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(Chest. 2004;125:2146-2155.)
© 2004 American College of Chest Physicians

Regional Deposition of Aerosolized Interferon-{gamma} in Pulmonary Tuberculosis*

Rany Condos, MD; Frank P. Hull, MD; Neil W. Schluger, MD, FCCP; William N. Rom, MD, MPH, FCCP and Gerald C. Smaldone, MD, PhD, FCCP

* From Bellevue Chest Service, Division of Pulmonary and Critical Care Medicine, NYU School of Medicine, New York; Division of Pulmonary and Critical Care Medicine, Columbia University College of Physicians & Surgeons, New York; and Division of Pulmonary and Critical Care Medicine, State University of New York at Stony Brook, Stony Brook, NY.

Correspondence to: Rany Condos, MD, Assistant Professor of Medicine, NYU School of Medicine, Division of Pulmonary and Critical Care, 550 First Ave, Rm 7 North 24, New York, NY 10016; e-mail: rany.condos{at}med.nyu.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Aerosol interferon-{gamma} (IFN-{gamma}) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-{gamma} treatment.

Design: Particle size was determined with a cascade impactor, and deposition of IFN-{gamma} mixed with 99mTc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-{gamma} were measured in BAL using enzyme-linked immunosorbent assays.

Study patients/intervention: Fourteen patients with pulmonary TB received IFN-{gamma} aerosol (500 µg) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-{gamma} aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited 99mTc-labeled IFN-{gamma} aerosol was partitioned between upper airways and lungs using attenuation correction measurements. 133Xe equilibrium scanning, 133Xe washout, and 99mTc- macroaggregate injection defined regional lung volume, ventilation, and perfusion.

Results: Upper airway deposition was significant often exceeding lung deposition (53.9 ± 7.09 µg vs 35.8 ± 2.73 µg, respectively [mean ± SE]). IFN-{gamma} levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 ± 0.43 µg before vs 24.76 ± 8.71 µg after, p ≤ 0.017), and IFN-{gamma} levels correlated with regional deposition of IFN-{gamma} aerosol (r = 0.823). Four-quadrant analysis of regional lung deposition best correlated with regional perfusion (r = 0.422, p = 0.013) with penetration of aerosol into areas of obvious radiographic infiltration on chest radiograph.

Conclusions: Aerosol therapy with IFN-{gamma} in patients with pulmonary TB is widely distributed and results in significant enhancement of IFN-{gamma} levels in the lower respiratory tract. In patients without lung destruction, IFN-{gamma} aerosol may be an adjuvant to enhance the local immune response.

Key Words: BAL • gamma scintigraphy • interferon-{gamma} • nebulizer • tuberculosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Aerosolized medications can achieve high local levels of drug in the epithelial lining fluid of the airways and lower respiratory tract.12 Achievement of high levels may be particularly important in the treatment of chronic bacterial infections. Patterns of deposition, as well as amount deposited in the lung may be an important guide to therapy.345 In multidrug-resistant tuberculosis (MDR-TB), oral therapy frequently fails despite the use of multiple second-line antituberculous drugs, even when compliance to these drugs is confirmed by directly observed therapy.6 Significant systemic toxicity is associated with many of these agents, limiting their utility in clinical practice. Drugs administered topically to the lungs, via aerosols, are attractive in that they may achieve higher levels in the lung with fewer systemic side effects.78 However, radiologic studies9101112 often suggest nonuniform lung involvement with resulting uncertainty regarding adequate penetration and deposition of therapeutic aerosols. Tagging aerosol with a radioactive isotope allows deposition to be imaged and quantified by a gamma camera, and can provide a meaningful assessment of lung deposition in nonuniform lung disease.5131415

