The upper and lower respiratory tracts form a continuum for infectious agents

We distinguish between upper and lower respiratory tract infections, but the respiratory tract from the nose to the alveoli is a continuum as far as infectious agents are concerned (Fig. 18.1). There may, however, be a preferred ‘focus’ of infection (e.g. nasopharynx for coronaviruses and rhinoviruses); but parainfluenza viruses, for instance, can infect the nasopharynx to give rise to a cold, as well as the larynx and trachea resulting in laryngotracheitis (croup), and occasionally the bronchi and bronchioles (bronchitis, bronchiolitis or pneumonia).

Figure 18.1 The respiratory tract as a continuum. * Asymptomatic nasopharyngeal colonization is common. ** Magnitude of rhinitis, laryngitis, etc. is shown by area between black and blue lines.

Two useful generalizations can be made about upper and lower respiratory tract infections:

Table 18.3 The two types of respiratory invader – professional or secondary

Table 18.4 Common cold viruses and their mechanisms of attachment

Rhinoviruses and coronaviruses together cause more than 50% of colds

Viruses are the most common invaders of the nasopharynx, and a great variety of types (Table 18.4) are responsible for the symptoms referred to as the common cold. They induce a flow of virus-rich fluid which is called rhinorrhoea from the nasopharynx, and when the sneezing reflex is triggered, large numbers of virus particles are discharged into the air. Transmission is therefore by aerosol and also by virus-contaminated hands (see Ch. 13). Most of these viruses possess surface molecules that bind them firmly to host cells or to cilia or microvilli protruding from these cells. As a result, they are not washed away in secretions and are able to initiate infection in the normally healthy individual. Virus progeny from the first-infected cell then spread to neighbouring cells and via surface secretions to new sites on the mucosal surface. After a few days, damage to epithelial cells and the secretion of fluid containing inflammatory mediators such as bradykinin lead to common cold-type symptoms (Fig. 18.2).

Figure 18.2 The pathogenesis of the common cold. For simplification, the epithelium is represented as one cell thick.

Common cold virus infections are diagnosed by clinical appearance

In view of the large variety of viruses and because common colds are generally mild and self-limiting with no systemic spread in healthy individuals, determining the aetiology may only be helpful from an epidemiological perspective. Diagnosis becomes important when the lower respiratory tract is involved, as for instance with influenza viruses or in children with respiratory syncytial virus (RSV) infection. The diagnosis can be made using a number of different methods that include detecting viral antigens in exfoliated cells in samples such as nasopharyngeal aspirates or throat swabs using:

Alternatively, collecting an acute and convalescent serum sample and looking for a rise in virus-specific antibodies can confirm the diagnosis retrospectively.

Due to the increased sensitivity in detecting respiratory viruses by PCR, together with automated sample extraction and detection methods, many laboratories use molecular methods for making a diagnosis using combined nose and throat swab samples.

Treatment of the common cold is symptomatic

It is often said that a common cold will resolve in 48    h if vigorous treatment with anticongestants, analgesics and antibiotics is undertaken. There are no vaccines to protect against the common cold viruses as the vaccines would have to be polyvalent to cover this antigenically diverse group of viruses, and treatment is for the most part symptomatic.

About 70% of acute sore throats are caused by viruses

Microorganisms that cause sore throats (acute pharyngitis) are listed in Table 18.5. Those viruses that infect the upper respiratory tract inevitably encounter the submucosal lymphoid tissues that form a defensive ring around the oropharynx (see Fig. 18.1). The throat becomes sore either because the overlying mucosa is infected or because of inflammatory and immune responses in the lymphoid tissues themselves. Adenoviruses are common causes, often infecting the conjunctiva as well as the pharynx to cause pharyngoconjunctival fever. Epstein–Barr virus (EBV) and cytomegalovirus (CMV) multiply locally in the pharynx (Fig. 18.3), and herpes simplex virus (HSV) and certain coxsackie A viruses multiply in the oral mucosa to produce a painful local lesion or ulcer. Certain enteroviruses (e.g. coxsackie A16) can cause additional vesicles on the hands and feet and in the mouth (hand, foot and mouth disease; Fig. 18.4).

