What happens to lung capacity with age?

Due to increasing life expectancy and low fertility, the European Union (EU) is an ageing society. Currently, 16% of its population is aged >65 yrs compared with an estimated 7% for the entire world. Further ageing of the EU population is projected over the next two decades, as shown in figure 1⇓ for the UK, whose current population aged >65 yrs is identical to the EU average. By 2021, nearly 10% of the UK population is projected to be aged >75 yrs, with increased male survival reducing the current striking preponderance of females in the aged population. These demographic trends are important for the future patterns of healthcare and disease. Therefore, it is encouraging that three papers in the current issue of the European Respiratory Journal 1–3 address “normal” ageing of different aspects of airway function and study older subjects compared with many earlier studies.

Fig. 1—

UK population projections in millions up to 2021. ▪: females ≥65 yrs of age; •: males ≥65 yrs of age; ♦: females ≥75 yrs of age; ▴: males ≥75 yrs of age. Total UK population in 2001 was 60 million.

Changes in pulmonary elastic and resistive properties, and in maximum expiratory flow with increasing age, were first described 40 yrs ago, admittedly by small cross-sectional studies of young adults versus elderly subjects. These studies established that the maximum size of the lungs (total lung capacity) did not change with age, but functional residual capacity (FRC) and residual volume (RV) both increased so that inspiratory capacity and vital capacity (VC) both declined 4. The increase in FRC was due to an increase in relaxation volume of the respiratory system, which arose from changes in the static recoil pressure of both the chest wall and the lungs. Static recoil pressure of the lungs (PL) fell at all lung volumes with increasing age 5, 6. The fall in PL contributed to the increase in RV, but this was usually overshadowed by an increased tendency to airway closure at small volume 7, itself reflecting a reduced airway transmural pressure. Changes in the shape of the expiratory PL/lung volume (VL) curve increased static lung compliance. All these changes are a minor version of the changes found in advanced emphysema.

Ageing changes in resistive properties were first studied soon after the development of the body plethysmograph technique to measure airway resistance (Raw) by Briscoe and DuBois 8. They observed that specific airway resistance (sRaw = Raw×VL) measured at low flow close to FRC was, on average, similar in childhood and old age; one of the few pulmonary function measurements not to change with age. This suggested that the major factor determining Raw in normal subjects was lung size, which was confirmed later by a much larger study 9. Nevertheless, adequate reference values for resistance have only been developed recently, based on increasing use of the simple forced oscillation technique, which measures the resistance of the total respiratory system (Rrs), including flow resistance of lung tissue and the chest wall, as well as the resistance of the extra- and intra-thoracic airways measured by Raw 10. Some reference values for Rrs have been developed for healthy children and for adults aged up to 70 yrs 10. In the present issue of the European Respiratory Journal, Guo et al. 1 report values of Rrs in a large group of 223 healthy, nonsmoking subjects aged 65–100 yrs (mean age 83 yrs). They found that: 1) Rrs was slightly lower in aged subjects than previously reported in younger adults; 2) Rrs was higher in females (the majority of subjects) than males; and 3) Rrs was inversely related to height. Although FRC was not measured, Rrs was probably measured at a slightly greater VL than in previous studies of younger adults. Therefore, lower values of Rrs do not challenge the findings of Briscoe and DuBois 8, that sRaw remains similar over the full age range. Perhaps an unchanging sRaw is itself unexpected, because Butler et al. 11 also proposed that reductions in Raw with lung inflation were driven by the accompanying change in PL, which they regarded as a surrogate for the distending pressure of the intrathoracic airways. The most obvious explanation for retaining a normal or even reduced Rrs in old age is that changes in airway elasticity occurred in parallel with those in alveolar elasticity, so that aged airways have a bigger circumference at a standard distending pressure than the airways of younger adults 6.

