Copyright ©ERS Journals Ltd 2004 Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis1 Respiratory Diseases Division, and 2 Anaesthesiology and Intensive Care Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico S. Matteo, University of Pavia, Pavia, Italy CORRESPONDENCE: I. Cerveri, Division of Respiratory Diseases, IRCCS Policlinico S. Matteo, via Taramelli 5, 27100, Pavia, Italy. Fax: 39 0382423150. E-mail: i.cerveri@libero.it Keywords: Bronchoalveolar lavage, follow-up studies, pulmonary alveolar proteinosis, respiratory function tests
Received: September 11, 2003
Whole lung lavage (WLL) is still the gold-standard therapy for pulmonary alveolar proteinosis (PAP). The few studies on the duration of the effect of WLL, belonging to a rather remote period, show significant but transient benefits. In 21 patients with idiopathic PAP, the duration of any benefit and, in 16 of them, the time course of lung function improvement (at baseline, 1 week, 6 months, 1 yr and then every 2 yrs after WLL) were evaluated. The present WLL technique takes longer, is invasively monitored and partially modified with respect to past techniques. More than 70% of patients remained free from recurrent PAP at 7 yrs. The bulk of the improvement in spirometric results was almost completely gained in the immediate post-WLL period due to the efficient clearance of the alveoli. At a median of 5 yrs, recovery of diffusing capacity of the lung for carbon monoxide was incomplete (75±19% of the predicted value) and there were residual gas exchange abnormalities (alveolar to arterial oxygen tension difference 3.6±1.5 kPa (27±11 mmHg)) and exercise limitation, probably explained by engorgement of lymphatic vessels. In conclusion, whole lung lavage for idiopathic pulmonary alveolar proteinosis is currently a safe procedure in an experienced setting, and provides long-lasting benefits in the majority of patients. Idiopathic pulmonary alveolar proteinosis (PAP) is a rare disease of unknown cause characterised by the presence of massive quantities of proteinaceous eosinophilic periodic acid/Schiff-positive material in the alveoli 1, and by an excess of surfactant components in lung fluid 2. Whole lung lavage (WLL), introduced by Ramirez 3 in the late 1960s, is still the gold-standard therapy. Indeed, this technique has been much improved over the years, thus enhancing effective removal of material from the alveoli 4. As usually happens with rare disorders, there are only a few published reports of long-term studies including >10 subjects, assessed and followed in a single clinical centre. Based on a review of such series retrieved from the literature, it was recently concluded that, within 5 yrs of diagnosis, almost two-thirds of the evaluable published cases had undergone WLL, with >80% attaining significant, albeit only transient, benefit 5. Nevertheless, the authors emphasised that, in the absence of a randomised trial or even a formal prospective study, the true impact of massive removal of lung surfactant, i.e. WLL, on the natural history of PAP is difficult to ascertain. Moreover, the reports reviewed spanned several decades and most patients were diagnosed and treated before the 1990s, whereas peri- and post-operative WLL procedures and the global management of the disease subsequently improved substantially 46. It has recently been shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) appears to benefit a subset of adult patients with PAP, and may represent an alternative to WLL in treating this disease. Pending more definitive approaches to manipulation of the GM-CSF/anti-GM-CSF antibody balance, the present authors believe that information regarding established therapies is particularly needed 7. To the present authors' knowledge, there have been no reports in the 1990s dealing with series of PAP patients prospectively studied using lung function parameters following WLL. Taking advantage of a WLL programme established 12 yrs ago, in 1990, in Pavia Hospital (Pavia, Italy), the only centre in Italy with such a programme, lung function and gas exchange were evaluated at scheduled time points in the long-term follow-up of a relatively large series of PAP patients. The aim of the present study was to determine the impact of WLL, focusing particularly on the duration of any benefit in order to evaluate whether this was transient or long-lasting. Moreover, exploiting the long-term follow-up with simultaneous measurements of different respiratory parameters, the time course of functional improvement after WLL was investigated in an attempt to shed light on the mechanism by which this technique acts.
