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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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In the recipients of allo-HSCT, the difference in the reported incidence is due in part to asymptomatic or subclinical manifestations in most of viral infections and the changing epidemiology of viruses as well as differences in diagnostic methods. Till now, large-sampled epidemiological data on overall incidence of viral infections are absent in the recipients of allo-HSCT. The limited data show that community acquired respiratory viruses (CARVs) and herpesviruses are the most common pathogens. Among the causes of CARVs respiratory tract infections, a preponderance of respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are reported, followed by influenza virus and human metapneumovirus (HMPV). In herpesvirus family, the incidence of herpes simplex virus (HSV) and varicella zoster virus (VZV) infections as well as cytomegalovirus (CMV) diseases have significantly decreased because of the effective prophylaxis. The reports on human herpes virus (HHV)-6 diseases are increasing in allo-HSCT recipients.
In the recipients of allo-HSCT, most viral infections are opportunistic and closely related with immune status. Thus, factors influencing engraftment and immune reconstitution all potentially impact viral infections. Peripheral blood stem cell transplantation is associated with fewer viral infections than bone marrow and cord blood transplantation due to better hematopoietic and immune reconstitution. Compared with HLA-match related transplantation, HLA-mismatch related and unrelated transplantation have an increasing risk of viral infections because immune reconstitution is delayed by the intensified GVHD prophylactic strategy, such as the use of ATG. GVHD may delay immune reconstitution and is considered an independent risk factor of viral infections. In addition, other factors, such as the serologic status of donors and recipients before transplantation as well as the age of recipients, may also affect the incidence of viral infections. For example, CMV-seronegative recipients receiving graft from CMV-seropositive donors are at high risk of CMV diseases. Children are high-risk population of CARVs infections.
Clinical signs of classical swine fever usually appear 5–10 days after infection (occasionally longer). An individual pig may show one of four types of clinical effect; Peracute (sudden death, especially at the beginning of a farm outbreak), Acute (fever, depression, weakness, anorexia, conjunctivitis, diarrhoea or vomiting, purple discoloration of abdominal skin, or necrosis of the tips of extremities, and neurological signs), Chronic (weight loss, hair loss, dermatitis, discoloration of abdomen or ears) and subclinical. Affected pigs may recover or relapse, depending on the severity of the disease. Reproductive effects is also common; abortions, stillbirths, mummifications and also congenital tremor of piglets.
In post-pubertal males, the most common complication of mumps infection is orchitis. In the era prior to the advent of the MMR vaccine, orchitis occurred in between 12% to 66% of post-pubertal males with mumps. In the post-vaccination era, orchitis has been reported in 15% to 40% of post-pubertal males.12 Orchitis typically occurs about 10 days after the onset of parotitis, although it can be seen up to six weeks later. Orchitis is typically unilateral, but bilateral orchitis manifests in 15–30% of cases.13 Orchitis may be accompanied by epididymitis up to 85% of the time.17
Mumps orchitis can lead to a range of testicular complications. True infertility following mumps orchitis is rare but subfertility has been seen in up to 13% of patients. Subfertility can occur even without accompanying testicular atrophy.7, 18–20 Testicular atrophy (any reduction in testicular size) occurs in 30–50% of patients with orchitis.6 Abnormalities of spermatogenesis have been observed to occur in up to half of patients for up to three months after recovery from the acute illness.20 Mumps orchitis and subsequent testicular atrophy have been weakly associated with the development of testicular tumors, including cancer, with an incidence of 0.5%.7, 21, 22
Other complications of mumps infection include meningitis, which may occur in up to 10% of cases. When meningitis does occur, it is typically seen 3–4 days after the onset of parotitis.6 Acute encephalitis and encephalomyelitis are rare. When acute encephalitis due to mumps occurs, it is typically self-limiting. Acute encephalomyelitis, on the other hand, tends to be much more severe. Case fatality rates for acute encephalomyelitis due to mumps virus are up to 10%, while the overall case fatality rate due to CNS complications from mumps virus has been reported to be about 1%.23
Sensorineural hearing loss is another CNS complication of mumps infection. Permanent unilateral hearing loss has been reported to occur in 1 of every 20,000 cases. Bilateral hearing loss is much less frequent. Other rare CNS complications include Guillain Barre Syndrome, transverse myelitis, facial palsy, cerebellar ataxia and flaccid paralysis.7
Oophoritis (ovarian inflammation) has been reported to occur in 5% of post-pubertal females. Symptoms of oophoritis may include lower abdominal pain, vomiting and fever. Long-term sequelae of oophoritis, while rare, may include infertility or premature menopause. Mastitis (breast inflammation) has also been reported as a complication of mumps infection in post-pubertal females.7 In some studies, mumps infection in early pregnancy has been linked with spontaneous abortion, with one study identifying a 27% rate of fetal death after first trimester mumps infection compared with 13% in a control group.7, 24 A second, more recent study has not shown the same association between spontaneous abortion and mumps infection in early pregnancy.25 As of early 2016, there is no reported association between perinatal mumps infection and significant congenital malformations.7
Other rare complications associated with mumps infection include pancreatitis (with rare reported cases of severe hemorrhagic pancreatitis), ECG abnormalities (depressed ST segments, prolonged PR intervals and inverted T waves), myocarditis, polyarthritis, abnormal renal function (with rare reports of severe or fatal nephritis), hepatitis, acalculous cholecystitis, kerato-uveitis, hemophagocytic syndrome and thrombocytopenia.7 (Table)
Mumps typically begins with a prodrome of low-grade fever, myalgias, anorexia, malaise and headache. Over the next 1–3 days, the patient develops earache and tenderness over the parotid gland, which becomes noticeably enlarged and painful (Figure 1). Parotitis is typically seen in 31–65% (with some authoritative texts citing 60–70%) of cases of mumps infection. In about three quarters of patients, the other parotid gland becomes involved.12,13 The parotitis is nonsuppurative and typically progresses for about three days and lasts for approximately one week.13 Patients often have trismus and have difficulty chewing and speaking. In about 10% of cases, other salivary glands, especially the submandibular gland, can become involved and can mimic anterior cervical lymphadenopathy.