Table 18.5 Microorganisms that cause acute pharyngitis

Figure 18.3 Infectious mononucleosis caused by Epstein–Barr virus. The tonsils and uvula are swollen and covered in white exudate. There are petechiae on the soft palate.

(Courtesy of J.A. Innes.)

Figure 18.4 Ulcers on the hard palate and tongue in hand, foot and mouth disease due to coxsackie A virus.

(Courtesy of J.A. Innes.)

Cytomegalovirus can be transmitted by saliva, urine, blood, semen and cervical secretions

Cytomegalovirus is the largest human herpesvirus (Fig. 18.5) and is species specific; humans are the natural hosts. Cytomegalovirus refers to the multinucleated cells, which together with the intranuclear inclusions, are characteristic responses to infection with this virus. CMV was originally called ‘salivary gland’ virus and is transmitted by saliva and other secretions. In addition, CMV can be transmitted by sexual contact, as semen and cervical secretions may also contain this virus, and by blood transfusions (although leukodepletion reduces the risk significantly) and organ transplants from CMV antibody-positive donors. The CMV load will be high in the urine from babies with congenital CMV infection and careful hand washing and disposal of nappies will reduce the risk of transmission to susceptible individuals. CMV can be detected in breast milk, but this is of doubtful significance in transmission.

Figure 18.5 Electron micrograph of cytomegalovirus particles. This is the largest human herpes virus, with a diameter of 150–200    nm, and a dense DNA core.

(Courtesy of D.K. Banerjee.)

Cytomegalovirus infection is often asymptomatic, but can reactivate and cause disease when cell-mediated immunity (CMI) defences are impaired

After clinically silent infection in the upper respiratory tract, CMV spreads locally to lymphoid tissues and then systemically in circulating lymphocytes and monocytes to involve lymph nodes and the spleen. The infection then localizes in epithelial cells in salivary glands and kidney tubules, and in cervix, testes and epididymis, from where the virus is shed to the outside world (Table 18.6).

Table 18.6 The effects of cytomegalovirus (CMV) infection

Site of infection	Result	Comment
Salivary glands	Salivary transmission	Via kissing and contaminated hands
Tubular epithelium of kidney	Virus in urine	Probable role in transmission by contaminating environment
Cervix, testis/epididymis	Sexual transmission	Up to 107 infectious doses/ml of semen in an acutely infected male
Lymphocytes, macrophages	Virus spread through body via infected cells Mononucleosis may occur Immunosuppressive effect	Probable site of persistent infection
Placenta, fetus	Congenital abnormalities	Greatest damage in fetus after primary maternal infection rather than reactivation

CMV is a ‘well-behaved parasite’, causing little or no damage to the host unless it infects the fetus or placenta to cause congenital abnormalities or it reactivates following depressed cell-mediated immunity (post-transplant, immunosuppression) to cause viraemia, fever, hepatitis or pneumonia.

Infected cells may be multinucleated or bear intranuclear inclusions, but pathologic changes are minor. The virus inhibits T-cell responses, and there is a temporary reduction in their immune reactivity to other antigens.

Although specific antibodies and CMI responses are generated, these fail to clear the virus (see Ch. 16), which often continues to be shed in saliva and urine for many months. The infection is, however, eventually controlled by CMI mechanisms, although infected cells remain in the body throughout life and can be a source of reactivation and disease when CMI defences are impaired.

CMV owes its success in our species to its ability to evade immune defences. For instance, it presents a poor target for cytotoxic T (Tc) cells by interfering with the transport of major histocompatibility complex (MHC) class I molecules to the cell surface (see Ch. 10), and it induces Fc receptors on infected cells (see Ch. 16).