Information for healthcare professionals: the US Centers for Disease Control and Prevention (CDC) and its public health partners are investigating cases of lung injury associated with the use of e-cigarette or vaping products. At the time of publication, more than 2600 US cases have been identified (60 fatal cases), but the outbreak seems to be in decline

the CDC has identified vitamin E acetate as a chemical of concern, although evidence is not yet sufficient to exclude other substances of concern and it may be that there is more than one cause

as of January 2020, MHRA is aware of two potential cases of e-cigarette or vaping associated lung injury in the UK (one reported as a Yellow Card), both of which were reported as having a fatal outcome Actions needed from healthcare professionals: have a high index of suspicion in patients presenting with respiratory symptoms where there is a history of e-cigarette use or vaping in the past 30 days

use the Yellow Card Scheme website to report any suspected side effects or safety concerns with e-cigarettes and the e-liquids used for vaping

for all patients, ask about e-cigarette use or vaping routinely (see Advice to routinely document history) as you would do about cigarette smoking

E-cigarette use or vaping associated lung injury: background

Authorities in the USA are investigating a multistate outbreak of e-cigarette or vaping associated lung injury, also known as EVALI (see Description of US cases). The US outbreak peaked in summer 2019 and at the time of publication, the outbreak in the USA seems to be in decline.

Currently, the volume and pattern of adverse respiratory events reported in association with e-cigarette use or vaping in the UK do not seem to reflect the trends emerging from the USA. This difference of magnitude may be due to differences in regulations, nicotine strengths available, chemical substances and devices used, and proportional use by younger populations. However, it may also be due to a lower index of suspicion among healthcare professionals in the UK.

As of January 2020, MHRA has received one Yellow Card report of EVALI in the UK, occurring during a similar time period to the US outbreak. The Yellow Card report includes sufficient data to suggest similarities to EVALI cases in the USA (in terms of meeting the US criteria for a case of EVALI, the symptoms and investigation findings and clinical progression), although further details are being sought. The MHRA has also been informed of another potential case of lung injury relating to vaping in this time-period (January 2019 to January 2020). Both of these cases were reported as having a fatal outcome.

Prompt reporting of suspected adverse reactions, including probable or possible cases of e-cigarette or vaping associated lung injury (EVALI), to the Yellow Card Scheme will assist the MHRA to take action as necessary to protect public health in case of the emergence of a similar situation as in the USA.

Description of US cases

From March 2019 to January 2020, more than 2600 cases of EVALI and 60 associated deaths were reported in the USA (for latest information see the CDC). Where data on hospitalisation status are known, 95% of cases were hospitalised and a proportion required intensive care. Most cases presented with non-specific respiratory symptoms such as cough, dyspnoea (shortness of breath), and chest pain, often with associated gastrointestinal symptoms, fever, chills and weight loss.

Radiological findings include pulmonary infiltrates on chest X-rays and bilateral ground glass infiltrates on CT thorax. The CDC considers some chronic conditions, including cardiac disease, chronic respiratory disease, and diabetes, as well as increasing age, to be potential risk factors for rehospitalisation and death.

The CDC states that most cases (86%) reported the use of tetrahydrocannabinol (THC). A small proportion of cases (11%) report use of nicotine liquids exclusively. THC is illegal in the UK under the Misuse of Drugs Act (1971). Vitamin E acetate, used as an additive in THC-containing vaping products, has been identified by the CDC as a chemical of concern. However, evidence is insufficient to rule out the contribution of other chemicals and there may be more than one cause. Vitamin E, along with other vitamins, is not permitted as an ingredient in notifiable nicotine e-cigarettes or e-liquids in the UK (see UK context and cases).

The underlying pathology or mechanisms contributing to lung injury remain unknown. Pathologies described include lipoid pneumonia, chemical pneumonitis, giant cell interstitial pneumonitis, and hypersensitivity pneumonitis.

UK context and cases

It is estimated that 3.6 million people use e-cigarettes in the UK. Nicotine-containing e-cigarettes and e-liquids have been regulated since the introduction of the Tobacco and Related Products Regulations (TRPR) in 2016. The MHRA is the competent authority for the notification scheme in the UK.

