Clinical, Bronchoscopic, and Imaging Findings of e-Cigarette, or Vaping, Product Use–Associated Lung Injury Among Patients Treated at an Academic Medical Center

Key Points Question What are the typical clinical, radiographic, and bronchoscopic findings and clinical outcomes of e-cigarette, or vaping, product use–associated lung injury (EVALI)? Findings This case series of 31 patients found that EVALI typically presented as a flu-like illness with elevated inflammatory markers and an organizing pneumonia pattern on computed tomography imaging. Bronchoscopy showed lipid-laden macrophages and had a high rate of false-positive results for infection. Meaning The findings of this study suggest that EVALI has a characteristic clinical and radiographic presentation and that bronchoscopy has limited utility in its evaluation.

Utah has experienced among the highest per capita EVALI rates in the United States. 10,21The University of Utah Medical Center (UUMC) is a quaternary care academic medical center in Salt Lake City, Utah, serving a large referral area.We identified a case of EVALI at UUMC during the final week of June 2019.Bronchoalveolar lavage (BAL) specimens from this and subsequent patients revealed the presence of lipid-laden microphages (LLMs), which led to suspicion the illness was a form of exogenous lipoid pneumonia. 2,22We now know that this is probably inaccurate, 13,[23][24][25] but it prompted a local practice of routine bronchoscopy for patients suspected of having EVALI.As a result, most of the first 31 patients seen at UUMC underwent bronchoscopy with extensive molecular and microbiological testing during the first 5 months of the outbreak.
In this article, we describe the presentation, evaluation, and clinical course of patients diagnosed with EVALI at UUMC.A high rate of bronchoscopy, detailed characterization of imaging findings by 2 thoracic radiologists, and follow-up data for most patients resolve some of the remaining uncertainties regarding EVALI and provide a more complete picture of a typical case than has, to our knowledge, been reported.

Methods
The initial 6 cases of EVALI identified at UUMC were cared for by 1 of the authors (S.K.A., M.M.C., S.D.M., L.M.K. C.S.P., S.M.R, or S.J.C.) between June 24 and August 16, 2019, and have been previously reported 2 ; they are included in this analysis as well.Thereafter, as the magnitude of the outbreak became apparent, institutional emails and informal communications encouraged clinicians to admit patients with suspected EVALI to a service staffed by the pulmonary faculty (pulmonary inpatient or medical intensive care unit [ICU] services, as appropriate) or to contact the pulmonary services for consultation and arranging outpatient follow-up.An ad hoc vaping clinic was created within the general pulmonary clinic to facilitate follow-up after discharge and to accommodate outpatient referrals.In addition, 2 of us (S.K.A. and S.J.C.) acted as liaisons between UUMC and the Utah Department of Health to report cases and facilitate exchange of information.These processes assured that few, if any, patients with EVALI were not identified for this report.Only cases reviewed by 2 of us (S.K.A. and .S.J.C.) and determined to be a confirmed or probable diagnosis of EVALI based on the CDC case definition (ie, e-cigarette use within 90 days of symptom onset, radiographic infiltrates, a negative preliminary infectious workup, and no other plausible diagnoses) were included. 18We stopped including patients when the current analysis was begun on December 10, 2019.Internal review board approval was granted for this case series, and informed consent was

Laboratory Findings
Laboratory and bronchoscopic findings are summarized in

Bronchoscopic Features
Among all 31 patients, (77%) underwent bronchoscopy with BAL.Three of the last 4 inpatients (75%) in the series did not undergo bronchoscopy because by mid-November we had stopped performing routine bronchoscopy; the final patient had bronchoscopy because of recurrent symptoms resulting in readmission.The cytologic differential from BAL fluid showed a predominance of macrophages (median [IQR], 53% [33%-79%]) followed by neutrophils (median [IQR], 28%

Evaluation for Infection
9][30] This patient had a

Imaging
Chest radiography revealed multifocal, multilobar opacities, variable in extent and distribution, consistent with foci of alveolar consolidation.Twenty-six patients (84%) underwent CT scanning (Table 3).eFigure 1 in the Supplement shows examples of the major patterns seen on CT imaging.
The OP pattern was the sole pattern in 18 examinations (69%) and the dominant pattern in 5 (19%).
The HP pattern was the dominant pattern in 2 examinations (8%).The AEP pattern was dominant in 1 examination (4%).The ELP pattern was nondominant in 1 examination (4%), and the ALI pattern was nondominant in 1 examination (4%).No examinations manifested the DAH pattern.Table 4 summarizes major characteristics of each pattern.Subpleural sparing was present in 15 examinations (58%).Airway wall thickening (eFigure 2 in the Supplement) was present in 21 patients (81%).a Percentages may not sum to 100 due to rounding.Totals and percentages for all patterns sum to greater than 26 and 100%, respectively, because some examinations were classified as having more than 1 pattern.
b Organizing pneumonia was the sole pattern in 18 examinations and the dominant pattern in 5 examinations.
c Hypersensitivity pneumonitis was the dominant pattern in 2 examinations.
d Dominant pattern.
e Nondominant pattern.
f Any subpleural sparing includes patients in the yes and some categories.