The central nervous system (CNS), a marvel of intricate cellular and molecular interactions, maintains life and orchestrates homeostasis. Unfortunately, the CNS is not immune to alterations that lead to neurological disease, some resulting from acute, persistent or latent viral infections. Several viruses have the ability to invade the CNS, where they can infect resident cells, including the neurons. Although rare, viral infections of the CNS do occur. However, their incidence in clinical practice is difficult to evaluate precisely. For instance, in cases of viral encephalitis involving the most prevalent viruses known to reach the CNS (mainly herpesviruses, arboviruses and enteroviruses), an actual viral presence can only be detected in 3 to 30 cases out of 100,000 persons. Considering all types of viral infections, between 6000 and 20,000 cases of encephalitis that require hospitalization occur every year in the United States, representing about 6 cases per 100,000 infected persons every year. As the estimated charge for each case lies between $58,000 and $89,600, an evaluation of the total annual health cost is of half a billion dollars. Due to the cost associated with patient care and treatment, CNS viral infections cause considerably more morbidity and disabilities in low-income/resource-poor countries.
Very common worldwide, viral infections of the respiratory tract represent a major problem for human and animal health, imposing a tremendous economic burden. These respiratory infections induce the most common illnesses and are a leading cause of morbidity and mortality in humans worldwide, causing critical problems in public health, especially in children, the elderly and immune-compromised individuals. Viruses represent the most prevalent pathogens present in the respiratory tract. Indeed, it is estimated that about 200 different viruses (including influenza viruses, coronaviruses, rhinoviruses, adenoviruses, metapneumoviruses, such as human metapneumovirus A1, as well as orthopneumoviruses, such as the human respiratory syncytial virus) can infect the human airway. Infants and children, as well as the elderly represent more vulnerable populations, in which viruses cause 95% and 40% of all respiratory diseases, respectively. Among the various respiratory viruses, some are constantly circulating every year in the human populations worldwide, where they can be associated with a plethora of symptoms, from common colds to more severe problems requiring hospitalization. Moreover, in addition to the many “regular” viruses that circulate and infect millions of people every year, new respiratory viral agents emerge from time to time, causing viral epidemics or pandemics associated with more serious symptoms, such as neurologic disorders. These peculiar events usually take place when RNA viruses like influenza A, human coronaviruses, such as MERS-CoV and SARS-CoV, or henipaviruses, present in an animal reservoir, cross the species barrier as an opportunistic strategy to adapt to new environments and/or new hosts. These zoonoses may have disastrous consequences in humans, and the burden is even higher if they have neurological consequences.
Border disease is an important disease in sheep, caused by infection of the foetus in early pregnancy. Surviving lambs are persistently viremic, and the virus is present in their excretions and secretions, including semen. Ruminants and possibly also pigs can be readily infected by contact with these persistent excretors or with acutely infected sheep. Acute infections in immunocompetent animals usually are transient and subclinical and result in immunity to challenge with homologous but not heterologous strains of virus. The disease is characterised by low birth weight and viability, poor conformation, tremor, and an excessively hairy birth coat in normally smooth-coated breeds. Kids may also be affected, and a similar condition occasionally occurs in calves. The disease has been recognized in most sheep-rearing areas of the world.
Epithelial cells that line the respiratory tract are the first cells that can be infected by respiratory viruses. Most of these infections are self-limited and the virus is cleared by immunity with minimal clinical consequences. On the other hand, in more vulnerable individuals, viruses can also reach the lower respiratory tract where they cause more severe illnesses, such as bronchitis, pneumonia, exacerbations of asthma, chronic obstructive pulmonary disease (COPD) and different types of severe respiratory distress syndromes. Besides all these respiratory issues, accumulating evidence from the clinical/medical world strongly suggest that, being opportunistic pathogens, these viruses are able to escape the immune response and cause more severe respiratory diseases or even spread to extra-respiratory organs, including the central nervous system where they could infect resident cells and potentially induce other types of pathologies.
Like all types of viral agents, respiratory viruses may enter the CNS through the hematogenous or neuronal retrograde route. In the first, the CNS is being invaded by a viral agent which utilizes the bloodstream and in the latter, a given virus infects neurons in the periphery and uses the axonal transport machinery to gain access to the CNS. In the hematogenous route, a virus will either infect endothelial cells of the blood-brain-barrier (BBB) or epithelial cells of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus (CP) located in the ventricles of the brain, or leukocytes that will serve as a vector for dissemination towards the CNS. Viruses such as HIV, HSV, HCMV, enteroviruses such as coxsackievirus B3, flaviviruses, chikungunya virus (CHIKV) and echovirus 30 have all been shown to disseminate towards the CNS through the hematogenous route. Respiratory viruses such as RSV, henipaviruses, influenza A and B and enterovirus D68 are also sometimes found in the blood and, being neuroinvasive, they may therefore use the hematogenous route to reach the CNS. As they invade the human host through the airway, the same respiratory viruses may use the olfactory nerve to get access to the brain through the olfactory bulb. On the other hand, these viruses may also use other peripheral nerves like the trigeminal nerve, which possesses nociceptive neuronal cells present in the nasal cavity, or alternatively, the sensory fibers of the vagus nerve, which stems from the brainstem and innervates different organs of the respiratory tract, including the larynx, the trachea and the lungs.
