Respiratory Tract Infections

This is an abridged extract from the full chapter ‘Respiratory tract viruses’ from the Oxford Textbook of Medicine (6th ed.), Section 8.5: Viruses (Oxford, 2020). Read for free here.

Malik Peiris
Six human coronaviruses are currently known, four of them being new viruses discovered since the SARS outbreak in 2003. Coronaviruses are taxonomically subdivided into four groups; the human coronaviruses 229E and NL-63 are alphacoronaviruses while OC43, HKU1, SARS-CoV, and MERS-CoV are β‎-coronaviruses. There are no known human γ‎- or deltacoronaviruses yet recognized. Human coronaviruses OC43 and 229E have long been recognized as important causes of the common cold but coronaviruses cause a range of respiratory illnesses. SARS-CoV and MERS-CoV area newly emerged pathogens of zoonotic origin. Human coronaviruses are difficult to culture from clinical specimens and laboratory diagnosis largely relies on molecular methods.
Infection with OC43 and 229E occur in early childhood and 85 to 100% of adults have antibody to both virus types. NL-63 has a similar epidemiology but less is presently known of HKU1. SARS-CoV emerged from an animal reservoir, adapted to human transmission, and caused a global outbreak in 2003 that affected 29 countries across five continents. Determined public health interventions interrupted transmission of this virus and it is no longer transmitting within humans. However, the precursor virus remains in the animal reservoir (bats, Rhinolophus spp.) and these could, at some future date, readapt to cause human disease. MERS-CoV was first recognized in a patient with fatal pneumonia in Saudi Arabia in 2012 but the virus has been endemic in dromedary camels for many decades. Zoonotic human infection has so far been confined to the Arabian Peninsula or the Middle East and might sometimes be mild and not recognized. Severe disease occurs mainly in older people on in those with underlying comorbidities. Clusters of human transmission have occurred within healthcare facilities. Patients who acquired infection in the Middle East and travelled elsewhere have sometimes caused outbreaks in other parts of the world.
Volunteer reinfection studies with 229E show that 1 year after initial infection, protection from reinfection and illness following a challenge from the homologous virus is incomplete. Comparable data are not available for the newly recognized NL-63, HKU1, or SARS-CoV.
In common with rhinoviruses, coronaviruses 229E induce little or no damage to the respiratory mucosa. The mucosal discharge is caused by the release of mediators from affected host cells. SARS-CoV and MERS-CoV have a predilection to infect alveolar pneumocytes in the lower respiratory tract and consequently caused a severe viral pneumonia. Disease severity of SARS was markedly age related. Children had mild disease whereas those over 50 years had a poor prognosis. The basis for this age-related pathogenesis is unknown. The virus receptor for 229E is CD13, both SARS-CoV and NL-63 utilize the human ACE-2 molecule for virus entry while MERS-CoV binds to human DPP4 (CD26).
Clinical findings
Coronaviruses 229E and OC43 typically cause upper respiratory tract infection and the common cold but also cause a range of other respiratory manifestations and are significant pathogens in elderly people. NL-63 and HKU1 cause both upper and lower respiratory disease. NL-63 appears to be an important cause of croup, bronchiolitis, and pneumonia. HKU1 appears to be an important pathogen particularly in those with underlying respiratory complications.
SARS typically presented with lower respiratory tract manifestations and radiological changes with minimum involvement of the upper respiratory tract. Many patients had diarrhoea resulting from viral replication in the gastrointestinal tract. Overall case fatality was 9.6%. Terminal events were severe respiratory failure associated with acute respiratory distress syndrome and multiple organ failure. Age, comorbidities, and viral load in the nasopharynx and serum during the first 5 days of illness correlated with an adverse prognosis.
Clinical features of MERS are broadly similar to those of SARS; fever, chills, or rigors, cough (dry or productive), and shortness of breath being the common presenting symptoms. Diarrhoea or vomiting were reported by around one-third of patients. Upper respiratory symptoms are uncommon. Chest radiographic abnormalities can include unilateral or bilateral hilar infiltrates, patchy infiltrates, segmented or lobar opacities or ground glass opacities, with the lower lobes being generally more affected than the upper lobes, early in the illness. Lymphopenia, thrombocytopenia and high lactate dehydrogenase levels are seen in around one-third of patients. Reported case fatality ranges from 30 to 40%, but this is probably because milder cases are not being recognized.
