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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MERS cases have been reported to have low white blood cell count, and in particular low lymphocytes.
For PCR testing, the WHO recommends obtaining samples from the lower respiratory tract via bronchoalveolar lavage (BAL), sputum sample or tracheal aspirate as these have the highest viral loads. There have also been studies utilizing upper respiratory sampling via nasopharyngeal swab.
Several highly sensitive, confirmatory real-time RT-PCR assays exist for rapid identification of MERS-CoV from patient-derived samples. These assays attempt to amplify upE (targets elements upstream of the E gene), open reading frame 1B (targets the ORF1b gene) and open reading frame 1A (targets the ORF1a gene). The WHO recommends the upE target for screening assays as it is highly sensitive. In addition, hemi-nested sequencing amplicons targeting RdRp (present in all coronaviruses) and nucleocapsid (N) gene (specific to MERS-CoV) fragments can be generated for confirmation via sequencing. Reports of potential polymorphisms in the N gene between isolates highlight the necessity for sequence-based characterization.
The WHO recommended testing algorithm is to start with an upE RT-PCR and if positive confirm with ORF 1A assay or RdRp or N gene sequence assay for confirmation. If both an upE and secondary assay are positive it is considered a confirmed case.
Protocols for biologically safe immunofluorescence assays (IFA) have also been developed; however, antibodies against betacoronaviruses are known to cross-react within the genus. This effectively limits their use to confirmatory applications. A more specific protein-microarray based assay has also been developed that did not show any cross-reactivity against population samples and serum known to be positive for other betacoronaviruses. Due to the limited validation done so far with serological assays, WHO guidance is that "cases where the testing laboratory has reported positive serological test results in the absence of PCR testing or sequencing, are considered probable cases of MERS-CoV infection, if they meet the other conditions of that case definition."
According to World Health Organization, the interim case definition is that a confirmed case is identified in a person with a positive lab test by "molecular diagnostics including either a positive PCR on at least two specific genomic targets or a single positive target with sequencing on a second."
The WHO has published several testing protocols for the disease. The standard method of testing is real-time reverse transcription polymerase chain reaction (rRT-PCR). The test is typically done on respiratory samples obtained by a nasopharyngeal swab; however, a nasal swab or sputum sample may also be used. Results are generally available within a few hours to two days. Blood tests can be used, but these require two blood samples taken two weeks apart and the results have little immediate value. Chinese scientists were able to isolate a strain of the coronavirus and publish the genetic sequence so laboratories across the world could independently develop polymerase chain reaction (PCR) tests to detect infection by the virus. As of 4 April 2020, antibody tests (which may detect active infections and whether a person had been infected in the past) were in development, but not yet widely used. The Chinese experience with testing has shown the accuracy is only 60 to 70%. The FDA in the United States approved the first point-of-care test on 21 March 2020 for use at the end of that month.
Diagnostic guidelines released by Zhongnan Hospital of Wuhan University suggested methods for detecting infections based upon clinical features and epidemiological risk. These involved identifying people who had at least two of the following symptoms in addition to a history of travel to Wuhan or contact with other infected people: fever, imaging features of pneumonia, normal or reduced white blood cell count or reduced lymphocyte count.
A study asked hospitalized COVID-19 patients to cough into a sterile container, thus producing a saliva sample, and detected virus in eleven of twelve patients using RT-PCR. This technique has the potential of being quicker than a swab and involving less risk to health care workers (collection at home or in the car).
Along with laboratory testing, chest CT scans may be helpful to diagnose COVID-19 in individuals with a high clinical suspicion of infection but is not recommended for routine screening. Bilateral multilobar ground-glass opacities with a peripheral, asymmetric and posterior distribution are common in early infection. Subpleural dominance, crazy paving (lobular septal thickening with variable alveolar filling), and consolidation may appear as the disease progresses.
Chicken respiratory diseases are difficult to differentiate and may not be diagnosed based on respiratory signs and lesions. Other diseases such as mycoplasmosis by Mycoplasma gallisepticum (chronic respiratory disease), Newcastle disease by mesogenic strains of Newcastle diseases virus (APMV-1), avian metapneumovirus, infectious laryngotracheitis, avian infectious coryza in some stages may clinically resemble IB. Similar kidney lesions may be caused by different etiologies, including other viruses, such as infectious bursal disease virus (the cause of Gumboro disease) and toxins (for instance ochratoxins of Aspergillus ochraceus), and dehydration.
