Search

Home > Teaching > MBChB Resource Material > Respiratory infections

Respiratory infections

Infections of the respiratory tract are very common in both adults and children. Most are fairly mild and remain confined to the upper respiratory tract (URT). However, in infants and young children, URT infections may spread downwards and cause more severe, sometimes life threatening infections.

Upper vs lower respiratory tract infections

Clinical-anatomical definitions

Upper Respiratory Tract

1. Colds
Main feature is a watery to mucoid, sometimes purulent nasal discharge ("coryza"). Often preceded by a sore throat and may sometimes be accompanied by fever. May be followed by transient opportunist bacterial infection. (Rhinoviruses, Coronaviruses and others.)

2. Pharyngitis ("sore throat")
Generalised erythema of pharynx not localised to the tonsils. Some fever may be present. (Adenovirus)

3. Tonsilitis
Local infection of tonsils = red, swollen with exudate on the surface. (Adenovirus)

4. Sinusitis & Otitis Media
Inflammation of mucous membranes lining sinuses and middle ear. Impaired drainage of these spaces may lead to bacterial infection. (Bacterial infections are usually secondary to viral infection of the nose and pharynx.)

Lower Respiratory Tract

a) Laryngo-Tracheo Bronchitis (Croup)
An acute inflammation of larynx and trachea. Often preceded by coryzal symptoms, followed by fever, hoarseness, cough and signs of upper airway obstruction, namely stridor. This condition may be life threatening in young children. (para-influenza viruses, RSV, herpes simplex)

b) Acute Bronchitis
Inflammation of bronchi, accompanied by fever, cough, wheezing and "noisy chest". (RSV, Para-influenza viruses, Adenovirus)

c) Acute Bronchiolitis
Inflammation and narrowing of terminal bronchioles. Bronchiole diameter is larger during inspiration than during expiration and this leads to hyperinflation of air sacs distal to bronchiole. Complete plugging of bronchioles with air resorption leads to patchy collapse. These features can be seen on x-ray. The illness usually starts with a fever and coryzal symptoms, followed by respiratory distress and wheezing. The condition can be life-threatening in babies and small children. (Respiratory Syncitial virus, Para-influenza virus)

d) Pneumonia & Bronchopneumonia
Infection of the lung tissue itself. Symptoms include: fever, respiratory distress and cyanosis. Often not much clinical "consolidation". Again, can be life-threatening. (RSV, Adenovirus, Influenza)

What causes these infections?

By far the majority of respiratory tract infections are of viral origin. Despite this, almost all serious respiratory infections are treated with antibiotics and a "presumed viral" diagnosis is only made when the patient fails to respond. Part of the problem is that diagnostic facilities to confirm a viral aetiology are only available at specialised centres.

There are many viruses that infect the respiratory tract. An important concept is that any one particular clinical syndrome may be caused by a number of different viruses. Similarly, any one virus may cause a variety of different clinical syndromes.

Most respiratory viruses cause localised infections: replication and shedding of virus remains confined to the respiratory tract. Transmission is through inhallation of virus shed in respiratory droplets. Because infection is confined to the body surface, immune responses are poor and individuals may suffer repeated infections. Also infants are susceptible in the early months of life as there is minimal protection from maternal antibody.

The respiratory tract is also commonly a target in generalised viral infections: for example, pneumonia may complicate infection caused by measles, varicella and cytomegalovirus. In addition, shedding of virus from the respiratory tract is the major route of transmission for measles, mumps, rubella, parvovirus, varicella and many others.

The Viruses

Influenza
Para-influenza 1, 2, 3 and 4
Respiratory syncitial virus
Human metapneumovirus
Adenovirus
Cytomegalovirus (Immuno-compromised patients)
Rhinovirus
Coronaviruses

Para-influenza viruses 1, 2, 3 and 4

There are 4 antigenically distinct para-influenza viruses that infect humans.