The decline with increasing age in tests of forced expiration, such as forced expiratory volume in one second (FEV1), FEV1/VC and maximum flows at different lung volumes is of wider practical importance. These changes are, in part, simply due to the smaller VC, but this is not the whole explanation because FEV1/VC also declines with age. Although this change is often attributed to “occult” disease of the small airways not detected by resistance measurements, all the changes in maximum expiratory flow with increasing age in healthy subjects can be explained by a direct effect of the loss of PL in reducing the effective driving pressure for maximum expiratory flow, without having to postulate any intrinsic narrowing of the airways 6, 12.

A practical problem in assessing results of spirometry in older subjects is that often reference values have been derived by linear extrapolation of decline rates from studies with few subjects aged >70 yrs 1, thus, ignoring any acceleration in the rate of decline in FEV1 that occurs with increasing age 13. Fortunately, in the past 10 yrs several studies have reported reference values from data sets which included reasonable numbers of aged subjects up to 80–85 yrs of age 14–18. This obviously assists investigators trying to detect mild obstructive disease in the elderly. So far, these newer cross-sectional studies do not provide conclusive evidence of acceleration of decline in FEV1 with increasing age. The problems in actually acquiring “normal” data in an elderly population are well illustrated by a second paper in this issue of the European Respiratory Journal by de Bisschop et al. 2. From an initial 2,612 elderly subjects aged 66–88 yrs, who were identified as living in their own homes in a suburb of Bordeaux (France), the authors ended up with only 116 subjects in their healthy, never-smoker control group, two-thirds of whom were female.

The novelty in the study by de Bisschop et al. 2 was their assessment of expiratory flow limitation (EFL) during resting tidal breathing, using the negative expiratory pressure technique. They found EFL at rest was common in old age, and was found in some elderly subjects with dyspnoea in the absence of overt cardiopulmonary disease. Tidal EFL at rest might further reduce the available ventilatory reserve during exercise by preventing any of the increased tidal volume being developed by reducing end-expired lung volume (EELV), an important change consistently found in younger subjects. Studies that have examined tidal and maximum flow-volume curves during progressive exercise in elderly subjects all agree that EFL is observed over a much larger part of the exercise tidal volume than in younger subjects, but in exceptionally fit old subjects, EELV still usually falls on exercise 19, 20. In untrained subjects achieving much lower levels of ventilation, DeLorey and Babb 21 confirmed that EELV usually falls in “senior” subjects (mean age 70 yrs), but not in “elderly” subjects (mean age 88 yrs!). While a reduced ventilatory reserve potentially contributes to the decreased exercise ability and increased dyspnoea on exertion found with increasing age, other common important changes include reduced habitual activity and physical deconditioning, an impaired cardiac response, and loss of quadriceps mass and strength 22.

While accurate reference values for established lung function tests in old age are clearly needed, studies of the effects of ageing are required on many other less studied aspects of lung biology. A third paper in this issue of the European Respiratory Journal 3, which describes an age-related slowing of clearance of inhaled 6 μm particles from the peripheral airways, is interesting because of the epidemiological evidence that short-term morbidity and mortality related to particulate exposure is concentrated in elderly subjects.

Overall, current knowledge of the basic mechanisms altering pulmonary structure and function with increasing age is very limited. One thing that is known is that the extent of the ageing process in the lungs shows great inter-individual variation at all levels from microscopic structure 23 up to the maximum exercise performance 19–21. If we understood how such ageing changes could be minimised, it might be possible to improve the quality of the “added years” of survivors into old age.

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Pleural effusion is a relatively common clinical condition that requires a differential diagnosis as it may represent the primary manifestation of certain diseases; however, it is commonly observed as a secondary manifestation or complication of other diseases. Primary causes include cardiac failure, infectious aetiology (75% bacterial and 25% viral), and malignancy (mostly lung and breast cancer), while the other diseases comprise pulmonary embolism, liver cirrhosis, subphrenic abscess or pancreatitis 1. In addition, symptoms associated with pleural effusions, such as cough, dyspnoea and chest pain, are nonspecific. Therefore, the history of the patient, physical findings and laboratory tests are necessary for the clinician to narrow down the differential diagnosis 2.

