Gooi, J.

Lavergne, S.

Naisbitt, D.

Park, K.

Peckham, D.

Whitaker, P.

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S50 6. Immunology/Inﬂammation
191 Long-term prognostic signiﬁcance of a positive BPI-ANCA
test in CF − a prospective 10 year follow-up study
U. Lindberg1, L. Mared1, M. Carlsson2, M. Segelmark3. 1Lund University
Hospital, Dep of Pulmology, Lund, Sweden; 2AstraZeneca AB, Lund, Sweden;
3Lund University Hospital, Dep of Nephrology, Lund, Sweden
Objective: Several studies have shown a high frequency of antineutrophil cytoplas-
mic antibodies (ANCA) in CF, especially those with anti-bactericidal/permeability
increasing protein (BPI) speciﬁcity. Earlier studies have shown correlation between
BPI-ANCA and poor prognosis in CF and between BPI-ANCA and factors as iv
antibiotic courses, low BMI and presence of multi drug resistant P. aeruginosa. In
this study we followed 46 adult CF patients for ten years to elucidate the prognostic
signiﬁcance of a positive BPI-ANCA.
Methods: 46 adult CF patients were sampled for IgA-BPI-ANCA between 1995
and 1998 and followed prospectively until death, lung transplantation or ten years
of follow-up. Lung function was measured as % of expected FEV 1.0 and PsA
colonisation was categorised according to the Leeds classiﬁcation. Patients were
divided into three groups regarding lung function; FEV1> 80%, FEV1 50−80%
and FEV1< 50%pred.
Results: 15/46 patients reached end-point, 13 of these were BPI-ANCA+. None
of the 16 patients with the best preserved lung function experienced end-point,
regardless of BPI-ANCA level and Leeds classiﬁcation. In the 13 patients with the
lowest lung function all belonged to Leeds 1 or 2 and all except one was BPI-ANCA
positive, nine reached end-point. The median BPI-ANCA level of the patients with
end-points was 251 ELISA units as compared to 69 for the 31 patients who did not
reach end-point.
Conclusion: High BPI-ANCA level is associated with poor long-term outcome
among adult CF patients. However, a positive BPI-ANCA seems to have a strong
prognostic signiﬁcance only among patients already having a reduced lung function
and a chronic PsA infection.
192 Prevalence and mechanism of adverse reactions to colistin in
patients with cystic ﬁbrosis
P. Whitaker1, S. Lavergne2, J. Gooi3, D. Naisbitt2, K. Park2, D. Peckham1.
1Regional Adult CF Unit, St James’s Hospital, Leeds, United Kingdom; 2MRC
Centre for Drug Safety Science, School of Biomedical Sciences, University of
Liverpool, Liverpool, United Kingdom; 3Department of Immunology, St James’s
Hospital, Leeds, United Kingdom
Colistin is a polymyxin antibiotic that is active against Pseudomonas Aeruginosa.
While some patients develop allergic reactions and non speciﬁc symptoms of
neurotoxicity, there is little published data on the frequency and mechanism for
colistin induced allergic reactions in patients with CF.
We retrospectively reviewed the Unit’s database and determined the frequency
of allergic reactions to colistin. We then prospectively performed a lymphocyte
transformation test (LTT) in both allergic and non allergic patients with CF and
healthy controls. Supernatants from the LTT were then collected and the cytokine
proﬁles assessed.
180 adult patients with CF had received iv colistin. Of these, 51 individuals (28%)
had developed a drug reactions resulting in stopping the treatment early. Reactions
included rash (14), headache (11), paraesthesia (9), swollen lips (7), dizziness (6),
chest tightness (3), and arthralgia (1). An LTT was undertaken in 11 allergic patients
with CF (rash 7, headache 3, paraesthesia 1). The controls included 7 tolerant
patients and 5 non-CF naive subjects, in this latter group all LTT were negative.
Nine patients (82%) with a history of adverse reactions, including 3 patients with
a history of severe headache, were LTT positive. This suggests immunological
memory and sensitisation. Supernatant levels of IL-1, IL-10, and IFN-g were
signiﬁcantly elevated in patients with adverse reactions.
Allergic reaction to colistin is relatively common. Some of the neurological adverse
reactions may be related to a direct effect of cytokine release. Recent studies have
reported an association between IL-1 levels and cluster headaches in the general
population.
193 Cytokine proﬁles in different matrices before and after therapy
for acute exacerbation in cystic ﬁbrosis (CF) patients
N. Faelli1, A.S. Tirelli2, D. Costantini1, A. Bifﬁ1, V. Motta1, M. Conese3,