Virology

Para-myxoviruses: pleomorphic, enveloped ssRNA viruses; approximately 150-200nm in diameter. There are two types of glycoprotein in the evnelope, namely the HN (haemagglutinin / neuraminidase) and the F (Fusion). They have an inner helical core that protects the ssRNA genome.
Haemagglutinin binds, agglutinates red blood cells
Neuraminidase enzyme that degrades sialic acid (detaches the virion from the cell surface)
Fusion causes membrane fusion, syncitium formation

Epidemiology

Causes respiratory tract infections in all age groups. Infection occurs throughout the year with peak in spring. First infections occur in early childhood and are more likely to be symptomatic. Immunity following infection is poor and re-infections are common, although often subclinical. Virus may be shed for up to three weeks post infection and also by patients with asymptomatic infections. This serves as an important reservoir to infect new susceptibles.
Spread:
Respiratory droplets, fomites (virus is delicate and does not survive long in the environment.)
Clinical Syndromes:
Acute laryngo-tracheo bronchitis (Croup)
Bronchiolitis, Pneumonia
Re-infections cause "common cold" symptoms.

Respiratory Syncitial Virus (RSV)

Virology

Pneumovirus (sub-genus of paramyxoviridae)
Enveloped, ssRNA viruses
Lacks the HN glycoprotein typical of the para-myxovirus group, but contains the fusion protein.
Gets its name from the fact that it causes large syncitia in cell culture

Epidemiology

The virus has a world wide distribution. It is the prime cause of bronchiolitis in young infants. There is no protection against RSV from maternal antibody and infants exposed in the first 6 months of life can develop life threatening disease. The virus is highly infectious and most children are exposed in their first year of life. Infection occurs in seasonal epidemics, mainly during the early winter months. Re-infections are common throughout life, but are of lesser severity, often sub-clinical.
Spread:
Respiratory droplets, fomites
NB A patient may shed virus for up to three weeks post infection.

Clinical syndromes

Bronchiolitis, Broncho-pneumonia infants < 6 months of age.
Laryngo Tracheo bronchitis infants, young children
Acute bronchitis adults, especially the elderly.
Common cold syndrome re-exposure in children and adults

Vaccine attempts

In the 1960s an attempt was made to produce a vaccine for RSV, using killed whole virus. Unfortunately, following exposure to live virus, vaccinated children developed more severe disease than the unvaccinated children. The killed virus vaccine appears to have sensitised these children and induced a hypersensitivity response. This drew attention to the possibility that much of the lung damage caused by RSV could be due to immune mechanisms. Because of the importance of RSV in childhood infections, intensive efforts to make a vaccine have continued, however, no vaccine is as yet in general use.

Human Metapneumovirus

Virology

Pneumovirus (sub-genus of paramyxoviridae)
Enveloped, ssRNA viruses
Lacks the HN glycoprotein typical of the para-myxovirus group, but contains the fusion protein

Epidemiology

Causes seasonal epidemics mainly in early Spring. Spread is via respiratory droplets, fomites

Clinical syndromes

(very similar to RSV)
Bronchiolitis, Broncho-pneumonia infants < 6 months of age.
Laryngo Tracheo bronchitis infants, young children
Acute bronchitis adults, especially the elderly.
Common cold syndrome re-exposure in children and adults

Adenovirus

Virology

Adenoviridae
Unenveloped icosahedral ds DNA viruses,
approximately 80 nm in diameter.
There are 41 human adenoviruses which are divided into 6 sub-genera A-F.

Classification of human adenoviruses and their associated clinical syndromes:

Sub group Viruses Target organ of disease
A 12, 18, 31 GIT
B 3, 7, 11, 21 Pharynx, lungs, conjunctiva, Urinary tract
C 1, 2, 5, 6 Pharynx
D 8, 9, 19 Eye (keratoconjunctivitis)
E 4 Upper respiratory tract, eye
F 40, 41 GIT

Epidemiology

Adenovirus infections are not strongly seasonal. Infections occur throughout the year. The virus is highly resistant to inactivation and viable virus may remain on environmental surfaces. Nosocomial transmission of adenovirusleading to outbreaks is common in paediatric ICUs. Transmission is through respiratory droplets, fomites and ingestion.

