Vaping – A Serious Safety Signal

There is a major safety issue being discussed widely in the US on e-cigarettes and vaping. There have been significant adverse events and deaths in the US with them. In Europe and elsewhere this seems to be less of an issue because these events have not really occurred there (yet). [See https://www.cnn.com/2019/09/17/health/vaping-us-uk-e-cigarette-differences-intl/index.html]

Nonetheless, this situation is worth examining as it is an excellent example of how adverse events and signaling are done.

Background

First, a brief comment on electronic cigarettes (e-cigarettes) and vaping. E-cigarettes are devices that contain a battery which allows the production, by heating of a liquid to create a vapor (aerosol) which is then inhaled by the user. This simulates the hand/mouth action of regular cigarette smoking. The main idea, at least initially, was to provide an alternate way to deliver nicotine without inhaling smoke. The primary indication is to reduce the use of cigarettes and to help people stop smoking. This is somewhat controversial though the FDA and other agencies do feel e-cigarettes have a role to play in smoking cession though it is not clear this method is better than other methods including patches and other delivery systems. Some are concerned that the use of e-cigarettes in non-smokers, particularly teens and children, may lead to cigarette smoking. Most e-cigarettes are manufactured in China.

The vapor in e-cigarettes also contains ultrafine particles of particulate substances and chemicals including glycerin, flavorings and toxic substances such as heavy metals, nanoparticles and even carcinogens. Different manufacturers’ products have different ingredients. The general consensus though is that e-cigarettes are less harmful than smoked cigarettes as they contain fewer toxins and often lower doses. Of course, the nicotine still remains a toxin in the e-cigarettes. Some people are able to create their own cartridges with various other approved, unapproved and/or illegal substances, particularly cannabis: THC and CBD. These products have been around since about 2003 but use has skyrocketed in the last several years.

The Current Issues

Over the last several months cases of severe pulmonary disease have been reported. The FDA, CDC and other health organizations have issued summaries and warnings about this ongoing situation. Here is a summary as of late September from the New York State Department of Health’s Advisory: Update unexplained vaping-associated pulmonary illness issued September 20, 2019  and the CDC.

• 530 cases of lung injury have been reported in 38 states including 7 deaths in 6 states. The age range has been from 14-69 years of age. Two thirds of the cases are in people between 18 and 34. 16% are below 18. Three quarters are male.

 

• A large variety of products have been used with the vast majority (~75%) have reported using nicotine and marijuana, THC and/or CBD. About 20% used cannabis containing products only and about 4% reported use of nicotine only. Many different brands and products were used.

 

• The clinical presentation includes cough, pleuritic chest pain, dyspnea, headache, fever as well as nausea, diarrhea, fatigue and weight loss. Onset occurred from days to weeks before medical help was sought. Most cases, at least in New York, required hospitalization and many patients required intubation. X-rays showed bilateral opacities usually in the lower lobes. CT imaging showed diffuse bilateral ground-glass opacities. Bronchoscopy was usually unremarkable but some did show lipid-filled macrophages. There is no specific treatment beyond supportive care though some have reported improvement with steroids.

 

• The cases basically started coming to the attention of physicians and the health authorities in June and July of this year in Wisconsin. Cases started appearing elsewhere in the next few weeks.

 

• 36 million marijuana vape pens and cartridges were sold from Aug 31, 2018 to Aug. 31, 2019 in 4 western states where recreational marijuana is legal. It is estimated that about 14 million people in the US are using nicotine e-cigarettes. In 2018 over 3.6 million US young people including 1 in 5 high school students and 1 in 20 middle school students used e-cigarettes per the US Surgeon General’s advisory (See: e-cigarettes.surgeongeneral.gov). Many of the products are small and easy to conceal. Some give off no odors thus concealing the use of cannabis and other substances.

The Course of Events

• Within a couple of weeks of the initial cases in June and July, it was clear that this was a signal and the issue was picked up by state health agencies, FDA and CDC. This was fairly rapid as one of the very striking early cases was in an 18-year-old girl with no particular reason for respiratory failure. By the time the sixth case was seen, the common factor in all was recognized to be vaping. The Wisconsin hospital held a press conference in late July and soon other health facilities reported similar cases.

 

• The CDC and FDA then moved in with the CDC looking for the likely cause or causes. Vitamin E has been suspected but it was not present in all cases. As of now, no clear cause has been identified.