We have previously demonstrated clinical improvement in a small group of patients with MDR-TB failing conventional therapy and treated with aerosolized interferon-{gamma} (IFN-{gamma}).16 These patients received 500 µg of IFN-{gamma} via nebulizer three times a week for 1 month with no significant toxicity. In addition, sputum acid-fast bacilli (AFB) smear findings became negative after 1 month of treatment. In this study, we used radioaerosol techniques and the gamma camera to measure the dose and distribution of aerosol IFN-{gamma} deposited in the lungs of patients with pulmonary mycobacterial disease. Because oropharyngeal deposition was significant, accurate assessment of lung deposition required independent assessment of the upper airway deposition.1718 Regional deposition in the lungs was compared to chest radiograph abnormalities and quantified as a function of regional lung volume, ventilation, and perfusion. Deposition of aerosol in involved lung was correlated to IFN-{gamma} levels in BAL fluid from the same involved regions before, during, and after aerosol therapy.19


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical Study
Fourteen patients with culture-confirmed mycobacterial pulmonary diseases were recruited for a phase I aerosol IFN-{gamma} study (Table 1 ). There were 4 women and 10 men recruited for the study, with an average age of 42 years (range, 22 to 70 years) [Table 1]. All patients had chest radiographic findings and symptoms highly suggestive of active mycobacterial disease. Sputum AFB smear findings were positive in 12 patients and negative in 2 patients. All had culture-confirmed pulmonary mycobacterial disease. Three patients with MDR-TB and one patient with Mycobacterium avium intracellulare (MAI) had positive AFB smear findings despite prolonged (average 8 months), appropriate directly observed therapy. In these patients, aerosol IFN-{gamma} was added to their tuberculosis (TB) or MAI treatment. The rest of the patients had a new diagnosis of TB made, and IFN-{gamma} was added within 7 days of beginning conventional TB treatment. The drug regimen and organisms are listed in Table 1. Chest radiograph findings ranged from diffuse bilateral reticular infiltrates to cavitary disease. One patient with a left pneumonectomy and cavitary disease in the right lung was also studied. Three patients were HIV-positive, with a mean CD4 count of 245. None of the patients were asthmatic or had a history of asthma, and peak flows were measured and recorded in all patients before and after each aerosol treatment The percentage change in peak flow from baseline for all patients was 0 ± 7% (± SE) with no decrease in peak flow in any patient of > 10%. All patients provided informed consent as approved by NYU School of Medicine Human Subjects Review Committee.


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  		Table 1.. Characteristics of the Study Group*

 
All patients received aerosolized IFN-{gamma} (500 µg three times a week) in addition to conventional antimycobacterial therapy. The nebulizer (Misty-Neb; Allegiance Healthcare Corporation; McGaw Park, CA) was filled with 500 µg IFN-{gamma} and normal saline solution to a final volume of 4 mL. The drug was administered via nebulizer at a flow rate of 8 to 10 L/min. Data recorded included symptoms, peak flows, as well as weekly induced-sputum smears and cultures.

Patients underwent a research BAL of the radiographically involved areas of the lung within 7 days of beginning antimycobacterial chemotherapy. At the end of 1 month, the patients underwent repeat BAL of the same involved lung. Seven patients had repeat BAL performed within 1 h of their last aerosol treatment of IFN-{gamma}. Five patients had BAL performed > 24 h from the time of their last aerosol IFN-{gamma} treatment.

BAL
For each subject, BAL was performed with a flexible bronchoscope with local xylocaine anesthesia. Six 50-mL aliquots of sterile saline solution were instilled and subsequently recovered by gentle suction from radiographically involved segments. The BAL fluid was filtered through two layers of sterile cotton gauze to remove mucus, and centrifuged at 1,000 revolutions per minute for 10 min. All BAL fluids were concentrated (3 to 10 x) [Centriprep-10; Amicon; Beverly, MA] for measurement of IFN-{gamma} by radioimmunoassay kits purchased and used according to the recommendations of the manufacturer (R&D; Minneapolis, MN). The concentrations were determined with a microtiter plate reader. All samples were assayed in duplicate. Results were reported as picograms per milliliter of BAL fluid.

