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 the WHO, a probable case is
- a person with a fever, respiratory infection, and evidence of pneumonia or acute respiratory distress syndromeandtesting for MERS-CoV is unavailable or negative on a single inadequate specimenandthe person has a direct link with a confirmed case.
- A person with an acute febrile respiratory illness with clinical, radiological, or histopathological evidence of pulmonary parenchymal disease (e.g. pneumonia or acute respiratory distress Syndrome)and an inconclusive MERS-CoV laboratory test (that is, a positive screening test without confirmation)anda resident of or traveler to Middle Eastern countries where MERS-CoV virus is believed to be circulating in the 14 days before onset of illness.
- A person with an acute febrile respiratory illness of any severity andan inconclusive MERS-CoV laboratory test (that is, a positive screening test without confirmation) andthe person has a direct epidemiologic link with a confirmed MERS-CoV case.
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.
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
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).
Because FIP is an immune-mediated disease, treatment falls into two categories: direct action against the virus itself and modulation of the immune response.
Non-effusive FIP is more difficult to diagnose than effusive FIP because the clinical signs tend to be more vague and varied: the list of differential diagnoses is therefore much longer. Non-effusive FIP diagnosis should be considered when the following criteria are met:
1. History: the cat is young (under 2 years old) and purebred: over 70% of cases of FIP are in pedigree kittens.
2. History: the cat experienced stress such as recent neutering or vaccination
3. History: the cat had an opportunity to become infected with FCoV, such as originating in a breeding or rescue cattery, or the recent introduction of a purebred kitten or cat into the household.
4. Clinical signs: the cat has become anorexic or is eating less than usual; has lost weight or failed to gain weight; has pyrexia of unknown origin; intra-ocular signs; icterus.
5. Biochemistry: hypergammaglobulinaemia; raised bilirubin without liver enzymes being raised.
6. Hematology: lymphopenia; non-regenerative—usually mild—anaemia.
7. Serology: the cat has a high antibody titre to FCoV: this parameter should be used with caution, because of the high prevalence of FCoV in breeding and rescue catteries.
Non-effusive FIP can be ruled out as a diagnosis if the cat is seronegative, provided the antibody test has excellent sensitivity. In a study which compared various commercially available in-house FCoV antibody tests, the FCoV Immunocomb (Biogal) was 100% sensitive; the Speed F-Corona rapid immunochromatographic (RIM) test (Virbac) was 92.4% sensitive and the FASTest feline infectious peritonitis (MegaCor Diagnostik) RIM test was 84.6% sensitive.
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.
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.
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.
Recent work has been done by virologists to learn more about the interference in infection of host cells and how DI genomes could potentially work as antiviral agents. The Dimmock & Easton, 2014 article explains that pre-clinical work is being done to test their effectiveness against influenza viruses. DI-RNAs have also been found to aid in the infection of fungi via viruses of the family "Partitiviridae" for the first time, which makes room for more interdisciplinary work.
The best prevention against viral pneumonia is vaccination against influenza, adenovirus, chickenpox, herpes zoster, measles, and rubella.
The diagnosis of DPB requires analysis of the lungs and bronchiolar tissues, which can require a lung biopsy, or the more preferred high resolution computed tomography (HRCT) scan of the lungs. The diagnostic criteria include severe inflammation in all layers of the respiratory bronchioles and lung tissue lesions that appear as nodules within the terminal and respiratory bronchioles in both lungs. The nodules in DPB appear as opaque lumps when viewed on X-rays of the lung, and can cause airway obstruction, which is evaluated by a pulmonary function test, or PFT. Lung X-rays can also reveal dilation of the bronchiolar passages, another sign of DBP. HRCT scans often show blockages of some bronchiolar passages with mucus, which is referred to as the "tree-in-bud" pattern. Hypoxemia, another sign of breathing difficulty, is revealed by measuring the oxygen and carbon dioxide content of the blood, using a blood test called arterial blood gas. Other findings observed with DPB include the proliferation of lymphocytes (white blood cells that fight infection), neutrophils, and foamy histiocytes (tissue macrophages) in the lung lining. Bacteria such as "H. influenzae" and "P. aeruginosa" are also detectable, with the latter becoming more prominent as the disease progresses. The white blood, bacterial and other cellular content of the blood can be measured by taking a complete blood count (CBC). Elevated levels of IgG and IgA (classes of immunoglobulins) may be seen, as well as the presence of rheumatoid factor (an indicator of autoimmunity). Hemagglutination, a clumping of red blood cells in response to the presence of antibodies in the blood, may also occur. Neutrophils, beta-defensins, leukotrienes, and chemokines can also be detected in bronchoalveolar lavage fluid injected then removed from the bronchiolar airways of individuals with DPB, for evaluation.