The cause of pleural effusion may be determined in most cases, depending on clinical presentation, imaging techniques and pleural fluid analysis. Pleural fluid analysis is the most useful test and, together with clinical information, usually allows the diagnosis of pleural effusion in ∼75% of patients 3. A definite diagnosis can generally be obtained in ∼25% of cases, after finding malignant cells or microorganisms. In ∼50% of cases, only a presumptive diagnosis can be obtained based on clinical impression. After excluding an infection as the cause of the pleural effusion, clinical orientation upon pleural fluid analysis is possible in a greater percentage of patients. In cases where a diagnosis cannot be obtained, observation of the patient, repeated pleural fluid analysis or more invasive procedures may be indicated. Even after invasive procedures, such as thoracoscopy, are used, the cause of the pleural effusion cannot be established in up to 15% of patients 4.

Thoracocentesis is indicated in all clinically significant pleural effusions of unknown origin and in effusions that do not respond to treatment. Pleural fluid biochemical analysis allows the classification into transudates (caused by imbalances between the hydrostatic and oncotic pressures in the chest) or exudates (due to alterations in local factors involved in pleural fluid accumulation), according to the levels of serum and pleural fluid protein, lactate dehydrogenase and cholesterol. Additionally, nucleated cells, glucose, pH, amylase, cytological examination and immunological markers may be determined in pleural fluid to aid diagnosis 1. Bacterial culture should be performed in purulent effusions, and the presence of microorganisms, such as mycobacteria, fungi and parasites, should be investigated if there is suspicion 5. Diagnosis of viral effusions is mainly based on clinical information, but serum antibody titres, virus culture or detection of specific antibodies in pleural fluid may also be useful 1. Amongst viral causes, Thijsen et al. 6 report, in this issue of the European Respiratory Journal, the detection of Epstein-Barr virus (EBV) DNA in a high percentage of pleural effusions of unknown cause. The authors suggest a possible aetiological contribution of this virus to pleural effusions and describe potential mechanisms involved in EBV reactivation in pleural fluid.

EBV infects >90% of the population worldwide and, like other herpes viruses, it is able to establish a lifelong latent infection with intermittent reactivation to lytic replication. EBV is mostly transmitted through saliva, and primary infection usually occurs subclinically in infancy and childhood. However, in industrialised countries, infection may not take place until adolescence or young adulthood, causing infectious mononucleosis in >50% of cases. After primary infection, EBV persists in the organism in latently infected memory B-cells with occasional shedding into saliva 7, 8. The number of EBV latently infected cells remains stable over years, but may vary among different individuals 9. EBV viral loads in normal adults (healthy carriers) are usually undetectable, with 0.1–24 latently infected B-cells per million peripheral blood mononuclear cells (PBMC) in the circulation 10 and low numbers of viral genomes per infected cell 11. However, viral loads may rise up to 5,000–50,000 genomes per million PBMC at diagnosis of EBV-related malignancies, such as Hodgkin's disease, post-transplant lymphoproliferative disease and AIDS-associated lymphoma 12, 13.

Although the virus rarely causes disease in immunocompetent individuals, latent genes are potentially oncogenic and EBV has been associated with a wide variety of lymphoid and epithelial diseases, both benign and malignant. EBV may infect almost any organ and infection might be associated to complications, such as neurological involvement, including Guillain-Barré syndrome, myocarditis or liver failure, amongst others 14, 15. EBV infection has been found in the pleural space in association with B-cell lymphomas, including primary effusion lymphoma, which is aetiologically linked to human Herpesvirus 8 16, 17, and phyotorax-associated lymphoma 18. However, the role of EBV in nonlymphoma pleural effusions has not been extensively studied. Interstitial pneumonitis has been associated with chronic active EBV infection and primary infection, both in children and in adults, and pleural effusion has been observed as a rare complication of EBV infection 19–21.