The regulations include requirements for notification, including submission of data relating to ingredients and emissions to the MHRA, annual reporting, product information, labelling and vigilance, as well as restrictions on advertising. The TRPR ban certain ingredients including vitamins, colourings, caffeine, and taurine, as well as ingredients that are known to have carcinogenic, mutagenic or reprotoxic (CMR) properties. In addition to this, MHRA has published ingredients guidance listing substances that should not be included in e-cigarettes and refill containers due to their known risk to human health. it is illegal to sell e-cigarettes or e-liquids to anyone under the age of 18 years.

As of 8 January 2020, we are aware of 244 suspected adverse reaction reports (182 relating to respiratory terms) to the MHRA’s Yellow Card Scheme and received via industry associated with e-cigarettes or e-liquids. Of these, 20 reports describe 27 serious respiratory events including lipoid pneumonia, hypersensitivity pneumonitis, pulmonary fibrosis, pleural effusion, pneumothorax, lower respiratory tract infection, and infectious pneumonia. Four Yellow Card reports included a fatal outcome. However, not all are considered to be causally associated. Two of these reports were received between January 2019 and January 2020; one reports EVALI as discussed in the background section.

Case definitions of e-cigarette or vaping associated lung injury

Since there are no standard diagnostic criteria, on the basis of expert advice, we have devised UK case definitions definitions of e-cigarette or vaping associated lung injury to facilitate identification.

Probable cases Cases should be considered probable if they meet ALL of the following criteria: 1) Using an e-cigarette or vaping in 30 days prior to symptom onset AND 2) Pulmonary infiltrate, such as opacities on plain-film chest X-ray, or ground glass opacities on CT chest AND 3) Absence of respiratory infection. Minimum criteria to be excluded: Negative respiratory viral screen (eg, influenza, adenovirus, rhinovirus, coronavirus)

Negative testing for all other clinically-indicated respiratory infectious diseases (eg, urine antigen for Streptococcus pneumoniae and Legionella, sputum culture, bronchoalveolar lavage culture, blood culture and opportunistic respiratory infections if appropriate) AND 4) No evidence of alternative diagnosis (eg, cardiac, autoimmune, malignancy) Possible cases Cases should be considered possible if they meet criteria 1, 2, and 4, but a respiratory infection is identified via culture or PCR, and the clinical team believes infection is not the only cause of underlying lung injury OR the minimum criteria to exclude infection are not met due to testing not having been performed and the clinical team believes the infection is not the only cause of the underlying lung injury. Cases that do not strictly meet the criteria Cases that do not strictly meet the criteria, for example if use of e-cigarette or vaping stopped more than 30 days before symptom onset, are still of interest and should be reported.

How to report suspected side effects or safety concerns to the Yellow Card Scheme

Report any suspected side effects or safety concerns with e-cigarettes and e-liquids via the e-cigarette reporting tool for the electronic Yellow Card Scheme. Information provided to the Yellow Card Scheme is kept safe, secure and confidential.

If you report a case of EVALI, please specify if it meets the criteria for a probable or possible case and provide full details of the vaping product, vaping history, and other potentially relevant clinical details, including combustible cigarette smoking history, and investigation results. If a product sample is available for analysis, please also specify this via the Yellow Card report.

In response, we may contact you to collect further details regarding the case via a patient reporting form. The form should be returned to yellowcard@mhra.gov.uk or to Freepost Yellow Card Scheme (no other address details or postage required). The form is also available here: PDF and Word document version.

The MHRA has also sent a letter to healthcare professional organisations to raise awareness of these reporting arrangements.

Routinely document e-cigarette history

As part of routine clinical practice, clinicians are advised to document use of e-cigarettes or vaping devices in medical records for all patients as they would with smoking.

Clinicians should routinely document:

Name or brand of product used

Type of product (if known)

Duration and frequency used

Substances vaped (for example, nicotine or recreational substances)

Strengths of substances

Publication notice The information in this article reflects understanding at the time of publication in January 2020. This is an emerging issue and clinicians are advised to remain engaged with further information from the MHRA, public health bodies, and other sources around this enhanced surveillance scheme and safety information for electronic cigarettes.

Article citation: Drug Safety Update volume 13, issue 6: January 2020: 1.