AAT Deficiency - Brief Information

AIR Research

The COPDX Plan: Australian and New Zealand Guidelines for the management of
Chronic Obstructive Pulmonary Disease 2003.

C/- The Australian Lung Foundation, PO Box 847, Lutwyche, QLD 4030, Australia.
mckenzied@sesahs.nsw.gov.au

Decline in FEV1 in patients with PiZ alpha-1-antitrypsin deficiency: the
Australian experience.

Department of Respiratory Medicine, St.Vincent's Hospital, Melbourne, Victoria,
Australia. jburdon@bigpond.com

OBJECTIVE: Alpha-1-antitrypsin (alpha1antitrypsin) deficiency is a rare
hereditary disorder which characteristically presents with emphysema at an early
age. The aim of the present study was to determine whether the rate of decline
of lung function in alpha1antitrypsin-deficient subjects in Australia was
similar to that found elsewhere. METHODOLOGY: Patients registered with the
Australian Alpha-1-Antitrypsin Replacement Program were studied. All patients (n
= 50) had a serum alpha1antitrypsin concentration of < 0.3 g/L and had had
spirometry measured over at least 2 years. They were compared with a group of
normal volunteers (hospital staff, n = 107) with normal alpha1antitrypsin levels
and phenotypes and with no clinical history of lung disease. All had spirometry
measured for periods ranging from 2 to 6 years. The rate of decline of forced
expiratory volume in 1 s (FEV1) for each subject was calculated by least squares
linear regression using FEV1 against the time from entry into the study.
RESULTS: The group mean (+/- SD) rate of decline in FEV1 was significantly
greater (P < 0.01) in the alpha1antitrypsin-deficient patients (88 +/- 71
mL/year) than for the normal controls (-15 +/- 48 mL/year). There was no
difference in decline in FEV1 when the data was analysed for gender and for
index versus non-index cases. CONCLUSION: The results confirm previous reports
of an accelerated rate of decline of FEV1 in patients with alpha1antitrypsin
deficiency. Our results indicate that the rate of decline of lung function in
alpha1antitrypsin deficient subjects in Australia is similar to that found in
reported series from elsewhere.

Fibre-optic bronchoscopy in adults: a position paper of The Thoracic Society of
Australia and New Zealand.

Wood-Baker R, Burdon J, McGregor A, Robinson P, Seal P; Thoracic Society of
Australia and New Zeeland.

Department of Respiratory Medicine, Royal Hobart Hospital, Hobart, Tasmania,
Australia.

Fibre-optic bronchoscopy in adults is a common procedure in clinical respiratory
practice. Under controlled conditions it is safe, resulting in relatively few
significant adverse events. The present position paper updates guidelines
previously published by The Thoracic Society of Australia and New Zealand and is
based on evidence obtained by searching the Medline and Embase databases. The
level of evidence to support recommendations is indicated in the text. Where no
evidence has been found, the guidelines reflect the opinions of the authors.
Specific recommendations are made regarding sedation and anaesthesia, the
cleaning of bronchoscopes and the training of bronchoscopists.

Department of Respiratory Medicine, St Vincent's Hospital, Fitzroy, Victoria,
Australia.

OBJECTIVE: The aim of the present study was to determine treatment practices for
spontaneous pneumothorax (PTX) in Australia. METHODOLOGY: A questionnaire
regarding treatment of PTX was posted to all medically qualified members of the
Thoracic Society of Australia and New Zealand resident in Australia. RESULTS:
Fifty-three per cent (n = 226) of questionnaires were returned. Twenty-one
responses were judged to be informal and rejected from analysis. The results
indicate a general agreement in the treatment of small and large PTX but a wide
variation in PTX of intermediate size. CONCLUSION: Opinion regarding the optimal
treatment for PTX of intermediate size was found to vary considerably. There is
a need for evidence-based development and publication of best practice
guidelines for PTX.

Sudden onset of breathlessness. What are the possibilities in the pregnant
patient?

