in the left axillary region but the chest X-ray was apparently normal. Skin tests showed immediate (type I) hypersensitivity to cat fur, grass pollen and Aspergillus fumigatus. At bronchoscopy, the left lingular bronchus was plugged with golden, tenacious mucus.
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