Viral Respiratory Infections — Questions

Why A

Cytomegalovirus is the leading cause of heterophile-negative infectious mononucleosis. It produces fever, malaise, a biochemical hepatitis and atypical lymphocytes, but usually without the prominent pharyngitis and lymphadenopathy of Epstein–Barr virus, and it tends to occur about a decade later in life. It is confirmed by CMV IgM with low-avidity IgG, or by detecting CMV DNA.

Epstein–Barr virus causes the heterophile-positive form. Hepatitis A, adenovirus and acute HIV can share some features but are not the classic cause of this syndrome.

a. Likely viral cause. In an infant with profound immunosuppression and diffuse interstitial infiltrates, the most likely viral cause is cytomegalovirus (CMV) pneumonitis.

b. Differential diagnoses. The key differentials are Pneumocystis jirovecii pneumonia (PJP) and miliary tuberculosis, both common in advanced paediatric HIV, together with lymphoid interstitial pneumonitis and bacterial pneumonia.

c. Management. Confirm CMV with a quantitative PCR (blood, and bronchoalveolar lavage where feasible) and treat with ganciclovir. Because PJP cannot be excluded and is rapidly fatal, start empirical high-dose co-trimoxazole (with corticosteroid if hypoxaemic), investigate and treat for tuberculosis as indicated, and provide oxygen and supportive care. Underpinning all of it, start or optimise antiretroviral therapy to restore immune function.

a. Investigating nosocomial spread. Confirm each case by multiplex nucleic acid amplification (PCR) on nasopharyngeal aspirates, and construct a case definition and line list with dates of admission and symptom onset. Nosocomial acquisition is suggested when symptoms begin after an incubation period spent on the unit and when cases cluster in time and place; epidemiological linkage is strengthened by molecular typing or sequencing showing a shared strain. Screen symptomatic contacts and staff, since adults and older children with mild colds are a common source.

b. Prevention. Cohort infected infants and their staff, and apply strict hand hygiene with gowns, gloves and eye protection, since RSV spreads by contact and large droplets. Restrict and screen visitors and staff with respiratory symptoms, defer elective admissions of susceptible infants during the outbreak, and educate staff. Offer passive prophylaxis (nirsevimab, or palivizumab) to eligible high-risk infants, and maintain surveillance for new cases until the outbreak resolves.

• Identity. The fringe of surface spikes (haemagglutinin and neuraminidase) identifies an orthomyxovirus, that is influenza (family Orthomyxoviridae), a segmented negative-sense RNA virus.
• Antiviral therapy. Treat with a neuraminidase inhibitor (oseltamivir, or intravenous zanamivir or peramivir in severe disease) or the cap-dependent endonuclease inhibitor baloxavir.
• Timing. Antivirals work best started early, ideally within 48 hours, though a mortality benefit is seen even later in hospitalised patients.
• Supportive care. Manage hypoxaemia with oxygen and escalating respiratory support, up to mechanical ventilation or extracorporeal membrane oxygenation.
• Complications. Treat bacterial superinfection, commonly pneumococcal, with appropriate antibacterial agents.

• Antigenic drift. The gradual accumulation of point mutations in the surface glycoproteins haemagglutinin (HA) and neuraminidase (NA), so that antibody from prior infection or vaccine recognises the virus less well.
• Consequence of drift. It drives the annual seasonal epidemics and the need to update the vaccine each year.
• Antigenic shift. A sudden, major change through reassortment of the segmented genome when two influenza A viruses co-infect one cell, producing a novel haemagglutinin (and sometimes neuraminidase) subtype.
• Consequence of shift. Because the population has little immunity to the new subtype, shift carries pandemic potential, and it is confined to influenza A.

• Target cells. RSV infects the ciliated epithelium of the small airways, the bronchioles.
• Epithelial injury. It causes epithelial necrosis, submucosal oedema and increased mucus, forming dense plugs of debris and fibrin.
• Airflow obstruction. These plugs obstruct the small airways, and the resulting ventilation-perfusion (V/Q) mismatch produces hypoxaemia.
• Immune contribution. Host responses add to the injury, with a role for immunoglobulin E, an altered T-cell cytokine profile and leukotrienes; polymorphisms in innate-immune genes influence severity.
• Immunity and reinfection. Infection stays largely confined to the mucosa and provokes only transient immunity, so reinfection recurs throughout life.