Although the CNS seems difficult for viruses to penetrate, those pathogens that are able to do so may disseminate and replicate very actively and will possibly induce an overreacting innate immune response, which may be devastating. This situation may lead to severe meningitis and encephalitis that can be fatal, depending on several viral and host factors (including immunosuppression due to disease or medications) that may influence the severity of the disease.
Recently, a very interesting manuscript produced by Bookstaver and collaborators underlined the difficulties of precisely deciphering the epidemiology and identifying the causal agent of CNS infections. These difficulties are mainly due to the tremendous variation in the symptoms throughout the disease process and to the myriad of viruses that can cause CNS infections. As stated in their report, these authors underlined that the clinical portrait of viral infections is often nonspecific and requires the clinician to consider a range of differential diagnoses. Meningitis (infection/inflammation in meninges and the spinal cord) produces characteristic symptoms: fever, neck stiffness, photophobia and/or phonophobia. Encephalitis (infection/inflammation in the brain and surrounding tissues) may remain undiagnosed since the symptoms may be mild or non-existent. Symptoms may include altered brain function (altered mental status, personality change, abnormal behavior or speech), movement disorders and focal neurologic signs, such as hemiparesis, flaccid paralysis or paresthesia. Seizures can occur during both viral meningitis and encephalitis. Furthermore, viral encephalitis may also be difficult to distinguish from a non-viral encephalopathy or from an encephalopathy associated with a systemic viral infection occurring outside the CNS. Considering all these observations, it is therefore mandatory to insist on the importance of investigating the patient’s history before trying to identify a specific viral cause of a given neurological disorder.
In humans, a long list of viruses may invade the CNS, where they can infect the different resident cells (neuronal as well as glial cells) and possibly induce or contribute to neurological diseases, such as acute encephalitis, which can be from benign to fatal, depending on virus tropism, pathogenicity as well as other viral and patient characteristics. For instance, 30 years ago, the incidence of children encephalitis was as high as 16/100,000 in the second year of life, while progressively reducing to 1/100,000 by the age of 15. More recent data indicate that, in the USA, the herpes simplex virus (HSV) accounts for 50–75% of identified viral encephalitis cases, whereas the varicella zoster virus (VZV), enteroviruses and arboviruses are responsible for the majority of the other cases in the general population. Several other viruses can induce short-term neurological problems. For example, the rabies virus, herpes simplex and other herpes viruses (HHV), arthropod-borne flaviviruses such as the West Nile virus (WNV), Japanese encephalitis virus (JEV), chikungunya virus (CHIKV), Zika virus (ZIKV), alphaviruses such as the Venezuelan, Western and Eastern equine encephalitis viruses and enteroviruses affect millions of individuals worldwide and are sometimes associated with encephalitis, meningitis and other neurological disorders. The presence of viruses in the CNS may also result in long-term neurological diseases and/or sequelae. Human immunodeficiency virus (HIV) induces neurodegeneration, which lead to motor dysfunctions and cognitive impairments. Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease associated with reactivation of latent polyoma JC virus (JCV). Progressive tropical spastic paraparesis/HTLV-1-associated myelopathy (PTSP/HAM) is caused by human T-lymphotropic virus (HTLV-1) in 1–2% of infected individuals. Measles virus (MV), a highly contagious common virus, is associated with febrile illness, fever, cough and congestion, as well as a characteristic rash and Koplik’s spots. In rare circumstances, significant long-term CNS diseases, such as post-infectious encephalomyelitis (PIE) or acute disseminated encephalomyelitis (ADEM), occur in children and adolescents. Other examples of rare but devastating neurological disorders are measles inclusion body encephalitis (MIBE), mostly observed in immune-compromised patients, and subacute sclerosing panencephalitis (SSPE) that appears 6–10 years after infection.
Yet, with the exception of HIV, no specific virus has been constantly associated with specific human neurodegenerative disease. On the other hand, different human herpes viruses have been associated with Alzheimer’s disease (AD), multiple sclerosis (MS) and other types of long-term CNS disorders. As accurately stated by Majde, long-term neurodegenerative disorders may represent a “hit-and-run” type of pathology, since some symptoms are triggered by innate immunity associated with glial cell activation. Different forms of long-term sequelae (cognitive deficits and behavior changes, decreased memory/learning, hearing loss, neuromuscular outcomes/muscular weakness) were also observed following arboviral infections.
Including the few examples listed above, more than one hundred infectious agents (much of them being viruses) have been described as potentially encephalitogenic and an increasing number of positive viral identifications are now made with the help of modern molecular diagnostic methods. However, even after almost two decades into the 21st century and despite tremendous advances in clinical microbiology, the precise cause of CNS viral infections often remains unknown. Indeed, even though very important technical improvements were made in the capacity to detect the etiological agent, identification is still not possible in at least half of the cases. Among all the reported cases of encephalitis and other encephalopathies and even neurodegenerative processes, respiratory viruses could represent an underestimated part of etiological agents.
ZIKV infection is transmitted mainly by Aedes aegypti mosquitoes, sexual contact, or blood transfusion. It is typically a mild, asymptomatic disease in the general population.
The disease is a self-limiting febrile illness lasting 4–7 days. Infection can be followed by neurological consequences including Guillain-Barre syndromes and microcephaly or other congenital neurological syndromes after vertical transmission from an infected mother to her fetus during pregnancy.