BACKGROUND: Breathlessness is common during pregnancy and is usually due to
hormonal changes or mechanical factors. However, it is important to ensure that
no other cause for this symptom is present, and to exclude underlying or
co-existent conditions.

Comparison of efficacy and ease of handling of salmeterol and terbutaline powder
inhalers.

A multicentre, randomised, open, parallel-group study was performed to compare
the efficacy, tolerability and ease of handling of salmeterol xinafoate 50
micrograms twice daily via the Diskus inhaler with terbutaline sulphate 500
micrograms four times daily via the Turbuhaler inhaler. Two hundred and
sixty-three patients (aged 18-79 years, baseline FEV1 50-90% predicted, mean
PEFR 85% of response to salbutamol) were randomised to treatment with salmeterol
(n = 136) or terbutaline (n = 127). A statistically significant difference in
favour of salmeterol was seen between treatment groups for the primary efficacy
variable, mean morning PEFR (difference in adjusted means 25.4 l/min, p <
0.001). Within the groups randomised to each device, ease of handling
assessments favoured the Diskus inhaler over the Turbuhaler inhaler. More
patients liked the Diskus inhaler than the Turbuhaler inhaler (98% vs 72%, p <
0.001). The Diskus inhaler received better scores than the Turbuhaler inhaler
for all features assessed in the device questionnaire.

The proteinase-antiproteinase theory of emphysema: a speculative analysis of
recent advances into the pathogenesis of emphysema.

This review concerns the reasons why only an estimated 10-15% of patients with
alpha-1-antitrypsin (A1AT) deficiency develop the destructive lung disease known
as emphysema. The arguments presented revolve around the
proteinase-antiproteinase balance in the 'microenvironment' of the epithelial
space of the lung. Attention is focused on the balance between destructive
enzymes such as neutrophil elastase and protective proteins such as A1AT,
secretory leucocyte proteinase inhibitor (SLPI), human elastase inhibitor (HEI)
and elafin. When neutrophil elastase is already attached to the elastin fibres
the smaller molecules SLPI and elafin appear to be better inhibitors of this
enzyme than larger inhibitors such as A1AT and HEI. Furthermore, SLPI and elafin
may provide the first line of defence against proteinase attack from neutrophil
elastase. In trying to explain the variability in the clinical expression of
A1AT-deficiency and the development of emphysema, the importance of changes to
A1AT, SLPI and elafin molecules induced by smoking and/or oxygen free radicals
has been considered. It is possible that emphysema only develops in patients who
have SLPI/elafin deficiency as well as A1AT deficiency.

Function of a rare variant of alpha-1-antitrypsin, phenotype P(i) EFranklin S, a
poor inhibitor of human neutrophil elastase.

Department of Chemical Pathology, St. Vincent's Hospital Melbourne, Fitzroy,
Victoria, Australia.

A 31-year-old woman with the rare alpha-1-antitrypsin (A1AT) phenotype P(i)
EFranklin S presented to this laboratory. Since little is known about the
EFranklin protein, a study was established to investigate the biochemical
properties of this glycoprotein, notably its inhibitory activity against human
neutrophil elastase (HNE), compared with that of the more common A1AT variants M
and Z. The serum A1AT level of 1.8 g/l (reference range 0.8-2.2 g/l) and
anti-neutrophil elastase capacity (ANEC) value of 28 microM (reference range
15-42 microM) of this variant were normal. However, the association rate
constant (AC) of the isolated and purified EFranklin protein 2.7 (0.4) x 10(6)
M-1 s-1 at 25 degrees C was significantly lower compared with that in the normal
M variant 9.1 (0.9) x 10(6) M-1 s-1. This implies that this form of A1AT is
expressed at normal levels in serum but is functionally impaired as an inhibitor
of HNE. The in vivo serum inhibition time of HNE was estimated to be 66 ms for
the purified EFranklin protein compared with 20 ms for the M protein. While this
protein is not an efficient inhibitor of HNE, there are sufficient molecules in
the serum to achieve 100% inhibition of HNE and to protect the lung against
proteinase attack. In conclusion, individuals who inherit the rare EFranklin
variant in conjunction with the M or S A1AT molecules do not appear to have a
high risk for the development of emphysema.

