I read with great interest the paper by de Jong et al. [1]. The authors conclude from a carefully conducted study that scores derived from CT scans are more sensitive in detecting progression of cystic fibrosis in children and adults than pulmonary function tests. I have no difficulty in accepting any such outcome. However, it seems that undue reliance was placed on predicted pulmonary indices, and that the value of a control group was not fully appreciated. The interpretation of longitudinal data on lung function is bedeviled by the fact that lung volumes and ventilatory flows increase due to growth up to age 30+ years, and decline thereafter [2]. Since in the type of study carried out by de Jong a matched control group is usually too costly to be feasible, it is often replaced with predicted values, as was done in this study. This approach has potential problems which I will illustrate in children and adolescents.

The authors selected prediction equations for their youngest subjects that have been shown to fit a cross-section of healthy European children and adolescents well [3]. In using them they implicitly assumed that healthy individuals will track along the cross-sectional predicted values. Improvement or decline in these indices in sick children then indicates either improvement or deterioration in their condition. However, cross-sectional prediction equations do not describe the longitudinal trajectory of individuals. The top panel in figure 1 shows the mean FEV1 and its 95% confidence interval, expressed as either Z-score or per cent predicted, in over 350 healthy non-smoking boys followed up at half year intervals for up to 7 years; their cross-sectional data contributed to the prediction equations [3] used by de Jong et al. In this study the variability of FEV1 within subjects tested on 5 consecutive days was 2.7% [4], relatively small compared to 11.6% between individuals [3]. Whilst the overall mean FEV1 is very nearly 100% predicted, there is a clear trend with a minimum at about age 13-14 yr. The lower panel illustrates the pattern in 6 boys. Five show a steady rise after age 13-14 yr, in three of them preceded by a decline of up to one unit Z-score (11% predicted); one boy seems to be tracking at about a constant level. Although the selected reference equation has gone a long way in accommodating the changing relationship between body and lung dimensions at these ages [3] and the above pattern would be more pronounced with older prediction equations, this equation nor any other one available does not describe individual growth curves. In de Jong's study Z-scores were recorded at three year intervals. Note how even in a healthy individual in this age range such scores might have easily gone up or down by as much as one unit, a fall in the youngest subjects being compensated by a rise in the older ones. Similar reasoning holds for girls and for adults.

These observations underline the fact that cross-sectional spirometric reference values, apart from being imperfect, do not describe the growth and decline of pulmonary function within individuals. It follows that it might be useful to analyse separately longitudinal changes in those under 13 year, and in older adolescents possibly up to 30 yr. Even then spirometric findings need to be compared to findings in a matched control group. Given the difficulties in interpreting longitudinal spirometric data, obviously the CT technique provides an apparently reliable and reproducible as well as practical alternative for assessing the progression of lung disease in cystic fibrosis, albeit a costly one.

Dear Editor,

We read with great interest the case report by Moore et al (1) on the diaphragm weakness of two patients after anatomically distant surgery. We are currently following a patient who had bilateral paralysis of the diaphragm after a nephrectomy for renal cancer. The patient, a 60 year old male, non-smoker, without any concomitant cardiac or lung disease, underwent surgery in August 2004 and immediately after the operation he complained of orthopnea. Chest x-rays showed the elevation of both hemi- diaphragms, which was not present preoperatively, along with a restrictive ventilatory defect detected by spirometry (TLC 61% pred, VC 72% pred, FEV1 67% pred, FEV1/VC 70%). The diagnosis of bilateral paralysis was confirmed by EMG and respiratory muscle strength assessment in October 2004. Because of a nocturnal oxygen desaturation, he started with nightly non-invasive ventilation. Up to now he has also undergone periodic courses of respiratory muscle training. In 2004 and 2005, he was periodically checked and an improvement in VC was found, but not in PImax nor in TwPdi. Moreover, the December 2005 check-up revealed that nocturnal oxygen desaturation significantly improved and that the patient stopped the ventilation support.

