Molgradex – GM-CSF and PAP
Granulocyte macrophage-colony-stimulating factor (GM-CSF) causes variable improvement in autoimmune pulmonary alveolar proteinosis (aPAP). Upon response to short-term treatment, patients are divided into responders and non-responders. The aim of this study was to test the hypothesis that long-term inhaled GM-CSF (iGM-CSF) is effective in all patients and that attainment of remission permits gradual de-escalation of the dose to the lowest effective safe dose.
Patients were treated with iGM-CSF 250 μg once a day given 4 days on and 4 days off for as long as necessary (the “as far as it takes” protocol). Upon remission, defined as absence of symptoms, oxygen desaturation <4 % at the walking test, and significant radiographic reduction of the infiltrates, or at least two of the above, the iGM-CSF dose was de-escalated. In the case of relapse, the patient was repositioned at the previous effective dose. Patients were investigated at 6-month intervals. To detect hematopoietic effects, blood cell counts, CD34+ cells, granulocyte macrophage progenitor colony-forming-units, and burst-forming-unit erythroid were measured.
Six (five female) patients 43.8 ± 15.7 years of age were treated for 14-65 months and all responded to treatment. Remission was achieved after 25.6 ± 10 months. Three patients maintained remission at their lowest effective dose. Two patients relapsed at de-escalating doses. One patient remains on full-dose treatment. iGM-CSF had no impact on any of the hematological parameters tested.
In aPAP, long-term adherence to the dose schedule permitted remission in all patients. Long-term treatment with iGM-CSF also permitted the definition of lower effective doses, minimizing disease burden and treatment costs safely, since no stimulating activity on hematopoiesis was observed, a fact that is of paramount importance for those aPAP patients needing lifelong treatment.
Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.
To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.
During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P < .01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC ≥ 80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P < .0005).
These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare pulmonary disease caused by functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF). Administration of GM-CSF represents a potential therapeutic strategy in management of aPAP. Herein, we systematically review the efficacy of GM-CSF therapy in aPAP.
We searched the PubMed and EmBase databases for studies reporting the use of GM-CSF in aPAP. We calculated the proportion with 95% Cl to assess the response and relapse rates of GM-CSF therapy in individual studies and pooled them using a random-effects model. Statistical heterogeneity was assessed using the 12 and Cochran Q tests. Publication bias was analyzed using funnel plot and Egger and Begg-Mazumdar tests.
Our initial searches yielded 1,585 studies. Of these, five observational studies (involving 94 patients) were included for analysis. Three studies used the subcutaneous route, and two studies used the inhalational route for GM-CSF administration. The response rate of GM-CSF varied from 43% to 92%, with the pooled response rate being 58.6% (95% Cl, 42.7-72.9). The relapse rate in GM-CSF responders was 29. 7% (95% Cl, 10.5-60.4). There was no evidence of statistical heterogeneity or publication bias for the outcome of response. GM-CSF therapy was associated with minor complications, such as fever and local complications at the site of administration.
GM-CSF represents a useful approach in the treatment of aPAP. The optimal indication, dose and duration of therapy, and the factors predicting response and relapse need to be defined by future studies.
Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied.
To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP.
We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa(O(2)) of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO(2)] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 microg Days 1-8, none Days 9-14; x six cycles; 12 wk); low-dose therapy (125 microg Days 1-4, none Days 5-14; x six cycles; 12 wk), and follow-up (52 wk).
Measurements and Main Results
Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO(2) of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO(2) and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year.
Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.
AeroVanc – MRSA and Cystic Fibrosis
minimizing systemic exposure and associated toxicity. The high local concentrations of antibiotic may
enable more effective treatment of multi-drug resistant pathogens. This review explores barriers to effective
treatment with inhaled antibiotics. In addition, potential opportunities for improvements in treatment are
Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions.
We performed a retrospective analysis using data reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 2006 to 2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included P aeruginosa, methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Haemophilus influenzae, Burkholderia cepacia complex, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans. Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010 to 2012, when the CFFPR collected NTM species.
