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E-cigarette or vaping-associated lung injury (EVALI): a review of international case reports from outside the United States of America

Lachlan J. Sund, Paul I. Dargan, John R. H. Archer & David M. Wood

Pages 91-97 | Received 29 Sep 2022, Accepted 14 Dec 2022, Published online: 13 Jan 2023

DOI: https://doi.org/10.1080/15563650.2022.2160342

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To link to this article: https://doi.org/10.1080/15563650.2022.2160342

Abstract

Introduction

E-cigarette or vaping-associated lung injury has been reported extensively throughout the United States without a corresponding number of international cases. Cannabinoid-based products have been implicated in the majority of cases.

Objectives

To collate published reports of E-cigarette or vaping-associated lung injury outside the United States and to identify the reasons behind the discrepancy in reported cases between the United States and the international community.

Methods

PubMed and Healthcare Databases Advanced Search were used to identify published case reports of E-cigarette or vaping-associated lung injury prior to February 2021 using the search terms “e-cigarette”, “e-cigarettes”, “vaping”, “vape” and, “lung injury”, “pulmonary”, “respiratory”. Cases occurring in the United States were excluded. Non-United States case reports were excluded if they did not meet the Centers for Disease Control and Prevention “probable case” criteria. This requires use of a vaping device within 90 days of symptom onset, the presence of pulmonary infiltrates on plain film chest radiography or ground glass opacities on computerised tomography, clinical suspicion that infection was not the underlying cause of lung injury, and the absence of other plausible medical processes to account for the presentation. Patient demographics, nature of exposure, symptomatology and outcome were compared to 125 cases from three regional United States based case series, which were chosen on the basis of having complete data for these comparative factors.

Results

Seventeen international cases from 13 countries were identified for analysis. There was a male predominance in both non-United States and United States cohorts (76% vs 58–83%), with a marginally higher median patient age in non-United States cases (31 vs 27, 19, 27 years). Reported use of nicotine/flavoured e-liquids was more common in non-United States cases (100% vs 58–67%), and use of cannabinoid-based products was less common (24% vs 78–92%). The most common symptoms across all cohorts were shortness of breath (76% vs 85–91%), cough (59% vs 78–83%) and fever (47% vs 78–83%). The majority of patients were hypoxic (76% vs 69–86%) and required hospital admission (88% vs 90–94%). Fewer of the non-United States patients required intensive care admission (24% vs 55–67%) though their median length of stay was longer (15 days vs 5, 6, 7 days).

Discussion

Uniformity amongst non-United States cases in regards to nicotine based and/or flavoured e-liquid exposure may underestimate the role of these substances in e-cigarette or vaping-associated lung injury. This is consistent with prior United States based research demonstrating increased presentations to emergency departments prior to the recognised “outbreak” of e-cigarette or vaping-associated lung injury at a time of increased nicotine based e-liquid uptake. A longer length of hospital stay, lower rate of intensive care admission and a higher rate of bronchoscopy in the non-United States cohort could be indicative of clinician inexperience internationally. It is unclear why the non-United States cases also had a lower incidence of gastrointestinal symptoms however this may also be explained by poorer diagnostic awareness.

Conclusions

E-cigarette or vaping-associated lung injury is not limited to cannabinoid-based products. Apparent similarities in patient demographics, clinical features, and clinical course between non-United States and United States cases raise concern for underreporting of E-cigarette or vaping- associated lung injury internationally.

Introduction

E-cigarette or vaping-associated lung injury (EVALI) has been extensively reported within the United States (US) in recent years. During a period of formal reporting between 31 March 2019 and 18 February 2020, the US Centers for Disease Control and Prevention (CDC) recorded 2,807 EVALI hospitalisations and or deaths within the US [Citation1]. A significant proportion of these cases were associated with the use of cannabinoid-based products − 82% self-reported vaping a cannabinoid-based product within 90 days of symptom onset, compared to 57% for nicotine-containing products. A decline in cases was associated with the removal of vitamin E acetate from tetrahydrocannabinol (THC)-containing vaping solutions after Blount et al. [Citation2] identified vitamin E acetate within the bronchoalveolar lavage fluid of all 29 patients they evaluated with EVALI. Despite the decline, cases continue to be reported suggesting that other compounds and or additives in vaping products may also be linked to EVALI [Citation3].

Prior to the identification of vitamin E acetate, three regional US EVALI case series had all concluded that a specific mechanism of toxicity remained unknown [Citation4–6]. These series, which included two multicentre cohort studies in Utah (60 patients) and Illinois and Wisconsin (53 patients combined), and a single centre cohort study in the state of New York (12 patients), also demonstrated higher rates of cannabinoid-based product use prior to symptom onset. In addition to e-liquid content, two of these authors’ speculated whether vaping devices or practices might also contribute to the disease process [Citation5,Citation6].