Clinical Features

Adenoviruses infect the mucous membranes of the eye, respiratory and gastro intestinal tract, and occasionally the urinary tract. Local lymph nodes are often involved (enlarged and tender). Most infections remain localised to the body surface. Most infections are asymptomatic and those that do manifest clinically are usually acute and self-limiting. Some subtypes may be harboured asymptomatically for years.

Syndromes

1. Asymptomatic Infection
Adenoviruses may be isolated from the respiratory tract and stools of healthy persons. Some subtypes cause persistent silent infection of the tonsils.
2. Acute pharyngitis with fever
Adenoviruses are a common cause of an acute sore throat.
3. Pharyngoconjunctivical fever
Acute conjunctivitis (pink eye) together with a sore throat and fever.
4. Acute follicular conjunctivitis
"Pink eye" Highly infectious, non purrulent conjunctivitis
5. Epidemic kerato-conjunctivitis (shipyard eye)
Mild trauma to the eye may facilitate a damaging adenoviral infection of the cornea (spread by multi-shared towels).
6. Pneumonia (and pneumonitis in children)
Severe destructive pneumonia mainly seen in young babies following measles. Outbreaks commonly occur in respiratory intensive care units. Babies on ventilators with artificial airways are particularly at risk.
7. Epidemic acute respiratory disease
An epidemic form of acute lower respiratory tract nfection,characteristically seen in military camps. Has been prevented by enteric capsulation of a live vaccine strain (subtypes 4 and 7) which bypasses the respiratory tract and sets up a silent infection in the gut, giving protection against acute respiratory infection.
8. Gastro-enteritis
Diarrhoea may occur as part of a generalised adenoviral infection in young children. In addition, subtypes 40 and 41 cause acute gastroenteritis in children, which may lead to dehydration and death.
9. Mesenteric Adenitis
Children may present with abdominal pain due to enlarged tender mesenteric lymph nodes. Occasionally an enlarged node may invaginate the bowel wall and be gripped by peristaltic waves leading to intussusception of the bowel.
10. Immunocompromised host
In transplant, AIDS or other immunocompromised patients, adenoviruses may cause haemorrhagic cystitis.

Rhinoviruses

Virology

Picornaviruses:
small, un-enveloped ssRNA viruses
100 antigenically distinct serotypes

Clinical Syndromes

Most famous for causing common cold syndrome in children and adults, but may cause lower respiratory tract infections in young infants (first encounter).

Epidemiology

Infections throughout the year, but seasonal peak in Spring. Spread by respiratory droplets and fomites.

Common cold syndrome:

Aetiological agents:
Rhinoviruses: approximately 100 serotypes account for approximately 50% of colds
Coronaviruses 2 serotypes account for 2-10% colds
Other enteroviruses
RSV
Para-influenza etc
Clinical features
Incubation period is short: 1 to 3 days followed by headache, sore throat, fullness in the nose. Then there is a profuse watery discharge from the nose which gradually thickens and becomes muco-purulent and decreases in volume. The infection resolves in about a week.
Treatment
No specific treatment, but numerous symptomatic treatments are available
Complications
A cold may temporarily upset the mucosal cilia and predisposes to secondary invaders especially bacterial infections, e.g. sinusitis (pneumococcus, haemophilus, etc) and bronchitis and possibly pneumonia. These may require antibiotic treatment.
Epidemiology
An infected person is infectious in the first two days of coryza. Colds are readily acquired from breathing room air from a room crowded with infected people or handling fomites, tissues contaminated with respiratory secretions. Wet cold weather per sé does not cause colds, but may predispose to infection from other persons. Colds are ubiquitous around the world except in very isolated communities.
Prevention
The enormous diversity of cold-causing viruses essentially rules out a vaccine. Vitamin C and bacterial vaccines are unproven.

