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Papers by Monique Malouf

The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation

To assess the efficacy and complications of different interventional bronchoscopic techniques use... more To assess the efficacy and complications of different interventional bronchoscopic techniques used to treat airway complications after lung transplantation. Retrospective study. Heart-lung transplant unit of a university hospital. From November 1986 to January 2000, interventional bronchoscopy was performed in 41 of 312 lung transplant recipients (13.1%) for tracheobronchial stenosis, bronchomalacia, granuloma formation, and dehiscence. Dilatation, stent placement, laser or forceps excision. Mean (+/- SE) improvement in FEV(1) in 26 patients undergoing dilatation for a stenotic or a combined lesion was 93 +/- 334 mL or 8 +/- 21%. In seven of these patients not proceeding to stent placement, mean improvement in FEV(1) was 361 +/- 179 mL or 21 +/- 9%. Patients needing stent placement after dilatation had a mean change in FEV(1) after dilatation of - 5 +/- 325 mL or 3 +/- 23%, and an improvement of 625 +/- 480 mL or 52 +/- 43% after stent insertion. Mean improvement in FEV(1) for patients treated with stent insertion for bronchomalacia was 673 +/- 30 mL or 81 +/- 24%. Complications of airway stents were migration (27%), mucous plugging (27%), granuloma formation (36%), stent fracture (3%), and formation of a false passage (6%). Mortality associated with interventional bronchoscopy was 2.4% (1 of 41 patients). For patients with airway complications successfully undergoing interventional bronchoscopy, the overall 1-year, 3-year, and 5-year survival rates were 79%, 45%, and 32%, respectively, vs 87%, 69%, and 56% for those without airway complications (p < 0.05). Only a small number of patients with airway stenosis after lung transplantation will respond to bronchial dilatation alone. Patients with airway complications after lung transplantation have a higher mortality than patients without airway complications.

The Indian journal of chest diseases & allied sciences

Lung transplantation has become an accepted treatment modality for end stage lung disease includi... more Lung transplantation has become an accepted treatment modality for end stage lung disease including emphysema, fibrosing alveolitis, cystic fibrosis, pulmonary hypertension and bronchiectasis. Despite the use of potent immunosuppressive drugs, acute rejection occurs frequently, especially in the first few weeks and months after transplantation. Bacterial, viral and fungal infections frequently occur in lung transplant recipients. Rapid diagnosis and adequate treatment of infections is needed. The side effects with the use of long term immunosuppressive agents includes renal toxicity, hypertension, neurotoxicity, hyperlipidemia, leucopoenia, hyperglycaemia, weight gain, osteoporosis and malignancy. However, obliterative bronchiolitis (OB) which is regarded as a chronic rejection process remains the dominant cause of morbidity and mortality in the long-term survivors of lung transplantation. This article focuses on the postoperative and long term management of lung transplant recipients.

The Journal of Heart and Lung Transplantation, 2015

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, Jan 11, 2015

Heart and lung transplant recipients have among of the highest incidence rates of post-transplant... more Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients. Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors. The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart...

The Medical journal of Australia, Jan 3, 2007

To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults. Pr... more To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults. Prospective cohort study set in an LTx unit at an adult tertiary referral hospital from 1991 to 2006. 37 consecutive adolescent lung transplant recipients including 13 males and 24 females (mean age, 16.7+/-2.0 [SD] years; range 12-19 years) who received heart-lung (six patients) or bilateral LTx (31 patients) for cystic fibrosis (29), congenital heart disease (four), acute respiratory failure (two), or another disorder (two). Two patients were transplanted after invasive ventilation, five after non-invasive ventilation and two after extracorporeal membrane oxygenation. Overall survival compared with an adult cohort; survival free of bronchiolitis obliterans syndrome (BOS); overall and BOS-free survival in those transplanted before and after January 2000. Mean waiting time was 273 days (range, 5-964 days; median, 163 days), mean donor age was 28 years (range, 9-53 years). Median inpatient ...