Deposition Study
Six patients with Mycobacterium tuberculosis and one patient with MAI underwent deposition studies. All patients had active disease with multiple sputum culture findings positive for M tuberculosis or MAI (Table 1). A gamma camera (Picker-Dyna 4C; Picker Corporation; Highland Heights, OH) with a 15-inch field of view, 37 photomultiplier tubes, and low-energy parallel hole collimator was used for our study. For the deposition and perfusion scans, the energy level was set at 140 keV, 15% window suitable for 99mTc. For lung volume and ventilation using 133Xe, a peak level of 80 Kev was chosen. Peak and uniformity calibrations were performed prior to each study. Image processing software (Nuclear Power 3.0.7; Scientific Imaging; Littleton, CO) allowed for storage and analysis of all images.

The Misty-Neb nebulizer was characterized on the bench using a standard protocol developed in the Stony Brook laboratory.20 A 4-mL solution consisting of 500 µg of IFN-{gamma} (InterMune Pharmaceuticals; Palo Alto, CA) [approximately 1,500 µL with the balance being normal (0.9%) saline solution] was radiolabeled by adding 2.5 mCi 99mTc-labeled human serum albumin (HSA) [Nycomed-Amersham; Arlington Heights, IL, approximately 20 µL, 2.5 mCi]. The nebulizer was connected to a ventilator (Harvard Apparatus; South Natick, MA) to measure aerosol output and particle size. An adult breathing pattern was used with tidal volume of 750 mL, respiratory rate of 20 breaths/min, and a duty cycle of 0.50. Radioactivity in the nebulizer was measured in a well counter prior to nebulization. Aerosol was drawn into a cascade impactor (GS-1; CA Measurements; Sierra Madre, CA) continuously from the inspiratory limb at a flow of 1.0 L/min.

Using the gamma camera, the particle distribution was determined by analyzing the radioactivity on each stage of the impactor. As a first approximation, drug activity in the aerosol was assumed to be proportional to radioactivity. This is usually the case for simple solutes in aqueous solutions.7 A plot of log activity on each stage of the impactor vs probability (Fig 1 ) described the aerodynamic distribution of the particles.



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  		Figure 1.. Relationship between aerodynamic diameter and cumulative percentage of aerosol.

 
Measurement of Regional Lung Volume, Ventilation, and Aerosol Deposition
133Xe ventilation scans were performed using 10 mCi of 133Xe introduced into the closed circuit of a "Pulmonex"-Xenon trap (Atomic Products; Center Moriches, NY) during tidal breathing. A 60-s posterior equilibrium image was obtained by scanning the patient after the counts per 15-s interval became constant (variation < 5%). Following the equilibrium image, the patent inspired room air and regional ventilation was determined by measuring 133Xe washout from the lungs (serial 2.5-s images over 5 min). Then the patient inhaled radiolabeled IFN-{gamma} aerosol. Immediately after the nebulizer treatment, the patient swallowed a glass of water that effectively washed the oropharyngeal activity into the stomach. Subsequent pharyngeal images showed minimal counts (< 1% of the lung or stomach counts) confirming the effectiveness of this maneuver. A posterior image on the gamma camera (deposition image, 60-s acquisition) was then obtained that encompassed both lungs and the stomach.

Attenuation Corrections for the Lungs and Stomach
Attenuation correction (AC) for the chest wall was performed using a calibrated injection of a known quantity of 99mTc-macroaggregated albumin (5 to 10 mCi) through a peripheral IV line. After embolization to the lungs, a single posterior image was obtained using the gamma camera. Counts from that image were subtracted from a background image obtained just prior to the injection. Net counts from the perfusion image were divided by the activity injected to yield an AC factor for the thorax (units = counts per min per microcurie).

To quantify upper airway deposition we measured a separate AC factor for the stomach. A known source (approximately 500 µCi 99mTc-macroaggregated albumin) was placed on a small piece of bread and swallowed by the patient with water. A posterior image of the stomach was then acquired. This image allowed calculation of the attenuation attributable to the stomach.

