Article Text

Download PDFPDF

Lung infections • 4
Pathogenesis of lower respiratory tract infections due toChlamydia, Mycoplasma,Legionella and viruses
  1. Paul Andersen
  1. Department of Infectious Diseases, Marselisborg Hospital, DK-8000 Århus C, Denmark

    Statistics from

    Acute infection of the lower respiratory tract comprises bronchitis, bronchiolitis, and pneumonia. From a clinical point of view it may be difficult to distinguish these disease entities and one infection may progress into another. The most common pathogens causing these infections are the primary respiratory viruses (respiratory syncytial virus (RSV), influenza virus, adenoviruses, parainfluenza virus, and rhinovirus1 2), Mycoplasma pneumoniae,3 and Chlamydiaspecies.4-6 Legionella may cause pneumonia and non-pneumonic upper respiratory tract infection and approximately 85% of c ases are caused by L pneumophila. Long lasting sequelae such as bronchiectasis, lung fibrosis, and decreased lung function are seen after lower respiratory tract infections7-10 and it has been debated whether respiratory tract infection can cause chronic bronchial asthma.6 11-13

    Acute bronchitis and bronchiolitis

    Acute bronchitis is an inflammatory condition of the bronchi often caused by infectious agents, although in many cases no aetiology can be established.14 15 It shares many pathological and clinical features with bronchiolitis, and the same agents may induce both conditions. Most cases of acute bronchitis of known aetiology are due to respiratory viruses such as influenza virus, adenovirus, RSV, rhinovirus, and coronavirus,1 2 16 and a few are caused by M pneumoniae, Bordetella pertussis andC pneumoniae.4 5 15 17 Legionella infections limited to the bronchial tree are not described.


    The pathogenesis has not been studied for all agents, but the transmission of disease is thought to occur through droplet spread from an infected person. After inhalation the infectious agent may adhere to different receptors such as acid containing glycoproteins or the adhesion molecule ICAM-1 on respiratory epithelial cells.18 19 The infectious chlamydial particle is the elementary body that attaches itself to and enters a susceptible cell where it changes to the larger metabolically active reticulate body.20 Viable chlamydiae may be present at the site of infection and induce an inflammatory response.20 M pneumoniae attaches to ciliated epithelial cells by a specialised terminal organelle.18 Metabolic and ultrastructural alterations in the affected cell are seen and these result in epithelial cell damage and ciliostasis. Some epithelial cell lines produce cytokines when stimulated with other bacteria such as Escherichia coli,21 and epithelial cells might therefore play a more active role in the mucosal immune response after extracellular bacterial infection. In acute respiratory viral diseases a number of different inflammatory mediators such as kinins and cytokines have also been demonstrated. In some infections such as influenza extensive infiltrations with polymorphonuclear leucocytes (PMN), oedema, and degeneration of epithelial cells are seen,22 whereas in others such as rhinovirus infection the cytopathic effects are either absent or minor in degree.23


    The cardinal symptom of acute bronchitis is cough, while wheezing occurs in 10–90% of cases.6 14 15 24 25 Transient bronchial hyperreactivity has been found several weeks after influenza A infection in subjects with no previous history of bronchospasm,25 and in 40 patients with acute bronchitis and without pre-existing pulmonary disease wheezing was reported in 62%.14 A reduction in forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) was found during the acute illness, and 37% had bronchial hyperreactivity measured by histamine challenge testing six weeks later.14In patients with bronchial asthma26 27 it has been shown that acute exacerbations of wheezing and decreased PEF were associated with respiratory tract infections caused by rhinoviruses, coronaviruses, influenza virus, RSV, parainfluenza virus, andChlamydia in 80–85% of cases. Thus, in both asthmatic and non-asthmatic patients pulmonary symptoms and changes in airway function occur during and after viral respiratory illness.14 25 This may be due to cholinergic hyperresponsiveness or immunological reactions.14 28-30