Treatment and prevention
There are presently no clinically validated antiviral treatments for human coronaviruses disease, although several drugs have been documented to have in vitro activity against SARS-CoV and MERS-CoV and some (ribavirin, interferon, HIV protease inhibitors) have been used in uncontrolled settings with inconclusive results. Passive immunotherapy is currently being explored for treatment of MERS. Several experimental vaccines were developed for SARS, but with its disappearance from the human population, the incentive to take these forward to human clinical trials and licensing has waned. Vaccines for MERS-CoV for humans and for camels are in preclinical trials.
Currently there are 54 adenovirus types classified in six groups (A–F). Adenoviruses in subgroups A to D cause respiratory, ocular, hepatic, genitourinary, or gastrointestinal system disease in immunocompetent or immunocompromised individuals. Only respiratory diseases are considered here.
Productive replication and excretion of infectious virus can occur for a prolonged period (see next). In addition, adenoviruses can establish chronic persistence or ‘latency’, the virological basis and clinical significance of which is poorly understood.
Adenovirus infections are common during childhood (usually serotypes 1, 2, 5 in early childhood, 3 and 7 during school years or later), but continue to occur throughout life. Reinfection with the same serotype occurs but is usually asymptomatic. Serotypes 1, 2, 5, and 6 are typically endemic, types 4 and 7 more typically associated with outbreaks, and type 3 can occur in either situation. Recently, adenovirus 14p1 (previously designated 14a) has been spreading in the United States of America and elsewhere and is associated with more severe disease especially within military facilities.
Clinical features
Adenovirus respiratory illness often leads to upper respiratory tract infection with coryza and sore throat. Fever may last up to 2 weeks. The sore throat may be exudative and clinically difficult to differentiate from streptococcal infection. Adenoviral infection may present as pharyngoconjunctival fever. Otitis media is a complication in children. Unlike other respiratory viral infections, adenoviruses may be associated with elevated white blood cell counts (exceeding 15 × 109/litre), C-reactive protein, or erythrocyte sedimentation rate, and thus more easily confused with bacterial diseases.
Though uncommon, pneumonia can occur sporadically or in epidemics (e.g. caused by serotypes 4 and 7), particularly in closed communities such as the military where stress and physical exertion may predispose to lower respiratory tract involvement. Community outbreaks of adenoviral pneumonia have been reported. Radiological appearance varies from diffuse to patchy interstitial infiltrates and pleural effusion may be present. Adenovirus type 7 pneumonia can lead to permanent lung damage, including bronchiectasis, bronchiolitis obliterans, and unilateral hyperlucent lung syndrome.
Adenoviral infection may disseminate and present as ‘septic shock’ in neonates. Manifestations in immunocompromised patients include hepatitis (especially in liver transplant recipients), colitis and haemorrhagic cystitis (in stem cell and organ transplant recipients) in addition to pneumonia. The serotypes associated with disease in these patients may differ from those typically found in the immunocompetent patient, and include the subgroup B2 serotypes 11, 34, and 35. With improving control of other common viral diseases of immunocompromised patients (e.g. cytomegalovirus), the role of adenovirus infections is being increasingly appreciated.
Isolation or PCR detection of an adenovirus from a clinical specimen presents a challenge in interpretation. Adenoviruses are excreted for a prolonged period after initial infection, especially, but not exclusively, from faeces. In children, one-third of patients shed viruses for longer than 1 month and 14% longer than 1 year. The clinical significance of a positive result depends on the specimen, the method, and the serotype. Isolation of viruses from the respiratory tract carries greater significance than that from faeces. Patients who have symptomatic adenoviral diseases have higher viral loads than those with asymptomatic carriage. Thus, a rapidly growing virus, a positive antigen detection test from a respiratory specimen (both reflecting higher virus load), or a detectable serological response all point to greater clinical significance.
Immunocompromised patients might be infected with unusual serotypes. The detection of the virus in the peripheral blood or in multiple body sites suggests greater clinical significance and is an indication that therapeutic intervention needs to be considered.
Treatment and prevention
Most adenoviral infections in immunocompetent patients are self-limited and require no specific therapy; however, some infections, especially but not exclusively in immunocompromised patients, are severe and life-sthreatening. Intravenous cidofovir has been used for treatment of adenoviral infections in the immunocompromised, but nephrotoxicity and neutropenia limit its use. Orally administered brincidofovir (lipid ester derivative of cidofovir) appears to provide better clinical outcome with fewer side effects, but clinical trials are ongoing.
Live attenuated oral vaccines containing serotypes 4 and 7 (associated with outbreaks in military conscripts) are now used for military personnel in the United States and are safe and effective, but not licensed for general use.
Peiris, M. (2020). Respiratory tract infections. In: J. Firth, C. Conlon and T. Cox, ed., Oxford Textbook of Medicine, 6th ed. [online] Oxford: Oxford University Press. Available at:[Accessed 30 Jan. 2020].