Transplantation, 2005

We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronc... more We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronchoscopy. We undertook this study to assess the sedative drug doses administered during bronchoscopy in lung transplant recipients and to assess if there is a change in the dosage requirements over time following lung transplantation. Methods. In all, 773 transbronchial biopsy procedures performed via flexible bronchoscopy were analyzed in 140 consecutive lung transplant recipients. Conscious sedation was achieved with intermittent boluses of intravenous midazolam and fentanyl. Intravenous propofol boluses of 10 to 30 mg were administered when optimal sedation was not achieved with midazolam doses of 0.20 to 0.25 mg/kg and fentanyl 2 to 2.5 micrograms/kg. Results. Mean doses of midazolam and fentanyl administered were 0.15Ϯ0.07 mg/kg (range 0.02 to 0.44 mg/kg) and 1.8Ϯ0.8 micrograms/kg (range 0.1 to 6.67 micrograms/kg) respectively. Midazolam and fentanyl doses administered to patients with cystic fibrosis were the highest compared to those with other disease types (PϽ0.0001). Examining the sedative doses administered over time following transplantation, there was a significant linear (PϽ0.001) and quadratic (Pϭ0.0023) effect of time for midazolam and a significant linear (Pϭ0.003) and a trend (Pϭ0.08) for a quadratic effect for fentanyl. Propofol was effectively used in seven lung transplant recipients in whom adequate sedation could not be achieved with high doses of midazolam and fentanyl. Conclusions. There is an increase in sedative drug requirement with time for both midazolam and fentanyl after transplantation, which is significantly higher in patients with cystic fibrosis.

Journal of Breath Research, 2012

The diffuse parenchymal lung diseases (DPLDs) are a group of clinicopathological entities which h... more The diffuse parenchymal lung diseases (DPLDs) are a group of clinicopathological entities which have recently undergone reclassification. The commonest type of idiopathic DPLD is interstitial pulmonary fibrosis (PF), which is histologically characterized by usual interstitial pneumonia (UIP), with inflammatory changes in the alveoli and subsequent collagen deposition. A similar type of inflammatory change can also be seen with connective tissue disorders. Many mediators are involved, but it is difficult to study these in a non-invasive manner in patients. The aim of the study detailed in this paper was to investigate inflammatory and oxidative stress biomarkers in PF and correlate these with lung function. 20 PF patients and 20 controls participated in the study. Exhaled breath condensate (EBC) was collected over 10 min using a refrigerated condenser, after fractional exhaled nitric oxide (FeNO) and carbon monoxide (eCO) measurement. EBC total nitrogen oxides (NOx), hydrogen peroxide (H(2)O(2)), 8-isoprostane (8-iso), 3-nitrotyrosine (3-NT), pH and total protein were measured. EBC biomarkers were significantly raised in PF compared with controls: EBC 3-NT (2.5 (0.7-8.9) versus 0.3 (0.1-1.1) ng ml(-1), p = 0.02); pH (7.6 ± 0.3 versus 7.4 ± 0.2, p = 0.004); 8-isoprostane (0.2 (0.1-0.4) versus 0.08 (0.04-0.2) ng ml(-1), p = 0.04) and total protein (24.7 ± 21.1 versus 10.7 ± 7.0 µg ml(-1), p = 0.008). FeNO and eCO were also increased (8.6 (7.1-10.4) versus 6.6 (5.6-7.8) ppb, p = 0.04, and 4.5 ± 1.7 versus 2.7 ± 0.7 ppm, p = 0.001, respectively), but no significant differences were found for NOx or H(2)O(2). In conclusion, inflammatory and oxidative stress biomarkers are raised in patients with PF compared with controls. EBC may be useful for detecting and monitoring lung inflammation in PF.

The Journal of Heart and Lung Transplantation, 2015

Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant ... more Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx. Between December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days). Mean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001). To our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined.