Prevalence studies on “current” adult vaping, usually defined as at least weekly use, have demonstrated comparable rates of e-cigarette use between the US and other international countries. In the 2019 US National Health Interview Survey, the current vaping prevalence was reported as 4·5%, compared to a rate of 5·2–7·2% reported in the United Kingdom (UK) [Citation7,Citation8]. Despite a similar prevalence of use, only three EVALI case reports have been published within the UK [Citation8–11]. Peer-reviewed studies have been conducted in at least 34 other countries, where local prevalence has ranged between 0·2% and 4% [Citation8]. Public Health England previously attributed the lower incidence of EVALI cases to a more regulated vaping products market [Citation8,Citation12]. In particular, recreational use of cannabinoid-based products containing THC remains illegal in the UK. However, Blundell et al. [Citation13], in their UK survey of 2,501 adults aged 16 and over on vaping practices, reported that 6·2% of respondents had previously vaped cannabis. This is comparable to a rate of 9·9% in a similar US survey of 1548 adults aged 18 and over [Citation14].

Given the apparent similarities in vaping practices between the US and the UK and a comparable prevalence of “current” vaping amongst other international countries, we decided to review published case reports of EVALI outside of the US.

Objectives

To collate published reports of EVALI outside the United States and to identify the reasons behind the discrepancy in reported cases between the US and the international community.

Methods

PubMed and Healthcare Databases Advanced Search were used to identify published case reports of EVALI prior to February 2021 using the search terms “e-cigarette”, “e-cigarettes”, “vaping”, “vape” and, “lung injury”, “pulmonary”, “respiratory”. Author affiliations were used to determine the location of a case report if the location was not stated within the report. Cases occurring in the US were excluded. The reference lists of identified cases were then reviewed to ensure cases were not omitted. Non-US case reports were excluded if they did not meet the CDC case definition for a “probable case” of EVALI. This requires use of a vaping device within 90 days of symptom onset, the presence of pulmonary infiltrates on plain film chest radiography or ground glass opacities on computerised tomography, clinical suspicion that infection was not the underlying cause of lung injury, and the absence of other plausible medical processes to account for the presentation [Citation15].

For the included cases, data on patient demographics, nature of exposure, symptomatology and outcome were extracted and then compared to the 125 cases from the three aforementioned US-based EVALI case series [Citation4–6]. These case series were chosen because they reported complete data on the above factors.

Categorical data are expressed as absolute numbers and percentages, non-parametric data are presented as a median (interquartile range (IQR) and/or absolute range).

Results

Non-US cases

Eighteen case reports and one series of three cases were identified by the search. One case each from France, India, Japan and Germany did not meet the case definition for “probable” EVALI and were excluded [Citation16–19]. Within the excluded cases, radiological findings were not disclosed in the French case, alternative medical diagnoses were as likely in the Indian and German cases, and the Japanese case involved a “heat not burn cigarette” rather than a vaping device.

The 17 cases that met the case definition were from 13 countries. Three cases were included from England and Germany, and one case each from Australia, Belgium, Canada, Denmark, Ecuador, Guam, Ireland, India, Japan, Spain and Switzerland [Citation9–11,Citation19–31].

Comparison of non-US cases with the US case series

Patient demographics and exposure history for the non-US cases and US case series are compared in Table 1. The median age of non-US cases was marginally higher at 31 years (IQR 19–47, range 16–62) in comparison to 27 years in the Utah series (IQR 22–36), 19 years in the Illinois and Wisconsin series (range 16–53), and 27 years in the New York series (IQR 21–35). There was a male predominance throughout non-US and US cohorts. All non-US patients reported vaping nicotine-based or flavoured products prior to the onset of symptoms compared to 24% for cannabinoid-based products. This is in contrast to the US case series in which was a higher rate of reported cannabinoid-based product use (78–92%) compared to nicotine-based or flavoured products (58–67%). Exclusive use of nicotine-containing e-cigarettes was also higher amongst non-US cases (76% vs 8–17%). Mode of acquisition was not frequently reported for the non-US cases, with only two cases reporting “over-the-counter” sourcing of e-liquids. A third case reported online purchasing of flavoured products but did not report how the same patient sourced their cannabinoid-based product. Five other cases described the use of commercially available e-liquids. A final case reported prior use of “trademarked” products with a change to unbranded, unregulated flavours.

The most common presenting complaints in the non-US cases were shortness of breath (76%), cough (59%) and fever (47%), as seen in Table 2, which was consistent with those reported symptoms in the US case series. Of note, only one patient (6%) in the non-US cases reported nausea, compared to 64–75% in the three US case series. Similar trends were observed for abdominal pain (6% vs 27–47%) and chest pain (6% vs 43–55%).

