IP Fellows Reading List

Pulmonary Alveolar Proteinosis

Whole lung lavage-technical details, challenges and management of complications

https://pubmed.ncbi.nlm.nih.gov/28740686/

Review

Reference: Awab A, Khan MS, Youness HA. Whole lung lavage-technical details, challenges and management of complications. J Thorac Dis. 2017;9(6):1697-1706.

Summary: Whole lung lavage (WLL) is the first-line therapy for moderate-to-severe pulmonary alveolar proteinosis. This article reviews WLL and its indications, timing, technical aspects, and complications. Authors include their protocol, images and diagrams of their equipment set-up, and a sample worksheet used during their procedures.

Efficacy of whole-lung lavage in pulmonary alveolar proteinosis: a multicenter international study of gelf

https://pubmed.ncbi.nlm.nih.gov/28118623/

Clinical Trial

Reference: Gay P, Wallaert B, Nowak S, et al. Efficacy of whole-lung lavage in pulmonary alveolar proteinosis: a multicenter international study of gelf. Respiration. 2017;93(3):198-206.

Background: This study assesses the efficacy of whole lung lavage (WLL) in pulmonary alveolar proteinosis (PAP).

PICO:

Population –

• 33 patients from 12 centers across France, Belgium, Switzerland, Greece, and Canada
• Ages ranged from 13 to 77-years-old (median 44)
• 81.1% had primary PAP
• 72% of patients had resting hypoxemia

Intervention –

• Patients underwent whole lung lavage. There were practice variations that were not controlled for: prior use of GM-CSF (15.2%), use of general anesthesia with selective intubation (97.0%), use of flexible bronchoscopy (18.2%), use of intraprocedural thoracic percussion (36.4%), and completion of bilateral WLL in the same procedure (12.1%).

Comparison –

• None

Outcome –

• Procedures lasted a median of 150 minutes (range 35-270 min) and used a median of 12 L of saline (range 1-40 L)
• During the initial treatment period, 51.5% did not require further WLL after a single lung lavage, 39.4% required a second lavage, and 9.1% required more than two lavages
• 18.2% of patients had an “excellent” response, 33.3% “improved,” 21.2% were “stable,” and 27.3% were “worse” after WLL as determined by the treating physician
• On average, PaO2 improved by 6.375 mmHg with a trend towards improved KCO by 4.238%. There were no improvements in PFTs
• The most common complication was worsening hypoxemia in 12.1% of patients. There were two deaths, but it was not made clear whether the patients died as a result of the procedure or the underlying disease
• Relapse was seen in 57% of patients

Take home: WLL is the primary treatment for PAP, although its effects were often modest and/or transient in this study population. Approximately half of patients who underwent WLL were noted to have a positive clinical response to WLL but over half relapsed. There were significant variations in procedural techniques between sites which may have affected outcomes.

Whole lung lavage treatment of Chinese patients with autoimmune pulmonary alveolar proteinosis: a retrospective long-term follow-up study

https://pubmed.ncbi.nlm.nih.gov/26481735/

Clinical Trial

Reference: Zhao YY, Huang H, Liu YZ, Song XY, Li S, Xu ZJ. Whole lung lavage treatment of Chinese patients with autoimmune pulmonary alveolar proteinosis: a retrospective long-term follow-up study. Chin Med J (Engl). 2015;128(20):2714-2719.

Background: This is a relatively larger retrospective analysis following longer-term outcomes in patients with autoimmune pulmonary alveolar proteinosis (PAP).

PICO:

Population –

• 120 patients with autoimmune PAP in China followed for a mean follow-up time of 8.6 years
• Mean age was 43 years and there were 2.75x more men than women

Intervention –

• Whole lung lavage (WLL) for a resting PaO2 of <65 mmHg, A-a gradient of >40 mmHg, or shunt fraction of >10%. WLL was repeated for increasing symptoms, decrease in PaO2 by >10 mmHg, or resting or exertional hypoxemia. Patients with mild-to-moderate symptoms underwent surveillance only.

Comparison –

• None

Outcome –

• 20% of patients required multiple WLL, 46.7% required a single WLL, and 33.3% underwent surveillance only
• Of those who required multiple WLLs, 25% went in remission, 54% remained stable, and 21% continued to progress by the end of the follow-up period (mean 8.6 years)
• All patients who only required a single WLL went into remission. 1 patient in this group died from lung cancer
• In the surveillance group, 27.5% went into spontaneous remission and 70% remained stable. 1 patient died due to a pulmonary infection
• There were no severe complications after WLL reported
• Following WLL, PaO2, FVC, TLC, DLCO, and 6-minute walk distance (performed 4-6 weeks after WLL) improved while A-a gradient and LDH decreased
• A lower baseline DLCO (<42.1% predicted) was associated with a need for a second WLL

Take home: WLL was relatively safe and effective in most patients in this single-institution study. Most patients (60%) were in remission at the end of the follow-up period. Only 5 (4.2%) had progressive disease despite multiple WLLs. Authors suggest using a low baseline DLCO (<42.1% predicted) for prognostication and to identify patients who are at high risk for needing a second WLL.

Inhaled gm-csf for pulmonary alveolar proteinosis

https://pubmed.ncbi.nlm.nih.gov/31483963/

Clinical Trial

Reference: Tazawa R, Ueda T, Abe M, et al. Inhaled gm-csf for pulmonary alveolar proteinosis. N Engl J Med. 2019;381(10):923-932.

Background: A frequent cause of pulmonary alveolar proteinosis (PAP) is due to neutralization or dysfunction of GM-CSF. A prior study by this group evaluated use of inhaled GM-CSF in unremitting or progressive autoimmune PAP and demonstrated improvement in dyspnea, oxygen requirements, and distance walked in 6 minutes (Tazawa et al. Am J Respir Crit Care Med. 2010 Jun 15;181(12):1345-1354). Authors sought to evaluate GM-CSF use in mild-to-moderate autoimmune PAP in this double-blinded, placebo-controlled trial.

PICO:

Population –

• 64 patients ages 16-80 with autoimmune PAP in Japan.
• Patients were either asymptomatic with a PaO2 of <70 mmHg on room air or symptomatic with a PaO2 <75 mmHg.
• Patients with severe PAP (i.e., PaO2 <50 mmHg) were excluded from this study given concerns for potential exacerbations in the placebo arm. Patients who had recently undergone WLL or GM-CSF treatments were also excluded.

Intervention –

• Inhaled recombinant human GM-CSF (sargramostim) 125 ug BID for 7 days, every other week, for a total of 24 weeks.

Comparison –

• Placebo

Outcome –

• Primary outcome: The A-a gradient changed by an average of -4.50 in the treatment arm vs 0.17 in the placebo arm.
• Secondary outcomes: The mMRC dyspnea scores, vital capacity, and distance walked in 6 minutes were unchanged. The median lung field density on CT improved in the treatment arm by -36.08 Hounsfield units and the median DLCO percent-predicted improved by 6.87.
• There were no significant differences in the rate of adverse events between the two groups.

Take home: In mild-to-moderate PAP, there are modest objective improvements with use of inhaled GM-CSF (i.e., A-a gradient, lung field density on CT, and DLCO) but no meaningful clinical improvement (i.e., mMRC dyspnea score and distance walked in 6 minutes). While prior studies on GM-CSF use in severe PAP have demonstrated some benefits, there does not appear to be significant clinical benefit in mild-to-moderate disease.