Regional Deposition Calculations
Using the computer, regions of interest were drawn over the 133Xe equilibrium scan: a region over the entirety of both lungs called the whole lung zone, and another region centered over the large central airways comprising 33% of the area of both lungs that we called the central zone. The area remaining after the central zone was deducted from the whole lung zone was called the peripheral zone.21 The 133Xe regions of interest were then superimposed over the 99mTc deposition image (Fig 2 ).



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  		Figure 2.. Photographs of lung images from eight patients: areas of interest outlined on left using patient 1 as example, and chest radiographs shown below 99mTc-HSA deposition images. C = central; P = peripheral; U = upper; L = lower.

 
The ratio between the central and peripheral lung counts was calculated in a manner that normalized for differences in relative lung thickness by dividing the central/peripheral (C/P) 99mTc counts by the C/P 133Xe counts. This ratio defined the specific C/P ratio. Using the resulting specific C/P values, a ratio of 1.0 reflects deposition proportional to regional volume. Because the central region outlines both central airways and the lung parenchyma surrounding them, a specific C/P ratio of unity reflects predominantly alveolar deposition. Increasing specific C/P ratios greater than unity indicate increasing deposition in the proximal airways.

A similar calculation was performed for upper and lower lung regions. The specific regions of interest consisted of the outline of the whole lung regions as defined by the 133Xe equilibrium scan divided into upper and lower regions by an arbitrary measure of 50% of the height of the lung (Fig 2). By dividing the upper/lower (U/L) 133Xe regions by the U/L 99mTc counts, a specific U/L ratio was defined, which related aerosol deposition in the upper and lower parts of the lungs to regional lung volume.

Four-Quadrant Analysis
The U/L lung regions also defined "four quadrants" of the lungs that provided a schema for regional analysis of factors influencing aerosol deposition in different parts of the lungs. Deposition measurements are often normalized for lung volume as it is obvious that, all things being equal, measurement of deposited radioactivity in two dimensions will be proportionate to the volume of lung present in a given region. In addition to the aerodynamic distribution of the particles, deposition may be affected by other factors such as regional ventilation. Finally, in earlier patient studies, preservation of regional lung perfusion was correlated to regional deposition of particles.14 Based on these past observations, four-quadrant deposition data from the present study were plotted against regional volume (measured by 133Xe equilibrium scan), regional ventilation (133Xe washout), and regional perfusion (99mTc-macroaggregated albumin perfusion scan). (133Xe washout was calculated as the half-time of the 133Xe activity over time as measured from the washout study.15)

Finally, a region of interest was drawn around the stomach defined via the swallowing study. Those parts of the stomach region that overlapped the peripheral region of the right lung were excluded from the calculation of lung deposition.22 Regional drug deposition was determined by measuring all counts in a given area (eg, lung or stomach). The attenuation correction factor of the organ was applied to these raw counts to obtain the actual activity deposition in that area of interest.

Statistics
Deposition of aerosolized IFN-{gamma} in the lungs of patients with pulmonary mycobacterial disease was determined by converting radioactivity in microcurie as a fraction of the amount of radioactivity originally placed in the nebulizer and expressed as micrograms of IFN-{gamma}. A mean amount of deposition for all patients was analyzed, as were cytokine levels, using descriptive statistics including mean and SE. The Student paired t test was used for comparisons of BAL fluid, and p < 0.05 was chosen for statistical significance. Regression analysis was performed relating regional BAL levels of IFN-{gamma} to deposited aerosol in the same lung region.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Aerosol Characterization
Aerosol mass median aerosol diameter (MMAD) was 3.2 µm as determined by cascade impaction (Fig 1). The distribution was not log normal, as the curve turned upward for the stages capturing the larger particles. A significant proportion (44%) were particles > 5 µm.

Clinical Characteristics
All patients tolerated their treatment well and showed clinical and bacteriologic improvement after 1 month of adjunctive aerosol therapy (Table 1). Eleven of 12 study subjects with positive AFB smear findings converted to negative, and the 12th individual had a reduction from numerous AFB seen to rare. No adverse events were recorded.