Viral RNA by RT-PCT in the stool.
We conducted a retrospective, comparative survey of the pediatric cases of viral encephalitis caused by respiratory viruses that were submitted at the National Institute for Infectious Diseases “Prof. Dr. Matei Balş” over the last 2 years (2011-2013).
We emphasize the importance of using molecular diagnostic tests which can provide rapid diagnosis and lead to appropriate therapeutic strategies and epidemiological measures.
The viral cause of an infectious disease can be established by fulfilling Koch’s postulates as modified by Rivers, for which six criteria are required: universal presence of virus in every diseased host, isolation from hosts, cultivation in pure culture, production of a comparable disease by injecting the virus into a suitable recipient, re-isolation of the virus, and detection of a specific immune response to the virus. In 2003, when the new human infectious disease SARS (severe acute respiratory syndrome) broke out, these criteria helped to establish the causal relationship between SARS and SARS-associated coronavirus. However, unlike infectious diseases, cancer occurrence is a complex and chronic process, and the association and causative relationship between virus and carcinogenesis was debated for a long time until viruses were verified in some cancers.
Epstein-Barr virus (EBV) was the first virus detected within human cancer cells. In 1964, Epstein’s group discerned virus-like particles by electron microscopy in a cell line derived from Burkitt’s lymphoma. During the following 20 years, significant discoveries helped to establish the relationship between viruses and tumors, including the recovery of hepatitis B virus (HBV) particles in the serum of patients with hepatitis; the isolation of the human T-cell leukemia virus (HTLV-1) from lymphocytes of a patient with cutaneous T-cell lymphoma; and identification of human herpesvirus 8 as the cause of Kaposi’s sarcoma. However, the role of EBV in NPC initiation is far more difficult to be clarified.
EBV is a member of the herpesvirus family and infects more than 90% of the world’s population. Primary infection usually occurs in childhood and is asymptomatic in developing countries. In western countries, EBV infection may be delayed until adolescence, usually with the occurrence of infectious mononucleosis. EBV can exist in the human host without serious consequences for a lifetime. Nasopharyngeal carcinoma (NPC) is considered to be associated with EBV infection, but whether EBV plays a causal role in NPC or is only associated with its development remains controversial. In this article, we will discuss the relationship between EBV infection and NPC initiation.
The ocular manifestations of viral infections in neonates and children vary greatly and can range from innocuous to vision threatening (73). The majority of viral conjunctivitis in children are caused by adenovirus, a DNA virus, which can cause a range of human diseases, including upper respiratory tract infection. Viral conjunctivitis is associated with epidemic keratoconjunctivitis, pharyngoconjunctival fever and acute haemorrhagic conjunctivitis (74). Signs include eyelid oedema and tender pre-auricular lymphadenopathy, prominent conjunctival hyperaemia, follicles and punctate epithelial keratitis. In viral infections in children, the involvement of the anterior segment is mild and self-limited; spontaneous resolution usually occurs within 2–3 weeks, except in cases of congenital infection, which are often associated with significant alterations in ocular structures.
Neonatal conjunctivitis (also known as ophthalmia neonatorum) is defined as conjunctival inflammation developing within the first month of life. It is the most common type of infection in neonates, occurring in up to 10% of neonates. It is often identified as a specific entity distinct from conjunctivitis in older infants as it is often the result of infection transmitted from the mother to the infant during delivery (74). Molluscum contagiosum ocular infection in children is caused by a specific double-stranded DNA poxvirus, which typically affects otherwise healthy children with a peak incidence between the ages of two and four. Transmission occurs through contact, with subsequent autoinoculation. Presentation is with chronic unilateral ocular irritation and mild discharge, while lesions are usually self-limiting. Primary infection with herpes simplex virus (HSV) is usually associated with eyelid and periorbital vesicles, papillary conjunctivitis, discharge and lid swelling. Dendritic corneal ulcers can also be present, particularly in patients with atopic infection can lead to eczema herpeticum, which can be very severe (75–77). Varicella-zoster virus (VZV) is a serious, but rare, viral infection in children, in which prolonged inflammation may lead to corneal thinning or perforation, glaucoma and cataract formation (74).
Involvement of the posterior structures mostly related to HSV and VZV is potentially sight-threatening. Retinal or optic nerve involvement should be suspected in any child, who complains of an acute onset of blurred vision in the absence of anterior segment inflammation or opacities in the ocular media. Optic neuropathy may occur as an isolated sign, although it is more often associated with a more generalised involvement of the central nervous system (77,78). While specific therapy is not always available, the early diagnosis of ocular viral disease in children should aid in the amelioration of acute symptoms and in the prevention of long-term complications.
MERS is most well characterised as a respiratory disease of humans. Extensive inflammation and immune evasion are hallmarks of severe disease ascribed to CoVs. Among confirmed MERS cases, fever, cough, and dyspnoea are the most common clinical manifestations. The mean incubation period for MERS is between 2 and 13 days. Longer periods are associated with a reduced risk of death. MERS-CoV infection also results in mild and subclinical outcomes.
The typical MERS case is a Saudi male aged between 21 and 60 years, often presenting to a hospital with pneumonia, or worse. Severe MERS occurs most frequently among those with comorbidities including diabetes mellitus, cirrhosis, and others affecting respiratory, renal, and cardiac systems. Downregulation of innate immune response mediators associated with some of these disorders may be related to the severity of MERS. It may be that the high frequency of severe MERS reflects elevated prevalence of certain comorbidities in the Middle East region. Comorbidities did not feature among SARS cases, as they have among cases of MERS; MERS-CoV is a highly opportunistic pathogen.