In 2012, the pathogens of highest prevalence and incidence were MSSA and P aeruginosa, followed by MRSA. The prevalence of A xylosoxidans and B cepacia complex were relatively low. From 2006 to 2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P aeruginosa and B cepacia complex, but significantly increased for MRSA. From 2010 to 2012, the annual percent change in overall prevalence of NTM and Mycobaterium avium complex increased.
The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology.
Risk factors for methicillin-resistant Staphylococcus aureus (MRSA) in Cystic Fibrosis (CF) and the impact on CF disease progression are still under debate.
The objectives of this study were to determine clinical variables associated with MRSA colonization and examine impact on FEV1 evolution in CF patients.
A retrospective case–control study using the University Hospital of Brussels CF clinic patient registry from 2002 to 2010, comparing clinical variables and decline of FEV1 of MRSA positive patients with age and sex matched controls, chronically colonized with S. aureus.
Thirty of the 165 CF patients, chronically colonized with S. aureus, had cultures positive for MRSA (18.2%). Excluding patients under 4 years, the prevalence became 15.2% (23/151). Chronic colonization (i.e., three or more consecutive positive cultures) was found in 19/151 (12.6%). The MRSA positive group showed a higher proportion of patients with genotype F508del, less pancreas sufficient patients, more bronchiectasis and more frequent hospitalization.
The FEV1 recorded one year prior to, and at the moment of MRSA acquisition, was lower but not significantly different from that obtained in controls (72.9% ± 26.6 vs 84.3 ± 21.8 and 68.2% ± 27.1 vs 81.4% ± 24.3 respectively, pN0.1). However, FEV1 decline over 2- and 6-year periods, were significantly greater in the chronic MRSA group than in the controls (−5% ± 5.5 vs −2.5 ± 2.3 over 2 years (p = 0.043) and −1.8% ± 4.6 vs −1.0% ± 1.9 over a 6-year period (p = 0.026)).
In our center the prevalence of MRSA in CF patients, chronically colonized with S. aureus and over the age of 4 years, was 15.2%
(12.6% chronic infection). MRSA colonization was shown to be associated with a genotype F508del, presence of bronchiectasis and hospitalization. Our spirometric data also show that a MRSA episode entails an FEV1 decline that is almost double that predicted for CF patients who can remain unaffected by MRSA.
The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the respiratory tract of individuals with cystic fibrosis (CF) has increased dramatically; however, its impact on outcomes in CF is unclear. Because the time between infection with bacteria in CF and death can be decades, observational studies with long periods of follow-up are well suited to address the current gap in knowledge.
To determine whether isolation of MRSA from the respiratory tract of CF patients is associated with worse survival compared with patients who never have a culture positive for MRSA.
Detection of MRSA in the respiratory tract of CF patients was associated with worse survival.
Patients with cystic fibrosis periodically experience pulmonary exacerbations. Previous studies have noted that some patients’ lung function (FEV1) does not improve with treatment.
To determine the proportion of patients treated for a pulmonary exacerbation that does not recover to spirometric baseline, and to identify factors associated with the failure to recover to spirometric baseline.
Cohort study using the Cystic Fibrosis Foundation Patient Registry from 2003–2006. We randomly selected one pulmonary
exacerbation treated with intravenous antibiotics per patient and compared the best FEV1 in the 3 months after treatment with the best FEV1 in the 6 months before treatment. Recovery to baseline was defined as any FEV1 in the 3 months after treatment that was greater than or equal to 90% of the baseline FEV1. Multivariable logistic regression was used to estimate associations with the failure to recover to baseline FEV1.
Measurements and Main Results
Of 8,479 pulmonary exacerbations, 25% failed to recover to baseline FEV1. A higher risk of failing to recover to baseline was associated with female sex; pancreatic insufficiency; being undernourished; Medicaid insurance; persistent infection with Pseudomonas aeruginosa, Burkholderia cepacia complex, or methicillin-resistant Staphylococcus aureus; allergic bronchopulmonary aspergillosis; a longer time since baseline spirometric assessment; and a larger drop in FEV1 from baseline to treatment initiation.