Two respiratory members of the Paramyxoviridae are:

• Parainfluenza viruses (types 1 to 4), causes of croup, colds and lower respiratory tract disease.
• Measles virus (or mumps virus).

Note that respiratory syncytial virus and human metapneumovirus are no longer paramyxoviruses, having been moved to the family Pneumoviridae, so they do not count.

• Classification. Human metapneumovirus is a pneumovirus (family Pneumoviridae), closely related to respiratory syncytial virus (RSV).
• Disease in children. It is a major cause of bronchiolitis and pneumonia in young children, and of colds higher in the tract.
• Resemblance to RSV. Its illness is clinically indistinguishable from RSV, though generally somewhat milder.
• Other groups. It reinfects through life and causes significant lower-tract disease in the elderly and the immunocompromised.
• Diagnosis and management. Diagnosis is by multiplex nucleic acid amplification (PCR); there is no vaccine, and management is supportive.

A complete answer covers vaccination and other preventive measures, then the antiviral and supportive treatment of established infection.

Prevention: vaccination

Annual vaccination is the mainstay. Because the virus undergoes antigenic drift, the strains are reviewed and the vaccine reformulated each year. It is directed at priority groups: the elderly, pregnant women, people with chronic medical conditions or HIV, and healthcare workers. Most vaccines are inactivated and produced in eggs or cell culture, with a live attenuated intranasal option for children.

Prevention: chemoprophylaxis and infection control

Antiviral chemoprophylaxis with a neuraminidase inhibitor or baloxavir can protect high-risk contacts after exposure. Droplet and contact precautions, hand hygiene and cohorting limit spread, and preventing nosocomial influenza on paediatric and transplant units is a particular priority.

Treatment: antivirals

The neuraminidase inhibitors (oseltamivir, and intravenous zanamivir or peramivir in severe disease) and the cap-dependent endonuclease inhibitor baloxavir are active against influenza A and B. They work best started within 48 hours, but an observed mortality benefit justifies later treatment in hospitalised patients. The older M2 inhibitors are obsolete because circulating strains are resistant.

Treatment: supportive care and complications

Severe influenza is managed with oxygen and escalating respiratory support up to ventilation or extracorporeal membrane oxygenation. Bacterial superinfection, most often pneumococcal, is common and is treated with appropriate antibacterial agents; early corticosteroids are generally avoided.

A complete answer defines the syndrome, names the viral causes, explains the pathogenesis, and weighs the place of modern molecular diagnostics against a largely clinical diagnosis.

Clinical syndrome and epidemiology

Bronchiolitis is a syndrome of infants whose central defect is obstruction to expiratory airflow. Coryza is followed after a day or two by wheeze, tachypnoea, hyperinflation and, in the severe, hypoxaemia and apnoea. It is a disease of infancy, peaking at two to six months, with the highest risk in those born prematurely or with congenital heart disease, chronic lung disease or immunodeficiency.

Viral causes

Respiratory syncytial virus (RSV) causes the majority, and almost all cases in its epidemic season. Human metapneumovirus produces an indistinguishable illness, and rhinovirus, parainfluenza, influenza and adenovirus account for the rest.

Pathogenesis

Infection necroses the bronchiolar epithelium, with oedema and mucus forming plugs that obstruct the small airways; ventilation-perfusion mismatch produces the hypoxaemia. Host immune responses and innate-gene polymorphisms modulate severity.

The role of modern viral diagnostics

The diagnosis is essentially clinical, and identifying the virus rarely changes supportive management. The value of multiplex nucleic acid amplification (PCR), which is highly sensitive and detects a wide panel of agents, lies mainly in cohorting and infection control on the ward, in surveillance, and in the immunocompromised. A nasopharyngeal aspirate outperforms a swab, and rapid antigen tests are quicker but less sensitive. A chest radiograph is used chiefly to exclude a bacterial pneumonia, not to diagnose bronchiolitis.