In June 2015, an outbreak in the Republic of Korea found confirmed cases presented with fever, cough, and upper respiratory tract signs and symptoms, progressing within a week to lower respiratory tract distress with lymphopenia and elevated liver enzymes. MERS can progress to acute respiratory distress syndrome and multiorgan system failure requiring intensive supportive care. Extra pulmonary infection does occur, likely resulting from haematogenous transport of virus, which is an area in need of further study. Similarly, little is known about sequelae following MERS-CoV infection; in one study, those who survived acute respiratory distress syndrome were well one year later. Another study identified delayed neurological manifestations during treatment of MERS cases, but lacked long-term follow-up.
Death occurs among 30–40% of MERS cases; approximately 40% of cases in the KSA, and 20% of cases in the Republic of Korea, where mortality ranged from 7% among younger age groups to 40% among those aged 60 years and above. Among studies of fatal cases, death occurred between 5–15 days after symptom onset. Because the extent of subclinical or mild infections in the community remains unquantified, mortality figures may be overestimates.
MERS-CoV variants exist as a single antigenic group in lineage C of the genus Betacoronavirus. When MERS-CoV infection is subclinical or less severe, humoral immune responses may be weak, delayed, short-lived, or undetectable. Humans can still be reinfected if they have pre-existing neutralising antibodies, similarly to what is seen in camels. However, survivors of symptomatic MERS do develop antibodies, including neutralising antibodies, which decline but persist for 1–3 years. Whether these antibodies prevent future infection remains to be examined. Those with mild or subclinical MERS still develop CD8+ T-cell responses, and survivors of more severe MERS, including those who do not mount an antibody response, develop both CD8+ and CD4+ T-cell responses.
Acute respiratory tract infections (ARTIs) are a frequent cause of morbidity and mortality and a common reason for both outpatient visits and hospitalisations. Among humans worldwide, RNA viruses the agents that cause ARTI most frequently—usually a self-limiting upper respiratory tract syndrome. Coronaviruses (CoVs) are recombining, enveloped viruses with long positive-sense RNA genomes. They are ancestrally zoonotic in origin, having adapted to bind a diverse range of cellular receptors. Four human coronaviruses (HCoVs) have evolved, initially from bats, camelids, and rodents, to become distinct global, endemic, seasonal pathogens causing mild to moderate ARTI among humans.
The HCoVs occupy two of four genera in the subfamily Coronavirinae. Human coronavirus 229E and Betacoronavirus-1 subspecies HCoV-OC43 have been known for more than 50 years, while Human coronavirus NL63 and Human coronavirus HKU1 were first characterised in 2004 and 2005, respectively.
A Severe acute respiratory syndrome-related coronavirus (SARS-CoV) briefly emerged into the human population during 2002–2004 but was controlled and is not known to circulate today. Its brief but severe emergence sparked renewed study of CoVs. In 2012, another novel, severely pathogenic CoV was identified in the Kingdom of Saudi Arabia (KSA); 80% of over 2000 human cases have been recorded over five years. Both SARS-CoV and the new Middle East respiratory syndrome coronavirus (MERS-CoV; belonging to the species Middle East respiratory syndrome-related coronavirus) evolved from ancestral, but different, bat CoVs. Travel history and laboratory analysis would be required to differentiate MERS from SARS, if it still occurred. To date, most MERS cases have been limited to countries in the Arabian Peninsula with rare travel-related spillovers. One case precipitated a large healthcare multi-facility outbreak in the Republic of Korea in 2015.
A confirmed case of MERS occurs when a person, irrespective of signs or symptoms, has a laboratory-reported MERS-CoV infection. A probable case requires a minimum of a clinically diagnosed acute febrile disease, an epidemiologic link, and a partial laboratory diagnostic profile.
We briefly review recent literature and the current understanding of MERS and MERS-CoV highlighting some knowledge gaps.
IM is the main clinical manifestation of Epstein Barr virus (EBV) infection (86). Other agents, such as CMV, toxoplasma and adenovirus, produce a similar illness. The incubation period ranges from 33 to 49 days (87). Clinical presentation is usually prolonged (average 16 days) and ranges from a non-specific flu-like illness to the more distinctive triad ‘fever, pharyngitis, lymphadenopathy-splenomegaly’. Other clinical manifestations include fatigue, hepatitis and eyelid oedema. Possible complications are meningoencephalitis, haemolytic anaemia, thrombocytopenia, rash, conjunctivitis, haemophagocytic syndrome, myocarditis, neurologic diseases, pancreatitis, parotitis, pericarditis, pneumonitis, psychological disorders and splenic rupture. Laboratory findings include the elevation of liver enzymes and lymphocytosis with a marked increase in the number of atypical lymphocytes in the peripheral blood (87). Additionally, immunophenotypic alterations of lymphocytes have been described in the various phases of EBV infection (88). More specifically, a reduction of B-lymphocytes and an increase in the number of CD3+CD8+, T-lymphocytes, with a subsequent decrease in the CD3+CD4+/CD3+CD8+ ratio is noted (89).
In the study by Panagopoulou et al (86), which was presented at the Workshop, researchers aimed to examine whether there is an association between the immunophenotypic alterations and the variability of the clinical presentation of IM. Although several studies (89–91) have examined the immunophenotype of lymphocytes in EBV infection, very few (89) have correlated these with the clinical course. The presented study (86) showed that the immunophenotypic analysis of cytotoxic T cells provides important information on the physiology of the immune response to EBV infection. Additionally, it may potentially play a predicting role, providing information on the expected clinical course, potential complications and the time to recovery from EBV infection.