Transplantation, 2001

Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO... more Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO) that is a fibroproliferative process and regarded as the histological marker of chronic rejection. To study further the pathogenesis of BO we attempted to establish primary fibroblast cell cultures from transbronchial lung biopsies (TBBs)of lung transplant recipients. One to two TBB samples from each patient were collected in sterile phosphate-buffered saline. Biopsies were cut into small pieces and placed onto 25-cm2 culture flasks for cell culture and kept under standard cell culture conditions (21% O2, 5% CO2, 37 degrees C). Culture medium consisted of RPMI 1640, 10% fetal calf serum, L-glutamine, HEPES, and antibiotics. After reaching confluence, fibroblasts were passaged into 75-cm2 flasks. The success rate of establishing fibroblast cultures from transbronchial lung biopsies was 54% (27/50). Cell growth was independent of patient age, transplant type, underlying lung disease, indication for transbronchial lung biopsies, grade, or type of re jection and infection. We have established a novel method of culturing fibroblasts from lung transplant recipients. We consider this method as an unique human in vitro model to study the pathogenetic mechanisms leading to BO.

Transplant Infectious Disease, 2001

Respirology, 2011

We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor ... more We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor with anti-fibroproliferative activity to prevent disease progression or death in patients with IPF, a progressive, fatal disease with no known effective therapy. Eighty-nine patients with surgical lung biopsy confirmed IPF were enrolled in a 3-year investigator-driven, placebo-controlled, double-blinded, multicentre study of everolimus. The everolimus (n = 44) and placebo (n = 45) groups were matched for demographic variables (gender, P = 0.46) and baseline lung function parameters (FVC, P = 0.29; TLC, P = 0.45; DL(CO) , P = 0.41 and PaO(2) , P = 0.34). Independent risks for disease progression were everolimus (hazard ratio (HR) 2.37, 95% CI: 1.40-4.00, P < 0.01, log rank) and male gender (HR 2.76, 95% CI: 1.47-5.17, P < 0.01, log rank). Three-year transplant-free survival was 36 ± 7% (everolimus) versus 51 ± 8% (placebo) (Kaplan-Meier, P = 0.11, log rank). Independent risks for transplant-free survival were male gender (HR 2.33, 95% CI: 1.07-5.05, P = 0.03, log rank) and baseline DL(CO) (% predicted) (HR 0.96, 95% CI: 0.93-0.99, P = 0.02, log rank). Everolimus use was associated with more rapid disease progression in a well-defined cohort of patients with IPF confirmed by surgical lung biopsy followed for 3 years.

Respirology, 2002

the transplanted lung CHHAJED PN, MALOUF MA, TAMM M, HOPKINS PM, PLIT M, GLANVILLE AR. Respirolog... more the transplanted lung CHHAJED PN, MALOUF MA, TAMM M, HOPKINS PM, PLIT M, GLANVILLE AR. Respirology 2002; 7: 377-379

Respirology, 2003

We present our experience with the use of the Ultraflex (nitinol) stents in the management of air... more We present our experience with the use of the Ultraflex (nitinol) stents in the management of airway complications in lung transplant (LT) recipients. Nine LT recipients underwent insertion of uncovered Ultraflex stents. Mean change in FEV1, duration to formation of granulation tissue and follow-up post-stent insertion were compared with results obtained in LT recipients who had undergone Gianturco stent (n = 10) and Wallstent insertion (n = 16). Mean improvement in FEV1 after insertion of Gianturco, Wallstent and Ultraflex stents was 670 +/- 591 mL, 613 +/- 221 mL and 522 +/- 391 mL, respectively. No patient with an Ultraflex stent developed mucus plugging or stenosis at stent extremity at a follow up of 263 +/- 278 days. The mean and median duration to stenosis at stent extremity for patients with Gianturco stents was 102 +/- 85 days and 73 days, respectively, compared with 132 +/- 87 days and 142 days, respectively, for patients with Wallstents. Stricture formation in the middle of the Ultraflex stent occurred bilaterally, at the level of anastomosis in one patient in whom stent placement was undertaken in the presence of inflammation. Stent migration in one patient was related to undersizing of the stent diameter relative to the airway diameter. A larger diameter relative stent was subsequently inserted successfully. Ultraflex stents appear to have fewer long-term complications when used in the management of airway complications following LT.