Diaphragm paralysis is associated with renal cancer and is considered to be a paraneoplastic syndrome (2,3), however, in our patient the temporal link between the surgical operation and paralysis is evident. Moreover, during the operation and after the perioperative period our patient did not undergo a central venous cannulation nor did he experience any electrolyte disturbance. Postoperatively, the patient also underwent magnetic resonance imaging, which excluded any injury to his spinal cord. Therefore, the similarity between the case histories presented by Moore et al (1) and our patient appears to be evident.

Additionally, we think that the patient’s follow-up is of interest. So far, the patient’s VC has recovered 0.48 L, being 4.2 L and 86 % of predicted value in clinostatism. Furthermore, VC now accounts for 2.3 L and 47% of predicted in orthostatism and can assure a normal oxygen saturation during the sleep. However, the patient’s diaphragm is still paralysed, since the TwPdi value is extremely low (3 cm H2O) and the fall in VC from clinostatism to orthostatism is significant (45%). The recovery of the VC might be due only to the increase in strength of the accessory inspiratory muscles, likely due to the respiratory muscle training courses. This finding further supports the recommendation by Moore et al (1) to measure the diaphragm strength apart from the global inspiratory muscle strength in patients with raised hemi-diaphragms after surgery.

References

1. Moore AJ, Moxham J, Polkey MI. Diaphragm weakness as a cause of breathlessness after anatomically distant surgery. Thorax 2005; 60:786-787

2. Thomas NE, Passamonte PM, Sunderrajan EV, et al. Bilateral diaphragmatic paralysis as a possible paraneoplastic syndrome from renal cell carcinoma. Am Rev Respir Dis 1984; 129:507-509

3. Rijnders B, Decramer M. Reversibility of paraneoplastic bilateral diaphragmatic paralysis after nephrectomy for renal cell carcinoma. Ann Oncol 2000; 11:221-225.

RSV infection in prematurely born infants

We thank Drs Clifford and Deshpande for their comments on our paper [1]. Both are concerned about the cost-effectiveness of Palivizumab. Our paper, however, was not about the cost-effectiveness of Palivizumab but to examine prospectively healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants. Importantly, we demonstrated an effect not only on hospital admission, but also on GP attendances and subsequent cough and wheeze.

In response to Dr Clifford’s specific comments:
• We take conflicts of interest statements very seriously.
• We cannot comment on the percentage of smokers in the non-consenters, as it would be unethical to collect detailed data on parents who had refused to take part in the study.
• It is a pity Dr Clifford did not contact us directly as we would have been very pleased to have given him our raw data, if he wished to undertake an appropriately designed cost effectiveness study, and contacting us would have revealed that the two infants who received Palivizumab and had an RSV LRTI were not admitted to hospital.
• We agree it is very important to find effective ways to stop antenatal women and house-holders of premature babies smoking. As our data demonstrate current methods are clearly ineffective.

In response to Dr Deshpande:
• We apologise the duration of oxygen therapy was given in a confusing fashion, as postmenstrual age (wks), not as number of weeks since birth.
• The 40% rate of BPD at 36 weeks post menstrual age is very similar to the 46% reported recently [2].
• We have recently reported [3] that diminished lung function is a risk factor for RSV infection and subsequent respiratory morbidity, but in that paper also report that RSV infection is an independent risk factor for days of cough and wheeze.

In conclusion, we emphasize our study was not about the cost- effectiveness of Palivizumab, but to assess health care utilisation and respiratory morbidity following RSV infection. From the results of all studies, hypotheses are generated and need to be tested – hence our comments regarding consideration of giving Palivizumab to infants who have siblings and whose mothers smoked during pregnancy. We hope our comments will encourage researchers to undertake an appropriately designed study to test this.

References

1 Broughton S, Roberts A, Fox G, Pollina E, Zuckerman M, Chaudhry S, Greenough A. Prospective study of healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants. Thorax 2005;60:1039-1044.

