With respiratory virus

Findings associated with poor outcomes include an increase in white blood cell counts with lymphopenia, a prolonged prothrombin time indicating coagulopathy , and elevated levels of liver enzymes, lactate dehydrogenase, D-dimer, interleukin-6, C-reactive protein, and procalcitonin Gandhi et al. The pathogenesis of severe SARS-CoV-2 infection is complex, and we are still learning about it at the time of this writing.

The viral spike glycoprotein binds to the cell surface receptor ACE2 Hoffmann et al. The physiological role of ACE2 is in regulation of blood pressure; ACE2 metabolizes angiotensin II, a vasoconstrictor, to generate angiotensin , which is a vasodilator. Cells lining the mucosal surfaces of the nose and lungs are endowed with ACE2, which facilitates infection of the respiratory tract.

However, ACE2 is also expressed on cells in many other tissues, including the endothelium, heart, gut, and kidneys, making these organs susceptible to infection by the virus. SARS-CoV-2 infection of respiratory epithelial cells activates monocytes, macrophages, and dendritic cells, resulting in secretion of a range of proinflammatory cytokines, including interleukin-6 IL IL-6 release instigates an amplification cascade that directly results in T helper 17 Th17 differentiation, among other lymphocytic changes.

Circulating IL-6 and soluble IL-6 receptor complexes indirectly activate many cell types, including endothelial cells, resulting in a flood of systemic cytokine production that contributes to hypotension and acute respiratory distress syndrome ARDS. A puzzling phenomenon has been seen in COVID pneumonia: some patients have extremely low blood oxygen levels, but they do not complain of breathlessness.

It has been suggested that oxygen uptake in COVID pneumonia is impeded because of clogged and constricted blood vessels in the lungs rather than because of congestion from accumulation of edema fluid in the alveoli, as seen in other viral pneumonias. The benefit of anticoagulants in the treatment of severe COVID disease is therefore of great interest. It is becoming clear that the pathogenetic cascade triggered by SARS-CoV-2 infection damages many organs in the body, from the kidneys to the brain.

Such pathophysiological changes are rarely seen with other respiratory virus infections. The scale of the COVID pandemic, with more than 3 million cases and , deaths in countries in a 4-month period, has driven an urgent search for drugs with antiviral activity against SARS-CoV The fastest path to finding an effective treatment may be to repurpose licensed drugs that are approved for use in humans for other indications. Drugs that target specific viral proteins or critical host cell processes have been selected for evaluation against SARS-CoV-2 in vitro and in clinical trials Figure 2.

More than clinical trials have been registered around the world listed on ClinicalTrials. In RCTs, participants are allocated by chance alone randomly to receive an intervention or drug or one among two or more drugs or interventions; randomization minimizes bias in measuring the effectiveness of a new intervention or treatment. Some of the drugs that were evaluated are the HIV protease inhibitor combination of lopinavir-ritonavir, chloroquine, hydroxychloroquine, and remdesivir. Lopinavir-ritonavir and hydroxychloroquine have not shown clear clinical benefits to date, although some RCTs are still ongoing.

Clinical improvement regarding need for oxygen support and mechanical ventilation have been reported with use of remdesivir in a compassionate use study, where the drug was used in patients with severe disease outside of a clinical trial when no other treatments were available.

A placebo-controlled RCT of remdesivir in China failed to demonstrate a statistically significant clinical benefit in treated patients Wang et al.

Cytokine release syndrome and the observation of elevated levels of serum IL-6 and other proinflammatory cytokines in patients with severe COVID has prompted trials of drugs that inhibit the IL-6 pathway, such as tocilizumab and sarilumab.

Antibodies that can block the infectivity of the virus can be derived from the plasma of recovered patients or from monoclonal antibodies generated from B cells from recovered patients or phage display libraries. Antibodies can also be administered to prevent infection in individuals who are known to be at risk of infection Figure 2 , referred to as immunoprophylaxis.