The Journal of Heart and Lung Transplantation, 2002

Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after s... more Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD. In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded. Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients. Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

The Journal of Heart and Lung Transplantation, 2005

Community-acquired viral infections, such as respiratory syncytial virus (RSV), represent a risk ... more Community-acquired viral infections, such as respiratory syncytial virus (RSV), represent a risk factor for bronchiolitis obliterans syndrome (BOS), the major limiting factor for long-term survival after lung transplantation (LTx). RSV often presents with acute bronchiolitis and may be fatal in 10% to 20% of patients. Standard therapies for RSV include nebulized ribavirin with or without steroids, but are costly and inconvenient. We investigated the utility of intravenous (IV) ribavirin with steroids for the treatment of RSV infection after LTx. RSV was identified in nasopharyngeal and throat swabs (NPS) using indirect fluorescent antibody (IFA) testing in 18 symptomatic patients, which was confirmed by viral culture in 14. Data were collected for the period between April 2002 and October 2004. The study included 10 men and 8 women, mean age 42 +/- 15 (range 18 to 63) years. Transplant procedures were 5 single LTx and 13 bilateral LTx. RSV diagnosis was made on Day 1,374 +/- 1,270 (range 61 to 4,598, median 935) post-operatively. Underlying diagnoses included cystic fibrosis (n = 9), emphysema (n = 7) and pulmonary fibrosis (n = 2). All 18 patients received intravenous (IV) ribavirin (33 mg/kg on Day 1 and 20 mg/kg/day thereafter in 3 divided doses) with oral prednisolone (1 mg/kg) until repeat NPS were negative for RSV on IFA. Median therapy was 8 days (6 to 15). The mortality rate was 0%. Mean FEV1 fell from 2.1 +/- 1.0 liter (0.7 to 3.7 liters) to 1.8 +/- 0.9 liter (0.5 to 3.6 liters) (p < 0.001), but recovered to 2.1 +/- 0.9 (0.7 to 3.7 liters) within 3 months and was maintained at follow-up of 521 +/- 328 days (141 to 1,023 days, median 302). Only 1 patient developed bronchiolitis obliterans syndrome (BOS). Complications included mild hemolytic anemia (blood hemoglobin fell from 122 +/- 22 [84 to 154] g/liter to 107 +/- 18 [75 to 138] g/liter, p = 0.02). Cost savings per 8-day course were $US15,913 when compared with nebulized therapy at 6 g/day (p < 0.001). This is the largest reported series of treated RSV cases after LTx and the first to show that therapy with IV ribavirin and oral corticosteroids is well tolerated and effective. Cost utility vs nebulized therapy has been established. Early diagnosis and management are essential to prevent airway epithelial injury and subsequent BOS.

The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation

To assess the efficacy and complications of different interventional bronchoscopic techniques use... more To assess the efficacy and complications of different interventional bronchoscopic techniques used to treat airway complications after lung transplantation. Retrospective study. Heart-lung transplant unit of a university hospital. From November 1986 to January 2000, interventional bronchoscopy was performed in 41 of 312 lung transplant recipients (13.1%) for tracheobronchial stenosis, bronchomalacia, granuloma formation, and dehiscence. Dilatation, stent placement, laser or forceps excision. Mean (+/- SE) improvement in FEV(1) in 26 patients undergoing dilatation for a stenotic or a combined lesion was 93 +/- 334 mL or 8 +/- 21%. In seven of these patients not proceeding to stent placement, mean improvement in FEV(1) was 361 +/- 179 mL or 21 +/- 9%. Patients needing stent placement after dilatation had a mean change in FEV(1) after dilatation of - 5 +/- 325 mL or 3 +/- 23%, and an improvement of 625 +/- 480 mL or 52 +/- 43% after stent insertion. Mean improvement in FEV(1) for patients treated with stent insertion for bronchomalacia was 673 +/- 30 mL or 81 +/- 24%. Complications of airway stents were migration (27%), mucous plugging (27%), granuloma formation (36%), stent fracture (3%), and formation of a false passage (6%). Mortality associated with interventional bronchoscopy was 2.4% (1 of 41 patients). For patients with airway complications successfully undergoing interventional bronchoscopy, the overall 1-year, 3-year, and 5-year survival rates were 79%, 45%, and 32%, respectively, vs 87%, 69%, and 56% for those without airway complications (p < 0.05). Only a small number of patients with airway stenosis after lung transplantation will respond to bronchial dilatation alone. Patients with airway complications after lung transplantation have a higher mortality than patients without airway complications.