    Chlamydia pneumoniae can cause prolonged acute bronchitis with wheezing6 15 31 32 and Hahn and coworkers6 found that nine (47%) of 19 patients with acute C pneumoniae infection had bronchospasm during their respiratory illness. They also found that 29% of 71 adults withC pneumoniae antibody titres above 32 had or developed asthmatic bronchitis after a respiratory illness compared with only 7% of a matched control group. In another study33 C pneumoniae could be isolated from the nasopharynx of 11% of asthmatic children with an acute episode of wheezing but in only 4.9% of a control group. Thus, infection with C pneumoniae can trigger acute episodes of wheezing in asthmatic children and Allegra and coworkers34 found a similar association in adults.C pneumoniae infection may predispose to bronchospasm during subsequent infections with other respiratory pathogens, or a prolonged infection and exposure to C pneumoniae may explain a protracted illness.32 Similar to findings in some viral respiratory tract infections with wheezing,29 30 specific IgE antibodies could be demonstrated in C pneumoniae infection.35 IgE antibodies were detected by an immunoblotting technique in 85% of 14 asthmatic children aged 5–15 years with culture proven C pneumoniae respiratory infection and also in 18–22% of culture negative asthmatics and asymptomatic children.35Antibodies to a 98 kD protein that seem to be C pneumoniaespecific were most commonly recognised.36 Some serum samples also reacted with epitopes present in C trachomatis, but the pattern of reactivity was different with the two species.35 These findings suggest that type 1 allergy may be implicated in the pathogenesis of C pneumoniae infection. The role of C trachomatis as a respiratory pathogen after the neonatal period is controversial.C trachomatis was isolated from pharyngeal swabs in seven of 20 children with wheezing37 and serological evidence of acute infection with C trachomatis was found in 19.2% of Argentinian children aged 1–18 months with acute lower respiratory tract infection.38 On the other hand, C trachomatiscould not be isolated from 48 children newly admitted to an asthma clinic in the UK,39 and Hahn and coworkers6 did not find any correlation between C trachomatis antibody titres and wheezing in children and adults with lower respiratory tract infection. Thus, the role of C trachomatis and C psittaci in bronchitis and wheezing is still undetermined and further studies are needed.

    Mycoplasma pneumoniae infection may result in bronchitis about 30 times more often than it causes pneumonia17 and it may be accompanied by paroxysmal cough, probably related to the cilial dysfunction, and by wheezing.1 11 15 In children with “wheezing associated respiratory illness” M pneumoniae was isolated in 3% of infants aged 0–2 years and in 52% of schoolchildren aged 9–15 years.1 In another studyM pneumoniae was cultured from 25% of asthmatics aged 0–31 years during a period with wheezing and in only 5% of subjects without asthma,40 but no association between wheezing and isolation of M pneumoniae could be found in a Japanese study.41 Based on serological tests, Seggev and coworkers42 concluded that M pneumoniaeinfection could cause exacerbation of asthma but this finding could not be confirmed by other workers.40 IgE antibodies to M pneumoniae have been detected in a few patients43and it has been suggested that they have a possible role in the pathogenesis. However, it should be borne in mind that antibodies could result from stimulation with cross reacting antigens and that a number of different antibodies are found in patients with M pneumoniaeinfection.44


    Bronchiolitis is an acute infection of the small bronchi and bronchioles in children below the age of 2–3 years. Some authors may include older children and use the term “wheezing associated respiratory infection”.1 RSV is the major cause of bronchiolitis, accounting for 45–75% of the cases, while parainfluenza virus is responsible for 15–30%. Rhinovirus, adenovirus, and influenza virus have each been isolated in 3–10% andM pneumoniae has been found in a small percentage.1 2 30 Serological evidence of C trachomatis and C pneumoniae infection in bronchiolitis has been described in a few cases.38 Legionella species may cause inflammation in bronchioles in connection with pneumonia,45 but a clinical syndrome of bronchiolitis due to these bacteria has not been reported.