C. Colombo1. 1Cystic Fibrosis Centre Fondazione IRCCS Ca Granda-Ospedale
Maggiore Policlinico Milan, Milan, Italy; 2Laboratory of Clinical Pathology,
Fondazione IRCSS Ca’ Granda-Ospedale Maggiore Policlinico Milan, Milan,
Italy; 3Department of Biomedical Sciences, University of Foggia, Milano, Italy
In CF simple and non-invasive biomarkers of lung inﬂammation are urgently needed
to monitor disease progression, identify exacerbations, and evaluate therapeutic
efﬁcacy. We studied the simultaneous presence of twelve biomarkers by a biochip
array (Randox) in three different matrices (serum, sputum, exhaled breath con-
densate [EBC]) in 24 CF patients (age: 18.8±4.8 years [mean±SD]; range:12.0–
27.5 years, 13M) before and after antibiotics given for an acute exacerbation. In
serum, there was a trend for a signiﬁcant decrease in IL-2, IL-4, IL-6, IL-10, IFN-g,
IL-8, MCP-1, EGF and VEGF levels. In sputum, IL-1a, IL-1b, IL-4, IL-6, IL-10,
TNF-a, IL-8 and VEGF levels decreased already at 6 days of therapy and remained
constantly lower than baseline, while MCP-1 and EGF levels signiﬁcantly increased.
In EBC, the biomarker behaviour was more heterogeneous. In one group (IL-1a,
IL-2, IL-6, IL-8, EGF) they ﬁrst increased and then signiﬁcantly lowered at 1 month
post-treatment. In the other group (IL-1b, IL-10, VEGF, IFN-g) biomarker levels
were always lower at all the time points post-treatment than baseline. On the other
hand, IL-4 and TNF-a appeared to change in a bimodal fashion: they ﬁrst decreased
at 6 days, increased to value higher than baseline at 15 days and ﬁnally decreased
to levels lower than baseline at 30 days post-treatment. Overall, these results show
that different biomarkers are responsive to treatment in each considered matrix
and indicate that only correlation studies with FEV1 will elucidate which of these
biomarkers is more sensitive of therapeutic efﬁcacy.
194 Different interferon gamma responses in cystic ﬁbrosis patients
with and without Mycobacterium abscessus (M. abscessus)
F. Perrin1,2, R. Dofﬁnger3, P. Seddon4, R.G. Ruiz1, D. Kumararatne3, D. Bilton2,
London and Brighton NTM Collaboration. 1King’s College Hospital NHS
Foundation Trust, London, United Kingdom; 2Royal Brompton & Hareﬁeld NHS
Foundation Trust, London, United Kingdom; 3Addenbrooke’s Hospital, Cambridge,
United Kingdom; 4Brighton and Sussex University Hospitals NHS Trust, Brighton,
United Kingdom
Introduction: Nontuberculous mycobacteria (NTM) are emerging CF pathogens,
particularly M. abscessus. Non-CF patients with disseminated NTM disease associ-
ated with interferon gamma (IFN-g) deﬁciency respond to IFN-g therapy. We have
been testing the ability of whole blood from CF patients with NTM lung disease to
produce IFN-g after stimulation. Anecdotally, some with impaired IFN-g responses
compared to normal controls have beneﬁted from subcutaneous IFN-g. It is unclear
whether an impaired response is a feature of CF itself or of the M. abscessus
disease. We present pilot data to answer this question.
Method: 7 CF patients with M. abscessus lung disease by ATS criteria who had
had IFN-g studies, were matched by age, disease severity (FEV1) and other gram-
negative pathogens to 8 CF patients without NTM. Whole blood from each subject
was stimulated with phytohaemagglutinin (PHA) (positive control), IL12/IL18 and
lipopolysaccharide (LPS). IFN-g production, determined by ELISA, was expressed
as % of the response measured in blood taken simultaneously from healthy controls.
Results: IFN-g production was lower in CF patients than healthy controls on
stimulation with all activators. M. abscessus patients had lower IFN-g production
than non-NTM patients when stimulated with PHA − median 30.6% (range 2.4–
100) vs 51.5% (2.2–100) and IL12/IL18 − 18.9% (8.9−91) vs 78.5% (50–100).
Both groups had low responses to LPS − 10.95% (1.3–100) vs 14.5% (0.18−100).
Conclusion: CF patients with M. abscessus have signiﬁcantly reduced IFN-g
production in vitro compared to non-NTM patients. Larger prospective studies are
required to conﬁrm this and to determine the therapeutic role of IFN-g.


Prevalence and mechanism of adverse reactions to colistin in patients with cystic fibrosis 

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Prevalence and mechanism of adverse reactions to colistin in patients with cystic fibrosis

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