Asthma in pregnancy and lactation. A position paper for the Thoracic Society of
Australia and New Zealand.

Department of Respiratory Medicine, Austin and Repatriation Medical Centre,
Heidelberg, VIC.

Evaluation of impairment, disability and handicap caused by respiratory
disease--the Thoracic Society of Australia and New Zealand.

Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human
neutrophil elastase.

Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have
very low serum levels and are predisposed to emphysema. There have also been
reports of emphysema being associated with the heterozygous phenotype FZ. To
investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F
alpha 1AT against human neutrophil elastase (HNE) was compared with that of
common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was
used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F
(partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera.
The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD
0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1
respectively. F was found to have reduced activity much like that of Z, the
alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and
FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo
inhibition time for FZ was almost three times longer than for MZ, indicating
greater exposure to proteolytic damage from free elastase for FZ than MZ
individuals. In conclusion, F alpha 1AT is expressed in serum at low normal
levels but is dysfunctional in its ability to inhibit HNE. Individuals who
coinherit the F and a deficiency allele such as Z or Null, are likely to have a
high risk for the development of emphysema. The disease risk for F homozygotes
remains to be determined.

Effect of inhaled morphine on the development of breathlessness during exercise
in patients with chronic lung disease.

BACKGROUND: Inhaled morphine has previously been shown to increase exercise
endurance in patients with chronic lung disease. A similar study was performed
to determine whether inhaled morphine reduces the sensation of breathlessness in
this group of patients. METHODS: A randomised double blind study on the effect
of nebulised morphine on both exercise induced breathlessness and maximum
achievable power output using isotonic saline as a control was performed in 10
patients with stable chronic lung disease. Each subject performed a progressive
exercise test (Jones' stage I) on an electrically braked cycle ergometer. The
work load was increased by 10 watts per minute and subjects exercised to
exhaustion. At the end of each minute of exercise patients were asked to rate
their degree of breathlessness according to a modified Borg scale. All subjects
were randomised to receive either inhaled morphine sulphate 1 mg/ml (5 ml) or
isotonic saline (5 ml) by wet nebulisation. The effect of morphine and saline on
the achieved exercise capacity and the development of breathlessness during
exercise was tested on separate days. RESULTS: The mean dose of morphine inhaled
was 1.24 mg. There was no difference in maximum power output achieved, minute
ventilation at maximum power output, nor the degree of breathlessness at maximum
power output between the groups treated with morphine and placebo. The degree of
breathlessness was related to the power output achieved during exercise by a
power function relationship (mean r: morphine = 0.86, saline = 0.87). However,
there was a wide variation in the sensation for any given power output in both
groups. There was no difference in the group mean slopes (morphine = 1.15,
saline = 1.00) or intercepts (morphine = 0.07, saline = 0.15) in this
relationship between the morphine and saline treatment groups. CONCLUSIONS: In
patients with severe chronic lung disease inhaled morphine in the doses used in
this study does not relieve exercise induced breathlessness nor does it increase
maximum power output achieved during progressive exercise.

Alpha-1-antitrypsin PLowell: a normally functioning variant present in low
concentration.

BACKGROUND: Alpha-1-antitrypsin deficiency is associated with a high risk for
the development of emphysema, particularly for phenotype Pi ZZ, which is both
deficient and an abnormal inhibitor of the powerful proteolytic enzyme, human
neutrophil elastase. The rare variant PLowell is also expressed at abnormally
low levels, but its anti-elastase activity has not been described. AIM: To study
the anti-elastase activity of alpha-1-antitrypsin PLowell and compare it to the
common M, S and Z proteins. METHOD: Alpha-1-antitrypsin from a female patient
aged 75 years with the rare genotype PLowell NullBellingham was studied for its
ability to inhibit human neutrophil elastase in a time dependent manner.
RESULTS: PLowell has near normal function as an inhibitor of human neutrophil
elastase with an association rate constant of 7.4 x 10(6) M-1 S-1 at 25 degrees
C, similar to that of M and S. CONCLUSION: Alpha-1-antitrypsin PLowell is
associated with a severe deficiency of alpha-1-antitrypsin similar to Z, but
unlike that protein it has near normal function as an anti-elastase.