The enterovirus genus of single-stranded RNA viruses includes poliovirus, coxsackie A virus, coxsackie B virus, echoviruses and other viruses that affects millions of people worldwide each year. Over 100 human enterovirus serotypes have been identified based on antibody neutralization tests, including enterovirus 71 (EV71) and coxsackievirus 16 (CA16), the main causative agents of hand, foot and mouth disease (HFMD), which has emerged as an important public health problem in recent years, especially in Asia and Pacific regions. EV71 and CA16 usually infect infants and children under seven years old and present with a papulovesicular rash.1 A few children suffer complications such as myocarditis, pulmonary edema and aseptic meningoencephalitis, which can be fatal. Occasionally, HFMD is observed in adults.2,3
The major pathogens responsible for HFMD differ across countries. In China, HFMD is primarily associated with EV71, which caused the outbreaks of HFMD in Anhui province in 2008, in Guangdong province in 2009 and in Jiangsu province in 2012.4,5,6 However, in other countries, HFMD is mostly associated with CA16.7 The seroprevalence trends of these two viruses are changing over time. There are no vaccines or antiviral drugs available for HFMD. Although immunoglobulins and the antiviral agent ribavirin are commonly used, their efficacy remains uncertain.8 Thus, the development of effective vaccines to prevent HFMD is critical. Knowing the seroprevalence of EV71 and CA16 is necessary to generate a suitable and effective vaccine. The seroprevalence of EV71 and CA16 has been investigated in children and pregnant women,6,9,10,11 but little is known about the seroprevalence of these viruses in healthy adults, despite the fact that adults do suffer from HFMD and can present with serious symptoms.2,3 However, efforts to investigate the seroprevalence of these viruses in adults are increasing and may reflect the continued spread of these viruses.
Co-infection with enterovirus and a second virus, such as adenovirus, has been suggested as another possible pathogenic factor for HFMD.12 Adenoviruses are a family of double-stranded DNA viruses with more than 100 identified serotypes; adenoviruses cause a wide range of illnesses, from mild respiratory infections to multiorgan disease. Both enterovirus and adenovirus are transmitted via the respiratory or fecal–oral routes, and both can be neurotoxic. These two viruses can be shed for a prolonged period after infection in humans, so they can reach similar co-infection rates.13 During an HFMD outbreak in Sarawak in 1997, a subgroup B adenovirus and an enterovirus were isolated from three fatal cases, supporting the concept of co-infection with these viruses in humans.14
Pre-existing neutralizing antibodies in humans not only tell us the history and prevalence trends of certain pathogens but also indicate the nature of protective immunity in humans to the corresponding infections.15,16 In this study, we have investigated the prevalence of neutralizing antibodies to four viruses, EV71, CA16, adenovirus human serotype 5 (AdHu5) and chimpanzee adenovirus pan7 (AdC7), in the serum of healthy adults. AdHu5 is a subgroup C adenovirus and is one of the most common adenoviruses circulating in both children and adults. AdC7 originated in chimpanzees and is thought to be a rare serotype in humans, although little is known about its prevalence in the human population. Chimpanzee adenoviruses have been considered ideal carriers for the development of vaccines against a broad range of pathogens because their neutralizing antibodies are rare in humans, and this low antibody prevalence would circumvent the negative effects of pre-existing immunity to common human serotypes of adenovirus.17,18 Evaluating the prevalence of neutralizing antibodies to AdC7, compared with AdHu5, may provide evidence supporting the potential use of AdC7 as an additional or alternative vaccine carrier.
The majority of emerging infectious diseases (EIDs) of humans are zoonoses, and the majority of these originate in wildlife (1–3). These diseases are largely viral (e.g., severe acute respiratory syndrome [SARS] and Nipah virus) and represent a significant global health threat. Analyses of trends in EIDs suggest that the rate of infectious disease emergence is increasing (3) and that the emergence of new viruses is not yet constrained by the richness (number of viruses) or diversity (genetic variability) of unknown viruses in wildlife, which is thought to be high. Systematically measuring viral richness, abundance, and diversity (here termed “virodiversity”) in wildlife is hindered by the large number of host species (e.g., around 5,500 mammals), their global distribution and often remote habitats (4), and the expense of collection, sampling, and viral identification or discovery (5), and it has not yet been achieved for even a single host species. In this study, we repeatedly sampled a mammalian host known to harbor emerging zoonotic pathogens (the Indian Flying Fox, Pteropus giganteus) and used PCR with degenerate primers targeting nine viral families to discover a large number and diversity of viruses. We then adapted the techniques normally used to estimate biodiversity in vertebrates and plants to estimate the total viral richness within these nine families in P. giganteus. Our analyses demonstrate proof-of-concept and provide the first statistically supported estimates of the unknown viral richness of a mammalian host and the sampling effort required to achieve it.
West Nile virus (WNV) is a zoonotic Flavivirus belonging to the family Flaviviridae. The virus is transmitted by mosquitoes and causes fatal encephalitis in human, equines and birds.
WNV was first isolated and identified in 1937 from a woman presented with mild febrile illness in the Nile district of Uganda. It has been described in Africa, Europe, South Asia, Oceania and North America. Countries with incidence/serological evidence are presented in Fig. (1). In North America, more than 1.8 million people have been infected, with over 12,852 reported cases of encephalitis or meningitis and 1,308 deaths from 1999 to 2010. The mortality rate in human varies from 3-15% and can reach up to 50% in clinically affected horses. WNV in India has been confirmed by seroprevalence and by virus isolation on different occasions from mosquitoes bat and man [42, 45-47]. WNV infection has also been reported in animals and birds.