In laying hens, abnormal and reduced egg production are also observed in Egg Drop Syndrome 76 (EDS), caused by an Atadenovirus and avian metapneumovirus infections. At present, IB is more common and far more spread than EDS. The large genetic and phenotypic diversity of IBV have been resulting in common vaccination failures. In addition, new strains of IBV, not present in commercial vaccines, can cause the disease in IB vaccinated flocks. Attenuated vaccines will revert to virulence by consecutive passage in chickens in densely populated areas, and may reassort with field strains, generating potentially important variants.
Definitive diagnosis relies on viral isolation and characterization. For virus characterization, recent methodology using genomic amplification (PCR) and sequencing of products, will enable very precise description of strains, according to the oligonucleotide primers designed and target gene. Methods for IBV antigens detection may employ labelled antibodies, such as direct immunofluorescence or immunoperoxidase. Antibodies to IBV may be detected by indirect immunofluorescent antibody test, ELISA and Haemagglutination inhibition (haemagglutinating IBV produced after enzymatic treatment by phospholipase C).
Diagnosis can be made in several ways, encompassing a range of multi-faceted techniques:
- Isolation and detection of the virus in cell culture.
- Detection of viral antigens directly within bodily respiratory tract secretions using immunofluorescence, enzyme immunoassays or fluroimmunoassays.
- Polymerase chain reaction (PCR).
- Analysis of specific IgG antibodies showing a subsequent rise in titre following infection (using paired serum specimens).
Because of the similarity in terms of the antigenic profile between the viruses, hemagglutination assay (HA) or hemadsorption inhibition (HAdI) processes are often used. Both complement fixation, neutralisation and enzyme linked immunosorbent assays – ELISA, can also be used to aid in the process of distinguishing between viral serotypes.
There is no vaccine for SARS to date. Isolation and quarantine remain the most effective means to prevent the spread of SARS. Other preventative measures include:
- Disinfection of surfaces for fomites
- Wearing a surgical mask
- Avoiding contact with bodily fluids
- Washing the personal items of someone with SARS in hot, soapy water (eating utensils, dishes, bedding, etc.)
- Keeping children with symptoms home from school
Many public health interventions were taken to help control the spread of the disease; which is mainly spread through respiratory droplets in the air. These interventions included earlier detection of the disease, isolation of people who are infected, droplet and contact precautions, and the use of personal protective equipment (PPE); including masks and isolation gowns. A screening process was also put in place at airports to monitor air travel to and from affected countries. Although no cases have been identified since 2004, the CDC is still working to make federal and local rapid response guidelines and recommendations in the event of a reappearance of the virus.
Dogs will typically recover from kennel cough within a few weeks. However, secondary infections could lead to complications that could do more harm than the disease itself. Several opportunistic invaders have been recovered from the respiratory tracts of dogs with kennel cough, including Streptococcus, Pasteurella, Pseudomonas, and various coliforms. These bacteria have the potential to cause pneumonia or sepsis, which drastically increase the severity of the disease. These complications are evident in thoracic radiographic examinations. Findings will be mild in animals affected only by kennel cough, while those with complications may have evidence of segmental atelectasis and other severe side effects.
Several consequent reports from China on some recovered SARS patients showed severe long-time sequelae exist. The most typical diseases include, among other things, pulmonary fibrosis, osteoporosis, and femoral necrosis, which have led to the complete loss of working ability or even self-care ability of these cases. As a result of quarantine procedures, some of the post-SARS patients have been documented suffering from posttraumatic stress disorder (PTSD) and major depressive disorder.
To increase their effectiveness, vaccines should be administered as soon as possible after a dog enters a high-risk area, such as a shelter. 10 to 14 days are required for partial immunity to develop. Administration of B. bronchiseptica and canine-parainfluenza vaccines may then be continued routinely, especially during outbreaks of kennel cough. There are several methods of administration, including parenteral and intranasal. However, the intranasal method has been recommended when exposure is imminent, due to a more rapid and localized protection. Several intranasal vaccines have been developed that contain canine adenovirus in addition to B bronchiseptica and canine-parainfluenza virus antigens. Studies have thus far not been able to determine which formula of vaccination is the most efficient. Adverse effects of vaccinations are mild, but the most common effect observed up to 30 days after administration is nasal discharge. Vaccinations are not always effective. In one study it was found that 43.3% of all dogs in the study population with respiratory disease had in fact been vaccinated.