Patients and study design During the 12-yr period 19902001, a series of 21 patients from among those subjects with idiopathic PAP referred to Pavia Hospital from other hospitals were treated with WLL. The characteristics of these 21 patients are reported in table 1
After WLL, information was collected on the duration of benefit in all of the 21 patients; 16 of them agreed to participate in a long-term lung function study. Disease recurrence was defined as the recurrence, or significant progression, of respiratory symptoms attributable to PAP, or the application of further therapeutic interventions such as repeated lavage; episodes of infection were not considered to represent disease recurrence. The 16 patients included in the lung function study were scheduled for examination 1 week, 6 months, 1 yr and then every 2 yrs after WLL. Three of these patients interrupted the lung function study, after 3, 5 and 5 yrs, due to their living a long way from Pavia Hospital. The three patients who underwent more than one WLL interrupted the lung function study at their second WLL, which occurred 2, 3 and 3 yrs after the first WLL. Overall, 11 patients completed 3 yrs of lung function follow-up; the last examination among these 11 patients was at a median time of 5 yrs after WLL. All subjects gave their consent prior to entering the study, which was approved by the Ethical Committee of Pavia Hospital.
Whole lung lavage
Measurements made before and after whole lung lavage Spirometry with a helium analyser (Pulmonet III; Sensormedics, Anheim, CA, USA) was used to measure lung function. Forced expiratory volume in one second, forced vital capacity (FVC) and slow vital capacity were determined according to American Thoracic Society criteria 11. Lung volumes were measured by multibreath helium-dilution. Total lung capacity was obtained from the sum of the functional residual capacity and inspiratory capacity. Predicted values for spirometry and lung volumes were obtained from Quanjer et al. 12. Single-breath DL,CO was measured at least in duplicate (Transferscreen II; Jaeger, Würzburg, Germany) and compared to the predicted values of Cotes et al. 13. Arterial blood samples were taken at rest from a radial artery under room air conditions. Arterial oxygen (Pa,O2) and carbon dioxide tensions were measured using an automatic blood gas analyser (Ciba Corning Diagnostics Corp., Hedfield, MA, USA) and PA-a,O2 calculated using a simplified gas equation.
Exercise tolerance was assessed throughout follow-up, except at 1 week, in patients whose PaO2 was
Statistical analysis Additionally, differences between parameters before and 1 week after WLL and at the last examination were tested using a paired t-test. A p-value of <0.05 was considered significant; all tests were two-sided. Results are reported as mean±sd.
Before WLL, 12 of the 21 patients complained of severe dyspnoea at rest and the remainder had a subjective perception of reduced exercise tolerance with severe limitation of daily activities. Blood gas exchange was characterised by moderate-to-severe hypoxaemia accompanied by mild hypocapnia or normocapnia with a very high PA-a,O2 (6.3±2.0 kPa (47±15 mmHg)). Ten patients were receiving oxygen therapy because of persistent respiratory failure. One patient underwent WLL four times between 1990 and 1994 and two patients underwent two WLLs within 3 yrs. After WLL, no other patients showed significant progression of respiratory symptoms attributable to PAP. After 1995, no patients required more than one WLL. No major adverse effects occurred during WLL or during the immediate postoperative care. More than 70% of patients remained free from recurrent PAP manifestations at 7 yrs (fig. 1
The 16 patients included in the lung function follow-up study showed, at baseline, a moderate restrictive pattern with a disproportionate decrease in DL,CO (table 2
One week after WLL, a significant improvement in FVC was observed (table 2
DL,CO showed different behaviour: there was no increase by 1 week (table 2
Pa,O2 and PA-a,O2 improved markedly shortly after WLL (table 2
The mean distance in metres covered before exercise interruption was significantly longer at 6 months than at baseline (p<0.05, 6 months versus baseline post hoc comparison). This distance tended to increase up to 1 yr and the overall trend was significant (p<0.01) (fig. 5
Improvement in all parameters was maintained at the last examination, which was 3 yrs after the WLL in 11 patients and 7 yrs after WLL in two (table 3 3 yrs of observation was 5±2 yrs.