No specific diagnosis was reported in six (35%) of the non-US EVALI cases. A final diagnosis of lipoid pneumonia, hypersensitivity pneumonitis and bronchiolitis/respiratory bronchiolitis interstitial lung disease was given in two (12%) cases each. The following diagnoses were reported once (6%): giant cell pneumonia, fibrosing non-specific interstitial pneumonia, diffuse alveolar haemorrhage, eosinophilic pneumonia and acute diffuse alveolar damage with fibrosis. Specific diagnoses were not listed in the US case series.

Similar proportions of patients in the non-US cases and US case series were hypoxaemic at presentation (76% vs 69–86%) and required hospital admission (88% vs 90–94%), as shown in Table 3. While the frequency of intensive care admission was lower in the non-US case series, the rate of ECMO (Extracorporeal Membrane Oxygenation) use and bronchoscopy was higher. There was a longer length of stay in the non-US cases; the median length of stay was 15 days (IQR 12–32·5, range 7–47) in contrast to 5 (IQR 3–8), 6 (range 1–25) and 7 days (IQR 7–8) in the US. There was a low mortality rate amongst non-US and US cases (6% vs 0–3%).

Discussion

There were 17 published reports of EVALI outside of the US prior to February 2021, compared to the 2,807 cases reported to the CDC between March 2019 and 18 February 2020 and 125 EVALI cases published in three US case series in 2019. All 17 of the non-US cases met the criteria for a “probable case” of EVALI. Historically, a variety of presentations have been attributed to EVALI without a single, unifying diagnosis [Citation5,Citation6]. These include lipoid pneumonia, hypersensitivity pneumonitis and interstitial lung disease, consistent with the findings of this series.

The most significant finding from the non-US EVALI cases was that every case involved the use of nicotine-based and/or flavoured e-liquids prior to symptom onset, and only 24% of cases involved the use of cannabinoid-based vaping products. This is in direct contrast to the three US-based case series in which 78–92% of cases involved the use of a cannabinoid-based product. The use of vitamin E acetate as a thickening agent in vaping solutions containing THC and its association with the US EVALI “outbreak” has seen cannabinoid-based products more readily implicated in EVALI [Citation1,Citation12]. An association with vitamin E acetate has not been reported internationally, and the predominance of nicotine and flavoured e-liquid use amongst these cases suggests that EVALI is not limited to cannabinoid-based products. In addition, a review by Hartnett et al. [Citation32] immediately following the US outbreak identified that presentations to US emergency departments involving e-cigarettes actually began to rise from January 2017. Intriguingly this rise coincided with increased use of nicotine-containing e-cigarettes amongst US youths. It is, therefore, plausible that nicotine-containing and flavoured e-cigarettes have contributed to a greater number of EVALI cases than previously recognised.

Although the current EVALI case definition does not include symptomatology, there was a consistency between the international and US cases, with the three most common presenting complaints being shortness of breath, cough and subjective fever. A similar majority of patients were also hypoxaemic at presentation and required hospital admission. These findings were in contrast to the presence of gastrointestinal symptoms – a well-recognised component of EVALI presentations in the US (64–75% nausea and 26–45% abdominal pain). Only one patient (6%) each was reported to be suffering nausea or abdominal pain in the non-US cases. While the pathophysiology behind the manifestation of gastrointestinal symptoms remains unknown, Kalininskiy et al. [Citation6] described an “intense inflammatory response” and Blagev et al. [Citation5] have suggested these symptoms are part of a wider, systemic process. One possible explanation for the lower rates of gastrointestinal symptoms observed internationally is poorer diagnostic awareness, and Blagev et al. [Citation5] state the importance of recognising these symptoms as part of the EVALI “syndrome”. Diagnostic uncertainty and treatment inexperience could also be consistent with the international cases having a longer length of stay, a higher rate of bronchoscopy but a lower rate of ICU admission. The US EVALI “outbreak” resulted in the CDC publishing the EVALI case definition and instituting public health reporting. It is plausible that clinician understanding and awareness of the condition in the US improved as a result, leading to greater reporting of EVALI and active case surveillance between March 2019 and February 2020. Currently, there are no publications addressing clinician understanding of EVALI, although a number of both international and US studies have suggested knowledge of e-cigarettes, including adverse effects and use in smoking cessation remains suboptimal [Citation33–38].

Recently, there has been concern about the use of e-cigarettes as a smoking cessation aid, with user safety and new use amongst never smokers and youths cited as the main concerns [Citation39]. Public Health England recommendations are for the use of nicotine vaping products alongside smoking cessation medications and behavioural support for current smokers, with the advice of using regulated products only. Public Health England actively discourages the use of vaping amongst those who have never smoked and the provision of vaping products to those younger than 18 remains illegal. However, rates of vaping in UK 11–18 year olds rose from 1·2% in 2015 to 4·8% in 2019 [Citation8].