Severe acute respiratory syndrome

Severe acute respiratory syndrome (SARS) is an acute viral lower respiratory tract infection with a high mortality. It is a new disease of humans, caused by a novel coronavirus. The first cases occurred in November 2002 in Guangdong province (China). As a result of poor infection control measures the infection spread to other parts of the world. It is a zoonotic disease caused by a novel coronavirus isolated from Civet cats in a Chinese market. However, the reservoir in nature is thought to be bats, because genetically similar coronaviruses had been isolated from various of horseshoe bat species.
Clinical Features:
Incubation period is 2-10 days. The illness starts with a prodrome of fever, myalgia, malaise, mild respiratory symptoms and diarrhoea. This is followed by a lower respiratory phase: the patient develops a dry, non productive cough, dyspnoea and hypoxaemia. 20-25% require ICU admission. Mortality rates vary according to age, from <1% in patients less than24 years to >50% in patients greater than 65 years.
Transmission:
Respiratory droplets, fomites and ? stool.
Effective infection control measures include: hand hygiene, contact precautions, eye protection, environmental cleaning and airbourne precautions (N95 masks, negative pressure room).

Influenza

Introduction

Influenza or "flu" is a respiratory tract infection caused by influenza viruses. Contrary to common belief flu is not is a trivial illness. According to WHO statistics, influenza infection results in 250,000-500,000 deaths annually in industrialised countries alone. In addition, the influenza virus is able to mutate and cause pandemic with significant morbidity and mortality across the world. The most infamous 1918 "Spanish flu" pandemic was estimated to cause 50 million deaths worldwide.

Virology

  • Family: Orthomyxovirus
  • Genera: influenzavirus A,B,C
  • Single strand RNA virus with segmented genome
  • enveloped with two surface glycoprotein:
    • H - Haemagglutinin - responsible for viral attachment
    • N - Neuraminidase - responsible for viral exit from infected cell
  • Influenza A is the type that is responsible for pandemics. It can be further subtyped according to its H and N group. There are 16 H types and 9 N types of influenza A that exist in nature, mainly found in the natural reservoir wild aquatic birds. Only H1, 2 and 3 and N1 and 2 subtypes circulate widely in human.
  • Both Haemagglutinin and Neuraminidase are important antigens that confer subtype specific immunity and are therefore used in the vaccine formulations

Clinical presentation

Influenza virus is transmitted by respiratory droplets and has an incubation time of 2-3 days. Flu is a primarily respiratory tract infection but systemic symptoms are common.

Difference between flu and common cold:

Illness

Influenza

Common cold

Clinical spectrum

Often systemic

Mostly local

Speed of onset

Abrupt

Gradual

Fever

Usually high

Usually low-grade

Presentation

Chills, myalgia, malaise, sore throat

Sneezing, sore throat, nasal congestion

Fatigue

Marked

Mild

Course

Unwell for 1-2 weeks, chest problems common, severe malaise

Rapid recovery

Complications

More common and often severe - pneumonia

Uncommon

Occurrence

Seasonal

All year round

Reye's syndrome is a rare but severe complication seen in children with influenza (and other viral infections). This fatal condition causes encephalitis and liver disease in children treated with Aspirin. Therefore children with influenza infection should not be given aspirin.

Risk factors

Risk factors for severe influenza disease include pregnancy, chronic pulmonary, cardiac or renal disease, diabetes mellitus, individuals over 65 years and children less than 5 years.

Epidemiology

In temperate regions, influenza causes seasonal epidemics in the winter months (between April and September for the southern hemisphere). In tropical climates, influenza tends to occur all year round. Every few decades, a new influenza strain emerges that sweeps across the world infecting millions of people. This is called a pandemic.

Individuals can suffer repeated attacks of influenza because the antigenic structure of the virus is highly variable. Two viral evolutionary mechanisms account for antigenic change, namely drift (both influenza A and B) and shift (only for influenza A).

Drift (minor antigenic change)
The envelope glycoproteins (HA and NA) of influenza virus change their antigenic character gradually over time. This is due to random point mutations introduced during replication of the viral genome. The viral RNA polymerase has no proof-reading function and is therefore highly error prone. Herd immunity of the global population drives the selection of antigenically different strains on an ongoing basis and thus the subtypes that emerge yearly are slightly different from those that predominated in the preceding year. Drift results in annual epidemics of influenza A and B in humans.

