4 Dakin CJ, Numa AH, Wang HE, et al. Inflammation, infec-
`tion, and pulmonary function in infants and young children
`with cystic fibrosis. Am J Respir Crit Care Med 2002;
`165:904–910
`5 Ranganathan SC, Dezateux C, Bush A, et al. Airway function
`in infants newly diagnosed with cystic fibrosis. Lancet 2001;
`358:1964–1965
`6 Ramsey BW, Pepe MS, Quan JM, et al. Intermittent admin-
`istration of inhaled tobramycin in patients with cystic fibrosis.
`N Engl J Med 1999; 340:23–30
`7 Quan JM, Tiddens HAWM, Sy JP, et al. A two-year random-
`ized, placebo-controlled trial of dornase alfa in young patients
`with cystic fibrosis with mild lung function abnormalities.
`J Pediatr 2001; 139:813–820
`8 Stutman HR, Lieberman JM, Nussbaum E, et al. Antibiotic
`prophylaxis in infants and young children with cystic fibrosis:
`a randomized controlled trial. J Pediatr 2002; 140:299–305
`9 Konstan MW, Byard PH, Hoppel CL, et al. Effect of
`high-dose ibuprofen in patients with cystic fibrosis. N Engl
`J Med 1995; 332:848–854
`10 Eigen H, Rosenstein BJ. A multicenter study of alternate-day
`prednisone in patients with cystic fibrosis. J Pediatr 1995;
`126:515–523
`11 Frederiksen B, Lanng S, Koch C, et al. Improved survival in
`the Danish center-treated cystic fibrosis patients: results of
`aggressive treatment. Pediatr Pulmonol 1996; 21:153–158
`12 Oermann CM, Sockrider MM, Konstan MW. The use of
`anti-inflammatory medications in cystic fibrosis: trends and
`physician attitudes. Chest 1999; 115:1053–1058
`13 Heinzl B, Eber E, Oberwaldner B, et al. Effects of inhaled
`gentamicin prophylaxis on acquisition of Pseudomonas
`aeruginosa in children with cystic fibrosis: a pilot study.
`Pediatr Pulmonol 2002; 33:32–37
`14 Wiesemann HG, Steinkamp G, Ratjen F, et al. Placebo-
`controlled, double blind, randomized study of aerosolized
`tobramycin for early treatment of Pseudomonas aeruginosa
`colonization in cystic fibrosis. Pediatr Pulmonol 1998; 25:
`88–92
`inhaled
`15 Ratjen F, Do¨ring G, Nikolaizik WH. Effect of
`tobramycin on early Pseudomonas aeruginosa colonisation in
`patients with cystic fibrosis. Lancet 2001; 358:983–984
`16 Moss RB. Long-term benefits of
`inhaled tobramycin in
`adolescent patient with cystic fibrosis. Chest 2001; 121:55– 63
`17 Burns JL, Van Dalfsen JM, Shawar RM, et al. Effect of
`chronic intermittent administration of inhaled tobramycin on
`respiratory microbial flora in patients with cystic fibrosis.
`J Infect Dis 1991; 179:1190–1196
`18 Smith AL, Fiel SB, Mayer-Hamblett N, et al. Lack of
`association between in vitro antibiotic susceptibility testing of
`Pseudomonas aeruginosa isolates and clinical response to
`parenteral antibiotic administration in cystic fibrosis. Chest
`2003 (in press)
`
`So Many Drugs, So Little Time
`The Future Challenge of Cystic
`Fibrosis Care
`
`A fter the identification of the cystic fibrosis (CF)
`
`gene in 19891 and the emergence of gene ther-
`apy in the early 1990s, great hope existed that a cure
`for CF could be developed rapidly. The last decade
`has led to the realization that while a cure for CF is
`
`still the long-term goal, more immediate gains may
`be made by developing therapies that target the
`chronic cycle of infection and inflammation that
`drives the progressive lung disease seen in CF.2
`Therapies that improve or correct the abnormal ion
`transport that is characteristic of the respiratory
`epithelium in CF may also eventually be effective in
`slowing the progression of CF lung disease. Numer-
`ous new therapeutic agents targeting these areas are
`in development. Many are currently in clinical trials
`being conducted by the Cystic Fibrosis Foundation
`Therapeutics Development Network (CFF-TDN), a
`national multicenter network that has been designed
`specifically to accelerate the development of new
`therapeutic agents for the treatment of CF.