In the UK, nicotine-based vaping products are regulated under the Tobacco and Related Products Regulations (2016), whereby producers are required to submit their products to the Medicines and Healthcare products Regulation Agency (MHRA) for approval prior to sale [Citation40]. Coupled with the illegality of THC-containing substances, advocates for the use of e-cigarettes have suggested vaping in the UK is safer because of these regulations [Citation12].

Elsewhere the legal approach is varied. The Therapeutic Goods Administration in Australia recently restricted nicotine-containing e-liquids to prescription use only, citing increased use amongst young Australians and the impact of nicotine on neural development as the main concerns [Citation41]. A number of other countries, including India, Saudi Arabia, Egypt and much of Latin America, have completely outlawed e-cigarettes and vaping. Despite evidence supporting the effectiveness of vaping in smoking cessation, there appears to be growing international concern regarding the safety profile of vaping products and devices [Citation42].

Many of the chemical constituents of vaping solutions remain poorly characterised, and the National Academies of Sciences, Engineering and Medicine in the US have reported conclusive evidence that most products contain and emit numerous potentially toxic substances in addition to nicotine [Citation5,Citation43]. These substances include propylene glycol and vegetable glycerine, which are still used as base agents in many non-cannabinoid e-liquids [Citation44,Citation45].

Additionally, Public Health England openly acknowledges that the General Product Safety Regulations (2005) covering non-nicotine-containing e-liquids are less stringent, potentially exposing users to greater harm [Citation46,Citation47].

Furthermore, a subgroup of US EVALI patients who reported the use of nicotine-containing e-liquids was surveyed on their method of acquisition, with 32% declaring they had previously sourced their products informally (family/friends, dealers, online, or other sources) [Citation1]. Given the unregulated nature of informal acquisition, there is a potential for users who acquire e-liquids via this method to be placed at an increased risk of toxic exposure from other unknown constituents within e-liquids.

Supporters of e-cigarettes have previously suggested that under-reporting of the use of cannabinoid-based vaping products likely accounts for EVALI cases amongst nicotine and flavoured e-liquid users [Citation12]. This is controversial given that there are so few international cases reported, the veracity of survey responses is unlikely to vary between regions, and a previous UK survey demonstrated comparable rates of cannabis vaping to the US [Citation13]. In addition, patient demographics and common symptomatology appear to be similar across the non-US and US EVALI cases, and the specific diagnoses of the non-US cases are consistent with those previously reported in the US. Legalisation of recreational cannabis use and a subsequent increase in the availability of vaping devices and e-liquids in the US may have contributed to increased US case numbers. However, underreporting of EVALI internationally remains a concern as the acquisition of cannabinoid-based products is likely to be from an informal source [Citation1].

We do not feel that the Covid-19 pandemic was likely to have impacted the non-US cases, given 15 out of the 17 cases were either submitted or published prior to February 2020. A submission date was not reported for two of the case reports [Citation20,Citation27]. The case report of O’Carrol et al. [Citation27] (Dublin, Ireland) was published on the 18 March 2020, three weeks after the first reported case of Covid-19 in Ireland [Citation48]. The report of Poschenrieder et al. [Citation20] was published in August 2020. This patient had a negative infective screen, including the culture of bronchoalveolar lavage fluid, and returned a transbronchial biopsy suggestive of foreign body inhalation.

This research was subject to a number of limitations. Obviously, the non-US case numbers were small, thus preventing a more substantive statistical analysis. An element of underrecognition of EVALI by international physicians likely contributed to these low case numbers. In addition, the US case series were chosen on the basis of having the comparative characteristics of patient demographics, exposure, symptomatology, clinical course, and management, limiting the number of US cases included. It is possible that the 125 US cases included were not representative of the 2,807 EVALI cases reported to the CDC in regard to these comparative factors. It should also be noted that of the non-US cases, one case was from Canada (close proximity to the US), one was from Guam (a US territory), and the case from Spain was described as “imported” from the US, although the arrival date in Spain was not reported [Citation23,Citation26,Citation30].

Conclusions

This series of case reports documents that there were 17 non-US cases of EVALI prior to February 2021. In a period of less than 12 months between March 2019 and February 2020, there were 2,807 cases within the US formally reported to the CDC, and 125 EVALI cases published in three US case series in 2019. In contrast to these three US case series, every international case reported the use of either nicotine or flavoured e-liquids prior to the onset of symptoms, with a considerably lower rate of cannabinoid-based vaping product use. Aside from higher rates of gastrointestinal symptoms and ICU admission within the US case series and a longer length of stay with a higher rate of bronchoscopy amongst the non-US cases, patient demographics and common symptomatology were similar. It is likely that there is underreporting and potentially underrecognition of EVALI internationally. Further work is required to determine how vaping practices and the source(s) of vaping products used contribute to the development of EVALI, to improve clinician understanding, and to establish the true prevalence of EVALI outside of the US.

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