Alpha 1-antitrypsin deficiency and anti-proteinase 3 antibodies in
anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

alpha 1-antitrypsin (alpha 1-AT) is a naturally occurring inhibitor of
proteinase 3 (PR3) and elastase, two of the target antigens of anti-neutrophil
cytoplasmic antibodies (ANCA). An increased incidence of alpha 1-AT phenotypes
associated with dysfunctional alpha 1-AT or low serum levels has been reported
in patients with anti-PR3 antibodies. We have studied the relationship between
ANCA, and phenotypes and serum levels of alpha 1-AT. Phenotypes usually
associated with a moderate or severe reduction in alpha 1-AT serum levels or in
dysfunctional activity were found more often in individuals with anti-PR3
antibodies than in the general population: four of the 31 patients (13%) with
anti-PR3 antibodies had phenotypes MZ (n = 2), S (n = 1) or Z (n = 1) (P <
0.05). However, the corresponding alpha 1-AT serum levels were normal (n = 3) or
elevated (n = 1). None of the 31 sera with anti-PR3 antibodies had low levels of
alpha 1-AT. No abnormal alpha 1-AT phenotype was demonstrated in seven patients
with anti-elastase antibodies, despite a low level of alpha 1-AT in one serum.
Anti-myeloperoxidase antibodies are common in patients with ANCA, but no
abnormal phenotype or low serum alpha 1-AT level was demonstrated in any of 29
sera containing these antibodies. Finally anti-glomerular basement membrane
(GBM) antibodies occur occasionally in patients with ANCA-associated diseases,
but again none of 10 sera had an abnormal alpha 1-AT phenotype or low serum
level. ANCA were not demonstrated by indirect immunofluorescence in any serum
from 73 patients with abnormal alpha 1-AT phenotypes. These results confirm that
patients with anti-PR3 antibodies often have alpha 1-AT phenotypes that are
usually associated with low serum levels of alpha 1-AT or with dysfunctional
protein. Nevertheless, the incidence of anti-PR3 antibodies in patients with
abnormal alpha 1-AT phenotypes is very low. This probably reflects the rarity of
Wegener's granulomatosis, the major disease associated with anti-PR3 antibodies,
and the relative frequency of abnormal alpha 1-AT phenotypes. The mechanism for
the development of anti-PR3 antibodies in patients with abnormal alpha 1-AT
phenotypes is not clear, but may relate to the increased propensity of unbound
and uninhibited PR3 to stimulate autoantibody production.

OBJECTIVES: To compare the prevalence of asthma, hay fever and atopy in Asian
immigrants in Melbourne with that in Australian-born non-Asians and
Australian-born Asians, and to investigate the association of these conditions
with atopic status, length of stay in Australia and IgE levels in Asian
immigrants. DESIGN: We performed a cross-sectional study by telephone
interviews, using standard questionnaire items on respiratory and allergic
symptoms. A random sample of 636 recent Asian immigrants of ethnic Chinese
origin, 109 Australian-born Asians and 424 Australian-born non-Asians were
selected from the 1991 Melbourne Telephone Directory, using a presumptive
surname list. Skin tests to determine atopic status were performed on 269 Asian
immigrants and 167 of these also had serum levels of total and specific IgE
estimated. RESULTS: In the under 20 years age group the prevalence of wheeze or
asthma ever was higher in Australian-born non-Asians and Australian-born Asians
than in Asian immigrants (P < 0.001), and the prevalence of hay fever was higher
in Asian immigrants and Australian-born Asians than in Australian-born
non-Asians. In those older than 20 years, hay fever was almost twice as common
in Asian immigrants as in Australian-born non-Asians (P < 0.001 for 20-40 years
age group; P < 0.01 for > 40 years). The prevalence of hay fever and, to a
lesser degree, asthma in Asian immigrants increased significantly with length of
stay in Australia, independent of age at arrival, sex and atopic status (trend
test: P < 0.001 for hay fever; P = 0.05 for asthma). Atopy was more common in
Asian immigrants and Australian-born Asians than in Australian-born non-Asians
(P < 0.001) and was very strongly associated with both hay fever and asthma,
irrespective of length of stay. Pollen and mite sensitivities were more common
in Asian subjects (twice as common for Asian-born and 1.5 times for
Australian-born) than non-Asian subjects (P < 0.01). Among Asian immigrants,
elevated total IgE level (> 100 IU/mL) was strongly associated with a history of
hay fever (P < 0.01) and wheeze or asthma ever (P < 0.05), atopy (P < 0.001) and
the presence of specific IgE antibodies to grass pollen, dust mite, cockroach
and Ascaris antigens (P < 0.05 for all). CONCLUSION: We found substantial
differences in the prevalence of asthma, hay fever and atopy between Asian
immigrants, Australian-born Asians and non-Asians. The prevalence of hay fever
and asthma in Asian immigrants was strongly associated with length of stay in
Australia, suggesting that environmental factors are important in the
pathogenesis of these diseases.