    RSV may initially replicate in the epithelium of the upper respiratory airways and it then subsequently spreads downwards along the epithelium of the respiratory tract, mostly by cell to cell transfer. The bronchiolar epithelium is colonised by virus and necrosis may occur. Peribronchial inflammation with predominantly mononuclear cells and oedema is seen. Thick plugs composed of cell debris and fibrin are found, and they may lead to partial obstruction of the bronchioles, resulting in air trapping.46 This obstruction is probably the most important feature of acute bronchiolitis. The pathological process may progress and involve the alveolar walls leading to interstitial pneumonia. During recovery the bronchiolar epithelium regenerates within a few days. The elastic and muscular tissues are not damaged and the bronchial tree should recover completely.46

    In RSV bronchiolitis the pathogenesis of the inflammatory process may involve an abnormal immunological response. Children vaccinated against RSV with a formalin inactivated vaccine developed an antibody response without acquiring protective immunity, and when natural RSV infection occurred the vaccinated subjects developed a disease of increased severity.47 The vaccine not only failed to offer protection but also induced an exaggerated response to naturally occurring infection. RSV contains two surface glycoproteins—an attachment protein (G), and a fusion protein (F)—against which neutralising antibodies are usually directed.47 48Infants immunised with the formalin inactivated RSV vaccine developed a high titre of antibodies to the F glycoprotein and a poor response to the G protein, whereas older children developed high levels of antibodies to both proteins. However, in both groups the level of neutralising antibodies was lower than that obtained after natural RSV infection.48 Thus formalin treatment appeared to alter the epitopes of the glycoproteins in a way that resulted in production of non-neutralising antibodies. After natural RSV infection of vaccinated subjects the non-neutralising antibodies might have reacted with the virus antigens and elicited a local Arthus reaction in the bronchioles or alveoli, resulting in enhancement of pulmonary pathology.48 Studies of mice primed with single RSV proteins have shown that the G protein induces a strong specific antibody response but a weak specific IL-2 release from T lymphocytes. The F protein, on the other hand, is a potent stimulator of T helper cells.49 50 Mouse T cell lines primed with various RSV proteins, cultured in vivo and injected into RSV infected mice, revealed that the most severe illness was seen in mice receiving G specific cells whereas F specific cells caused only minimal enhancement of the disease. It has also been found that mice sensitised with G protein developed eosinophilic efflux into the bronchi, whereas mice sensitised with F protein developed PMN efflux.49 50Different RSV proteins may therefore stimulate different subsets of T helper lymphocytes.49 51 The G protein may stimulate Th2 cells which produce IL-4 and IL-5 and may lead to IgE production and eosinophilic chemotaxis. Although these findings should be interpreted cautiously, they might explain some of the pathological findings in patients with bronchiolitis in whom IgE, histamine, and eosinophilic cationic protein can be found in respiratory secretions.29 52 Leukotriene C4(LTC4) was detected in nasopharyngeal secretions in the acute phase of RSV bronchiolitis and it may be released from mast cells by an IgE mediated mechanism.53 The amount of histamine and IgE antibodies to RSV and parainfluenza virus in nasopharyngeal secretions correlated with the severity of the disease and with recurrent wheezing.29 30 54 It is therefore possible that local stimulation of Th2 helper lymphocytes (rather than Th1 lymphocytes) by RSV or other infectious agents may lead to or augment the risk of developing bronchiolitis with wheezing.


    After acute bronchitis increased airway reactivity to inhaled histamine which could be blocked by atropine was demonstrated.14 25 28 This cholinergic hyperresponsiveness may be a consequence of epithelial damage by respiratory pathogens with exposure and sensitisation of sensory fibres.55 However, the finding of specific IgE antibodies to RSV, parainfluenza virus, mycoplasma, and C pneumoniae 29 30 35 43 might suggest that type 1 allergy plays a role in bronchospasm and wheezing, although specific IgE antibodies have also been found in non-respiratory viral infections.56 In infants with RSV bronchiolitis during the first year of life one study13 showed that 23% had developed asthma—defined as three episodes of bronchial obstruction—at the age of three years compared with 9% in a control group. It was also found that the children recovering from bronchiolitis developed IgE antibodies to other antigens more often than control children.13 It is therefore possible that respiratory infection might stimulate Th2 cells and elicit IgE mediated bronchial asthma.27 49 50