The Indian journal of chest diseases & allied sciences

Lung transplantation has become an accepted treatment modality for end stage lung disease includi... more Lung transplantation has become an accepted treatment modality for end stage lung disease including emphysema, fibrosing alveolitis, cystic fibrosis, pulmonary hypertension and bronchiectasis. Despite the use of potent immunosuppressive drugs, acute rejection occurs frequently, especially in the first few weeks and months after transplantation. Bacterial, viral and fungal infections frequently occur in lung transplant recipients. Rapid diagnosis and adequate treatment of infections is needed. The side effects with the use of long term immunosuppressive agents includes renal toxicity, hypertension, neurotoxicity, hyperlipidemia, leucopoenia, hyperglycaemia, weight gain, osteoporosis and malignancy. However, obliterative bronchiolitis (OB) which is regarded as a chronic rejection process remains the dominant cause of morbidity and mortality in the long-term survivors of lung transplantation. This article focuses on the postoperative and long term management of lung transplant recipients.

The Journal of Heart and Lung Transplantation, 2015

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, Jan 11, 2015

Heart and lung transplant recipients have among of the highest incidence rates of post-transplant... more Heart and lung transplant recipients have among of the highest incidence rates of post-transplant lymphoproliferative disease (PTLD). Despite this, there is a paucity of data specific to this group. We collated data on heart, lung and heart-lung transplant recipients with PTLD to identify disease features and prognostic factors unique to this group of patients. Seventy cases of PTLD were identified from a single institution (41 heart, 22 lung, 6 heart-lung and 1 heart-kidney transplant) from 1984 to 2013. Demographics, immunosuppression, treatment, response, complications and survival data were analyzed. Uni- and multivariate Cox regression analyses were performed to identify prognostic factors. The incidence of PTLD was 7.59% in heart-lung, 5.37% in heart and 3.1% in lung transplant recipients. Extranodal disease (82%) with diffuse large B-cell lymphoma (72%) was the most common presentation. Bone marrow involvement (13%) and central nervous system disease (3%) were uncommon. Heart...

The Medical journal of Australia, Jan 3, 2007

To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults. Pr... more To describe the results of lung transplantation (LTx) in adolescents at a hospital for adults. Prospective cohort study set in an LTx unit at an adult tertiary referral hospital from 1991 to 2006. 37 consecutive adolescent lung transplant recipients including 13 males and 24 females (mean age, 16.7+/-2.0 [SD] years; range 12-19 years) who received heart-lung (six patients) or bilateral LTx (31 patients) for cystic fibrosis (29), congenital heart disease (four), acute respiratory failure (two), or another disorder (two). Two patients were transplanted after invasive ventilation, five after non-invasive ventilation and two after extracorporeal membrane oxygenation. Overall survival compared with an adult cohort; survival free of bronchiolitis obliterans syndrome (BOS); overall and BOS-free survival in those transplanted before and after January 2000. Mean waiting time was 273 days (range, 5-964 days; median, 163 days), mean donor age was 28 years (range, 9-53 years). Median inpatient ...

