Viruses: what is the minimum you should know about viruses causing respiratory disease and associated viruses.

During a viva voce exam or indeed any part of the practical examination when asked about the aetiology of a disease the candidate says “Viruses” and then sit back as if they have achieved A GREAT DEAL. Viruses have names, they may be DNA or RNA viruses, single or double stranded, or have a transcriptase enzyme which enables them to control host DNA in order to replicate. They have a genus and a family and have a tropism for different organs or sytems. This tropism means that the clinical symptoms are predominantly in that system but a systemic or widespread response may be seen. Detection of the virus is usually through the detection of the antigen in the involved tissue or blood, the visualisation of the virus in an electron microscope scan of the affected tissue, the presence of antibodies specific to the virus, release of enzymes from the organ or tissue affected like liver enzyme, muscle enzymes, tumour necrosis factor etc, or release of abnormal metabolites such as myoglobins in the urine in necrotic myositis causing rhabdomyolysis. A knowledge of the epidemiology of disease in the area that you practice in will help with the diagnosis.

Parainfluenza viruses.

Parainfluenza viruses (PIVs) are single-stranded, enveloped RNA viruses belonging to the genus Paramyxovirus in the Paramyxoviridae family. This family also includes mumps, measles, respiratory syncytial viruses, human metapneumovirus, and Nipah and Hendra viruses.

Nipah and Hendra viruses are two related zoonotic pathogens that have emerged in the Asia-Pacific region. Both are RNA viruses that belong to the Paramyxoviridae family. The viruses are able to jump the species barrier and infect a secondary animal host (eg, pigs or horses), and which then transmit infections to humans.

NIPAH VIRUS — Nipah virus was initially discovered when it caused an outbreak of viral encephalitis among pig farmers in Malaysia. The virus was named after a village in Malaysia, where the infected patient lived. Since then, there have been several outbreaks of acute Nipah encephalitis in various districts in Bangladesh, in the neighboring district of Siliguri in India, and in the Southern Philippines. Transmission is from bats though human to human transmission can occur.

HENDRA VIRUS infection — Hendra virus primarily infects horses. Human infection results from direct contact with infected horses. Animal–to-animal transmission has been demonstrated in dogs who had close contact with infected horses . No human-to-human transmission has been documented.

Clinical features of Hendra virus infection — Since Hendra virus was recognized, there have been about 100 infections in horses, and seven human infections with four fatalities. The initial two patients had an acute influenza-like illness with fever and respiratory symptoms. The third patient had a mild meningoencephalitis after nursing two ill horses that subsequently died. After apparent full recovery, the farmer developed seizures, coma and died. Both the patient and the horses’ tissues were seropositive for Hendra. MRI brain imaging showed focal high signal cortical lesions on T2 weighted sequences while the EEG showed persistent periodic epileptiform discharges

HUMANMETAPNEUMOVIRUS.

Human metapneumovirus (hMPV) is a paramyxovirus that was discovered in 2001 but has been responsible for respiratory tract infections for at least 60 years with a worldwide distribution.

HMPV is classified as a member of the family Pneumoviridae, which comprises large enveloped negative-sense RNA viruses. This taxon was formerly a subfamily within the Paramyxoviridae family but was reclassified in 2016 as a separate family with two genera, Metapneumovirus (which includes hMPV) and Orthopneumovirus (which includes respiratory syncytial virus).

TRANSMISSION — It is likely that transmission occurs by direct or close contact with contaminated secretions, which may involve large particle aerosols, droplets, or fomites, but not small particle aerosols. Physical separation at distances ≥6 feet therefore interrupts aerosol transmission. Nosocomial infections have been reported in hospitalized children, including in a pediatric hematology-oncology ward, and in hospitalized adults. Transmission to family members appears to be very efficient when an index case becomes ill, with an estimated five-day interval between the onset of symptoms in an index patient and the onset of symptoms in contact.

HMPV can cause upper and lower respiratory tract infection in patients of all age groups, but symptomatic disease most often occurs in young children or older adults. There is a seasonal predominance in spring and winter.

RESPIRATORY SYNCYTIAL VIRUS.