The major findings of the present study are that WLL is a safe procedure with long-lasting benefit, the proportion of subjects free from recurrent PAP being >70% at 7 yrs. The bulk of the improvement in spirometric parameters was almost completely gained during the period immediately following WLL due to the efficient clearance of alveolar spaces. The slow and incomplete recovery of DL,CO and the residual gas exchange abnormalities and exercise limitation may be explained on the basis of engorgement of lymphatic vessels within interlobular septa. No complications during (e.g. hypoxaemia during the emptying phase and haemodynamic instability) or after (e.g. endotracheal granuloma or stenosis, pleural collections and hydropneumothorax) WLL were observed in the present series. Over the time span of the study, the WLL technique improved continuously and the team's experience increased: as a probable consequence, no patient after 1995 in the present series required more than one lavage 4, 8. Careful assessment during the preparation and WLL, as well as the choice of the nondependent lung lavage procedure, allowed even severely impaired PAP patients to be treated safely and successfully. This may justify the invasive and prolonged nature of the present WLL, i.e. treatment sessions lasting >4 h per lung and requiring pulmonary and radial artery catheterisation, bronchodilator infusions and prolonged admission to the intensive care unit, compared to the standard procedures reported in the literature 5, 15. Recently, a less cumbersome procedure, bronchofibrescopic lobar lavage, has been proposed for carefully selected patients 16. Cheng et al. 16 underline the fact that this procedure is safe and does not require anaesthetic support; however, it is recommended only in milder disease, or, conversely, in particularly severe cases in which the physiological derangement of WLL, especially during the drainage phase, would not be tolerated or general anaesthesia would be hazardous 7. To date, the rarity of PAP has prevented formal prospective studies from elucidating the response to WLL, particularly in terms of the onset and duration of the benefit of such management. One further difficulty in evaluating therapeutic interventions in PAP is the variable natural history of the disorder and its possible, although infrequent, spontaneous resolution. In the present study, no patients showed any improvement in the months prior to WLL. The present study documents a median duration of overall benefit from WLL of 3 yrs, with 70% of patients followed beyond 3 yrs remaining free of recurrent PAP manifestations. In 55 reviewed instances, Seymour and Presneill 5 reported a median duration of clinical benefit of 15 months, with <20% of patients followed beyond 3 yrs remaining free of recurrent PAP manifestations. These results should not be too surprising, taking into account the fact that the cases reviewed were from a rather remote period, ranging late 1960s1980s, at the dawn of the WLL technique 2, 1720. In contrast, the present series was collected in the 1990s, when the procedure had already improved considerably 4, and the present refinements to the treatment may explain the improvement in the duration of response to WLL. The strength of the present lung function follow-up and its analysis lies in the simultaneous measurement of various respiratory parameters. The results allow some speculation to be made as to the mechanism by which WLL acts. With the exception of DL,CO, all parameters had improved significantly by 1 week after WLL. The immediate therapeutic efficacy of WLL has been supported by many clinical reports. The major feature of PAP is that the alveoli are flooded with lipoproteinaceous material. Removal of this material by WLL immediately improves lung volumes and probably also the ventilation/perfusion ratio, leading to the remarkable increase in Pa,O2. Interestingly, the improvement in DL,CO, occurring over 6 months, is slower than that of lung volumes and gas exchange. Furthermore, unlike the recovery of lung volumes, the recovery of DL,CO is incomplete in almost all patients at the end of the follow-up. This explains the persistent impairment in gas exchange and exercise tolerance: indeed, PA-a,O2 remains in the pathological range and the distance covered during exercise testing is always short considering the relatively young age of the subjects. These data are consistent with the HRCT scan pattern in PAP following WLL, in which, in comparison with pre-WLL features, there is a decrease in the extent of ground-glass opacities but a persistence of reticular opacities and interlobular septal thickening 21. This pattern may be explained on the basis of engorgement of lymphatic vessels within interlobular septa, providing more efficient clearance from alveolar spaces than before WLL. This could account for the slow recovery of DL,CO and the impairment in gas exchange and exercise tolerance.
There is increasing evidence that idiopathic PAP results from an autoimmune disorder, characterised by antibodies directed against GM-CSF, causing dysfunction of alveolar macrophages 22, 23. Whether the long-lasting beneficial effect of WLL is simply due to the removal of cellular debris from airspaces or to some interference with the neutralising activity of antibodies directed against GM-CSF remains to be established 8. Since the late 1990s, reports of single cases or small series have suggested that exogenous GM-CSF appears to benefit adult patients with PAP and may represent an alternative to WLL for treating the disease 2427. Recently, Seymour et al. 28 showed, in a study on 14 patients, that a subset of 43% of their patients with PAP exhibited clinical responses to recombinant GM-CSF therapy, and, in a subsequent paper, Seymour et al. 5 confirmed the benefit in In conclusion, whole lung lavage for idiopathic pulmonary alveolar proteinosis is currently a safe procedure in an experienced setting, and yields durable benefit in the majority of patients. Future research should investigate the efficacy of biological therapy with granulocyte-macrophage colony-stimulating factor in combination with whole lung lavage, particularly in those patients who respond less well to whole lung lavage and/or require more than one lavage because of recurrence of pulmonary alveolar proteinosis.
For editorial comments see page 503.
This article has been cited by other articles:
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||