The optimal timing for administration of antiviral drugs, immunomodulators, and therapeutic antibodies should be guided by the phase of the disease and the kinetics of viral replication and immune response Figure 2. A diverse group of viruses, including coronaviruses, rhinoviruses, RSV, parainfluenza, and influenza viruses, target the respiratory tract, cause a range of infections from rhinitis to pneumonia, and represent a large global burden of disease.

The viruses infect epithelial cells of the respiratory tract after binding distinct cell surface receptors, and infection rapidly triggers innate immune responses. However, viruses employ several strategies to inhibit antiviral immunity in the host.

T cell responses are critical for viral clearance, and antibody responses directed against respiratory viruses can protect against re-infection, although reinfection occurs over the course of a lifetime with many respiratory viruses.

COVID pneumonia differs from that caused by other respiratory viruses in the severity and duration of inflammation, which appears to be driven by an exuberant innate immune response, a flood of proinflammatory cytokines, and multiorgan dysfunction, driven by derangements in pulmonary and clotting physiology.

As the pandemic evolves, we are gaining a better understanding of the complex pathophysiology underlying COVID disease. Treatment strategies currently under study include antiviral agents, immunomodulators, antibodies, and adjunctive therapies. National Center for Biotechnology Information , U. Published online May Author information Copyright and License information Disclaimer. Kanta Subbarao: gro. Measures to prevent hypoxemia may vary from simple aspiration of respiratory secretions to mechanical ventilatory support, or even extracorporeal membrane oxygenation ECMO.

The only antiviral drug currently approved for the treatment of infants with HRSV is the synthetic nucleoside ribavirin, delivered by small-particle aerosol via mist tent, mask, oxygen hood, or ventilator. Although ribavirin trials have lacked power to provide definitive recommendation, the antiviral has been recommended for infants and young children with underlying conditions, such as congenital heart disease, cystic fibrosis, or immunosuppression.

This therapy can also be considered for premature babies, infants younger than 6 weeks of age, or severely ill. Ribavirin therapy may reduce the duration of hospital stay and requirement for mechanical ventilation. No vaccine is currently licensed for HRSV prophylaxis. The disease enhancement related to a Th2 bias, caused by formalin-inactivated vaccine in the s, significantly slowed progress toward an HRSV vaccine.

Intranasally delivered genetically engineered attenuated or vectored vaccines are the most promising alternative for newborns, whereas subunit vaccine candidates combined with adjuvants to promote a protective response could be an alternative to previously exposed children.

Passive immunization of high-risk infants with monthly applications of HRSV immunoglobulin during the seasonal outbreaks reduces the incidence and severity of HRSV infections in high-risk children. This costly intervention is the only available means of protecting high-risk children against serious HRSV disease. Monthly intramuscular injections of humanized monoclonal antibody palivizumab should be considered for passive immunoprophylaxis during HRSV season for high-risk infants, such as preterm babies less than 6 months old, children with congenital heart disease, and children less than 2 years of age with bronchopulmonary dysplasia.

A second-generation mAb motavizumab with increased affinity is on phase III clinical trials as of this writing, and a third-generation mAb numax-YTE has been developed to increase the antibody serum half-life, thus obviating the need for monthly dosing. Hospitalized infants with RSV infection should be isolated or grouped to prevent nosocomial cross-infection.

Hand washing, use of eye—nose goggles, gowns, gloves, and decontamination of surfaces and fomites are additional control measures. The virions are pleomorphic, with single-stranded negative-sense RNA, ranging from to nm in diameter Figure 1. The glycoprotein HN, with hemagglutinin HE and neuraminidase activities, promotes virus—cell attachment by binding to sialic acid present on the cell surface proteins.

Upon cleavage by proteolytic enzymes, viral protein F mediates the fusion of viral and cell membranes, with consequent release of the nucleocapsid in the cytoplasm. The virus life cycle occurs in a way similar to other Paramyxoviridae Figure 2. HPIV zinc-binding protein V is found in high intracellular levels, but in little quantity in viral particles, and plays roles controlling viral-RNA synthesis and counteracting host cell interferon type 1 response.