Few data are available about microscopic lesions and the pathophysiology of COVID-19. The main pathological findings at autopsy are:
- Macroscopy: pleurisy, pericarditis, lung consolidation and pulmonary oedema
- Four types of severity of viral pneumonia can be observed:
- minor pneumonia: minor serous exudation, minor fibrin exudation
- mild pneumonia: pulmonary oedema, pneumocyte hyperplasia, large atypical pneumocytes, interstitial inflammation with lymphocytic infiltration and multinucleated giant cell formation
- severe pneumonia: diffuse alveolar damage (DAD) with diffuse alveolar exudates. DAD is the cause of acute respiratory distress syndrome (ARDS) and severe hypoxemia.
- healing pneumonia: organisation of exudates in alveolar cavities and pulmonary interstitial fibrosis
- plasmocytosis in BAL
- Blood: disseminated intravascular coagulation (DIC); leukoerythroblastic reaction
- Liver: microvesicular steatosis
No specific treatment is available, but antibiotics can be used to prevent secondary infections.
Vaccines are available (ATCvet codes: for the inactivated vaccine, for the live vaccine; plus various combinations).
Biosecurity protocols including adequate isolation, disinfection are important in controlling the spread of the disease.
Despite decades of research, no vaccines currently exist.
Recombinant technology has however been used to target the formation of vaccines for HPIV-1, -2 and -3 and has taken the form of several live-attenuated intranasal vaccines. Two vaccines in particular were found to be immunogenic and well tolerated against HPIV-3 in phase I trials. HPIV-1 and -2 vaccine candidates remain less advanced.
Vaccine techniques which have been used against HPIVs are not limited to intranasal forms, but also viruses attenuated by cold passage, host range attenuation, chimeric construct vaccines and also introducing mutations with the help of reverse genetics to achieve attenuation.
Maternal antibodies may offer some degree of protection against HPIVs during the early stages of life via the colostrum in breast milk.
Standard titer measles vaccine is recommended at 9 months of age in low-income countries where measles infection is endemic and often fatal. Many observational studies have shown that measles-vaccinated children have substantially lower mortality than can be explained by the prevention of measles-related deaths. Many of these observational studies were natural experiments, such as studies comparing the mortality before and after the introduction of measles vaccine and other studies where logistical factors rather than maternal choice determined whether a child was vaccinated or not.
These findings were later supported in randomized trials from 2003 to 2009 in Guinea-Bissau. An intervention group of children given standard titer measles vaccine at 4.5 and 9 month of age had a 30% reduction in all-cause mortality compared to the children in the control group, which were only vaccinated against measles at 9 month of age.
In a recent WHO-commissioned review based on four randomized trials and 18 observational studies, it was concluded that "There was consistent evidence of a beneficial effect of measles vaccine, although all observational studies were assessed as being at risk of bias and the GRADE rating was of low confidence. There was an apparent difference between the effect in girls and boys, with girls benefitting more from measles vaccination", and furthermore "estimated effects are in the region of a halving of mortality risk" and "if these effects are real then they are not fully explained by deaths that were established as due to measles". Based on the evidence, the WHO's Strategic Advisory Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research".
The best prevention against viral pneumonia is vaccination against influenza, adenovirus, chickenpox, herpes zoster, measles, and rubella.
The live attenuated BCG vaccine developed against tuberculosis has been shown to have strong beneficial effects on the ability to combat non-tuberculosis infections.
Several studies have suggested that BCG vaccination may reduce atopy, particularly when given early in life. Furthermore, in multiple observational studies BCG vaccination has been shown to provide beneficial effects on overall mortality. These observations encouraged randomised controlled trials to examine BCG vaccination's beneficial non-specific effects on overall health. Since BCG vaccination is recommended to be given at birth in countries that have a high incidence of tuberculosis it would have been unethical to randomize children into 'BCG' vs. 'no BCG' groups. However, many low-income countries delay BCG vaccination for low-birth-weight (LBW) infants; this offered the opportunity to directly test the effect of BCG on overall mortality.