Chronic lung diseases and the perception of breathlessness: a clinical
perspective.

Breathlessness is an extremely common symptom. Its genesis is incompletely
understood but is known to be largely determined by many of the mechanical
factors associated with the act of breathing. As with all subjective sensations
various other factors including volition, behavioural style and other cortical
and subcortical factors play a part in its genesis. The relief of breathlessness
is primarily directed at the underlying disorder. In those conditions and
situations where specific therapy has little to offer or little impact it is
reasonable to consider ways of reducing the perception of breathlessness by
pharmacological means. However, to date there is no convincing evidence that use
of drugs in the pursuit of the relief of breathlessness has any specific effect
in modifying the perception of this often distressing symptom. Any reduction in
breathlessness achieved in this way can be adequately explained in terms of a
reduction in ventilation and other indices of respiratory mechanics.

Absence of alpha-1-antitrypsin (Pi Null Bellingham) and the early onset of
emphysema.

Department of Chemical Pathology, St Vincent's Hospital, Melbourne, Vic.,
Australia.

BACKGROUND: Alpha-1-antitrypsin is the body's major inhibitor of human
neutrophil elastase, a powerful proteolytic enzyme capable of degrading the
common tissue components. There are over 70 genetic variants of
alpha-1-antitrypsin, with the Z allele being of greatest clinical relevance.
Individuals homozygous for this allele (approximately one in 2500 in Caucasians)
have low serum alpha-1-antitrypsin levels (10-20% of normal) and are predisposed
to emphysema, especially if they smoke. Much rarer are mutations which result in
the complete or almost complete absence of alpha-1-antitrypsin in the serum.
AIM: To determine the cause of complete absence of alpha-1-antitrypsin in a
patient who at age 27 years had both emphysema and idiopathic cardiomyopathy.
METHODS: Molecular biology techniques were used to sequence the
alpha-1-antitrypsin gene. Allele specific amplification was used to show the
presence of the mutations in other family members. RESULTS: Investigation showed
that the proband was homozygous for the Pi Null Bellingham variant of
alpha-1-antitrypsin due to the mutation Lys 217 (AAG) to Stop (TAG). His
grandmother was heterozygous for Pi Null Bellingham and the additional rare
variant P Lowell, Asp 256 (GAT) to Val (GTT), a variant that also results in
alpha-1-antitrypsin deficiency. CONCLUSION: Patients with complete absence of
alpha-1-antitrypsin develop premature emphysema not having smoked or after only
minimal exposure, and much earlier than the more common Pi Z individuals who
have the usual form of alpha-1-antitrypsin deficiency.

The 'shrinking lungs syndrome'--an infrequently recognised feature of systemic
lupus erythematosus.