In the differential diagnosis (finding the correct diagnosis between diseases that have overlapping features) of some obstructive lung diseases, DPB is often considered. A number of DPB symptoms resemble those found with other obstructive lung diseases such as asthma, chronic bronchitis, and emphysema. Wheezing, coughing with sputum production, and shortness of breath are common symptoms in such diseases, and obstructive respiratory functional impairment is found on pulmonary function testing. Cystic fibrosis, like DPB, causes severe lung inflammation, excess mucus production, and infection; but DPB does not cause disturbances of the pancreas nor the electrolytes, as does CF, so the two diseases are different and probably unrelated. DPB is distinguished by the presence of lesions that appear on X-rays as nodules in the bronchioles of both lungs; inflammation in all tissue layers of the respiratory bronchioles; and its higher prevalence among individuals with East Asian lineage.
DPB and bronchiolitis obliterans are two forms of primary bronchiolitis. Specific overlapping features of both diseases include strong cough with large amounts of often pus-filled sputum; nodules viewable on lung X-rays in the lower bronchi and bronchiolar area; and chronic sinusitis. In DPB, the nodules are more restricted to the respiratory bronchioles, while in OB they are often found in the membranous bronchioles (the initial non-cartilaginous section of the bronchiole, that divides from the tertiary bronchus) up to the secondary bronchus. OB is a bronchiolar disease with worldwide prevalence, while DPB has more localized prevalence, predominantly in Japan. Prior to clinical recognition of DPB in recent years, it was often misdiagnosed as bronchiectasia, COPD, IPF, phthisis miliaris, sarcoidosis or alveolar cell carcinoma.
Vaccination helps prevent bronchopneumonia, mostly against influenza viruses, adenoviruses, measles, rubella, streptococcus pneumoniae, haemophilus influenzae, diphtheria, bacillus anthracis, chickenpox, and bordetella pertussis.
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.
In virology, defective interfering particles (DIPs), also known as defective interfering viruses, are spontaneously generated virus mutants in which a critical portion of the particle's genome has been lost due to defective replication. DIPs are derived from and associated with their parent virus, and particles are classed as DIPs if they are rendered non-infectious due to at least one essential gene of the virus being lost or severely damaged as a result of the defection. A DIP can usually still penetrate host cells, but requires another fully functional virus particle (the 'helper' virus) to co-infect a cell with it, in order to provide the lost factors. The existence of DIPs has been known about for decades, and they can occur within nearly every class of both DNA and RNA viruses.
Neonatal sepsis of the newborn is an infection that has spread through the entire body. The inflammatory response to this systematic infection can be as serious as the infection itself. In infants that weigh under 1500 g, sepsis is the most common cause of death. Three to four percent of infants per 1000 births contract sepsis. The mortality rate from sepsis is near 25%. Infected sepsis in an infant can be identified by culturing the blood and spinal fluid and if suspected, intravenous antibiotics are usually started. Lumbar puncture is controversial because in some cases it has found not to be necessary while concurrently, without it estimates of missing up to one third of infants with meningitis is predicted.
In order to ascertain if an individual has activated PI3K delta syndrome, usually one finds atypical levels of immunoglobulins. Methods to determine the condition are the following:
- Genetic testing
- Laboratory findings
- Symptoms exhibited
Prevention of bronchiolitis relies strongly on measures to reduce the spread of the viruses that cause respiratory infections (that is, handwashing, and avoiding exposure to those symptomatic with respiratory infections). In addition to good hygiene an improved immune system is a great tool for prevention. One way to improve the immune system is to feed the infant with breast milk, especially during the first month of life. Immunizations are available for premature infants who meet certain criteria (some cardiac and respiratory disorders) such as Palivizumab (a monoclonal antibody against RSV). Passive immunization therapy requires monthly injections during winter.
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.
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.