 

• The public health services and medical authorities have largely warned against using e-cigarettes until this issue is clarified including those who use both e-cigarettes and smoked cigarettes. Flavored e-cigarettes have been discouraged and the President has said flavored e-cigarettes should be banned. Most have counseled young people (and all others) to stop vaping cannabis altogether whether with or without nicotine. Broadly speaking, a cautious and conservative approach has been and should be used.
  The EU seems to have a different situation from the US. There seems to be less cannabis use and more nicotine vaping for cigarette withdrawal. Apparently no pulmonary cases have been reported from Europe so far.

 

• Little has been said about the device aspect (rather than the chemicals being inhaled) other than that this has been seen with a variety of devices from several sources.

Pharmacovigilance and Epidemiology

What we have here is an issue that combines three major areas of safety and vigilance: drugs/medications, devices and cannabis.

Discovery and Tracking

The pick up of this SAE took about 2 months. Arguably this is reasonably good as it has taken years to pick up other dramatic SAEs in young people (e.g. DES and vaginal cancer in young girls). Because the cases were so widespread across the country things were delayed. It should be clear now that this is an emergency as more serious cases and deaths are being reported and are expected to continue. CDC has said it will report to the public new cases every Thursday. New cases seen by health practitioners should be immediately reported to the appropriate local authorities and as complete a data set as possible obtained asap.

For those doing drug or device vigilance, this reinforces the need to pay close attention to “outlier cases”. That is, idiosyncratic, “weird” unexpected cases should rapidly raise a red flag. Otherwise healthy teenagers and those in their 20s who, for example develop life-threatening or fatal lung, kidney, heart disease, should be investigated very thoroughly and reported to the health agencies. Proactive awareness communications should be put out to those in contact with the public and health care professionals. Early discovery is critical.

Ownership

What we need now is one federal agency to spearhead the investigations with other agencies, universities, companies etc. on the team. There should be an obligatory registry of cases probably at the national level.

For those doing vigilance, it should be clear as to who in the company, government, university etc. “owns” the situation and is in charge.  He/she should be empowered and given the resources needed to do a PV investigation.  Subject matter experts and consultants should be made available.  The criticality and time frame should be clarified: emergency vs non-emergency.  There should be a committee and written SOPs in place to cover this. This is actually true for all signals.

Methodology

All reasonable means, techniques and experts should be used. Perhaps one could start a pharmacoepidemiology vaping study with cannabis now. This would be hard to design and do but at the very least should be considered at the CDC/FDA level.

For those doing vigilance, this means getting either internal or external consultants and experts to advise and help where internal resources are lacking. Data and information should not be hidden but a judicious mechanism used to release important data rapidly. Information should be sent up the chain in the health agency, company etc. Speculation should be separated from science. Folks from the device world should be brought into this situation if they are not already involved when a device is in play. Folks from the marketing and sales divisions should not be involved. The attorneys and regulatory group, of course, will be involved.

Communications

A communications strategy needs to be in place.  Again, with the direction of a federal agency and “czar/spokesman”, a rapid Vaping meeting (e.g. by web) of stakeholders should devise a strategy to communicate to patients and health providers the latest information and recommendations.  The science should be clearly separated from the speculation.  But it should also be stressed that unless one is vaping nicotine to stop smoking cigarettes, all others should stop vaping nicotine, cannabis etc. till this is clarified.  In states where marijuana and/or CBD is legal, one might consider a registry or sales only in limited venues (e.g. pharmacies).

For those doing vigilance, the company or institution should decide what to say and to whom. In general, there should only be one voice speaking for an institution. Once several people start talking, contradictory and conflicting views will emerge. In particular, the social media should be monitored and used for communications where appropriate. This is actually somewhat contradictory to various practices now since companies are not required to search the internet for safety data or SAE cases. The internet, blogs and other social media have been shown to be leading indicators giving early warning for some safety problems. Careful documentation must be kept.

Bottom Line

This signal and how the public, the government, the health care workers and the companies are responding is a fine example of what happens on a smaller scale with day to day signals seen with pharmaceuticals. It’s providing a good lesson and example of what looks clear in retrospect is actually very unclear during the acute phase of the safety issue.

It will be interesting to see how this plays out. Whether one or more causes is/are found (rapidly) remains to be seen. Whether we will see people having difficulty stopping cannabis vaping will be interesting as this may give us a better qualitative notion of how addictive cannabis is. We may also realize that the route of inhalation of medications has not been well studied other than for some pulmonary diseases and diabetes.

The history of the FDA is marked by the fact that major increases in FDA’s regulatory power often occurred after public health disasters (e.g. in 1906 and in the 1930s). Whether this becomes such a disaster with major regulatory changes following remains to be seen.