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C or r e sp ondence

Pathology of Vaping-Associated Lung Injury
To the Editor: Despite the accumulating data
on the clinical and imaging features of vapingassociated lung injury,1,2 its pathology is poorly
understood. We reviewed lung biopsies from 17
patients (13 men; median age, 35 years [range,
19–67]), all of whom had a history of vaping
(71% with marijuana or cannabis oils) and were
clinically suspected to have vaping-associated lung
injury. Presentation was acute or subacute in all
cases, with bilateral pulmonary opacities; all but
two patients presented in 2019. Eleven met the

criteria for a “confirmed” diagnosis of vapingrelated lung injury; the remaining six met the
criteria for a “probable” designation. In all cases,
histopathological findings showed patterns of
acute lung injury, including acute fibrinous pneumonitis, diffuse alveolar damage, or organizing
pneumonia, usually bronchiolocentric and accompanied by bronchiolitis (Fig. 1; also see the Supplementary Appendix, available with the full text of
this letter at NEJM.org). No histologic findings
were specific, but foamy macrophages and pneu-

A

B

C

D

F

Figure 1. Histopathology of Acute Lung Injury Associated with Vaping.
Most cases showed airway-centered acute lung injury (Panel A), often with severe bronchiolitis accompanied by
marked mucosal edema, sloughing of bronchiolar epithelium, and peribronchiolar organization (Panel B). All cases
showed accumulation of foamy or vacuolated macrophages in peribronchiolar airspaces with pneumocyte vacuolization (Panel C). Four cases showed severe injury, with diffuse alveolar damage and hyaline membranes (Panel D);
two of these patients died.

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mocyte vacuolization were seen in all cases and
may be useful diagnostic clues in an appropriate
clinical context. Pigmented macrophages were
sometimes present but were never a dominant
feature. Neutrophils were often prominent, but
eosinophils were rare and granulomas were not
seen. In two cases, bronchioloalveolar lavage fluid
was available and contained abundant foamy
macrophages. Despite treatment with glucocorticoids and maximum supportive care, two patients
with diffuse alveolar damage died.
To date, few reports of vaping-associated lung
injury have included histopathological findings.
Our cases corroborate many of these descriptions
and provide some preliminary insight into the
pathogenesis of this injury. Much recent attention
has been given to the possibility that vaping-associated lung injury may represent exogenous lipoid
pneumonia.3 However, none of our cases showed
histologic evidence of exogenous lipoid pneumonia and no radiologic evidence thereof has been
found2; this calls into question the diagnostic
utility of identifying lipid-laden macrophages or
performing oil red O staining on bronchioloalveolar lavage fluid as a marker of vaping-associated lung injury, as has been proposed.3,4 The
significance of this observation remains unclear,
particularly in patients with a known vaping history; until more data accumulate, our observations
suggest that this finding should be interpreted
with caution, as it may simply be a marker of exposure and not necessarily a marker of toxicity.
Although it is difficult to discount the potential
role of lipid, we believe that the histologic changes instead suggest that vaping-associated lung
injury represents a form of airway-centered chemical pneumonitis from one or more inhaled toxic
substances rather than exogenous lipoid pneumonia as such, but the agents responsible remain
unknown.

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Yasmeen M. Butt, M.D.
Maxwell L. Smith, M.D.
Henry D. Tazelaar, M.D.
Laszlo T. Vaszar, M.D.
Karen L. Swanson, D.O.
Mayo Clinic
Scottsdale, AZ

Matthew J. Cecchini, M.D., Ph.D.
Jennifer M. Boland, M.D.
Melanie C. Bois, M.D.
James H. Boyum, M.D.
Adam T. Froemming, M.D.
Mayo Clinic
Rochester, MN

Andras Khoor, M.D., Ph.D.
Isabel Mira-Avendano, M.D.
Mayo Clinic
Jacksonville, FL

Aiyub Patel, M.D.
UnityPoint Health
Peoria, IL

Brandon T. Larsen, M.D., Ph.D.
Mayo Clinic
Scottsdale, AZ
larsen.brandon@mayo.edu
Disclosure forms provided by the authors are available with
the full text of this letter at NEJM.org.
This letter was published on October 2, 2019, at NEJM.org.
1.  Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related
to e-cigarette use in Illinois and Wisconsin — preliminary report.
N Engl J Med. DOI:​10.1056/NEJMoa1911614.
2.  Henry TS, Kanne JP, Kligerman SJ. Imaging of vaping-associated lung disease. N Engl J Med. DOI:​10.1056/NEJMc1911995.
3.  Maddock SD, Cirulis MM, Callahan SJ, et al. Pulmonary lipidladen macrophages and vaping. N Engl J Med. DOI:​10.1056/
NEJMc1912038.
4.  Davidson K, Brancato A, Heetderks P, et al. Outbreak of electronic-cigarette–associated acute lipoid pneumonia — North
Carolina, July–August 2019. MMWR Morb Mortal Wkly Rep
2019;​68:​784-6.
DOI: 10.1056/NEJMc1913069
Correspondence Copyright © 2019 Massachusetts Medical Society.

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The New England Journal of Medicine
Downloaded from nejm.org by Jake Rinehart on October 9, 2019. For personal use only. No other uses without permission.
Copyright © 2019 Massachusetts Medical Society. All rights reserved.