Shift (major antigenic change)
Influenza viruses have segmented genomes (each gene is on a separate gene segment). If a single cell is simultaneously infected with 2 different influenza viruses, gene swapping can occur during the formation of new virus particles. This genetic change process is called reassortment. Antigenic shift occurs when progeny viruses acquire a new HA or NA gene usually from an animal influenza virus. The new virus will have very different antigenic characteristics from the parent virus. Global herd immunity to the new virus is usually very low and this can result in a new flu pandemic. This phenomenon only occurs with influenza A.

Diagnosis

The virus replicates in the cells lining the respiratory tract. Therefore an appropriate sample for influenza testing is a nasopharyngeal aspirate in children and throat swab in adult.
Influenza virus can be detected by direct antigen detection (immunofluorescence) in exfoliated cells, viral culture, or by means of molecular techniques such as polymerase chain reaction (PCR).

Control

There are three important pillars in the control of influenza virus: viral surveillance, vaccination, and antivirals. In order to monitor the ongoing influenza evolution, strains from patients with influenza are cultured at viral surveillance centres around the world. The strains isolated help to determine the composition of the vaccine the following year.

For the last 30 years, 2 influenza A strains (H1N1 and H3N2) and one influenza B strain have co-circulated in the human population. Vaccines are usually trivalent; consisting of envelope (HA and NA) antigen from all three circulating influenza strains. Vaccine viruses are cultured in embryonated hen's eggs and the envelope proteins are purified. The subtype composition of the vaccine is updated every year based on influenza isolates of the preceding year. The only contraindication to the vaccine is egg allergy and concurrent febrile illness. All patients with significant risk factors for influenza morbidity are advised to receive the vaccine annually. Health care worker and carers of high risk individuals should also be immunized annually.

There are two classes of antivirals against influenza viruses. M2 channel inhibitors Amatidine and Rimantidine prevent the entry of the virus to the cells. However due to the widespread resistance to this class of drug they are no longer used in the treatment of current influenza infection.
The neuraminidase inhibitors Zanamivir and Oseltamivir (Tamiflu) prevent the budding off of the newly formed virions. This class of antivirals is only effective if given early (first 48 hours of infection). Resistance to neuraminidase inhibitors is common among some subtypes of influenza virus.

Laboratory Diagnosis of viral respiratory tract (and other) infections

Antibody assays are used to diagnose many viral infections, but they are not suitable in the context of respiratory infections as everybody already has antibodies. This is because most people are repeatedly exposed to the same or similar viruses throughout life. In addition, many of the viruses that infect the respiratory tract are antigenically related, and exposure to one induces antibody that can cross react with many other viruses.

Detection of virus from respiratory secretions is the most convincing way of proving a viral aetiology:
1. Detection of virus infected cells by immunofluourescence or ELISA
2. Detection of virus by culture or multiplex PCR

1. Detection of virus-infected cells by Immunofluorescence

Demonstration of virus-infected cells in a patient's secretions.
During the course of a respiratory tract infection, virus-infected cells lining the respiratory tract will be shed into the lumen and coughed up in sputum. These cells can be identified using specific monoclonal antibodies. Infected cells synthesize and express viral proteins (antigens). The presence of these can be detected using specific mono-clonal antibodies labelled with fluorescene. The antibody binds to the cells if they express the corresponding antigen. The cells can then be visualized by examination under a fluorescent microscope. Positive cells fluoresce a bright green colour.
The limitation of the test is that you have to know what virus you are looking for. Many laboratories screen respiratory specimens with a panel of mono-clonal antibodies to: RSV, adenovirus, influenza and para-influenza virus.
The advantage is that one can get a very rapid answer as to which virus is causing the problem.

2. Detection of virus by culture or multiplex PCR.

Traditionally many respiratory viruses can be isolated in cell culture but this may take up to 3 weeks to result and therefore the result may not be clinically relavant. Shell vial culture is a modified culture technique combining cell culture and antigen detection by immunofluorescence. This techniques is able to detect presence of virus within 72 hours and is used in many virology laboratories. Polymerase chain reaction (PCR) amplifies and detects viral genome. Multiplex PCR can detect multiple types of respiratory viruses at the same time (infection by more than one virus is not uncommon). This is a very sensitive method and can identify presence of virus within 24 hours. This method is becoming the gold standard in respiratory virus identification.