In the first two randomised controlled trials receipt of BCG+OPV at birth vs. OPV only ('delayed BCG') was associated with strong reductions in neonatal mortality; these effects were seen as early as 3 days after vaccination. BCG protected against sepsis as well as respiratory infections.
Among BCG vaccinated children, those who develop a BCG scar or a positive skin test (TST) are less likely to develop sepsis and exhibit an overall reduction in child mortality of around 50%.
In a recent WHO-commissioned review based on five clinical trials and nine observational studies, it was concluded that "the results indicated a beneficial effect of BCG on overall mortality in the first 6–12 months of life. Relevant follow-up in some of the trials was short, and all of the observational studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria and "There was a suggestion that BCG vaccination may be more beneficial the earlier it is given". Furthermore, "estimated effects are in the region of a halving of mortality risk" and "any effect of BCG vaccine on all-cause mortality is not likely to be attributable to any great extent to fewer deaths from tuberculosis (i.e. to a specific effect of BCG vaccine against tuberculosis)". Based on the evidence, the WHO's Strategic Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research".
The distinction between viral upper respiratory tract infections is loosely based on the location of symptoms with the common cold affecting primarily the nose, pharyngitis the throat, and bronchitis the lungs. However, there can be significant overlap and multiple areas can be affected. The common cold is frequently defined as nasal inflammation with varying amount of throat inflammation. Self-diagnosis is frequent. Isolation of the viral agent involved is rarely performed, and it is generally not possible to identify the virus type through symptoms.
Vaccination helps prevent bronchopneumonia, mostly against influenza viruses, adenoviruses, measles, rubella, streptococcus pneumoniae, haemophilus influenzae, diphtheria, bacillus anthracis, chickenpox, and bordetella pertussis.
The only useful ways to reduce the spread of cold viruses are physical measures such as hand washing and face masks; in the healthcare environment, gowns and disposable gloves are also used. Isolation or quarantine is not used as the disease is so widespread and symptoms are non-specific. Vaccination has proved difficult as there are many viruses involved and they mutate rapidly. Creation of a broadly effective vaccine is, thus, highly improbable.
Regular hand washing appears to be effective in reducing the transmission of cold viruses, especially among children. Whether the addition of antivirals or antibacterials to normal hand washing provides greater benefit is unknown. Wearing face masks when around people who are infected may be beneficial; however, there is insufficient evidence for maintaining a greater social distance.
It is unclear if zinc supplements affect the frequency of colds. Routine vitamin C supplements do not reduce the risk or severity of the common cold, though they may reduce its duration. Gargling with water was found useful in one small trial.
In cases of viral pneumonia where influenza A or B are thought to be causative agents, patients who are seen within 48 hours of symptom onset may benefit from treatment with oseltamivir or zanamivir. Respiratory syncytial virus (RSV) has no direct acting treatments, but ribavirin in indicated for severe cases. Herpes simplex virus and varicella-zoster virus infections are usually treated with aciclovir, whilst ganciclovir is used to treat cytomegalovirus. There is no known efficacious treatment for pneumonia caused by SARS coronavirus, MERS coronavirus, adenovirus, hantavirus, or parainfluenza. Care is largely supportive.
Antibiotics do not help the many lower respiratory infections which are caused by parasites or viruses. While acute bronchitis often does not require antibiotic therapy, antibiotics can be given to patients with acute exacerbations of chronic bronchitis. The indications for treatment are increased dyspnoea, and an increase in the volume or purulence of the sputum. The treatment of bacterial pneumonia is selected by considering the age of the patient, the severity of the illness and the presence of underlying disease. Amoxicillin and doxycycline are suitable for many of the lower respiratory tract infections seen in general practice.
Diagnosis of effusive FIP has become more straightforward in recent years: detection of viral RNA in a sample of the effusion, by reverse-transcriptase polymerase chain reaction (RT-PCR) is diagnostic of effusive FIP. However, that does require that a sample be sent to an external veterinary laboratory. Within the veterinary hospital there are a number of tests which can rule out a diagnosis of effusive FIP within minutes:
1. Measure the total protein in the effusion: if it is less than 35g/l, FIP is extremely unlikely.
2. Measure the albumin to globulin ratio in the effusion: if it is over 0.8, FIP is ruled out, if it is less than 0.4, FIP is a possible—but not certain—diagnosis
3. Examine the cells in the effusion: if they are predominantly lymphocytes then FIP is excluded as a diagnosis.
Because FIP is an immune-mediated disease, treatment falls into two categories: direct action against the virus itself and modulation of the immune response.