RSV is a single-stranded, negative-sense ribonucleic acid (RNA) virus and a member of the Paramyxoviridae family. Two subtypes, A and B, are simultaneously present in most outbreaks, with A subtypes typically causing more severe disease. Several distinct genotypes within these subtypes predominate within a community; the dominant strains shift yearly, perhaps accounting for frequent reinfections

After replicating in the nasopharynx, RSV infects the small bronchiolar epithelium, sparing the basal cells, then extends to the type 1 and 2 alveolar pneumocytes in the lung, presumably by cell-to-cell spread or aspiration of secretions; lower respiratory tract infection occurs one to three days later. Pathologic findings of RSV include necrosis of epithelial cells, occasional proliferation of the bronchiolar epithelium, infiltration of monocytes and T cells centered on bronchial and pulmonary arterioles, and infiltration of neutrophils between the vascular structures and small airways. This leads to airway obstruction, air trapping, and increased airway resistance, and also is associated with a finding of neutrophilia in bronchoalveolar lavage.

RSV is highly restricted to the respiratory epithelium and is shed apically into the lumen of the airways. In very rare cases, RSV may be recovered from extrapulmonary tissues, such as liver, cerebrospinal fluid, or pericardial fluid. RSV has never been isolated from blood.

People who are susceptible tor RSV are babies below the age of 6 months, young children in day care, adults older than 60 years, children with Down’s syndrome, immunosuppressed patients i.e. organ transplant recipients, patients on chemotherapy or those who have hematological malignancy or myeloproliferative disorders and people with COPD among others such as adults in contact with young children with RSV. this virus has been implicated in apnoea in infants and the sudden infant death syndrome. Inappropriate antidiuretic hormone secretion may be associated with RSV infection.

INFLUENZA. A, B and C. RNA viruses.

ANTIGENIC PROPERTIES —  Among influenza A viruses that infect humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described. Influenza B viruses have a lesser propensity for antigenic changes, and only antigenic drifts in the hemagglutinin have been described. Influenza C has been reported to cause acute respiratory illnesses in children and, more rarely, in adults. Antigenic shifts recently in N antigen caused a changing epidemiology of influenza acquired from birds.

ANTIGENIC SHIFTS: Pandemics of influenza.

Influenza A was H1N1 initially. Pandemics occurred in 1917-18-19 in which a shift to H2N2 caused a severe global occurrence of influenza. This virus was called the swine or Spanish flu and this epidemic was associated with encephalitis lethargica which is no longer seen clinically. The extremely severe and extensive pandemic of 1918 and 1919 resulted in 50 to 100 million deaths worldwide and was exceptional in the high death rates that were seen among healthy adults aged 15 to 34 years.

Other epidemics occurred in 1957 with a shift to H3N1, 1969 a shift back to H1N1. Since 1977 avian viruses A/H1N1 and A/H3N2 subtypes along with influenza B viruses have frequently circulated at the same time . The emergence of a novel H1N1 human-swine-avian reassortant virus in March 2009 in North America resulted in a pandemic, and the pandemic H1N1 virus has continued to circulate since then.

H3N2 variant influenza — Since 2011, the United States Centers for Disease Control and Prevention (CDC) has reported over 420 cases of H3N2 variant (H3N2v) influenza A caused by reassortment of swine-origin H3N2 influenza A viruses and 2009 pandemic H1N1 influenza A viruses, most of which have occurred since July 2012. The H3N2v influenza virus contains the M gene from 2009 pandemic H1N1 influenza A virus, which may confer increased transmissibility to and among humans.

Avian H7N9 influenza — In the spring of 2013, human cases of novel avian influenza A H7N9 infection were detected in China. Since then, annual epidemics have occurred during influenza season. This is associated with herding and close association to swine and birds such as chicken or geese.

ANTIGENIC DRIFTS — Between the years of antigenic shifts, antigenic drifts have occurred almost annually and have resulted in outbreaks of variable extent and severity. Outbreaks due to antigenic

 

drifts are usually less extensive and severe than the epidemics or pandemics associated with antigenic shifts. Antigenic drifts are believed to result from point mutations in the RNA gene segments that code for the hemagglutinin or the neuraminidase; they are thought to occur sequentially as the virus spreads through a susceptible population. Changes in the hemagglutinin that result in antigenic shifts are of such great magnitude that they cannot be accounted for by point mutations alone.

TREATMENT. Should be started within 48 hours of onset.

Drugs recommended for initial use are neuroaminidase inhibitors oseltamivir or in case of oseltamir resistant influenza, zanamivir and for severely ill patients intravenous peramivir or osaltamir through a nasogastric tube. Inhaled zanamivir may be used in mild cases.

The adamantanes, amantadine and rimantadine, are active only against influenza A viruses, but high rates of resistance have developed among influenza A viruses, and these drugs are infrequently indicated.