Two cases of the 'Shrinking Lungs Syndrome' in patients with systemic lupus
erythematosus are described to highlight an infrequently recognised feature of
this condition. Respiratory muscle weakness, improved by steroid therapy, was
demonstrated in each patient and considered to be the mechanism underlying the
respiratory symptoms.

We report a case of lung infection, clinically resembling tuberculosis, caused
by Rhodococcus rubropertinctus. The patient had no apparent immunosuppression
which is unusual for disease caused by the 'rhodochrous' complex. The infection
responded successfully to oral anti-tuberculous therapy, which included
rifampicin, and to oral tetracycline.

Comparison of the effects of nebulized terbutaline with intravenous enprofylline
in patients with acute asthma.

Ruffin R, Bryant D, Burdon J, Marlin G, Mitchell C, O'Hehir R, Wilson J,
Woolcock A, Webb S.

We compared the bronchodilating effects of intravenously administered
enprofylline (2 mg/kg) with nebulized terbutaline (10 mg) in patients presenting
to hospital with acute asthma in a multicenter double-blind parallel study. One
hundred twenty three patients were randomized into the study, and 69 of these
fulfilled the inclusion criteria and a retrospective time to study entry
criterion; 34 received enprofylline and 35 received terbutaline. There was no
significant difference in maximum increase in forced expired volume in 1 second
(FEV1) between the enprofylline group (0.24 +/- 0.33 L) and the terbutaline
group (0.25 +/- 0.28 L) (p greater than 0.05), nor for the increase in FEV1 over
the 1-hour study period. Tremor was reported more in the group receiving
terbutaline, and nausea was reported more in the group receiving enprofylline.
Two patients experienced hypotension and one patient had a vasovagal episode
with enprofylline treatment. Both agents acted as bronchodilators with similar
efficacy in patients with acute asthma in this study.

Pattern of breathing during exercise in patients with interstitial lung disease.

The responses to exercise were studied in 41 patients with pulmonary fibrosis,
in whom vital capacity (VC) was reduced to 62% of predicted normal values.
Maximum power output (POmax) was 53% predicted; there was a significant
relationship between POmax and VC (r = 0.564). The maximum ventilation achieved
during exercise was also related to VC (r = 0.614). Although arterial oxygen
saturation (SaO2) fell by more than 5% in 13 of 31 patients, there was no
relationship between either SaO2 at POmax or the exercise related fall in SaO2
and POmax. Heart rate responses were higher than normal predicted values in
seven patients, all of whom showed a low POmax (36% predicted); this finding was
due only in part to a fall in SaO2. The ventilatory response to exercise was
within normal limits for the patients as a whole; those subjects with the lowest
POmax showed relatively higher ventilatory responses to exercise but the
difference was not significant. The pattern and timing of breathing was studied
in 32 patients and compared with control subjects matched by sex, age, and size.
Tidal volume (VT) was low in the patients; maximum VT was related to VC (r =
0.761), but at low values of VC VTmax was higher than in healthy subjects with
comparable VC. The total breathing cycle time (Ttot) fell with progressive
exercise in patients and controls; Ttot for a given ventilation was shorter in
the patients. Inspiratory time (Ti) was shorter in patients than controls, as
was Ti/Ttot. In most patients with diffuse pulmonary fibrosis exercise is
limited by a reduced ventilatory capacity, despite the adoption of a short Ti
and high inspiratory flow rate, both of which serve to optimise tidal volume and
breathing frequency and presumably reduce both the force developed by
inspiratory muscles and the sensation of breathlessness.

The use of levamisole as an adjunct to chemotherapy and radiotherapy in the
treatment of small cell carcinoma of the lung.

To test the efficacy of immunotherapy in the treatment of small cell carcinoma
of the lung, patients were allocated at random, in a double-blind controlled
trial, to treatment with either levamisole or placebo as an adjunct to
chemotherapy with multiple drugs (cyclophosphamide, vincristine, methotrexate
and adriamycin) and to radiotherapy. We report here the results of a pilot study
of 13 patients. The median survival period of the patients who were given
levamisole was 25 weeks. This was significantly shorter (P less than 0.05) than
that of the patients who were given placebo (46 weeks).