Based on the low variability exhibited among known SARS-CoV-2 genomic sequences, the strain is thought to have been detected by health authorities within weeks of its emergence among the human population in late 2019. The earliest case of infection currently known is thought to have been found on 17 November 2019. The virus subsequently spread to all provinces of China and to more than 150 other countries in Asia, Europe, North America, South America, Africa, and Oceania. Human-to-human transmission of the virus has been confirmed in all of these regions. On 30 January 2020, SARS-CoV-2 was designated a Public Health Emergency of International Concern by the WHO, and on 11 March 2020 the WHO declared it a pandemic.
The basic reproduction number (R0) of the virus has been estimated to be between 1.4 and 3.9. This means that each infection from the virus is expected to result in 1.4 to 3.9 new infections when no members of the community are immune and no preventive measures are taken. The reproduction number may be higher in densely populated conditions such as those found on cruise ships. Many forms of preventive efforts may be employed in specific circumstances in order to reduce the propagation of the virus.
There have been about 82,000 confirmed cases of infection in mainland China. While the proportion of infections that result in confirmed cases or progress to diagnosable disease remains unclear, one mathematical model estimated that on 25 January 2020 75,815 people were infected in Wuhan alone, at a time when the number of confirmed cases worldwide was only 2,015. Before 24 February 2020, over 95% of all deaths from COVID-19 worldwide had occurred in Hubei province, where Wuhan is located. As of 17 April 2020, the percentage had decreased to 2.1%.
As of 17 April 2020, there have been 2,234,109 total confirmed cases of SARS-CoV-2 infection in the ongoing pandemic. The total number of deaths attributed to the virus is 153,379. Many recoveries from confirmed infections go unreported, but at least 567,695 people have recovered from confirmed infections.
The diagnosis is typically made by clinical examination. Chest X-ray is sometimes useful to exclude bacterial pneumonia, but not indicated in routine cases.
Testing for the specific viral cause can be done but has little effect on management and thus is not routinely recommended. RSV testing by direct immunofluorescence testing on nasopharyngeal aspirate had a sensitivity of 61% and specificity of 89%. Identification of those who are RSV-positive can help for: disease surveillance, grouping ("cohorting") people together in hospital wards to prevent cross infection, predicting whether the disease course has peaked yet, reducing the need for other diagnostic procedures (by providing confidence that a cause has been identified).
Infants with bronchiolitis between the age of two and three months have a second infection by bacteria (usually a urinary tract infection) less than 6% of the time. Preliminary studies have suggested that elevated procalcitonin levels may assist clinicians in determining the presence of bacterial coinfection, which could prevent unnecessary antibiotic use and costs.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus strain that causes coronavirus disease 2019 (COVID-19), a respiratory illness. It is colloquially known as the coronavirus, and was previously referred to by its provisional name 2019 novel coronavirus (2019-nCoV). SARS-CoV-2 is a positive-sense single-stranded RNA virus. It is contagious in humans, and the World Health Organization (WHO) has designated the ongoing pandemic of COVID-19 a Public Health Emergency of International Concern. Because the strain was first discovered in Wuhan, China, it is sometimes referred to as "Wuhan virus" or "Wuhan coronavirus". Since the WHO discourages the use of names based on locations such as MERS, and to avoid confusion with the disease SARS, it sometimes refers to SARS-CoV-2 as "the COVID-19 virus" in public health communications. The general public frequently calls both SARS-CoV-2 and the disease it causes "coronavirus", but scientists typically use more precise terminology.
Taxonomically, SARS-CoV-2 is a strain of Severe acute respiratory syndrome-related coronavirus (SARSr-CoV). It is believed to have zoonotic origins and has close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus. An intermediate animal reservoir such as a pangolin is also thought to be involved in its introduction to humans. The virus shows little genetic diversity, indicating that the spillover event introducing SARS-CoV-2 to humans is likely to have occurred in late 2019.
Epidemiological studies estimate each infection results in 1.4 to 3.9 new ones when no members of the community are immune and no preventive measures taken. The virus is primarily spread between people through close contact and via respiratory droplets produced from coughs or sneezes. It mainly enters human cells by binding to the receptor angiotensin converting enzyme 2 (ACE2).