    Acute bronchitis may result in decreased lung function in both asthmatic and non-asthmatic patients.14 25 27 The abnormalities usually resolve after several weeks or months but some cases only resolved after eradication of a chlamydial infection.35 37 There have been no long term follow up studies to show that acute bronchitis may elicit chronic bronchial asthma. RSV bronchiolitis in infants has been associated with development of asthma and sensitisation to common allergens during the subsequent two years. However, these infants also had a heredity for atopy and asthma.13 This was not found in other studies12 and it cannot be ruled out that the infants who develop severe RSV infection are those with a predisposition for atopy and asthma. It is also possible that pulmonary infection early in life may have a deleterious effect on the developing respiratory system, although the bronchioles seem to recover completely.46Thus, it is not possible to determine whether respiratory tract infections can lead to chronic bronchial asthma, but it has been shown that they may increase the rate of other chronic respiratory diseases later in life.9 57 Early treatment might ameliorate the acute symptoms and may reduce the persistent wheezing. Patients with acute bronchitis may benefit from inhaled β2agonists.14 Nebulised budesonide decreases the severity of laryngotracheobronchitis caused by parainfluenza virus58and may also have an effect in other respiratory tract infections.


    The aetiology of community acquired pneumonia has usually been studied in hospital inpatients and pneumococci have been the predominant micro-organisms with viruses, Chlamydia,Mycoplasma, and Legionella causing less than 25% of cases.59 60 However, in less severe cases seen in outpatient clinics viruses, M pneumoniae, and C pneumoniae may dominate.61 62


    Infection with the usual respiratory viruses seems to spread downwards from the larger bronchi to the bronchioles and alveoli and this may explain why these infections often start with symptoms of bronchitis. All primary respiratory viruses cause similar pathological changes in the lower airways and lungs.46 Inflammation of bronchioles and alveolar parenchyma with foci of necrosis is seen and many alveoli are lined with thick hyaline membranes which may compromise air diffusion.46 As in bronchitis and bronchiolitis, changes in airway reactivity may persist for weeks or months after viral pneumonia.


    Chlamydial pneumonia may be caused by all three human pathogenic species. Newborn infants may be infected with C trachomatisduring delivery and develop pneumonia with dry cough and wheezing 4–6 weeks later.17 C trachomatismay also cause lower respiratory tract infection after the neonatal period since serological evidence of recent or acute C trachomatis infection was found in 20% of 89 children aged 1–18 months with pneumonia.38 It is uncertain how the infection is acquired by these children, but persistent unrecognised infection might be a possibility.20 C trachomatisinfection has also been reported in adults with pneumonia.63 However, previous serological tests have been less specific and it is possible that some of these cases were due to other species.

    Ornithosis is a systemic infection often accompanied by pneumonia.17 It is caused by C psittaci which is common in birds and some domestic animals. Infection is spread to man from infected birds by the respiratory route, either by direct contact or by aerosolisation of infectious discharge or dust. The agent is spread haematogenously from the respiratory tract to other sites, including the lungs. The trachea and bronchi become inflamed and the inflammation spreads to the bronchioles and alveolar walls. Unlike most viral pneumonias, chlamydial pneumonia results mainly in an intra-alveolar inflammatory response and, to a lesser extent, in interstitial inflammation.

    Primary infection with C pneumoniae in young people usually causes mild pneumonia accompanied by upper respiratory tract infection.4 62 Adults are more severely affected31 64 and an immunological pathogenesis due to repeated infections has been suggested. C pneumoniae andC psittaci infections have been associated with extrapulmonary manifestations31 65-67 that may be caused by haematogenous spread or immunological mechanisms. C psittaci has been cultured from blood in patients with endocarditis66 whereas other complications such as glomerulonephritis,67 reactive arthritis, or erythema nodosum31 65 may be immunologically mediated, though no study has so far reported deposition of chlamydial antigen in the lesions. In immune guinea pigs a genus specific 57 kD chlamydial protein can elicit a delayed hypersensitivity reaction,68supporting the assumption that immune reactions play a role in the pathogenesis of chlamydial infections.