`Many of these trials take advantage of CF being an
`endobronchial disease and deliver the new therapeutic
`agents by aerosolization. The CFF-TDN alone is cur-
`rently conducting clinical trials of six different inhaled
`CF therapeutic agents. The hope for these new aero-
`solized agents is that they would add to the effect of the
`many currently utilized aerosolized CF therapies (eg,
`tobramycin, human recombinant DNase, colistin, hy-
`pertonic saline solution, and bronchodilators).
`The good news is that the increase in the number
`of CF therapeutic options over the last few decades
`has resulted in an improvement in expected survival
`for CF patients. The median survival time is now
`⬎ 30 years, a significant
`improvement over the
`expected survival of only 15 years in 1970.3 The
`quality of
`life for individuals with CF also has
`improved, with about 30% completing college, 40%
`of adults with CF marrying, and 50% working full-
`time or part-time.3 A growing challenge, however, is
`that at the same time that the improvement in length
`and quality of life in individuals with CF is allowing
`them to participate in and experience the time
`demands of career and family, the complexity and
`length of time required to complete their CF ther-
`apies also is increasing. A current standard CF
`treatment regimen of airway clearance, inhaled mu-
`colytic agents, inhaled antibiotic agents, pancreatic
`enzymes, nutritional supplements, and exercise often
`requires ⱖ 2 h each day.
`The article by Geller and colleagues in this issue of
`CHEST (see page 28) demonstrating a method of more
`rapidly and efficiently delivering aerosolized tobramy-
`cin represents what is likely to be a research area of
`increasing importance in CF in the upcoming years:
`improving the delivery of inhaled medications. Aero-
`solized medications already are a cornerstone of CF
`therapy and will play an increasingly important role in
`the treatment of CF in the future. The use of a
`tobramycin solution for inhalation (TSI) [TOBI; Chi-
`ron; Emeryville, CA] already represents a significant
`
`www.chestjournal.org
`
`CHEST / 123 / 1 /JANUARY, 2003
`
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`
`Liquidia's Exhibit 1077
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`

`

`portion of the CF patient’s time commitment for
`therapy, requiring 20 to 25 h per month when used.
`Geller and colleagues compared the delivery of
`TSI by the standard PARI LC PLUS jet nebulizer
`(PARI Respiratory Equipment; Monterey, CA) and
`Pulmo-Aide compressor (DeVilbiss Corp; Somerset,
`PA) to delivery with a new aerosol device, the
`AeroDose 5.5 RP inhaler (Aerogen; Mountain View,
`CA). The AeroDose is slightly larger than a metered-
`dose inhaler and generates an aerosol by the rapid
`oscillation of a porous dome over the TSI, rather
`than by a jet of compressed air. An airflow sensor
`limits aerosol generation to inhalation only. With the
`use of AeroDose technology, Geller and colleagues
`demonstrated that TSI could be delivered in less
`than half the time normally required (8.0 vs 17.7
`min, respectively). With the decrease in wasted TSI
`(ie, the amount of a drug remaining in the nebulizer
`cup after treatment or aerosolized during exhala-
`tion), a dose of 90 mg aerosolized TSI resulted in
`sputum concentrations comparable to 300 mg TSI
`delivered by the standard methods. There was no
`difference in the incidence of cough or bronchos-
`pasm between the two delivery methods.
`For the individual with CF being treated with in-
`haled tobramycin, the utilization of AeroDose technol-
`ogy could result in time saved of ⱖ 10 h per month.
`Over the course of a year, individuals on alternating
`months of TSI therapy could gain more than a full work
`week of free time. A decrease in the time required to
`deliver TSI also would likely result in increased adher-
`ence to the TSI regimen, as adherence to therapy in
`CF patients has been shown to correspond to the
`simplicity of the treatment.4 AeroDose technology
`could have an even more significant impact on the time
`required for therapy as the number of aerosolized CF
`therapies increases in the future.
`But now for the caveat. While providing a promise
`of improved aerosol technology, the article by Geller
`and colleagues also demonstrates the challenges that
`will be faced in improving the delivery of aerosolized
`therapies to individuals with CF. First, further ad-
`vances in aerosol technology are still required. The
`AeroDose inhaler is not currently available, nor is it
`ready for widespread use by individuals with CF.