Primary HPIV infection occurs early in childhood and by age 5 virtually all children are seropositive. Reinfections are frequent, but disease severity in reinfections is inversely proportional to the titer of serum-neutralizing antibody elicited by the previous infection.

HPIV-3 causes spring and summer outbreaks in temperate areas, but circulates endemically throughout the year, especially in immunocompromised or chronically ill, whereas HPIV-4 occurs sporadically throughout the year in children and adults. In tropical regions, higher HPIV activity occurs during rainy seasons. HPIV spreads mainly within families and closed communities, such as nurseries, day care centers, and pediatric wards, with high secondary attack rates. The virus does not persist long in the environment and is transmitted mainly by large droplets and fomites.

Viral shedding usually lasts 3—10 days, but prolonged shedding for months has been reported in very young children and immunosuppressed hosts. HPIV replicates in ciliated cells causing cytolysis of the respiratory mucosa. The infection begins in the upper respiratory tract and disseminates down the respiratory tree. The larynx and trachea are mostly involved in the croup syndrome, and extensive involvement of the lower respiratory tree may be present in tracheobronchitis, bronchopneumonia, and bronchiolitis.

Similar to what occurs with HRSV, amplified inflammatory response induced by viral infection of epithelial cells causes mononuclear interstitial infiltrate, epithelial necrosis, inflammatory exudate into the alveoli, and hyaline membrane formation in the lungs.

In cases of croup, mononuclear inflammatory cell infiltrate is seen in the subglotic area. Host immunity is largely mediated by antibodies to the two surface proteins HN and F, and secretory antibody is the best marker of protection against HPIV.

However, this protection is limited and reinfections are frequent. T-cell immune response is involved in the clearance of virus, and immunocompromised hosts may develop progressive and even lethal disease. In addition to the host immune response, factors inherent to the virus may be central for pathogenicity, such as the varying susceptibility of the HPIV F protein to cleavage by proteolytic enzymes present in infected tissues. After a 2—4 days incubation period, patients with HPIV infections may develop rhinitis, pharyngitis, laryngotracheobronchitis croup , bronchiolitis, or pneumonia.

The remaining one-third of HPIV infections causes croup, bronchiolitis, or pneumonia. Barking or brassy cough, dysphonia, inspiratory stridor, and suprasternal retraction due to subglotic edema are cardinal features.

Most children recover in 2—5 days, but some may develop a bronchopneumonia—croup syndrome. Other less common manifestations are apnea, sudden infant death syndrome, parotitis, and myopericarditis, and there are suggestions that certain HPIV strains may become neuroinvasive.

Since immunity to HPIVs is incomplete, reinfections occur throughout life. The presence of HPIV in monolayers can be confirmed by hemadsorption with guinea pig erythrocytes and immunofluorescence.

Isolation of HPIV in the shell vial assay format has produced mixed results. If for HPIV on exfoliated respiratory epithelial cells has been used for decades, but its sensitivity is moderate to low. At present, only supportive and symptomatic treatment is available for HPIV infections. In patients with croup, nebulization with racemic epinephrine or budesonide has rapid effect, and short-term, high-dose systemic corticosteroids may reduce the need for intubation.

Inhibitors of the protein HN are effective in vitro and in animal models, but have not reached clinical use. No vaccines are currently available for the prevention of HPIV infections. Early trials with inactivated HPIV vaccine in the s were unsuccessful.

Reverse genetics has provided means for identifying the basis of attenuation of vaccine candidates. Live attenuated cold-adapted HPIV-3 vaccines were immunogenic for children and still hold promise for clinical application. As in the case of HRSV infections, hand washing, use of eye—nose goggles, gowns, and gloves, as well as decontamination of fomites, should be used to prevent nosocomial spread of HPIV.

These viral isolates had been recovered from respiratory secretions of 28 children with ARI occurring in winter time, over a period of 20 years. Electron microscopy of cell cultures showing CPE revealed paramyxovirus-like particles, and sequencing of randomly primed PCR products revealed genome sequence and organization consistent with a paramyxovirus of the subfamily Pneumovirinae, related to avian pneumovirus of the genus Metapneumovirus.