Aerosol Deposition
Individual doses of IFN-{gamma} deposited in the lungs of each patient are listed in Table 2 . Data are expressed as mean and SE. Percentages are related to the initial amount of drug placed in the nebulizer (500 µg). Patient 3 was studied twice. AC values of the chest as calculated by perfusion scan averaged 110.5 ± 6.65 counts per minute/µCi, while stomach AC averaged 41.9 ± 7.46. A mean 89.7 ± 7.10 µg or 17.9 ± 1.42% of IFN-{gamma} placed in the nebulizer (500 µg) was deposited in the patients. On average, approximately 40% of the deposition was in the lungs. The rest deposited in the oropharynx and was seen as activity in the stomach.


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  		Table 2.. Deposition Results

 
Regional Deposition
In Figure 2 (left), examples of all the different regions of interest are shown. They were derived from the 133Xe equilibrium image (not shown) and superimposed on the deposition image for patient 1. All images are oriented as chest radiographs with the right lung on the reader’s left. The regions of interest consisted of central and peripheral outlines as well as upper and lower quadrants of both lungs. Deposition data are quantified in Table 2. For all patients, calculation of C/P ratios revealed a mean specific C/P ratio of 1.39 ± 0.09, indicating relatively peripheral deposition (1.0 being the most peripheral possible). Specific U/L deposition ratios averaged 0.83 ± 0.10, indicating that per unit volume, deposition in the upper lobes was 83% of the lower. Chest radiographs for the patients are shown below the deposition images. The radiographs revealed heterogeneous involvement typical of mycobacterial disease. One patient (patient 2) had a pneumonectomy and an upper lobe cavitary lesion in the remaining lung. Others had bilateral upper lobe cavitary disease and bronchiectasis. A combination of airways and parenchymal involvement was seen. Despite asymmetric lung involvement by chest radiograph, deposition in the lungs appeared relatively uniform as shown on the deposition images except for the right lower lobe of patient 8, which was severely involved with multiple cavities and bronchiectatic changes on chest radiograph and CT scan.

Regional Physiology and Deposition
Deposition data from the four quadrants of the lungs defined by the upper and lower lung regions (Fig 2) were plotted against physiologic parameters of regional volume, ventilation, and perfusion (Fig 3 ). On a percentage basis, the distribution of particles deposited in the lungs did not correlate with regional lung volume (Fig 3, top; r = 0.224, p = 0.203). These data indicate that the distribution of deposited particles was affected by nonuniform factors across the lungs. When deposition was related to xenon washout (Fig 3, middle), for all patients, there was no correlation (r = 0.0679, p = 0.907). Patient 8 had very poor ventilation throughout both lungs (washout half-times ≥ 160 s) most likely secondary to obstructive lung disease, which was diagnosed later. When those four points were excluded the correlation improved (line shown in Fig 3; r = 0.518, p = 0.0047), suggesting that for some patients more poorly ventilated lung favored deposition. Overall, the best correlation seen was between regional deposition and regional perfusion (Fig 3, bottom; r = 0.422, p = 0.0130).



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  		Figure 3.. Four-quadrant analysis of deposition vs volume (top), washout (middle), and perfusion (bottom).

 
Correlation of Radioactivity With Interferon-{gamma} Activity
A subset of patients had BAL performed with measurements of IFN-{gamma} before and after aerosol deposition (Table 1). As shown in Figure 4 , the relationship of IFN-{gamma} in picograms per milliliter to microgram deposited was described by the following linear regression equation: y = 0.00299 + 0.0155x, r = 0.823, p = 0.232. There was little or no detectable IFN-{gamma} in any patients prior to treatment (open circles, Fig 4). This correlation between an independent assay and a deposition value measured by gamma camera suggests that the technetium radiolabel accurately represented IFN-{gamma} in patients receiving aerosol therapy. The positive correlation approached significance despite only four evaluable patients.



