Effect of Azithromycin on Bronchiectasis and Pulmonary Function in a Heart-Lung Transplant Patient With Severe Chronic Allograft Dysfunction: A Case Report

doi:10.1016/j.healun.2004.06.025

The Journal of Heart and Lung Transplantation

Volume 24, Issue 8, August 2005, Pages 1155-1158

https://doi.org/10.1016/j.healun.2004.06.025 Get rights and content

Azithromycin has been shown to be beneficial in several diseases with chronic neutrophilic inflammation of the airways, such as cystic fibrosis and bronchiolitis obliterans syndrome (BOS) after lung transplantation. Up to now, however, its healing effect on bronchiectasis has never been demonstrated. We report a heart-lung transplant patient who developed chronic rejection (BOS stage 3) with the appearance of gross bronchiectasis on a spiral computed tomography (CT) chest scan. Within 2 weeks after starting azithromycin, the patient’s forced expiratory volume in 1 second increased significantly and a repeat spiral CT chest scan 5 months later, showed a major improvement of the bronchiectasis. This case report illustrates that bronchiectasis may greatly improve after treatment with azithromycin and no longer needs to be considered an endstage finding in patients with severe BOS.

Section snippets

Case report

A 16-year-old girl with Eisenmenger’s syndrome underwent a heart-lung transplantation in 1991. This procedure was complicated by a bilateral diaphragm paresis, acute renal insufficiency, and several acute rejection episodes that required high doses of intravenous corticosteroids on at least 3 occasions during the first 2 post-operative months. The patient’s maintenance immunosuppressive treatment consisted of cyclosporin, azathioprine, and oral corticosteroids. Her FEV₁ gradually improved to

Discussion

We report this unique case of a heart-lung transplant patient, thought to have irreversible BOS as demonstrated by the declining FEV₁, the appearance of bronchiectasis, and the colonization pattern of the airways with gram-negative rods and fungi, who not only had significantly improved FEV₁ during treatment with azithromycin, but also seems to have had a major improvement of the bronchiectasis. Although the spiral CT scanning technique that was used is not ideal for the detection of

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Cited by (28)