Rather than an avian virus that can infect humans, the new agent is a primary human pathogen, and screening of banked serum samples for HMPV antibodies in the Netherlands indicates that this virus has been in circulation for at least 5 decades.

HMPV particles are enveloped, pleomorphic, spherical, or filamentous particles, of about nm in diameter. Like other paramyxoviruses, HMPV has a negative-sense, single-stranded RNA genome, and the viral replication occurs in a gradient manner. The protein M appears to control the switch from transcription to replication, and removal of the M gene leads to the accumulation of viral mRNAs and attenuation of viral replication. There is no apparent correlation between subgroups and disease severity.

Different strains of both subgroups A and B cocirculate in the same outbreak, but vary from location to location and from year to year. HMPV is rarely detected in samples from asymptomatic patients and has been associated with adult ARI, mainly in the elderly and in those with debilitating underlying conditions.

Little is known about HMPV-specific mechanisms of pathogenesis. Animal studies show disruption of the respiratory epithelium, epithelial cell sloughing, and inflammatory infiltrates in the lung.

In pathologic studies of humans with underlying diseases and HMPV infection, the main findings are acute and organizing lung injury, diffuse alveolar damage, sloughed epithelial cells with eosinophilic cytoplasmic inclusions, multinucleated giant cells, histiocytes, and hyaline membrane formation.

HMPV is now considered second only to HRSV as a cause of bronchiolitis, with chest X-rays revealing infiltrates, hyperinflation, and peribronchial cuffing. The most frequent symptoms of HMPV infections are fever, tachypnea, dyspnea, cough, hypoxia, wheezing, stridor, rhinitis, and sore throat, and otitis media is frequently present. HRSV in hospitalized infants and young children may require intensive care and mechanical ventilation, and coinfection by HMPV appears to increase the likelihood of severe HRSV disease by up to tenfold.

HMPV may cause more serious infections in patients with comorbid or immunosuppressive conditions, as well as in the very young and the elderly. In one study, all individuals older than 65 with LRTIs caused by HMPV had at least one underlying chronic or debilitating condition, including lymphoma, leukemia, or neurologic or cardiovascular diseases.

HMPV has been recognized as a frequent cause of acute wheezing in children. The virus grows poorly and the cytopathic effect, characteristically negative on hemadsorption testing, develops usually late after inoculation up to 23 days.

While this method is not as sensitive as real-time RT—PCR, it is readily applicable in diagnostic laboratories, where IF for respiratory viruses is routinely done. Other than supportive measures, oxygen therapy, bronchodilators, corticosteroids, and mechanical ventilation, there is no specific antiviral treatment for HMPV.

Humanized neutralizing monoclonal antibody to the F protein is active in experimentally infected animals and is likely to become available for prophylaxis of HMPV in the future. Human rhinoviruses HRVs are the most frequent respiratory pathogens of humans, and the most commonly detected viruses in samples from common cold sufferers. HRVs are small, nonenveloped, positive-stranded RNA viruses in the family Picornaviridae, genus Rhinovirus , distributed in two species, A 75 serotypes and B 25 serotypes.

Recently described new strains containing deletions in the VP1 region may constitute a new species C. HRV atomic structure was solved and revealed an icosahedral particle composed of 12 pentamers with a diameter of about 30 nm Figure 3. Surrounding a fivefold vertex of VP1 capsid proteins from adjacent pentamers, there is a 1.

The HRV genome is a 7. Following receptor binding, the viral positive-strand RNA is released into the cytoplasm, and translation of the single ORF produces one polyprotein that is cleaved cotranslationally to generate three precursors — P1 that originates capsid proteins, P2 and P3, originates nonstructural proteins and VPg.

Further cleavages of these precursors generate 11 end-products, and the last cleavage of VP0 into VP2 and VP4 occurs only at the final stages of virus maturation Figure 4. One of the P3 cleavage products, 3D, is an RNA-based RNA polymerase that will produce a negative-stranded full-length copy of the genome to be used as a template for the production of an expanding pool of positive-stranded RNAs.