Dosing — The usual dosing of oseltamivir for the treatment of influenza is 75 mg orally twice daily and of zanamivir is 10 mg (two inhalations) twice daily (table 2). The recommended dose of peramivir is 600 mg IV as a single dose. Dosing of oseltamivir and peramivir must be modified for renal insufficiency.

Doubling the dose of oseltamivir to 150 mg orally twice daily has been suggested for some severely ill patients with H5N1 avian influenza and was also suggested for certain severely ill patients (eg, immunocompromised hosts) during the 2009 to 2010 H1N1 influenza pandemic. However, there is no evidence that doubling the dose of either oseltamivir or IV zanamivir (an investigational agent) is more effective than the usual dose in hospitalized patients with or without severe illness.

VIRUSES CAUSING WHEEZING AND ASTHMA.

Virus infections may be associated with or be the cause of wheezing and asthma like symptoms in adults and children. Even though asthmatic patients are not more prone to viral infections but they do get more prolonged infections with viruses.

Respiratory viruses, such as influenza and respiratory syncytial virus (RSV), cause cytopathic damage to airway epithelium, promote inflammatory cytokine and chemokine production, and increase the exposure of allergens, microbes, and irritants to antigen-presenting cells. Viral infections may also induce the release of epithelial mediators such as thymic stromal lymphopoietin (TSLP), interleukin (IL) 25, and IL-33. In turn, production of IL-25, IL-33, and TSLP in epithelial cells may propagate eosinophilia and stimulate T helper cell type 2 (Th2) responses, increasing release of IL-4, IL-5, and IL-13, allergic cytokines that are known to promote asthma.

Viruses often involved are:

  • Respiratory syncytial virus — RSV is a frequent cause of wheezing and bronchiolitis in infants and young children. RSV is a single-stranded enveloped RNA virus separated into two antigenic subgroups, A and B.
  • Rhinovirus — RV refers to a genetically diverse species of nonenveloped, positive-stranded RNA viruses that are grouped into RV-A, RV-B, and RV-C serotypes . RV, in contrast to RSV and other respiratory viruses, has few cytopathic effects on airway epithelium or other tissues but does induce a significant airway inflammatory immune response. Specifically, RV propagates the release of cytokines and chemokines (IL-1, IL-6, IL-8, IL-11, IL-12, IL-18, TNF, IL-33 and CXCL8, CXCL10, CCL3, CCL5) and recruits eosinophils, monocytes, and T cells to the airway. Several studies have also indicated that patients with asthma may secrete reduced levels of type I (IFN-alpha and IFN-beta) and type III (IFN-gamma) interferons during RV infection, resulting in an impaired antiviral response.
  • Human metapneumovirus — Human metapneumovirus (hMPV) is an RNA paramyxovirus with phylogenetic similarity to RSV. hMPV is a frequent cause of acute respiratory illness in children adults, accounting for approximately 5 percent of acute respiratory illnesses in hospitalized children. Retrospective data suggest that young children hospitalized with hMPV lower respiratory tract infections have an increased risk of developing asthma at age five years. This increased risk of asthma development was similar to RSV-associated risk in this small study.
  • Influenza — Children and adults with asthma are at an increased risk of hospitalizations and respiratory morbidity during acute influenza respiratory infections.

CORONA VIRUSES.

  1. Middle East Respiratory Syndrome (MERS).
  2. Severe Acute Respiratory Syndrome  (SARS),

VIROLOGY — Coronaviruses are classified as a family within the Nidovirales order, viruses that replicate using a nested set of mRNAs (“nido-” for “nest”). The coronavirus subfamily is further classified into four genera: alpha, beta, gamma, and delta coronaviruses.

The human coronaviruses (HCoVs) are in two of these genera:

  • alpha coronaviruses (HCoV-229E and HCoV-NL63) 
  • beta coronaviruses (HCoV-HKU1, HCoV-OC43)
    • Middle East respiratory syndrome coronavirus [MERS-CoV], 
    • the severe acute respiratory syndrome coronavirus [SARS-CoV].

Both these diseases are zoonosis.  Dromedary camels appear to be the primary animal host for MERS-CoV. The presence of case clusters strongly suggests that human-to-human transmission also occurs. Bats may serve as a reservoir.

Severe Acute Respiratory Syndrome  (SARS),

Cases of SARS were first noted in Guangdong Province, China, in November 2002. Between November 16, 2002, and February 28, 2003, 792 cases were reported in this province. Healthcare workers and their contacts appeared to be disproportionately affected by the outbreak. The 2002 to 2003 outbreak resulted in 8096 cases with 774 deaths and a case-fatality rate of 9.6 percent. Older age was associated with a higher mortality rate, being as high as 43 percent in patients age 60 or older in Hong Kong compared with 13 percent in younger patients. Palm civets, catlike creatures are eaten as a delicacy in China, have been implicated as have horseshoe bats and other bat species as well. Human to human transmission is by droplet transmission and fomites.