Using open-magnitude scaling, we compared the perceived magnitude of externally
added resistive and elastic loads to breathing in normal subjects with that
perceived when the background load (i.e., the minimum load of the circuit) was
increased by the addition of either resistive or elastic loads of increasing
magnitude. The study was carried out over four experimental sessions. After a
control experiment (no added background load), the background load was increased
by the addition of either a resistive or an elastic load for a duration of 3
min. The perceived magnitude of a further series of loads, proportionately
increased, was then ascertained. This sequence was then repeated after a further
increase in background. The results showed that the perceived magnitude of the
load was closely related [mean r = 0.96 +/- 0.01 (SE)] to the magnitude of the
physical stimulus expressed as the peak inspiratory pressure by a power function
relationship in keeping with Stevens' law. After the increases in background
resistance or elastance, there were no significant differences in either
exponents or intercepts compared with basal conditions. There was no significant
difference in the perceived magnitude of the loads after adaptation. At the
smallest load, the perceived magnitude was less than expected from the control
experiment. However, this reduction did not reach statistical significance. In
the special senses, moderate-to-large stimuli show little change after
adaptation, whereas small stimuli are reduced. Although not conclusive, we
suggest that the relationship is similar with loaded breathing.

We studied the perception of breathlessness as a function of air flow
obstruction in 45 asthmatic subjects using a category scaling technique. Air
flow obstruction and breathlessness were induced by inhalations of histamine
acid phosphate in twofold-increasing concentrations from 0.03 to 16 mg/ml. The
FEV1 was measured after each inhalation of histamine, and the subject was asked
to rate his symptoms of breathlessness. The results showed that breathlessness
increased as the FEV1 decreased but, despite a close linear relationship in all
subjects (mean r = 0.88 +/- 0.15 SD), there was a considerable variation in the
severity of breathlessness for any particular degree of air flow obstruction
(mean intercept, 0.50 +/- 0.89 SD). However, the increase in sensory magnitude
with increasing air flow obstruction did not show the same degree of variability
(mean slope, 0.13 +/- 0.06 SD). The variability in breathlessness in asthmatic
patients is likely to have many components. Two of these components were
identified. First, we found that there was less respiratory distress in those
subjects in whom air flow obstruction was present at the onset of the study.
However, the presence of air flow obstruction at this time does not result in a
reduction in sensation for further increases in air flow obstruction as might be
expected from discrimination studies. Second, there was a significant
relationship (p less than 0.01) between bronchial responsiveness and the
magnitude of respiratory distress. Those subjects highly responsive to histamine
experienced less respiratory distress than the less responsive subjects.

Effect of ventilatory drive on the perceived magnitude of added loads to
breathing.

Using open-magnitude scaling we studied the importance of ventilatory drive on
the perceived magnitude of respiratory loads by applying a range of externally
added resistances (2.1-77.1 cmH2O X l-1 X s) to normal subjects at rest and at
three increasing levels of ventilatory drive induced by exercise, CO2-stimulated
breathing, and hypoxia. Under all conditions studied the perceived magnitude of
the added loads increased with the magnitude of the resistive load and as the
underlying level of ventilatory drive increased. When the results were expressed
in terms of peak inspiratory pressure, the perceived magnitude was related to
the magnitude of the peak inspiratory pressure by a power function (mean r =
0.97). These results suggest that the perceived magnitude of added resistive
loads increased with increasing ventilatory drive, in such a manner that the
increase in sensory magnitude is proportional to the increase in the inspiratory
muscle force developed and suggests that something dependent on this force
mediates the sensation.