The positive-stranded RNAs can be either translated into viral proteins or packaged as genome into newly assembled virions. The HRV replication cycle takes place in association with vesicle membranes in the cytoplasm and mature virions are released upon cell in lysis Figure 5.

Molecular graphics image of HRV The star-shaped region corresponds to the pentamers formed by convergence of five adjacent VP1 units star symbol.

Reproduced from Rossmann et al. Schematic representation of HRV genome and polyprotein organization. Processing pattern of rhinovirus polyprotein. All intermediate and final cleavages are carried out by 3C pro and its precursor, 3CD pro , except for the VP0 peptide cleavage into VP4 and VP1, which is done by an as yet unknown protease. Schematic overview of HRV replication cycle.

The RNA synthesis occurs anchored on vesicle membranes. Until recently, the recognized HRV serotypes were classified according to receptor specificity into three groups: The major group with 90 serotypes, whose receptor is intercellular adhesion molecule-1 ICAM-1 ; the minor group with 10 serotypes, whose receptor is the low-density lipoprotein receptor LDLR ; and HRV that shares properties with human enterovirus 68 and utilizes sialic acid residues on cell proteins as receptor.

The range of HRV serotypes and species by the currently accepted classification system, which is based on sequencing and phylogenetic comparisons rather than on receptor usage or antiviral susceptibility, is expected to expand as more sequence information is obtained from field strains. HRV is stable for days on environmental surfaces and is resistant to ethanol, ether, chloroform, and nonionic detergents, but is sensitive to UV light, pH lower than 5, and to halogens, such as chlorine, bromine, iodine, and phenolic disinfectants.

HRV is the predominant agent of ARI in the world and infections occur in people from all continents, including remotely located population groups, such as Bushmen from the Kalahari Desert, native Alaskans, and isolated Amazon Indian tribes. Rhinoviruses have been clearly shown as frequent cause of colds in the United States and in Western Europe and are frequently associated with ARI in children throughout the world.

Evidence suggests that indoor HRV transmission is favored by high relative humidity and crowding of young children, as occurs in the United States at the beginning of the school term, which may explain the autumn seasonal peak of HRV. HRV transmission requires close exposure and occurs mainly by hand-to-hand contact, followed by self-inoculation into the eye or nose, but can also happen by airborne spread. Children play a central role in spreading the virus in the household.

HRV replication is restricted to the respiratory epithelium, taking place in scattered ciliated cells of the nose and in nonciliated cells of the nasopharynx, and this tropism seems to be a consequence of receptor availability. These, in association with the stimulation of local parasympathetic nerve endings, result in the development of cold symptoms. Kinins, prostaglandins, proinflammatory cytokines, and chemokines may contribute to vasodilation, increased vascular permeability, influx of polymorphonuclear leukocytes, exocrine gland secretion, and nerve ending stimulation, resulting in nasal obstruction, rhinorrhea, sneezing, cough, and sore throat.

Serotype-specific neutralizing IgM, IgG, and IgA antibodies develop in most infected persons in 7—21 days and persist for years. Protection from infection is partially attributed to the presence of IgA antibody in nasal secretions, and recovery from illness is more dependent on cell-mediated immunity. HRV-induced colds are clinically indistinguishable from colds of other viral etiologies and the main symptoms are nasal discharge, nasal obstruction, sneezing, sore or scratchy throat, hoarseness, cough, and headache.

Facial and ear pressure may be present, but fever and malaise are uncommon. Infants and toddlers may display only nasal discharge and be otherwise asymptomatic. There is no clear association between distinct clinical outcomes and any particular serotypes or species of HRV. The majority of patients have obstruction and mucosal abnormalities of the sinus cavities, eustachian tubes, and the middle ear, which predispose to secondary bacterial sinusitis and otitis media.