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  		Figure 4.. Concentrations of IFN-{gamma} (picograms per milliliter) vs micrograms of aerosol deposited (depo); deposition measured in same quadrant as location of BAL (filled circles); controls are also shown (open circles), r = 0.823.

 
BAL IFN-{gamma} Activity and Therapy
Measurements of IFN-{gamma} in BAL before and after institution of aerosol therapy are reported in Figure 5 . On the left, prior to aerosol therapy, levels were near zero. BAL data after 1 month of treatment are separated according to when the BAL was done. The middle bar of the graph in Figure 5 is BAL obtained within 1 h of the last aerosol IFN-{gamma} treatment. The bar to the right is BAL obtained > 24 h after the last treatment. The middle bar (BAL 1 h after aerosol) demonstrates high levels of IFN-{gamma} after 1 month of TB and aerosol treatment. The contribution of the aerosol to BAL IFN-{gamma} is demonstrated by the third bar, which reflects IFN-{gamma} levels > 24 h after cessation of aerosol, but continuation of conventional oral therapy. The IFN-{gamma} levels were significantly increased immediately following aerosol treatment (p = 0.017).



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  		Figure 5.. Levels of IFN-{gamma} from BAL before (Pre) aerosol IFN-{gamma}, after 1 hour of TB treatment and aerosol IFN-{gamma} therapy, and 24 h after last treatment of aerosol IFN-{gamma}.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates that aerosol therapy can deliver levels of IFN-{gamma} to diseased areas of the lungs in patients with active TB.23 These levels were far grater than endogenous levels seen following oral therapy with conventional anti-TB agents. Aerosol IFN-{gamma} was well tolerated, and aerosol deposition of IFN-{gamma} was best correlated to regional perfusion.

There are few data relating measured aerosol distribution to regional deposition for clinical nebulizers. Our previous experience in patients with AIDS used devices designed to produce smaller particles. In adults receiving aerosolized pentamidine with MMAD of 1.0 µm, we found < 5% deposition in upper airways.24 In the present study, the MMAD of 3.2 µm was still within a range considered "respirable," and > 50% deposition in the upper airways was not expected. However, when compared to the particle distributions of the AeroTech II (CIS-US; Bedford, MA), a representative device used in our previous pentamidine studies, the interferon aerosol distribution was more polydisperse with a considerable fraction of particles > 5 µm (44% vs 5%), which were likely responsible for the increased upper airway deposition. Aerosols comprised of smaller particles may bypass the upper airway but, all other things being equal, smaller particles will have a reduced deposition in the lungs as they tend to be exhaled. Interferon is expensive, and the "efficiency of delivery" to the peripheral airways will be a combination of nebulizer efficiency, the regional distribution of deposited drug, and the percentage of those particles inhaled that actually deposit. A recent study25 that we have performed with the AeroEclipse I (Monaghan Medical; Plattsburgh, NY) nebulizer produced smaller particles than the Misty-Neb with a more uniform distribution than that shown in Figure 1 and less upper airway deposition. It is possible that reduced upper airway deposition may be associated with greater efficiency of delivery to the target airways and alveoli.2627

Although the intent of this study was not to look at efficacy, 13 of 14 patients had converted sputum smears from positive to negative after 12 treatments of aerosol IFN-{gamma} in combination with conventional antimycobacterial therapy. This effect may reflect adequacy of oral therapy; however, we noted that treatment with aerosol IFN-{gamma} was safe. There were no adverse systemic effects noted with aerosol treatment when a lung dose of 20 to 50 µg of IFN-{gamma} was achieved. While deposition was inefficient, significant distribution of the radiolabeled albumin:IFN-{gamma} aerosol was achieved throughout the lower respiratory tract, except in patient 8, in whom there was far advanced parenchymal and airways disease. A recent aerosol IFN-{gamma} clinical trial conducted in South Africa for MDR-TB was terminated prematurely due to lack of efficacy of the aerosol compared to placebo. Most of the patients were "salvage cases" who had repeatedly failed treatment and had far advanced pulmonary TB. In fact, > 95% of cases had radiographs classified as far advanced (70%) or moderately advanced (25%) [K Hillman, PhD; personal communication; December 2003]. In contrast, our patients, both MDR-TB and pan sensitive, had mild-to-moderate disease and were more likely to deposit aerosol in their lung and respond to immunomodulation by IFN-{gamma}. Patient 8, with moderately advanced lower lobe disease, had less deposition, suggesting that the lack of efficacy in the trial from South Africa probably was due to the inclusion of patients with destroyed lungs in whom aerosol and medical therapy would have been futile.

