Metal Fume Zebra

[niman]

In the first of this three-part series on Vaping-Associated Pulmonary Injury (VAPI), I will introduce a compound with the motive, means, and opportunity to cause the illness. 

http://www.coloradogreenlab.com/blog/part-1-metal-fume-zebra

[niman]

Part 1: Metal Fume Zebra 10/5/2019 29 Comments   In the first of this three-part series on Vaping-Associated Pulmonary Injury (VAPI), I will introduce a compound with the motive, means, and opportunity to cause the illness. Part 2 will identify the common point of origin linking vape users in the United States and why Europe is unaffected, and, finally, Part 3 will outline a rational harm-reduction based approach for evaluating the safety and continued use of these products.

[niman]

tl;dr;dr
19_1006 update: Signs and symptoms of vaping-associated pulmonary injury (VAPI) are consistent with chemical inhalation. Analysis of symptoms, commonality of exposure source (vape pen battery cartridges), and mechanism ("vaping") may indicate cadmium-derived metal oxide fume inhalation (metal fume fever, cadmium pneumonitis) as a possible cause of the syndrome ("VAPI").      

tl;dr
Public service announcement: Clinicians, when you hear vaping, think zebras, not horses.

The early symptoms of VAPI are often mild and resemble pneumonia ("horse"). Many of the VAPI ("zebra") patients presented in an outpatient setting, were initially diagnosed with respiratory infections, and treated with antibiotics (without improvement). Workups were negative for infectious agents, and chemical exposure of unknown type/origin is now believed to be the cause of VAPI. The majority of patients who develop this illness exhibit clinical improvement only after treatment with systemic corticosteroids.

The CDC encourages clinicians to report possible cases of e-cigarette or vaping-associated lung injury to their local or state health department for further investigation:
https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease/healthcare-providers/index.html

tl
Vapi Data Set. The VAPI data set published (September) in the New England Journal of Medicine (Layden, Ghinai et al. 2019) is the most comprehensive study to date, and includes clinical findings from 53 patients in Illinois and Wisconsin (Full text: https://www.nejm.org/doi/full/10.1056/NEJMoa1911614). Unless otherwise indicated, signs, symptoms, data, etc are in reference to this publication.   

 

July/August 2019. Hundreds of patients with an unusual respiratory illness began popping up in clusters across the United States. In the days and weeks prior to their hospitalization, these patients exhibited typical signs and symptoms of pneumonia and most were prescribed antibiotics as the first course of treatment. None of the patients (who were eventually diagnosed with vaping-associated pulmonary injury; VAPI) improved on antibiotics and lab workups revealed no evidence of pulmonary infection. 

The full range of findings is conflicting and no clear pattern has emerged regarding the source or cause of the illness.

Symptomatology
Patients have highly similar clinical characteristics and all developed the illness within a similar timeframe.

• All reported use of THC or nicotine e-cigarette devices ("vaping") prior to illness
• All displayed signs of damaged lung tissue
• Most progressed to hypoxemia and required hospitalization
• Some progressed to respiratory failure
• The majority of patients exhibited clinical improvement after treatment with systemic corticosteroids
• Most reported constitutional/gastrointestinal symptoms that preceded the onset of respiratory symptoms

Vaping Products
Most patients reported using vaping devices with THC and nicotine cartridges, but some reported exclusive use of only THC or only nicotine. A wide variety of cartridge brands and products were reported.

US-wide, US-specific
Cases are not specific to any one region of the United States, but the syndrome appears to occur only in vape users in the United States.  Other parts of the world with a high prevalence of vaping (ex. the European Union) are not reporting similar illnesses. More on that in second and third part of series.
 
Correlation ≠ Causation
The underlying cause is now believed to be chemical exposure, and not an infectious disease. The VAPI syndrome is strongly correlated with the use of black market THC vape cartridges, but the CDC has yet to conclusively identify a vaping product, substance, or additive common to all cases.

Metal Fume Fever
Unless you're a metalworker, work for OSHA, or, in my case, previously employed at a respiratory hospital, you've probably never heard of Metal Fume Fever (MFF).
 
There are only 1500-2500 cases of MFF reported in the United States each year, and the illness is typically restricted to individuals with very specific occupations (e.g. welders).

MFF is caused by inhalation of metal-containing fumes (ex. zinc oxide) produced by welding, soldering, and brazing. Typical symptoms of metal fume fever are non-specific ("flu-like"), and can include cough, raised temperature ("fever"), headache, chills, aches, dizziness, and a sweet or metallic taste in the mouth. More severe exposure can result in gastrointestinal symptoms, including nausea, vomiting, and diarrhea.  Metal fume fever caused by zinc oxide inhalation is the most frequently reported type of exposure and bears superficial resemblance to VAPI. Acute symptoms develop 4-12 hours following zinc fume exposure, but do not usually progress to lung damage. The zinc oxide-associated form of the illness typically self-resolves within 12- to 48-hours.

[niman]

Cadmium Pneumonitis
A far more serious form of metal fume fever occurs after inhalation of cadmium oxide fumes. The immediate effects are similar to those described above ("flu-like"), but unlike zinc oxide exposure, cadmium fume inhalation causes significant lung damage post-exposure (pneumonitis), and can progress to hypoxia, respiratory failure, and death.

The table below compares the clinical presentation of zinc oxide metal fume fever (MFF), cadmium pneumonitis (CP), and vaping-associated pulmonary injury (VAPI).

 

High Index of Suspicion
Silver solder (often contains cadmium) is used to make stable unions between dissimilar metals such as copper and stainless steel. In lower-end vape pens, large beads of this type of solder are present  on positive and negative heating element connections. Most vape pens use cadmiun-free solder. Unscrupulous manufacturers have a financial incentive to cut corners. It's happened before: https://en.wikipedia.org/wiki/2008_Chinese_milk_scandal  
 
Motive
Money and ease of use. Cadmium-containing silver solder is less expensive than cadmium-free alternatives, and has improved flow properties which facilitate the joining of dissimilar metals found in vape pen electrical components. 

Means
Cadmium is highly toxic to multiple organ systems. Upon inhalation, cadmium elicits a dose-dependent burst of inflammatory cytokines that promote the systemic effects (fever, headache, joint pain, etc) observed in metal fume fever (Blum, Rosenblum et al. 2014). Cadmium fumes also directly injure lung cells, leading to fluid accumulation, impaired lung function, and respiratory failure. Following absorption into the bloodstream, protein-bound cadmium slowly accumulates in the kidneys and may result in renal injury.

Opportunity
Upwards of 20-30 mg of solder alloy is permeated with vape juice liquid and directly in the airflow path through the vape pen.

Assessment
Blood cadmium levels are indicative of recent exposure, whereas urinary cadmium is indicative of chronic, longer term exposure. Normal blood cadmium is <5.0 ng/mL, with most results in the range of 0.5 to 2.0 ng/mL, whereas tobacco smokers typically have blood and urinary cadmium levels more than double those of nonsmokers (Mannino, Holguin et al. 2004).    

 

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Continued in Part 2: Vape Pen Vivisection