HRV is frequently associated with exacerbations of chronic obstructive pulmonary disease and asthma attacks in children over 2 years of age and in adults. In addition to colds, HRV has been increasingly recognized as a major cause of LRTI in children and immunocom- promised hosts, and has been detected over 3 times more often than HRSV in association with wheezing in the first year of life. Such models will boost the research on pathogenesis and antiviral therapies. HRV can be detected in respiratory secretions by isolation in cultures of susceptible cell lines.

Cell lines of primate origin support HRV propagation, but certain strains of HeLa cells and human embryonic fibroblasts provide higher sensitivity for HRV isolation from clinical specimens. HRV shedding peaks around 48 h after infection and declines rapidly, but may remain at low levels for up to 3 weeks. Unlike other picornaviruses, HRVs are acid-labile, a property that distinguishes them from enteroviruses.

Rapid assays for HRV detection, like immunofluorescence and other antigen detection methods, are not available, because of the large number of serotypes. The homotypic nature of HRV antibodies restricts serology to experimental settings. Real-time PCR multiplex assays directed to conserved sequences of different viral species and genera, as well as recently developed methods such as MultiCode-PLx and Mass-Tag, can detect several viral pathogens in a single run and are expected to become methods of choice for large-scale sample testing in the near future.

Several trials of antiviral agents for HRV have been conducted, but no specific treatment has been licensed, mainly because of the lack of potency, untoward side effects, and drug delivery problems. Symptomatic treatment can be done with a variety of nonprescription medications.

Systemic sympathomimetic decongestants may reduce nasal obstruction, first-generation antihistamines may reduce sneezing and rhinorrhea, and nonsteroidal anti-inflammatory drugs may reduce headache, cough, and systemic symptoms. It may be possible to reduce the exposure to HRV by hand washing after contact with a cold sufferer or after handling objects that may have been contaminated with respiratory secretions. Application of the virucidal agents, salicylic acid or pyroglutamic acid, to the hands reduced recovery of rhinovirus from the hand skin of treated persons.

However, the cost and the local side effects associated with the difficulty to make the drug available to homes in a timely fashion reduce the utility of this approach. Adenoviruses are nonenveloped, icosahedral DNA viruses of the genus Mastadenovirus , family Adenoviridae. The adenovirus capsid consists of three morphologically, antigenically, and functionally distinct types of capsomere: hexons, penton bases, and penton fibers that project from the penton bases Figure 6.

The hexon and penton bases contain complement fixing, group-specific antigens common to all human adenoviruses, whereas the fibers have primarily neutralizing and hemagglutination-inhibiting, type-specific antigens.

Serum neutralization permits the classification of human adenoviruses in 51 distinct serotypes, distributed in six species, A—F. Adenoviruses are commonly accompanied by small, single-stranded DNA parvoviruses known as adeno-associated viruses, which do not seem to cause any specific disease. Schematic organization of the adenovirus virion.

A naked icosahedral capsid contains a double-stranded DNA genome. The main capsid proteins are the hexon II , penton base III , and the penton fiber IV , which projects from each vertex and binds to cell receptor.

The fiber protein binds to the host cell through the protein Coxsackie B and adenovirus receptor CAR , a protein of the immunoglobulin superfamily that serves as high-affinity receptor for the attachment of adenovirus species A, C, D, E, and F. Plasma membrane protein CD46 is the ligand for the fiber of adenovirus species B. Virus assembly takes place in the nucleus, and the infectious cycle is completed by the release of up to 1 million virions upon cell lysis Figure 7.

Adenovirus replication cycle. After adsorption, virus is internalized by receptor-mediated endocytosis and directed to the nuclear pore where final disassembly occurs. The viral DNA genome is released into the nucleus and the early set of genes are expressed. Early viral gene products mediate further viral gene expression and DNA replication. Then the late viral genes are expressed, generating structural proteins, and assembly of progeny virions occurs.

New viruses are released by cell lysis. Adenoviruses are stable over a wide pH range 5—9 , resistant to isopropyl alcohol, ether, and chloroform. Respiratory diseases are among the most frequent manifestations of infections by adenoviruses, particularly in children under the age of 5 years. Respiratory infections by adenoviruses occur worldwide and with no apparent seasonality.

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