JAMA Network Open | Pulmonary Medicine
Clinical, Bronchoscopic, and Imaging Findings of EVALI

Readmissions
Two patients (6%) were rehospitalized after discharge.One (3%) was not initially treated with corticosteroids after a single dose of prednisone induced a manic reaction.After discharge, he resumed vaping THC and was readmitted with new lung opacities, a new subpleural cystic space in the right middle lobe, a contiguous pneumothorax, and pneumomediastinum, the last attributed to the Macklin phenomenon.He improved with chest tube drainage and reinstitution of corticosteroids.
The other patient was discharged with a 5-day course of prednisone but did not complete it.He was rehospitalized 3 days later with worsening hypoxemia and progressive pulmonary opacities.
Corticosteroids were reinstituted, and he improved with continued supportive care.

Follow-up
All patients survived, and 20 patients (65%) were seen in follow-up.Median (IQR) time to follow-up after hospital discharge was 16 (11-28)

Discussion
We report a retrospective series of cases of EVALI, an emergent flu-like respiratory illness with the potential for high morbidity and mortality, 11 seen at the University of Utah during the height of the epidemic in 2019.Our patients were evaluated and managed at an academic medical center using a relatively uniform and comprehensive diagnostic strategy with high rates of bronchoscopy and chest CT imaging as well as a substantial early follow-up rate.Thus, this series complements but extends data from previous reports and enhances our understanding of this novel disease.
Our findings confirm those of previous series by showing that EVALI presents as a flu-like illness with respiratory, constitutional, and gastrointestinal symptoms as well as elevated serum inflammatory markers.However, more patients in previous series were treated in an ICU and fewer underwent bronchoscopy.In the seminal series by Layden et al, 1 52 of 98 patients (53%) were cared for in an ICU, and 43 patients (44%) underwent bronchoscopy.In the series by Blagev et al, 12 33 of 60 patients (55%) were admitted to an ICU, and 19 patients (32%) underwent bronchoscopy.More recent additions to the literature, including those by Zou et al, 20 Henzerling et al, 14 and MacMurdo et al, 16 demonstrated similar ICU admission rates (range, 46%-47%) and bronchoscopy rates (range, 19%-47%).By comparison, only 8 (26%) of our patients were treated in an ICU, and a much larger proportion of all patients (22 [77%]) underwent bronchoscopy.The reason for the lower rate of ICU admission in our series is not readily apparent but may reflect a lower severity of illness or different thresholds for ICU utilization.Of note, the demographic characteristics of our cohort are comparable to other series 1,12,[14][15][16]20 in that they are comprised largely of young, White men who frequently use THC products, with substantial psychiatric comorbidity rates. Ths argues against underlying demographic dissimilarities as the cause of lower ICU admissions.There are several reasons for the high rate of bronchoscopy in our series.First, before EVALI became a well-recognized clinical entity, bronchoscopy was performed as part of a general diagnostic survey for infection, diffuse alveolar hemorrhage, acute eosinophilic pneumonia, and so on.[32][33][34][35] Second, the consistent identification of LLMs in BAL specimens reinforced this practice.Finally, we used bronchoscopy as the most sensitive means of excluding alternative diagnoses and reducing diagnostic uncertainty given that EVALI was considered a diagnosis of exclusion.33,36 Similar to previous series and case reports, we found LLMs in most cytological samples from BAL fluid.1,4,12,13,17 LLMs are a nonspecific cytopathological finding that are observed in a raft of diseases including lipoid pneumonia, amiodarone toxicity, and aspiration.22,25,37 It is unknown whether LLMs are a marker of EVALI, a marker of vaping, or a marker of vaping products that contain the causative agent of EVALI.13,17,23,24 Future studies are needed to determine whether LLMs are useful in the diagnosis of EVALI.Our data show only that they are typically present.