In the interesting article by Thijsen et al. 6, the authors report a relatively high percentage (40%) of EBV positivity in pleural fluid by real-time PCR among patients with pleural effusions. This percentage is even higher (59%) amongst patients with unexplained effusions. Although patients with a positive PCR result in pleural fluid were significantly more likely to also be positive in serum, 12 out of 18 patients had a PCR-positive result in pleural fluid, but not in serum. Moreover, all three patients with a viral load in pleural fluid >10,000 geq·mL−1 died within 6 months, while amongst the rest, only 16 out of 57 died. These and other findings led the authors to conclude that EBV could be directly involved in the pathogenesis of pleural effusion.

Even though the percentage of EBV-positive pleural fluids was significantly higher amongst patients with an unexplained pleural effusion diagnosis, EBV DNA was also found in pleural fluids from 15% of patients with a clear diagnosis of the pleural effusion (patients with transudates, empyema or malignancy). Besides, in patients with low viral loads in pleural fluid, the possibility that EBV DNA came from latently infected B-cells present in the fluid rather than from lytic replication could not be excluded. Therefore, additional information from the patients included in the study by Thijsen et al. 6 would be valuable to help define the clinical relevance of the presence of EBV in pleural effusions, as suggested below.

Several lines of evidence led Thijsen et al. 6 to conclude that EBV reactivation could take place locally in pleural fluid: 1) amongst EBV-positive pleural effusions, 12 out of 18 patients had a PCR-positive result in pleural fluid, but not in serum; 2) 50% showed a PCR-positive result in pleural fluid supernatant suggesting the presence of cell-free virus; and 3) two of the patients with a viral load >10,000 geq·mL−1 of pleural fluid died of unexplained interstitial pneumonia. Even though centrifugation to separate cells from supernatants was performed to try and minimise cell lysis, as stated by Thijsen et al. 6, treatment of supernatants with DNase previous to PCR would guarantee that the DNA detected was derived from virus particles and not from rupture of infected cells. All 18 patients with an EBV positive result in pleural fluid, for whom a serum sample was available, showed evidence of having a past infection according to the serological tests used (heterophilic antibodies, immunoglobulin (Ig)M against EBV viral capsid antigen (VCA), IgG against EBV VCA and EBV nuclear antigen (EBNA)). Assessing the presence of EBV early antigen-specific antibodies would be valuable to confirm the possibility of viral reactivation.

The detection of specific antibodies in pleural fluid has been suggested as a marker for the diagnosis of infectious aetiology 1. In the case of tubercular pleurisy, the detection of lipoarabinomannan antibodies in pleural fluid has been reported as a specific diagnostic tool 22. Testing pleural fluid from the patients included in the study by Thijsen et al. 6 for EBV-specific antibodies would give additional information to confirm the role of this virus in pleural effusions.

Thijsen et al. 6 also assessed viral transcription in pelleted pleural fluid cells through the detection of EBER by in situ hybridisation. All six patients with a viral load >1,000 geq·mL−1 and enough cells to perform the assay were negative, probably because the number of infected cells was low. Upon analysis of a second specimen, the patient with a highest viral load in pleural fluid showed EBV positivity in pelleted cells, but no EBNA-2 or latent membrane protein 1 expression was seen. Patterns of latency and viral reactivation could be assessed by means of RT-PCR for latent and lytic transcripts, including the ZEBRA transactivator, DNA polymerase BALF5, or glycoprotein BLLF1 23. This technique is usually more sensitive than in situ hybridisation for the detection of viral transcripts.

Viral loads in pleural fluid were relatively low in most patients (62% were 36–1,000 geq·mL−1; overall median was 454 geq·mL−1). Whilst highest values probably reflected active Epstein-Barr virus replication in pleural fluid, the meaning of intermediate values is difficult to establish. Thus, the motivating work by Thijsen et al. 6 leads the way for additional studies using quantitative PCR in patients with explained and unexplained pleural effusions to establish a cut-off for clinical relevance of Epstein-Barr virus viral load in pleural fluid. Although there are no formal guidelines about how to proceed with the evaluation of pleural effusions of unknown cause 4, and in practice most of them turn out to be malignant 2, perhaps Epstein-Barr virus infection or reactivation should be included in the differential diagnosis in these cases.

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