Transplantation, 2005

We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronc... more We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronchoscopy. We undertook this study to assess the sedative drug doses administered during bronchoscopy in lung transplant recipients and to assess if there is a change in the dosage requirements over time following lung transplantation. Methods. In all, 773 transbronchial biopsy procedures performed via flexible bronchoscopy were analyzed in 140 consecutive lung transplant recipients. Conscious sedation was achieved with intermittent boluses of intravenous midazolam and fentanyl. Intravenous propofol boluses of 10 to 30 mg were administered when optimal sedation was not achieved with midazolam doses of 0.20 to 0.25 mg/kg and fentanyl 2 to 2.5 micrograms/kg. Results. Mean doses of midazolam and fentanyl administered were 0.15Ϯ0.07 mg/kg (range 0.02 to 0.44 mg/kg) and 1.8Ϯ0.8 micrograms/kg (range 0.1 to 6.67 micrograms/kg) respectively. Midazolam and fentanyl doses administered to patients with cystic fibrosis were the highest compared to those with other disease types (PϽ0.0001). Examining the sedative doses administered over time following transplantation, there was a significant linear (PϽ0.001) and quadratic (Pϭ0.0023) effect of time for midazolam and a significant linear (Pϭ0.003) and a trend (Pϭ0.08) for a quadratic effect for fentanyl. Propofol was effectively used in seven lung transplant recipients in whom adequate sedation could not be achieved with high doses of midazolam and fentanyl. Conclusions. There is an increase in sedative drug requirement with time for both midazolam and fentanyl after transplantation, which is significantly higher in patients with cystic fibrosis.

Journal of Breath Research, 2012

The diffuse parenchymal lung diseases (DPLDs) are a group of clinicopathological entities which h... more The diffuse parenchymal lung diseases (DPLDs) are a group of clinicopathological entities which have recently undergone reclassification. The commonest type of idiopathic DPLD is interstitial pulmonary fibrosis (PF), which is histologically characterized by usual interstitial pneumonia (UIP), with inflammatory changes in the alveoli and subsequent collagen deposition. A similar type of inflammatory change can also be seen with connective tissue disorders. Many mediators are involved, but it is difficult to study these in a non-invasive manner in patients. The aim of the study detailed in this paper was to investigate inflammatory and oxidative stress biomarkers in PF and correlate these with lung function. 20 PF patients and 20 controls participated in the study. Exhaled breath condensate (EBC) was collected over 10 min using a refrigerated condenser, after fractional exhaled nitric oxide (FeNO) and carbon monoxide (eCO) measurement. EBC total nitrogen oxides (NOx), hydrogen peroxide (H(2)O(2)), 8-isoprostane (8-iso), 3-nitrotyrosine (3-NT), pH and total protein were measured. EBC biomarkers were significantly raised in PF compared with controls: EBC 3-NT (2.5 (0.7-8.9) versus 0.3 (0.1-1.1) ng ml(-1), p = 0.02); pH (7.6 ± 0.3 versus 7.4 ± 0.2, p = 0.004); 8-isoprostane (0.2 (0.1-0.4) versus 0.08 (0.04-0.2) ng ml(-1), p = 0.04) and total protein (24.7 ± 21.1 versus 10.7 ± 7.0 µg ml(-1), p = 0.008). FeNO and eCO were also increased (8.6 (7.1-10.4) versus 6.6 (5.6-7.8) ppb, p = 0.04, and 4.5 ± 1.7 versus 2.7 ± 0.7 ppm, p = 0.001, respectively), but no significant differences were found for NOx or H(2)O(2). In conclusion, inflammatory and oxidative stress biomarkers are raised in patients with PF compared with controls. EBC may be useful for detecting and monitoring lung inflammation in PF.