2 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, Wrage LA, Poole K. Validation of the National Institutes of Health concensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60.

3 Broughton S, Bhat R, Roberts A, Zuckerman M, Rafferty G, Greenough A. Diminished lung function, RSV infection and respiratory morbidity in prematurely born infants. Arch Dis Child 200691:26-30.

Dear Editor,

We read with interest the recent paper by Sin and colleagues (1) which, we believe, raises more questions that it answers.

A major concern is the fact that ascertainment of mortality was incomplete for a significant proportion of patients (973/5086), corresponding to 19% of the total (not the reported 12%), who did withdraw prematurely from the study. This loss to follow up was more likely to occur in the placebo group. The authors use the ISOLDE study (2) to claim that patients who withdrew prematurely were more likely to die and that therefore the hazard ratio is in fact an underestimate of the benefit of inhaled corticosteroids (ICS). However, the ISOLDE data are themselves contradictory on this point. The claim is based on an abstract from the ISOLDE study that states that 29 deaths occurred before withdrawal and 74 subsequently (3). On the other hand, the original ISOLDE article reported 68 deaths before withdrawal, which would leave only 35 afterwards.(2) The claim of a higher death rate after withdrawal may therefore be incorrect.

We believe that differential identification of deaths may have occurred as suggested by Figure 1 in the paper and that this could easily have biased the hazard ratio. The figure first implies a hazard ratio of 1, with no difference in mortality between the ICS and placebo group, during the first 9 months of follow-up, the only time period where every single patient is included and loss to follow-up is of no consequence. This initial 9-month period thus involves all 5086 patients and around 50 deaths, a quarter of all deaths. The subsequent apparent benefit of ICS is exclusively the result of spurts of excess mortality in the placebo group that occurred at unusually specific time points, namely between the 9th and 12th months of follow-up, as well as just after the 24th month. In contrast, the rate of mortality in the ICS group appears to be fairly constant at roughly 1.6 deaths per 100 per year throughout the 3-year follow-up. From the natural history of COPD, however, we would also expect a constant rate of mortality in the placebo group, albeit at a higher rate, if indeed ICS are beneficial. This observation of spurts of excess mortality in the placebo group at specific time points is more suggestive of a study design effect than of a real drug effect. Indeed, if ICS were effective, their benefit would be more likely gradual throughout the follow-up, rather than kicking in to prevent short spurts in mortality precisely at 9 and 24 months after initiation. This phenomenon suggests differential misclassification of deaths or informative censoring between the placebo and ICS groups. The authors could describe the 20 or so deaths, as well as the withdrawals, occurring in the placebo group between the 9th and 12th months of follow-up, and after the 24th month.

The reduction in all-cause mortality resulted from a reduction of deaths due to cancer and to other causes, but not a reduction in cardiac deaths, and is therefore not consistent with the mechanism of benefit of inhaled corticosteroids in reducing overall mortality which is usually postulated (4). Some of the apparent beneficial effect of ICS might be the result of withdrawal of these medications (5) which will occur in the placebo arm of the trials included in the ISEEC study. Such withdrawal might result in relative adrenal insufficiency. It would therefore be useful to stratify the analysis of the possible benefit of ICS in reducing mortality by prior use of corticosteroids, both inhaled and systemic. Such a stratified analysis should also be considered in the much anticipated TORCH study.

Pierre Ernst and Samy Suissa, McGill Pharmacoepidemiology Research Unit, McGill University.

Reference List

1. Sin DD, Wu L, Anderson JA et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005; 60(12):992-997.

2. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br Med J 2000; 320(7245):1297-1303.

3. Waterhouse JC, Fishwick D, Burge PS. What caused death in the ISOLDE study ? European Respiratory Journal 14[Supp. 30], 387S. 1999.

4. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170(7):760-765.

5. Wouters EF, Postma DS, Fokkens B et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax 2005; 60(6):480-487.