Horses and human are the main hosts. Animals other than horses may be susceptible to WNV, but rarely become ill. Antibodies have been found in serum samples from bats, horse, dogs, cats, racoons, opossums, squirrels, domestic rabbits, eastern striped skunks, cows, sheep, deer and pigs. The virus is transmitted to humans by mosquitoes. About 20% of the infected people develop fever with other symptoms. Fatal, neurologic illness occurs in less than 1% of infected people.
WNV is amplified by continuous transmission cycles between mosquitoes and birds. Generally Culex mosquitoes are the vectors and passerine birds are the vertebrate reservoirs in enzootic transmission cycles. The virus is carried in the salivary glands of infected mosquitoes and transmitted to susceptible birds during blood-sucking. Competent bird reservoirs sustain an infectious viraemia for 1 to 4 days subsequent to exposure, and then develop life-long immunity. Horses, human and most other mammals rarely develop the infectious levels of viraemia and are dead-end hosts. Few cases in human have been spread through blood transfusions, organ transplants, breast feeding and during pregnancy. The ticks observed to be infected naturally include Ornithodoros maritimus, Argas hermanni and Hyalomma marginatum and the virus has also been isolated from other species of hard ticks in Africa, Europe and Asia [36, 63, 64]. Swallow bugs (Oeciacus hirundinis) have been implicated as vectors in Austria. In most of the horses bitten by carrier mosquitoes, there is no disease. Approximately 33% of the infected horses develop severe disease and die or are affected severely. The time between the bite of an infected mosquito and appearance of clinical signs ranges from 3 to 14 days. The symptoms in horses may vary from none to trembling, skin twitching and ataxia. There can be sleepiness, dullness, listlessness, facial paralysis, difficulty in urination and defecation, and inability to rise. In some horses, there can be mild fever, blindness, seizures, and other signs.
There is no effective treatment for clinical WNV infection in humans, horses or any other animal. Vaccines are available for control of WNV in horses in the USA. Vaccination of horses protects valuable animals from a potentially fatal disease, but trade and competition practices make this undesirable as some countries use positive antibody tests and impose import restrictions. WNV encephalitis is so rare in human that vaccine development may not be feasible economically.
Transmission of zoonotic influenza A viruses to humans is commonly the cause of new pandemics, which typically result in high disease burden and increased symptomatic severity and mortality. In order to predict which populations may be at highest risk of infection and to develop more effective therapeutic interventions and vaccines, a thorough understanding of both viral and host contribution to pathogenesis is required. In both the recent 2009 H1N1 (pH1N1) pandemic and the on-going rare avian-to-human transmission of H5N1, numerous studies have taken an in-depth look at the impact of viral evolution and mutation on viral pathogenesis. Conversely, while both human and animal model studies of the host immune response to infection have identified correlates of severe disease, the contribution of host genetics to these correlates and to variability in susceptibility remains relatively unknown. Identification of host genetic polymorphisms contributing to altered susceptibility or disease severity has several benefits: identification of high-risk populations at greater need of prophylactic intervention, elucidation of host proteins important in virus-host interactions, and new targets for therapeutic interventions or vaccine development. Studies of host genetics have provided important contributions to the study of other infectious diseases, including HIV, SARS, and HCV. This paper will describe what is currently known about the impact of host immunogenetics in both pH1N1 and H5N1 infections and will identify highly relevant polymorphisms and genetic pathways that could be investigated in future work.
Interest in respiratory viruses has increased recently, due to the identification of several new viruses and the threat posed by others able to cross the interspecies barriers, as for severe respiratory acute syndrome (SRAS), avian influenza A H5N1, H7N9, H1N1v2009 and MersCoV.
Before the introduction of molecular approaches, the mainstays in the diagnosis of viral respiratory tract infections were serology, virus isolation in cell culture and immunofluorescence assays. All these techniques have a low sensitivity or can detect only a limited number of viruses. Sensitivity and the time required to obtain a result have been improved by the recent development of molecular tests, which can also detect viruses that were previously undetected, such as coronaviruses NL63, HKU1 and bocaviruses. The use of such tests has also demonstrated that the carriage of respiratory viruses is very rare in adults (2.1%).
The recent development of new multiplex PCR tests (mPCR) has facilitate the rapid detection of a broad range of respiratory viruses in clinical specimens and are increasingly used [7–10]. However, such tests are expensive and not yet taken into account by regulations or guidelines, so they are widely used. Nevertheless, their use has already improved descriptions of the epidemiology of respiratory viruses in various high-risk populations, such as neonates and preterm infants, children, immunocompromised patients, and the elderly. For the general adult population, recent studies have shown that viral pathogens can be detected in 53% of patients attending the emergency department with acute respiratory symptoms, and in 23 to 28% of those with community-acquired pneumonia. In the ICU, respiratory viruses are detected in 30 to 36% of patients with community-acquired pneumonia or nosocomial pneumonia, and are associated with high mortality rates [20–23]. However, the studies published to date were subject to several limitations, as they were based on different methods for detecting respiratory viruses, and were performed in specific populations, often only during the winter.
The objective of this study was to retrospectively describe the epidemiology of respiratory viruses with the use of mPCR in adults hospitalized in France, over a five-year period. Results are presented by season, type of clinical unit, patient age group and respiratory tract region involved.
Eastern equine encephalitis (EEE) commonly called triple E or, sleeping sickness is a rare but serious viral disease affecting horses and man. The disease is transmitted through mosquitoes and man and horses are dead-end hosts.