Management and prevention

Care is supportive, centred on correcting hypoxaemia, with attention to fluids and electrolytes; bronchodilators, corticosteroids and antibiotics do not help routine disease. Prevention now rests on nirsevimab (a long-acting monoclonal antibody) or maternal RSV vaccination, alongside strict hand hygiene and barrier precautions to limit nosocomial spread.

Drooling and severe distress without the barking cough suggest epiglottitis, a bacterial cellulitis of the epiglottis (classically Haemophilus influenzae type b) that is an airway emergency.

The barking cough, preceding coryza, fluctuating course and steeple sign are all features of viral croup.

A single dose of corticosteroid such as dexamethasone is the mainstay, shortening symptoms and reducing admission and intubation; nebulised adrenaline is added for rapid relief in severe cases.

Hypertonic saline is used in bronchiolitis rather than croup, and antibiotics, ribavirin and oseltamivir have no role in this viral illness.

Otitis media complicates a cold when mucosal inflammation obstructs the eustachian tube, impairing middle-ear drainage and ventilation; cold viruses can be recovered from a substantial proportion of middle-ear effusions in children.

The virus does not invade the cochlea or reach the ear by the bloodstream, and the process is neither autoimmune nor a reactivation.

Hantavirus cardiopulmonary syndrome is an immune-mediated capillary leak from widespread infection of vascular endothelium, most intense in the lung; the absence of coryza and the early interstitial oedema with thrombocytopenia help separate it from other causes of acute respiratory distress.

It is not primarily cytolytic or bacterial, and it is not an airway-obstruction process.

A mononucleosis-like illness with pharyngitis can be the presenting feature of primary HIV infection (the acute retroviral syndrome), often with fever, lymphadenopathy, rash and mucosal ulcers.

Recognising it matters because heterophile and early antibody tests may be negative, so an HIV RNA or antigen test is needed; the other agents do not produce this syndrome.

Influenza A and B are the typical causes of acute tracheobronchitis, and herpes simplex virus can cause a necrotising tracheobronchitis in some hosts.

Rhinovirus, parainfluenza and adenovirus contribute less often, and cytomegalovirus is a lower-tract pathogen of the immunocompromised rather than a cause of ordinary bronchitis.

Streptococcus pneumoniae is the commonest organism in post-influenza bacterial pneumonia, classically after a biphasic course: recovery from the viral illness, then a return of fever with consolidation.

Staphylococcus aureus (including methicillin-resistant strains) and Haemophilus influenzae are also important but less common; the others are not typical superinfecting agents here.

RSV in stem-cell transplant recipients frequently progresses from upper-tract symptoms to a fatal viral pneumonia, with a mortality of 50% or more, particularly before engraftment.

Early ribavirin with immunoglobulin is sometimes used, so it is not wholly untreatable, and palivizumab is an infant, not adult, prophylaxis.

Baloxavir inhibits the influenza cap-dependent endonuclease, the enzyme that snatches host messenger RNA caps to prime viral transcription.

The neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) act on a different enzyme, the M2 inhibitors are obsolete through resistance, and thymidine kinase is a herpesvirus target.

Parainfluenza type 3 behaves more like respiratory syncytial virus, causing bronchiolitis and pneumonia in infants, and is second only to it in that role; types 1 and 2 are the classic croup viruses.

Pharyngoconjunctival fever is an adenovirus syndrome and herpangina is caused by coxsackievirus A.

Pharyngoconjunctival fever is an adenovirus syndrome (types 3 and 7), combining fever, pharyngitis and bilateral conjunctivitis.

Coxsackievirus A causes herpangina, while the other agents give colds, influenzal illness or croup rather than this triad.

Nirsevimab is a long-acting monoclonal antibody against the RSV fusion (F) protein, giving passive protection across a season in a single dose and largely replacing monthly palivizumab.

The complementary strategy is active maternal vaccination in pregnancy; there is no live or inactivated infant RSV vaccine in routine use.

