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Inspired by some amazing @JohnsHopkinsDOM & @OslerResidency colleagues (@Dr_DanMD, @david_furfaro, @DxRxEdu to name a few), as well as the master @tony_breu, I’ve decided to take a stab at my first #pulmonology pathophysiology #tweetorial…

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Ever wonder why patients with cystic fibrosis (CF) tend to have more severe disease in the upper lung fields, especially on the right?

I have!

And the answer was not what I was expecting…

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First, it is important to remember that CF is caused by mutations in the CFTR gene, which ultimately leads to thick, viscous secretions due to the inability to secrete chloride.

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Here is a series of short clips that beautifully depict the role of CFTR in the lungs: (credit to @NatWestMD for sharing this with me)

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When this thick mucus accumulates, it becomes a nidus for airflow obstruction, infection, and inflammation. The @NEJM review article on Muco-Obstructive Lung Diseases from May 2019 does an amazing job explaining the pathophysiology behind this.
ncbi.nlm.nih.gov/pubmed/31091375

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For decades it has been observed that CF tends to cause more severe disease in the upper lobes, particularly on the right. Regional variation in inflammation (upper>lower lobes) on BAL has also been demonstrated.
ncbi.nlm.nih.gov/pubmed/3963622
ncbi.nlm.nih.gov/pubmed/9372672

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And more recent data has corroborated these findings:
ncbi.nlm.nih.gov/pubmed/22162514

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Interestingly, it was shown in 1985 (before newborn screening for CF was widespread) that a distinctly outlined orifice/thickening of the right upper lobe bronchus on lateral chest film in adolescents is a sensitive marker for CF.
ncbi.nlm.nih.gov/pubmed/3963622

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So back to our original question. Why might the upper lobes be affected more than the lower lobes in patients with CF, especially on the right?

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One commonly proposed mechanism includes reduced ventilatory excursion of the upper lobes when compared with the lower lobes (which have a closer proximity to the diaphragm), leading to inefficient clearance of secretions from upper lung regions via cough.

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While this explanation is attractive (and may very well contribute to worse disease in the upper lobes), it wouldn’t explain the right-sided predominance described above.

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Another possible mechanism is that the higher partial pressure of oxygen in the upper lobes provides a selective advantage for aerobic bacterial growth such as pseudomonas (the major implicated respiratory pathogen as CF patients age).

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Not only would this not explain the right-sided predominance, but studies have shown that airway inflammation is present in infants with CF who are as young as 4 weeks! (before colonization with CF-related pathogens)
ncbi.nlm.nih.gov/pubmed/7697234

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…not to mention that pseudomonas in patients without CF usually involves the lower lobes. Which brings us to the third answer…
ncbi.nlm.nih.gov/pubmed/4306124

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The prevalence of gastroesophageal (GE) reflux is higher in CF patients than the general population (as high as ~80%!), and reflux has been associated with more severe lung disease.
ncbi.nlm.nih.gov/pubmed/24964289

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The mechansim for reflux in CF is thought to be due to ⬇️ lower esophageal spincter (LES) pressure & ⬆️ transient LES relaxations, which can lead to intermittent aspiration of acidic stomach contents, especially when supine.
ncbi.nlm.nih.gov/pubmed/22777342

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A 2003 study showed that when a modified postural draining position was adopted (versus the standard Trendelenberg position) in CF patients, reflux decreased, as did respiratory complications, further supporting the ⬇️ LES pressure theory.
ncbi.nlm.nih.gov/pubmed/12567389

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Supine aspiration of acidic stomach contents compounds the vicious cycle of inflammation, infection, and progression of lung disease, particularly in the right upper lobe due to anatomical positioning.

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Before summarizing, lets revisit the original question once more:

Why does CF tend to cause more severe disese in the upper lobes, especially on the right?

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SUMMARY
✅ CF patients have ⬇️ LES pressure, leading to ⬆️ GE reflux
✅ Reflux leads to aspiration of acidic stomach contents, which triggers a cascade of inflammation & worsening lung disease
✅ Supine aspiration affects upper > lower lobes, R > L

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Obviously, this is just a theory, but interested to hear others thoughts! @NatWestMD @CMerloMD @sanjayvdesai @hopkinscf @ChadHoc @david_furfaro @DxRxEdu @CPSolvers