EEEV belongs to the genus Alphavirus of the family Togaviridae. It is closely related to Venezuelan equine encephalitis (VEE) virus and Western equine encephalitis (WEE) virus. This virus has North American and South American variants. The North American variant is more pathogenic. EEE is capable of infecting a wide range of animals including mammals, birds, reptiles and amphibians. The virus has been reported to cause disease in poultry, game birds and ratites. The disease has also been reported to occur in cattle, sheep, pigs, deer, and dogs though sporadically. The disease is present in North, Central and South America and the Caribbean. EEE was first recognized in the USA in 1831 from an outbreak where 75 horses died of encephalitic illness and EEE virus (EEEV) was first isolated from infection horse brain in 1933. The serological evidence and outbreaks of the disease have also been reported from horses in Canada and Brazil [119, 120]. Countries with incidence/serological evidence are presented in Fig. (3). EEEV infection in horses is often fatal. The human cases were identified first time in 1938 in the north-eastern United States. Thirty children died of encephalitis in this outbreak. The fatality rate in humans was 35%. The outbreaks of the disease also occurred in horses simultaneously in the same regions. A total of 19 human cases of the disease were reported in children between 1970-2010 in Massachusetts and New Hampshire. As per the CDC reports 220 confirmed human cases of the disease occurred in the U.S. from 1964 to 2004. In 2007, a citizen of Livingston, West Lothian, Scotland became the first European victim of this disease after infected with EEEV from New Hampshire. EEE has been diagnosed in Canada, the United States of America (USA), the Caribbean Islands and Mexico [122, 123]. Eighteen cases of Eastern equine encephalomyelitis occurred in six Brazilian states between 2005 and 2009.
Alternate infection of birds and mosquitoes maintains these viruses in nature. Culiseta melanura and Cs. morsitans species are primarily involved. Transmission of EEEV to mammals occurs via other mosquitoes which are primarily mammalian feeders and called as bridge vectors. Infected mammals do not circulate enough viruses in their blood to infect additional mosquitoes. The virus is introduced by mosquitoes, but feather picking and cannibalism also contribute towards the transmission of the disease within the flocks. Most people bitten by an infected mosquito do not develop any symptoms. The symptoms generally appear 3 to 10 days after the bite of an infected mosquito. The clinically affected patients may have pyrexia, muscle pains, headache, photophobia, and seizures. EEEV is one of the potential biological weapons. The disease in horses is characterized by fever, anorexia, and severe depression. Symptoms appear one to three weeks post-infection, and begin with a fever that may be as high as 106ºF. The fever usually lasts for 24–48 hours. In severe cases, the disease in horses progresses to hyper-excitability, blindness, ataxia, severe mental depression, recumbency, convulsions, and death. The nervous symptoms may appear due to brain lesions. This may be followed by paralysis, causing the horse to have difficulty raising its head. The horses usually suffer complete paralysis and die two to four days after symptoms appear. Mortality rates among horses range from 70 to 90%.
There is no cure for EEE. Severe illnesses are treated by supportive therapy consisting of corticosteroids, anticonvulsants, intravenous fluids, tracheal intubation, and antipyretics. Vaccines containing killed virus are used for prevention of the disease. These vaccinations are usually given as combination vaccines, most commonly with WEE, VEE, and tetanus. Elimination of mosquito breeding sites and use of insect repellents may help in control of the disease.
Approximately 20% of human cancers worldwide are associated with infectious agents, including parasites, bacteria, and viruses (Parkin, 2006). In 12% of cancers, seven different viruses have been causally linked to human oncogenesis (Table 1): Epstein–Barr virus (EBV), hepatitis B virus (HBV), human T-lymphotropic retrovirus type 1 (HTLV-1), high-risk human papillomaviruses (HPV), hepatitis C virus (HCV), Kaposi’s sarcoma herpesvirus (KSHV), and Merkel cell polyomavirus (MCV). The epidemiological and clinical information provides clues that indicate whether an infectious agent is involved in the development of cancer. Cancers that are related to immunosuppression, for example, are candidates for being caused by tumor viruses (Grulich et al., 2007). During the 20th century, various methods, ranging from the classical electron microscopic observation to the advanced molecular biology techniques, were used to identify cancer-causing viruses. Here, we will review the background and methods underlying the tumor virus discoveries during the past century as well as the newest virus discovery strategy, digital transcriptome subtraction (DTS) that we used to discover MCV.
A retrospective review was conducted of the clinical, lab tests, and radiologic findings for nine children and their families admitted to the Jinan Infectious Diseases Hospital identified to be nucleic acid-positive for SARS-CoV-2 from 24 January 2020 to 24 February 2020. Sample collection and pathogen identification after admission to the hospital, respiratory tract samples including sputum and nasopharyngeal swabs were collected from the patients, which were tested for influenza, avian influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, Mycoplasma pneumoniae and chlamydia, along with routine bacterial, fungal, and pathogenic microorganism tests. Real-time PCR used the SARS-CoV-2 (ORF1ab/N) nucleic acid detection kit (Bio-germ, Shanghai, China) and performed refer to previous literature. All the patients were recorded with basic information and epidemiological histories including (1) History of travel or residence in Wuhan and surrounding areas or other reported cases within 14 days of onset; (2) History of contact with new coronavirus infection (nucleic acid-positive) 14 days before onset; (3) history of contact with patients with fever or respiratory symptoms from Wuhan and surrounding areas, or from communities with case reports within 14 days before onset; (4) Cluster onset, along with disease condition changes.