1. Detection latency of a range of added elastic (0.95-4.50 kPa/l) and resistive
(0.73-3.29 kPa l-1 s) loads to breathing were measured in five normal subjects.
Detection latency was defined as the time from the onset of the breath to
detection of the load. 2. Detection latency followed a curvilinear relationship
when plotted as a function of the magnitude of the added loads. A similar
relationship was found with both elastic and resistive loads although detection
latencies to added elastances were longer than for added resistances. 3. When
the added load was expressed in terms of comparable magnitude (peak inspiratory
pressure) detection latencies for added elastances were found to be consistently
longer than for added resistive loads. 4. These studies show that the detection
latency to added inspiratory loads follows a reciprocal relationship, that
detection latencies for elastic and resistive loads are clearly different and
suggest that these loads are detected during the respiratory cycle at a time
when the mechanical information regarding muscular pressure is greatest.

Cystic fibrosis and bronchial hyperreactivity. Concomitant defects or cause and
effect?

Bronchial reactivity and lung-function tests were measured in 19 young adults
with cystic fibrosis. There was moderately severe airways obstruction without
hyperinflation, and mild hypoxaemia with normocapnia. Bronchial reactivity (fall
in FEV1 after the administration of methacholine aerosol) was increased in about
two-thirds of patients, and was markedly enhanced in nearly half of them. It was
considered that the airways obstruction characteristic of cystic fibrosis can
have a reversible element, and that this may provide a rationale for the use of
bronchodilators in some patients. Although bronchial hyperreactivity in cystic
fibrosis could represent concomitant underlying defects, a more attractive
suggestion is that the chronic inflammation of cystic fibrosis has, in turn, led
to acquired bronchial hyperreactivity.

Maximal mid-inspiratory to maximal mid-expiratory flow rate ratio in upper
airway obstruction.

The maximal mid-inspiratory to maximal mid-expiratory flow rate ratio
(MMIF/MMEF) was measured in 16 patients with upper airway obstruction, in eight
with pleural disease, in 25 with chest wall abnormalities, in 64 with various
lung diseases and in 28 normal subjects. MMIF/MMEF ratio values of less than 1.0
were recorded in eight out of 16 patients with upper airway obstruction, in nine
out of 25 patients with chest wall abnormalities and in one normal subject. Our
findings show that a MMIF/MMEF ratio less than 1.0 although suggestive, is not
diagnostic of upper airway obstruction. However, reduced MMIF/MMEF ratio in the
presence of airflow obstruction is specific in localizing obstruction to the
upper airway.

Forty-six of 59 patients with small cell carcinoma of the lung who were treated
with multiple drug chemotherapy and radiotherapy were subclassified according to
the World Health Organization classification. Subtyping was not possible in the
13 other patients who were diagnosed on sputum cytology findings alone. There
was no significant difference in extent of disease, response, duration of
response to treatment, or median survival between the different subtypes. Two
main difficulties arise in applying the subtyping classification. First, many
tumors showed features of several histologic subtypes, implying the existence of
a morphologic continuum within the general group of small cell anaplastic
carcinomas. Second, tissue crushing artefact was common. Our results do not
reveal any advantage in knowing the tumor subtype. It remains essential to
differentiate small cell anaplastic carcinoma from other forms of lung carcinoma
not responsive to chemotherapy.

Combination chemotherapy including high dose methotrexate and radiotherapy, in
the treatment of small cell carcinoma of the lung.

Twenty-nine (88%) of thirty-three patients who were treated with multiple drug
chemotherapy, including high dose methotrexate, and radiotherapy for small cell
carcinoma of the lung showed significant improvement in their clinical condition
and quality of life. Treatment was well tolerated and toxicity acceptable.
Cerebral metastases were not detected in any patient on presentation and only
developed in three patients (9%). Little information exists regarding the use of
high dose methotrexate in small cell carcinoma of the lung. There is no
evidence, on the data available, that high dose methotrexate is any more
effective than conventional doses.

Combination chemotherapy including high dose methotrexate and radiotherapy, in
the treatment of small cell carcinoma of the lung.

Combined chemotherapy and radiotherapy for the treatment of small cell carcinoma
of the lung.

Twenty-nine (88%) of 33 patients who were treated with multiple drug
chemotherapy and radiotherapy for small cell carcinoma of the lung showed
significant improvement in their clinical condition and quality of life.
Treatment was well tolerated and toxicity was acceptable.