The Journal of Heart and Lung Transplantation, 2015

Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant ... more Respiratory syncytial virus (RSV) causes serious respiratory tract infections in lung transplant (LTx) recipients, is associated with development of bronchiolitis obliterans syndrome, and has no proven effective therapy. We evaluated the efficacy, safety, and cost-effectiveness of oral ribavirin for the treatment of RSV infection after LTx. Between December 2011 and May 2014, 52 LTx recipients developed 56 episodes of symptomatic RSV infection, which was diagnosed by positive RSV polymerase chain reaction on nasopharyngeal swabs. An intravenous (IV) loading dose of ribavirin (33 mg/kg) was given in 52 of 56 episodes; an equivalent oral loading dose was given in 2 episodes. Oral ribavirin (20 mg/kg/day) was given by day 2 in 53 of 56 episodes. Median duration of therapy was 8 days (range 6-31 days). Mean forced expiratory volume in 1 sec decreased from 2.38 ± 0.78 liters to 2.07 ± 0.85 liters (p < 0.001) at presentation, recovered to 2.26 ± 0.82 liters at cessation of ribavirin, and was maintained at 2.31 ± 0.81 liters within 3 months. New-onset bronchiolitis obliterans syndrome developed in 1 of 38 patients (2.6%) at 3 months. Anemia worsened in 23 episodes, and de novo anemia developed in 5 episodes. Mean hemoglobin decreased from 118 ± 16 g/liter to 113 ± 21 g/liter (p = 0.015). There were 4 late deaths. Compared with IV therapy, mean drug cost saving was US $6,035 per episode, and mean inpatient bed days was reduced by 6.7 days (p < 0.001). To our knowledge, we report the largest series of LTx recipients treated with oral ribavirin for RSV. Oral ribavirin appears to be an effective, well-tolerated alternative to IV or inhaled ribavirin; provides considerable cost savings and reduces length of hospital stay. Potential long-term benefits in preventing development of chronic lung allograft dysfunction are yet to be determined.

Transplantation, 2001

Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO... more Survival after lung transplantation is limited by the development of bronchiolitis obliterans (BO) that is a fibroproliferative process and regarded as the histological marker of chronic rejection. To study further the pathogenesis of BO we attempted to establish primary fibroblast cell cultures from transbronchial lung biopsies (TBBs)of lung transplant recipients. One to two TBB samples from each patient were collected in sterile phosphate-buffered saline. Biopsies were cut into small pieces and placed onto 25-cm2 culture flasks for cell culture and kept under standard cell culture conditions (21% O2, 5% CO2, 37 degrees C). Culture medium consisted of RPMI 1640, 10% fetal calf serum, L-glutamine, HEPES, and antibiotics. After reaching confluence, fibroblasts were passaged into 75-cm2 flasks. The success rate of establishing fibroblast cultures from transbronchial lung biopsies was 54% (27/50). Cell growth was independent of patient age, transplant type, underlying lung disease, indication for transbronchial lung biopsies, grade, or type of re jection and infection. We have established a novel method of culturing fibroblasts from lung transplant recipients. We consider this method as an unique human in vitro model to study the pathogenetic mechanisms leading to BO.

Transplant Infectious Disease, 2001

Respirology, 2011

We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor ... more We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor with anti-fibroproliferative activity to prevent disease progression or death in patients with IPF, a progressive, fatal disease with no known effective therapy. Eighty-nine patients with surgical lung biopsy confirmed IPF were enrolled in a 3-year investigator-driven, placebo-controlled, double-blinded, multicentre study of everolimus. The everolimus (n = 44) and placebo (n = 45) groups were matched for demographic variables (gender, P = 0.46) and baseline lung function parameters (FVC, P = 0.29; TLC, P = 0.45; DL(CO) , P = 0.41 and PaO(2) , P = 0.34). Independent risks for disease progression were everolimus (hazard ratio (HR) 2.37, 95% CI: 1.40-4.00, P < 0.01, log rank) and male gender (HR 2.76, 95% CI: 1.47-5.17, P < 0.01, log rank). Three-year transplant-free survival was 36 ± 7% (everolimus) versus 51 ± 8% (placebo) (Kaplan-Meier, P = 0.11, log rank). Independent risks for transplant-free survival were male gender (HR 2.33, 95% CI: 1.07-5.05, P = 0.03, log rank) and baseline DL(CO) (% predicted) (HR 0.96, 95% CI: 0.93-0.99, P = 0.02, log rank). Everolimus use was associated with more rapid disease progression in a well-defined cohort of patients with IPF confirmed by surgical lung biopsy followed for 3 years.