`Ten of the 53 participants in the study experienced a
`malfunction of the AeroDose inhaler. These mal-
`functions required that the study design be altered to
`allow a new AeroDose inhaler to be used for each
`tobramycin dose. Future studies of the AeroDose
`inhaler will need to demonstrate reliability along
`with improved efficacy of drug delivery. Second,
`aerosol delivery devices may require custom design
`for specific CF medications. An AeroDose inhaler
`can hold only one third of the 90-mg TSI dose, which
`would require stopping twice to refill the inhaler. A
`
`reconfiguration of the AeroDose inhaler from its
`current design would be needed to take full advan-
`tage of the potential time savings of using AeroDose
`technology to deliver tobramycin. Last, creative
`combinations of research funding from the National
`Institutes of Health, private foundations, and indus-
`try will be required to fully develop customized
`inhaled drug delivery systems for patients with CF.
`As opposed to COPD or asthma patients, the 30,000
`individuals with CF in the United States are unlikely
`to provide sufficient potential financial gain for most
`pharmaceutical companies to justify committing the
`resources to develop, test, and gain Food and Drug
`Administration approval
`for CF-specific,
`inhaled
`drug-delivery systems. Despite the potential of the
`AeroDose inhaler to improve the quality of life of
`individuals with CF, Chiron Corporation is likely to
`think long and hard before committing itself to the
`development of a delivery system that might not
`significantly increase sales and may actually encour-
`age patients to split up their current single-dose,
`300-mg TSI vials into three 90-mg doses.
`In the big picture, there are a number of new
`technologies for the delivery of inhaled medications
`that currently are in development. These include the
`AeroDose inhaler, systems based on dry-powder
`delivery,
`liquid multidose inhalers, and breath-
`actuated nebulizers.5–7 Each one has different po-
`tential advantages and disadvantages, and it is not
`clear now which of these will be best-suited for the
`delivery of CF medications. What is clear is that the
`article by Geller and colleagues represents what will
`be an increasingly important topic of CF research:
`improving the delivery of inhaled therapies.
`It is not unrealistic to believe that one day an
`individual with CF may protect their lung function
`by the daily inhalation of a mucolytic agent, an
`antibiotic agent (or agents), an anti-inflammatory
`agent (or agents), and a chloride transport agonist
`agent. With this in mind, a commitment to continued
`improvement in the efficacy and speed of delivery of
`inhaled medications is essential for the CF research
`community. This will ensure that future improve-
`ments in CF treatment will be limited only by our
`ability to identify new therapies, and not by the time
`that individuals with CF have to perform them.
`
`Michael P. Boyle, MD, FCCP
`Baltimore, MD
`
`Dr. Boyle is Assistant Professor of Medicine, the Johns Hopkins
`University School of Medicine, and is Director,
`the Johns
`Hopkins Adult Cystic Fibrosis Program.
`Correspondence to: Michael P. Boyle, MD, FCCP, Assistant
`Professor of Medicine, Director, Adult Cystic Fibrosis Program,
`Division of Pulmonary and Critical Care Medicine, Johns Hop-
`kins Hospital, Jefferson B1–170, 600 N Wolfe St, Baltimore, MD
`21287-8922; e-mail: mboyle@jhmi.edu
`
`4
`
`Editorials
`
`Liquidia's Exhibit 1077
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`References
`1 Kerem B, Rommens JM, Buchanan JA, et al. Identification of
`the cystic fibrosis gene: genetic analysis. Science 1989; 245:
`1073–1080
`2 Chmiel JF, Berger M, Konstan MW. The role of inflamma-
`tion in the pathophysiology of CF lung disease. Clin Rev
`Allergy Immunol 2002; 23:5–27
`3 Cystic Fibrosis Foundation. Patient registry 2000: annual
`report. Bethesda, MD: Cystic Fibrosis Foundation, 2001
`4 Kettler LJ, Sawyer SM, Winefield HR, et al. Determinants of
`adherence in adults with cystic fibrosis. Thorax 2002; 57:459–
`464
`5 Anderson PJ. Delivery options and devices for aerosolized
`therapeutics. Chest 2001; 120(suppl):89S–93S
`6 Dolovich M. New propellant-free technologies under inves-
`tigation. J Aerosol Med 1999; 12(suppl):S9–S17
`7 Zierenberg B. Optimizing the in vitro performance of Respi-
`mat. J Aerosol Med 1999; 12(suppl):S19–S24
`
`Altitude Pulmonary Edema
`Below 8,000 Feet
`What Are We Missing?