For a randomly selected pulmonary exacerbation, 25% of patients’ pulmonary function did not recover to baseline after treatment
with intravenous antibiotics. We identified factors associated with the failure to recover to baseline, allowing clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment.
The prevalence in cystic fibrosis (CF) of respiratory cultures with methicillin-resistant Staphylococcus aureus (MRSA) has dramatically increased over the last 10 years, but the effect of MRSA on FEV1 decline in CF is unknown.
To determine the association between MRSA respiratory infection and FEV1 decline in children and adults with CF.
This was a 10-year cohort study using the Cystic Fibrosis Foundation patient registry from 1996–2005. We studied individuals who developed new MRSA respiratory tract infection. Repeated-measures regression was used to assess the association between MRSA and FEV1 decline, adjusted for confounders, in individuals aged 8–21 years and adults (aged 22–45 yr). Two different statistical models were used to assess robustness of results.
Measurements and Main Results
The study cohort included 17,357 patients with an average follow-up of 5.3 years. During the study period, 1,732 individuals developed new persistent MRSA infection (≥3 MRSA cultures; average, 6.8 positive cultures) and were subsequently followed for an average of 3.5 years. Even after adjustment for confounders, rate of FEV1 decline in individuals aged 8–21 years with persistent MRSA was more rapid in both statistical models. Their average FEV1 decline of 2.06% predicted/year was 43% more rapid than the 1.44% predicted/year in those without MRSA (difference, −0.62% predicted/yr; 95% confidence interval, −0.70 to −0.54; P < 0.001). Effect of MRSA on FEV1 decline in adults was not clinically significant.
Persistent infection with MRSA in individuals with CF between the ages of 8 and 21 years is associated with a more rapid rate of decline in lung function.
Aironite – Nitrite and HFpEF
Abnormalities in nitric oxide (NO) signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to NO in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use.
Determine whether inhaled nitrite improves hemodynamics in HFpEF.
Methods and Results
In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise, prior to and following treatment with inhaled sodium nitrite (90 mg) or placebo. The primary endpoint was the pulmonary capillary wedge pressure (PCWP) during exercise. Prior to study drug, HFpEF subjects displayed an increase in PCWP with exercise from 20±6 to 34±7 mmHg (p<0.0001). Following study drug administration exercise PCWP was substantially improved by nitrite as compared to placebo (baseline-adjusted mean 25±5 vs 31±6 mmHg, ANCOVA p=0.022). Inhaled nitrite reduced resting PCWP (-4±3 vs -1±2 mmHg, p=0.002), improved pulmonary artery compliance (+1.5±1.1 vs +0.6±0.9 ml/mmHg) and decreased mean pulmonary artery pressures at rest (-7±4 vs -3±4 mmHg, p=0.007) and with exercise (-10±6 vs -5±6 mmHg, p=0.05). Nitrite reduced right atrial pressures with no effect on cardiac output or stroke volume.
Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF.
The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models.
Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively.
Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH.
On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.
Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF). We evaluated the safety and efficacy of a potentially novel inhaled formulation of nitrite in PH-HFpEF patients as compared with Group 1 and 3 PH.
Cardiopulmonary hemodynamics were recorded after acute administration of inhaled nitrite at 2 doses, 45 and 90 mg. Safety endpoints included change in systemic blood pressure and methemoglobin levels. Responses were also compared with those administered inhaled nitric oxide.
Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 pulmonary arterial hypertension patients on background PH-specific therapy, and 6 Group 3 PH). Drug administration was well tolerated. Nitrite inhalation significantly lowered pulmonary, right atrial, and pulmonary capillary wedge pressures, most pronounced in patients with PH-HFpEF. There was a modest decrease in cardiac output and systemic blood pressure. Pulmonary vascular resistance decreased only in Group 3 PH patients. There was substantial increase in pulmonary artery compliance, most pronounced in patients with PH-HFpEF.
Inhaled nitrite is safe in PH patients and may be efficacious in PH-HFpEF and Group 3 PH primarily via improvements in left and right ventricular filling pressures and pulmonary artery compliance. The lack of change in pulmonary vascular resistance likely may limit efficacy for Group 1 patients.