The Use of Antiinflammatory Therapy and Macrolides in Bronchiectasis
2012, Clinics in Chest Medicine
Citation Excerpt :
There was also a significant decrease in exacerbations in the patients (P<.001), as well as a clinically significant decrease in sputum microbial isolates. Two additional single case studies documented benefit of azithromycin in either idiopathic bronchiectasis or bronchiectasis associated with chronic rejection in a heart-lung transplant recipient.56,57 An overview of all the studies documenting the effects of macrolides in patients with bronchiectasis is demonstrated in Table 2.
Azithromycin Attenuates Effects of Lipopolysaccharide on Lung Allograft Bronchial Epithelial Cells
2008, Journal of Heart and Lung Transplantation
Citation Excerpt :
Clinical use of azithromycin from three centers, including our own institution, demonstrated significant improvements in patients with the OB.17–19 In a further case report, addition of azithromycin resulted in an improvement in bronchiectesis in a post-transplant patient.50 Such findings are encouraging given the devastating nature of the problem and there is now an urgent need for translational mechanistic studies on macrolide therapy for selected patients.51
The bronchial epithelium is a source of mediators that may play a role in the airway inflammation and remodeling of post-transplant obliterative bronchiolitis (OB). Traditional strategies have failed to have an impact on OB. Recent studies have suggested a role for azithromycin in managing the condition. In this study we aimed to determine the effect of azithromycin on LPS-mediated epithelial release of factors relevant to airway neutrophilia and remodeling in a unique population of primary bronchial epithelial cells (PBECs) derived from stable lung allografts.
PBECs were established from bronchial brushings of stable lung transplant recipients and treated with lipopolysaccharide (LPS, 0.1, 1 and 10 μg/ml) for 48 hours. Interleukin-8 (IL-8), granulocyte macrophage colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) protein levels were measured by Luminex analyzer. PBECs were then incubated with LPS and azithromycin, and protein levels were again determined.
LPS caused a significant increase in IL-8 and GM-CSF at concentrations of 1 and 10 μg/ml, with no effect on VEGF release. Azithromycin caused a significant decrease in the LPS-stimulated IL-8 and GM-CSF release.
LPS upregulates release of IL-8 and GM-CSF from PBECs derived from stable lung allografts. Sub-microbicidal concentrations of azithromycin attenuate this and may, therefore, alleviate infection-driven neutrophilic airway inflammation and remodeling in the allograft airway.
Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells
2006, Biochemical and Biophysical Research Communications
Citation Excerpt :
AZM is receiving increasing interest for its therapeutic benefits in the treatment of CF. Equi et al. reported promising clinical effects without significant changes of IL-8 and neutrophil elastase levels in sputa of CF patients following treatment with AZM [36]. However our results are consistent with the reduction of IL-8 release described after lung transplantation, supporting anti-inflammatory properties of this macrolide [37–40]. The molecular basis of this effect has been more thoroughly investigated.
We aimed at identifying molecular mechanisms for anti-inflammatory effects of azithromycin (AZM) suggested by clinical evidences. IL-8 expression and DNA binding activity of two key pro-inflammatory transcription factors (TF), NF-κB and AP-1, were investigated in cystic fibrosis (CF) and isogenic non-CF airway epithelial cell lines. AZM reduced about 40% of IL-8 mRNA and protein expression (n = 9, p = 0.02, and n = 4, p = 0.00011) in CF cells reaching the levels of non-CF cells. In the presence of AZM we found about 50% and 70% reduction of NF-κB and AP-1 DNA binding, respectively (n = 3, p = 0.01, and n = 3, p = 0.0017), leading to levels of non-CF cells. The relevance of NF-κB and AP-1 in regulating IL-8 promoter transcriptional activity was demonstrated by gene reporter assays (n = 4, p = 8.54 × 10⁻⁷, and n = 4, p = 6.45 × 10⁻⁶). Our data support the anti-inflammatory effects of AZM in CF cells, indicating inhibition of transcription of pro-inflammatory genes as possible mechanism, thus providing a rationale for the possible use of specific TF inhibitors for therapy.
Immunomodulatory effects of antibacterial agents
2006, Reanimation
Le système immunitaire joue un rôle capital dans la défense naturelle, mais son activation excessive ou inappropriée peut avoir des conséquences néfastes pour l'hôte. La modulation du système immunitaire (« immunomodulation »), s'applique à diminuer les réponses excessives ou, à l'inverse, à renforcer les réponses insuffisantes de ce système. Parmi les agents thérapeutiques qui peuvent interférer avec le système immunitaire, les agents antibactériens sont très étudiés. Certains aspects sont largement reconnus cliniquement, comme les effets toxiques (agranulocytose) ou immunotoxiques (allergie), et la pénétration intracellulaire. Parmi les autres aspects, souvent observés in vitro, la modification directe des fonctions cellulaires est le sujet le plus débattu et controversé. Cette revue résume la littérature en ce domaine et présente les applications thérapeutiques potentielles.
The immune system plays a critical and beneficial role in host defence, but its unappropriate or excessive activation can lead to detrimental and disease-generating effects. Immunomodulation (i.e. the way to either decrease a damaging hyperimmune response or increase an inadequate response) has become a therapeutic challenge. Among the possible agents that can interact with the immune system, antibacterial agents have received much attention. Toxic and immunotoxic effects (neutropenia, allergy, auto-immunity) and intracellular bioactivity are widely acknowledged and have clinical significance. Modulation (stimulation–inhibition) of host cell activities is widely investigated and remains a controversial area. This review summarizes the relevant literature and debates some potential therapeutic applications.
Lung structure abnormalities, but normal lung function in pediatric bronchiectasis
2006, Chest
Citation Excerpt :
Actually, improvement following appropriate therapeutic interventions was demonstrated by the studies of Field46 reporting a fall in the annual hospitalization rate after medical or surgical treatment. Two anecdotal reports4748 of non-CF patients have shown near resolution of bronchiectasis after treatment with Nissen fundoplication plus gastrostomy in a child with chronic aspiration47 or after a course of azithromycin therapy in an adolescent patient who had undergone a heart-lung transplant with chronic lung rejection.48 Another report49 of 33 patients with bronchiectasis has shown that long-term treatment with azithromycin resulted in a significant reduction of infectious exacerbations, and in the improvement of several lung function parameters and clinical symptoms.
Bronchiectasis is not considered to be uncommon in children anymore. The relationship between pulmonary function and severity of bronchiectasis is still controversial.
To assess the extent and severity of bronchiectasis through high-resolution CT (HRCT) scan score, and to correlate it with clinical, microbiological, and functional data.
Forty-three white children with HRCT-diagnosed bronchiectasis were studied. Bronchiectasis extent, bronchial wall thickening severity, and bronchial wall dilatation severity were evaluated using the Reiff score. Clinical, microbiological, and spirometry results were related to total HRCT scan score and to subscores as well.
The percentages of affected lobes were as follows: right lower lobe, 65%; middle lobe, 56%; left lower lobe, 51%; right upper lobe, 37%; lingula, 30%; and left upper lobe, 30% (χ² = 18.4; p = 0.002). The mean (± SEM) HRCT score was 20 ± 2.6. Total score or subscores of bronchiectasis extent, bronchial wall thickening severity, and bronchial wall dilatation severity were not significantly related to FEV₁ and FVC. Seventy-four percent of patients had asthma. The age at the onset of cough correlated with age at the time of the HRCT scan (p = 0.004) and with the presence of asthma (p = 0.01). Positive findings of deep throat or sputum cultures were found more frequently in atopic patients (p = 0.02) and asthmatic (p < 0.01) patients, and in children who were < 2 years of age at the onset of cough (p < 0.01).
Normal lung function may coexist with HRCT scan abnormalities and does not exclude damage to the bronchial structure. Pulmonary function is not an accurate method for assessing the severity of lung disease in children with bronchiectasis.
High-resolution ct findings of obstructive and restrictive phenotypes of chronic lung allograft dysfunction: More than just bronchiolitis obliterans syndrome
2018, American Journal of Roentgenology