    After inhalation of infected material, M pneumoniaebinds to respiratory epithelial cells and induces inflammation.11 18 Locally produced secretory IgA may inhibit the binding to respiratory epithelium, and these antibodies seem to play a greater role than serum antibodies in the protection against repeated mycoplasmal infections.69 In fatal cases of mycoplasmal pneumonia micro-organisms are rarely demonstrated in lung tissue and corticosteroids have had some beneficial effects in severe cases.70 71 In immunocompromised patients with severe mycoplasmal infection the chest radiographic changes were minimal or absent.72 This could be explained by decreased immunological reactivity in these patients, and it would therefore support the assumption that immunological mechanisms play a pathogenic role. Several extrapulmonary complications occur in mycoplasmal infection11 and there is evidence to suggest that immune mechanisms, rather than direct infection, may also be responsible for these manifestations. Thus, M pneumoniae is seldom isolated from clinical specimens, apart from nasopharyngeal secretions.M pneumoniae may act as a polyclonal activator of lymphocytes73 and autoantibodies to various tissues and immune complexes have been demonstrated in a high proportion of patients.44 74 This might contribute to injury to extrapulmonary organs, although antibodies are also found in patients without extrapulmonary manifestations.44 Altered immune function induced by M pneumoniae may facilitate infection with other micro-organisms and explain why co-infection with other bacteria or viruses may result in severe disease.75


    Legionella pneumonia is most often caused by L pneumophilaand the prevailing mode of transmission is probably by direct inhalation of aerosols containing micro-organisms.76Aspiration of oropharyngeal content contaminated with legionellae77 seems unlikely since oropharyngeal colonisation is rare.78

    The histopathological lesions of Legionnaires’ disease are predominantly located in alveolar ducts and alveoli which contain a mixture of PMNs and macrophages with fibrin and cell debris. Leucocytes predominate in the early phase of infection followed by macrophages in the later phase.45 Abscess formation, indicating that the bacterium may produce irreversible damage, has been reported.45 79 Once the bacteria have entered the respiratory tract they will normally be cleared by the mucociliary system.79 80 However, the Legionellabacterium has several cell associated and extracellular factors that may help to establish infection.81 They possess flagella and fimbria that may mediate adherence to lung cell surfaces82 but this process may be inhibited byLegionella antibodies in bronchial secretions. The micro-organisms can evade this neutralisation by antibodies by producing proteases that may degrade both IgG and secretory IgA in the secretions83 and another legionella protease may inhibit the neutrophil chemotaxis and thus facilitate infection.84Cell mediated immunity also plays an important role in the defence against legionella infection85 and, in accordance with this, legionella pneumonia occurs more commonly in immunocompromised patients. Several bacterial virulence factors may help to invade cells, multiply intracellularly, and cause cell damage.81 The mode of action of many of these factors is not known and they may vary in different strains. The macrophage infectivity potentiator (Mip) is a basic protein with a molecular weight of 24 kD and it has been shown that L pneumophila strains defective in this factor exhibit reduced infectivity in cell cultures and that reintroduction of the Mip gene restores virulence.81 86 Some component ofL pneumophila such as Mip or cytotoxin87 88affects the respiratory burst of phagocytes during infection and this suppression may contribute to the intracellular survival of the bacteria.89 On the other hand, enhanced generation of toxic oxygen radicals might also be involved in the pulmonary damage seen in Legionnaires’ disease, and lung fibrosis has been described as a sequel of this illness.10 Legionellosis can be dominated by a diversity of extrapulmonary manifestations, probably due to haematogenous spread of bacteria following infection of the lungs. Renal failure, hypotension, and respiratory failure have been reported90 91 and these complications do not seem to be immunologically mediated.45


    Lower respiratory tract infection may be followed by long term sequelae and a direct link between acute respiratory tract infection in early infancy and development of chronic bronchitis and emphysema in adults has been established.9 Interstitial lung fibrosis has been reported after influenza pneumonia8 and Legionnaires’ disease,10 as well as bronchiectasis and abnormal lung function tests after adenovirus pneumonia.7 92 Symptoms recurring and persisting for years have been described in patients with ornithosis.93The occurrence of symptoms was related to a delay in the initiation of antibiotic therapy and to high antibody titres to chlamydial group antigens, which might suggest continued chlamydial infection.32 93 Thus acute pneumonia can lead to chronic pulmonary disease and it is a theoretical possibility that early antimicrobial treatment might prevent this.


    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.