`
`M any of the “dogmas of the quiet past”1 have
`
`given way to more well-founded concepts of
`disease in recent decades, as clinical science devel-
`oped more precise investigative tools and effective
`therapies. Some dogmas have remained intact. One
`of these holds that high-altitude pulmonary edema
`(HAPE) is unknown2 or rare3 below 8,000 to 9,000
`feet (2,440 to 2,745 m). Cases of HAPE at lesser
`altitudes are attributed to preexisting diseases such
`as skeletal or pulmonary vascular abnormalities.3,4 In
`the current issue of CHEST (see page 49), however,
`Gabry et al describe 52 lowlanders who acquired
`HAPE after skiing at 1,400 to 2,400 m between 1992
`and 2000. This remarkable account of previously
`healthy persons is all the more noteworthy because
`the skiers slept at a mean altitude of 1,300 m. (As
`Hultgren3 points out, HAPE is usually attributed to
`altitude of repose, rather than that of daily activity.)
`Whereas the altitude exposure of these skiers was
`much more mild than that of previous reports, their
`illnesses were not. The symptoms, cardiorespiratory
`signs, and radiographic abnormalities—83% of the
`patients had bilateral shadows extending over at least
`half of each lung—were severe. Gas exchange was
`equally deranged: the mean alveolar-arterial oxygen
`difference was 45 mm Hg. It is thus no surprise that
`these persons sought emergency medical care at the
`nearest hospital
`in Moutiers. This is a town of
`approximately 5,000, nestled 500 m (approximately
`1,640 feet) above sea level, in the valley where the
`Isere River wends its alpine way through the Taren-
`taise region of southeastern France. Some of the
`
`tallest peaks in Europe are nearby. For example,
`Mont Blanc (15,760 feet/4,807 m) is within 45 km
`(⬍ 30 miles). But these lofty heights are not readily
`accessible from Moutiers since the mountain passes
`are impassible in winter. Although the patients doc-
`umented by Gabry et al skied only at lower altitudes,
`they became very ill nonetheless.
`Because their findings are surprising, one wonders
`if Gabry et al were exhaustive in excluding other
`conditions that can masquerade as HAPE? Not
`completely. Infection is the most obvious candidate.
`Viral pneumonia might mimic HAPE both in its pre-
`sentation and its rapid resolution in healthy young
`patients such as Gabry et al describe. For decades
`preceding the identification of HAPE as a distinct
`clinical entity,5 many patients who probably had this
`condition were thought to have pneumonia. Was it
`the other way around in the patients of Gabry et al?
`If so, what type of pneumonia did they have? As the
`authors point out, influenza pneumonia usually af-
`fects the ill, immunosuppressed, or aged, rather than
`healthy 37-years-olds. This pneumonia has a pro-
`drome of 1 to 4 days that could be hard to distinguish
`from acute mountain sickness, but it often lasts 2 to
`3 weeks, especially if complicated by secondary
`bacterial infections.6 This was clearly not the case in
`the present patients, all of whom were hospitalized
`for less than a week. Given the retrospective nature
`of their analysis,
`it was beyond the reach of the
`authors to exclude infection by bacterial cultures or
`viral isolation from upper or lower airway secretions,
`or immunofluorescence, polymerase chain reaction,
`or enzyme-linked immunosorbent assay testing or
`other means. Future prospective investigations can
`incorporate such steps, however, thus establishing or
`excluding infectious etiology from the differential
`diagnosis in patients who appear to have HAPE at
`such modest altitudes.
`To exclude drug-induced pulmonary edema
`such as that due to heroin (smoked, snorted, or
`injected),7 the authors relied on the history of family
`and friends, and lack of pinpoint pupils, depressed
`respirations, and altered consciousness. The latter
`symptom was present in only 2 of their 52 patients,
`none of whom were treated with naloxone. Suspi-
`cious readers might insist on negative results of
`specific tests of urine or other body fluids to exclude
`this and other drugs,8 including cocaine,9,10 as causes
`of pulmonary edema in altitude visitors. Again, this is
`beyond the reach of a retrospective study. Assuming
`accuracy in the diagnosis of HAPE in 52 patients
`among the 11,420 admitted to the Moutiers emer-
`gency department over 9 years, one remains curious
`as to how many patients had pulmonary edema from
`other causes over the same time period. For exam-
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`CHEST / 123 / 1 /JANUARY, 2003
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