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The Journal of Heart and Lung Transplantation

Section snippets

Case report

Discussion

References (21)

The Registry of the International Society for Heart and Lung Transplantationtwentieth official adult heart-lung transplant report—2003

J Heart Lung Transplant

Long term azithromycin in children with cystic fibrosisa randomised, placebo-controlled crossover trial

Lancet

Bronchiolitis obliterans syndromean update of the diagnostic criteria

J Heart Lung Transplant

Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma

Chest

Unregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration

J Heart Lung Transplant

Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation

Chest

Maintenance azithromycin therapy for bronchiolitis obliterans syndrome

Am J Respir Crit Care Med

Azithromycin (Azi) treatment for chronic allograft dysfunction after lung transplantation (LTx)

Eur Respir J

Bronchiectasis detected with thin-section CT as a predictor of chronic lung allograft rejection

Radiology

Post-transplant obliterative bronchiolitis

Eur Respir Monograph

Cited by (28)

The Use of Antiinflammatory Therapy and Macrolides in Bronchiectasis

Azithromycin Attenuates Effects of Lipopolysaccharide on Lung Allograft Bronchial Epithelial Cells

Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells

Immunomodulatory effects of antibacterial agents

Lung structure abnormalities, but normal lung function in pediatric bronchiectasis

High-resolution ct findings of obstructive and restrictive phenotypes of chronic lung allograft dysfunction: More than just bronchiolitis obliterans syndrome

Case reportEffect of Azithromycin on Bronchiectasis and Pulmonary Function in a Heart-Lung Transplant Patient With Severe Chronic Allograft Dysfunction: A Case Report

Section snippets

Case report

Discussion

J Heart Lung Transplant

Lancet

J Heart Lung Transplant

Chest

J Heart Lung Transplant

Chest

Maintenance azithromycin therapy for bronchiolitis obliterans syndrome

Am J Respir Crit Care Med

Azithromycin (Azi) treatment for chronic allograft dysfunction after lung transplantation (LTx)

Eur Respir J

Bronchiectasis detected with thin-section CT as a predictor of chronic lung allograft rejection

Radiology

Post-transplant obliterative bronchiolitis

Eur Respir Monograph

Case report
Effect of Azithromycin on Bronchiectasis and Pulmonary Function in a Heart-Lung Transplant Patient With Severe Chronic Allograft Dysfunction: A Case Report