VIRAL INFECTIONS FOLLOWING LUNG TRANSPLANTS. 

A wide range of viral infections complicate lung transplantation. They include the community respiratory viruses (eg, influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, human metapneumovirus, rhinovirus), and viruses that affect other organs like herpes simplex virus, and varicella-zoster virus, and cytomegalovirus.  Adenovirus can be either a primary respiratory pathogen or the lungs can be involved as part of a disseminated infection.

Varicella pneumonia typically develops insidiously within one to six days after the rash has appeared with symptoms of progressive tachypnea, dyspnea, and dry cough; hemoptysis has occasionally been reported. Patients demonstrate impaired gas exchange with progressive hypoxemia. Chest radiographs typically reveal diffuse bilateral infiltrates; in the early stages a nodular component may be present, which can subsequently become calcified. Prompt administration of intravenous acyclovir has been associated with clinical improvement and resolution of pneumonia in selected series. The administration of steroids is controversial.

Cytomegalovirus (CMV), a member of the betaherpesvirus group, remains an important cause of morbidity and mortality in lung transplant recipients. It is the second most common infection among lung transplant recipients, after bacterial pneumonia .

CMV-induced immunosuppression may lead to infection with other opportunistic organisms. In addition, CMV infection and disease have been associated with acute and chronic rejection (chronic lung allograft dysfunction) in some but not all studies. Primary cytomegalovirus (CMV) infection is acquired through close physical contact involving direct inoculation with infected cells or body fluids. Following primary infection, CMV infection persists for life in apparently healthy people.

CMV infection following transplantation can be acquired in one of several ways:

  • By transmission with the donor organ from a CMV-seropositive donor
  • By transfusion of blood products from a CMV-seropositive blood donor
  • By reactivation of latent infection in a seropositive recipient
  • By close physical contact with a CMV-infected individual

CMV syndrome — Patients with a CMV syndrome have evidence of clinical disease but without end-organ involvement. Typical symptoms include fever, malaise, weakness, myalgias, and arthralgias. Many patients have leukopenia and thrombocytopenia that occur in the setting of viremia.

Treatment of active disease:

Treatment of active CMV disease generally involves both reduction of immunosuppression and antiviral therapy, typically with oral valganciclovir or intravenous (IV) ganciclovir. Acyclovir, valacyclovir, famciclovir, and oral ganciclovir should not be used for the treatment of CMV infection or disease. It is important to give appropriate doses of ganciclovir and valganciclovir, because inadequate dosing may reduce efficacy and lead to resistance, whereas supratherapeutic dosing may lead to toxicity.

ADENOVIRAL DISEASE.

Adenoviruses are a family of viruses that are an important cause of febrile illnesses in young children. They are most frequently associated with upper respiratory tract syndromes, such as pharyngitis or coryza, but can also cause pneumonia. Less commonly, adenoviruses cause gastrointestinal, ophthalmologic, genitourinary, and neurologic diseases. Most adenoviral diseases are self-limiting, although fatal infections can occur in immunocompromised hosts and occasionally in healthy children and adults. The adenoviruses are double stranded DNA viruses with 60 genomes divided into 7 groups.

The adenoviruses cause corrhyza, pharyngitis, otitis media in young children, adenoviruses can also cause a pertussis-like syndrome, bronchiolitis, or an exanthem.

Pneumonia. A number of adenovirus serotypes (1, 2, 3, 4, 5, 7, 14, 21, and 35) have been reported to cause pneumonia. Species B serotypes 3, 7, 14, and 21 have been associated with severe and complicated pneumonia. Adenovirus serotype 7 was recognized as an important cause of severe respiratory illness in a community outbreak in Oregon in 2014.

Acute respiratory disease. In young adults, a syndrome of acute respiratory disease can occur, especially under the special conditions of fatigue and crowding present in military training camps. Symptoms include fever, pharyngitis, cough, hoarseness, and conjunctivitis. Pneumonitis can also occur, resulting in rare deaths.

Adenoviruses can cause a wide range of diseases like conjunctivitis, hepatitis, diarrhoea, myocarditis, meningitis etc. Prolonged viral shedding can occur.

 

 

 

 

 

Published by

shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s