Respirology, 2002

the transplanted lung CHHAJED PN, MALOUF MA, TAMM M, HOPKINS PM, PLIT M, GLANVILLE AR. Respirolog... more the transplanted lung CHHAJED PN, MALOUF MA, TAMM M, HOPKINS PM, PLIT M, GLANVILLE AR. Respirology 2002; 7: 377-379

Respirology, 2003

We present our experience with the use of the Ultraflex (nitinol) stents in the management of air... more We present our experience with the use of the Ultraflex (nitinol) stents in the management of airway complications in lung transplant (LT) recipients. Nine LT recipients underwent insertion of uncovered Ultraflex stents. Mean change in FEV1, duration to formation of granulation tissue and follow-up post-stent insertion were compared with results obtained in LT recipients who had undergone Gianturco stent (n = 10) and Wallstent insertion (n = 16). Mean improvement in FEV1 after insertion of Gianturco, Wallstent and Ultraflex stents was 670 +/- 591 mL, 613 +/- 221 mL and 522 +/- 391 mL, respectively. No patient with an Ultraflex stent developed mucus plugging or stenosis at stent extremity at a follow up of 263 +/- 278 days. The mean and median duration to stenosis at stent extremity for patients with Gianturco stents was 102 +/- 85 days and 73 days, respectively, compared with 132 +/- 87 days and 142 days, respectively, for patients with Wallstents. Stricture formation in the middle of the Ultraflex stent occurred bilaterally, at the level of anastomosis in one patient in whom stent placement was undertaken in the presence of inflammation. Stent migration in one patient was related to undersizing of the stent diameter relative to the airway diameter. A larger diameter relative stent was subsequently inserted successfully. Ultraflex stents appear to have fewer long-term complications when used in the management of airway complications following LT.

The Journal of Heart and Lung Transplantation, 2002

Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after s... more Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD. In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded. Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients. Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

The Journal of Heart and Lung Transplantation, 2005

Community-acquired viral infections, such as respiratory syncytial virus (RSV), represent a risk ... more Community-acquired viral infections, such as respiratory syncytial virus (RSV), represent a risk factor for bronchiolitis obliterans syndrome (BOS), the major limiting factor for long-term survival after lung transplantation (LTx). RSV often presents with acute bronchiolitis and may be fatal in 10% to 20% of patients. Standard therapies for RSV include nebulized ribavirin with or without steroids, but are costly and inconvenient. We investigated the utility of intravenous (IV) ribavirin with steroids for the treatment of RSV infection after LTx. RSV was identified in nasopharyngeal and throat swabs (NPS) using indirect fluorescent antibody (IFA) testing in 18 symptomatic patients, which was confirmed by viral culture in 14. Data were collected for the period between April 2002 and October 2004. The study included 10 men and 8 women, mean age 42 +/- 15 (range 18 to 63) years. Transplant procedures were 5 single LTx and 13 bilateral LTx. RSV diagnosis was made on Day 1,374 +/- 1,270 (range 61 to 4,598, median 935) post-operatively. Underlying diagnoses included cystic fibrosis (n = 9), emphysema (n = 7) and pulmonary fibrosis (n = 2). All 18 patients received intravenous (IV) ribavirin (33 mg/kg on Day 1 and 20 mg/kg/day thereafter in 3 divided doses) with oral prednisolone (1 mg/kg) until repeat NPS were negative for RSV on IFA. Median therapy was 8 days (6 to 15). The mortality rate was 0%. Mean FEV1 fell from 2.1 +/- 1.0 liter (0.7 to 3.7 liters) to 1.8 +/- 0.9 liter (0.5 to 3.6 liters) (p < 0.001), but recovered to 2.1 +/- 0.9 (0.7 to 3.7 liters) within 3 months and was maintained at follow-up of 521 +/- 328 days (141 to 1,023 days, median 302). Only 1 patient developed bronchiolitis obliterans syndrome (BOS). Complications included mild hemolytic anemia (blood hemoglobin fell from 122 +/- 22 [84 to 154] g/liter to 107 +/- 18 [75 to 138] g/liter, p = 0.02). Cost savings per 8-day course were $US15,913 when compared with nebulized therapy at 6 g/day (p < 0.001). This is the largest reported series of treated RSV cases after LTx and the first to show that therapy with IV ribavirin and oral corticosteroids is well tolerated and effective. Cost utility vs nebulized therapy has been established. Early diagnosis and management are essential to prevent airway epithelial injury and subsequent BOS.