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Current clinical guidance is undecided regarding the role of bronchoscopy in the evaluation of patients with suspected or possible EVALI and emphasizes the role of clinical discretion in individual cases. 1,12,38,39Our data show that in suspected cases of EVALI during the apogee of the epidemic, bronchoscopy rarely contributed meaningfully to diagnosis.This suggests that in the absence of risk factors for or symptoms of a specific infectious or other alternative diagnosis, bronchoscopy is not routinely necessary, as has been argued by other authors. 16There were no complications of bronchoscopy in our patients, but a recent article reported a high rate of adverse events among younger patients, further arguing for limiting the use of bronchoscopy in typical cases of EVALI. 40r finding of 3 false-positive PCR results for Pneumocystis jirovecii may be surprising to some readers.The most stringent, criterion standard for a diagnosis of Pneumocystis pneumonia incorporates longitudinal evaluation of clinical and radiographic data as well as response to treatment or lack thereof.Using that standard, the specificity of PCR testing for Pneumocystis is on the order of 80% to 90%, 41,42 meaning that in persons without clinical Pneumocystis disease, 10% to 20% will have the organism detected by PCR due to colonization rather than infection.When a test with this level of specificity is used in a low prevalence population (such as ours, lacking risk factors for Pneumocystis pneumonia), most positive tests will be false-positives, as dictated by Bayes theorem.
Failure to incorporate information regarding disease prevalence into diagnostic estimates has been termed base rate neglect, 43 and it may go undetected in clinical practice if all positive PCR results are presumed to represent clinical illness and are treated for Pneumocystis pneumonia. 44Our series, by happenstance alone, buttresses these general principles of diagnostic reasoning because our patients were not treated and all improved, confirming that the PCR results were false-positives.
A wide array of patterns of injury on CT imaging have been reported in EVALI. 3,26,37,45,46Our series is among the first to document the variability of imaging patterns within a cohort.Most patients had the OP pattern as the exclusive finding, a feature witnessed to a high degree in other studies. 16The prototypical OP pattern comprises multifocal, multilobar, ground glass opacities, often contiguous with uninvolved pulmonary lobules, and sometimes with sparing of the peripheral, subpleural lung.We caution that this very prevalent imaging pattern does not predict pathologic findings in the lung.None of our patients had biopsies, but 1 report of 8 patients with EVALI showed OP on histopathological examination of biopsy specimens in just 4 cases (50%). 17l patients in our series had good outcomes, although nearly two-thirds had residual symptoms at follow-up.These symptoms as well as normal spirometry and abnormal diffusion capacity testing align with the findings in previous series. 12,15,20Because EVALI has substantial overlap with other causes of acute lung injury, it may have a similar natural history and result in residual respiratory morbidity on long-term follow-up. 47,48Follow-up CT imaging may be useful for reticular changes as well as quantitative evaluation of potential airway disease in patients with normal spirometry, as demonstrated in a large research study in obstructive lung disease. 27Longitudinal evaluation of symptoms and pulmonary function are also needed to better understand the natural history and long-term prognosis of EVALI.

JAMA Network Open | Pulmonary Medicine
Clinical, Bronchoscopic, and Imaging Findings of EVALI

Table 2 .
28,29,31ry Studies on Initial Presentationprolonged course, with a hospital stay of 21 days, including 14 days in the ICU receiving oxygen via high flow nasal cannula.Two patients (8%) had rhinovirus on PCR testing of BAL fluid.28,29,31Threesamples (13%) had positive PCR assays for Pneumocystis jirovecii that were considered false-positives because Pneumocystis direct fluorescence antibodies were negative and the patients recovered without treatment for Pneumocystis.One BAL culture (4%) had growth of Aspergillus nidulans, which was deemed a commensal organism or contaminant and not treated; this patient also recovered.Finally, 1 patient (4%) had intermediate positive acute serologies (immunoglobin M) for Mycoplasma pneumoniae.In addition to corticosteroids, he was treated with ceftriaxone and azithromycin, but they were discontinued after 2 days when the diagnosis of EVALI was made, and he recovered.

Table 4 .
Computed Tomography Classification Scheme Used to Establish Joint Consensus by the 2 Radiologists 26Adapted from Henry TS et al, 2019.26

Table 5 .
Treatment and Outcomes Corticosteroid regimens were variable but tended to consist of 40 to 60 mg of prednisone daily with a duration ranging from a few days to 2 weeks.Slightly more than one-third of patients(11 [36%]) were discharged while still receiving supplemental oxygen.