The symptoms of a cold are driven by the inflammatory response, not by destruction of tissue. Only a few ciliated nasal cells are infected and the lining stays largely intact, yet kinins and cytokines such as interleukin-8 produce the rhinorrhoea and sore throat.

Histamine plays little part, which is why non-sedating antihistamines do not help; there is no widespread cytolysis, early bacterial invasion or autonomic injury.

Pneumonia is the commonest serious complication of measles and a leading cause of measles deaths, sometimes as a direct viral pneumonitis and often through bacterial superinfection.

In the profoundly immunosuppressed, measles can cause a usually fatal giant-cell pneumonia in which the typical rash may be absent.

RSV and human metapneumovirus were moved into the family Pneumoviridae, out of the paramyxoviruses; RSV is an orthopneumovirus and human metapneumovirus a metapneumovirus.

The parainfluenza viruses, measles and mumps remain in the Paramyxoviridae, while influenza is an orthomyxovirus.

Herpangina is caused by coxsackievirus A, producing small vesicles on the soft palate that ulcerate.

Herpes simplex virus gives an anterior gingivostomatitis rather than the posterior palatal lesions of herpangina, and the other agents cause different pharyngitides.

Bronchiolitis obstructs expiratory airflow: infection necroses the bronchiolar epithelium and fills the small airways with oedema, mucus and cellular debris, and ventilation-perfusion mismatch produces the hypoxaemia.

Subglottic narrowing is croup, and the process is neither bacterial consolidation nor a primary surfactant or vascular problem.

Cytomegalovirus is the classic cause of severe pneumonitis after transplantation, with the greatest risk one to three months post-transplant; neutropenia, deranged liver enzymes and mucosal ulceration hint at the disseminated infection behind it.

The community respiratory viruses, adenovirus and herpes simplex virus also cause pneumonia in this group but less commonly.

The stridor arises from subglottic oedema at the level of the cricoid cartilage, the least distensible part of the airway because the cartilage forms a complete ring; swelling there narrows the airway and vibrates the airflow.

The obstruction is of the upper airway, not bronchospasm or alveolar collapse, and the vocal cords and laryngeal nerves are intact.

Varicella pneumonia is more severe in adults, particularly smokers and pregnant women; infiltrates appear in 10% to 20% of adults with chickenpox, and severity tracks the diffuseness of the rash.

It is uncommon in healthy children, and prior immunity, whether natural or vaccine-induced, protects.

Enterovirus D68 has emerged as a cause of severe respiratory illness in children, with outbreaks marked by wheeze and, in some children, acute flaccid myelitis.

The other enteroviruses listed cause hand-foot-and-mouth disease, aseptic meningitis, poliomyelitis or myocarditis rather than this respiratory syndrome.

SARS-CoV, MERS-CoV and SARS-CoV-2 are all betacoronaviruses, and each can cause severe pneumonia and acute respiratory distress syndrome; the four endemic common-cold coronaviruses cause only mild upper-tract illness.

Orthomyxoviruses (influenza), pneumoviruses (RSV and human metapneumovirus) and adenoviruses are separate families.

Human metapneumovirus causes a bronchiolitis and pneumonia clinically indistinguishable from respiratory syncytial virus (RSV), and like RSV it is a pneumovirus.

It affects immunocompetent young children, chiefly the lower tract, and there is no licensed vaccine.

Respiratory syncytial virus causes the majority of bronchiolitis, and during its epidemic season almost all of it, being recovered from about three-quarters of admitted infants.

Human metapneumovirus gives an indistinguishable but generally milder illness, and parainfluenza, rhinovirus and adenovirus account for a minority.

Parainfluenza viruses cause about three-quarters of croup, type 1 most often, and the seasonal peaks of croup follow parainfluenza activity.

Respiratory syncytial virus, influenza and adenovirus cause a minority of cases, and rhinovirus is only an occasional cause.

Rhinoviruses cause the majority of common colds, and with more than a hundred types they are met repeatedly through life; sensitive molecular testing detects them in an even larger share of cases.

Coronaviruses account for a smaller winter share, while respiratory syncytial virus, human metapneumovirus and parainfluenza viruses each cause fewer colds still.