In a study of normal volunteers, IFN-{gamma} was undetectable in the epithelial lining fluid (ELF) of the lungs after subcutaneous administration.28 When compared to subcutaneous therapy, aerosol delivery led to a measurable increase in IFN-{gamma} in the ELF, an observation that was absent with systemic administration.29 This effect disappears within 24 h of treatment, which we confirmed. Those patients who underwent research BAL within an hour of their last aerosol IFN-{gamma} treatment had significantly increased levels of IFN-{gamma} in the ELF. Those patient lavaged > 24 h since their last treatment had negligible IFN-{gamma} in their ELF. With the advent of more efficient delivery systems and adjustment of particle sizes, the effective dose of IFN-{gamma} may be delivered with much less needed in the nebulizer.

Regional analysis combined with our clinical observations and BAL data indicate that deposition in terminal airways was adequate. Mycobacterial diseases of the lung have an asymmetric lung distribution with predominant upper lobe involvement. The upper airway acted as a filter removing large particles resulting in pulmonary deposition of fine particles more peripherally as indicated by the average C/P ratio of 1.39 and U/L ratio of 0.83. Cavitary disease was present in most of our patients, and although discrete cavitary deposition was not measured in the current study, areas of cavitary disease had measurable amounts of aerosol deposition. Previous studies30 have shown that aerosol can deposit in cavities; although this deposition may be modest, it probably exceeds intracavitary delivery by the systemic route.

Aerosol therapy should not be excluded in pulmonary TB despite perceived lack of uniform ventilation due to upper lobe disease. Indeed, in the present study there was an overall increase in deposition in those areas with reduced ventilation. Deposition was reduced only in those parts of the lung that appeared virtually destroyed on the chest radiograph. The correlation between deposition and perfusion in our tuberculous patients has been seen previously in patients with from chronic rejection following lung transplantation.15 The present observations support the notion that relatively healthy lung (ie, well perfused) represents a peripheral geometry best suited for aerosol deposition. Combined with the lack of toxicity, targeted therapy of IFN-{gamma} may be an effective immune modulator in pulmonary tuberculosis. We previously published striking immune modulation of signal transduction activator of transciption, interferon regulatory factor-1, and interferon regulatory factor-9 in both involved and uninvolved lobes following aerosol IFN-{gamma} over 1 month.31 We are now conducting a randomized clinical trial comparing adjunctive aerosol IFN-{gamma} via the Aero-Eclipse I nebulizer added to antimycobacterial therapy in drug-sensitive TB compared to antimycobacterial therapy alone. The patients’ TB in this randomized clinical trial will have minimal-to-moderate cavitary disease, and will receive IFN-{gamma} over 4 months.


   Footnotes
 
Abbreviations: AC = attenuation correction; AFB = acid-fast bacilli; C/P = central/peripheral; ELF = epithelial lining fluid; IFN-{gamma} = interferon-{gamma}; MAI = Mycobacterium avium intracellulare; MDR-TB = multidrug resistant tuberculosis; MMAD = mass median aerosol diameter; TB = tuberculosis; U/L = upper/lower

Support was provided by National Institutes of Health grants M0100096, HL 059832, and Doris Duke T98048.

Received for publication August 4, 2003. Accepted for publication December 23, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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