Acute bronchiolitis is a rare condition in adolescence because the bronchioles, i.e., airways smaller than 2 mm in diameter, contribute less (<20%) to total airway resistance than they do in infants and young children (>50%) [2]. Therefore, extensive involvement of small airways must be present before clinical symptoms occur in adolescents or adults.

Our patients presented with severe bronchiolitis, requiring mechanical ventilation in three of four patients. The CT imaging pattern was unequivocally diagnostic of BD with a tree-in-bud pattern, i.e., the presence of direct radiographic findings of abnormal bronchioles. Common features of all cases were recent usage of inhalation hazards, and similar CT pattern and clinical courses. The slightly raised serology results for Mycoplasma pneumoniae (Patients 1 and 3) or Chlamydophila pneumoniae (Patients 2 and 3) were insufficient explanations for the extensive CT findings. Additionally, no signs of vascular causes, particularly the intravenous compound injection typical for cellulose granulomatosis [3], were present.

As a projection imaging modality, subtle variations in lung density may be under-represented in conventional chest X-rays. Therefore, the shown discrepancy between unremarkable or moderate findings on chest X-ray and extensive CT abnormalities with a diffuse and homogenously disseminated tree-in-bud pattern are noteworthy for clinicians. The most feasible underlying entity is diffuse acute panbronchiolitis, which must be differentiated from the Asian “diffuse panbronchiolitis”. The latter is a well-characterized chronic condition in adults, defined by criteria by the Japanese Ministry of Health and Welfare. It is characterized by bronchiolitis and chronic sinusitis, which typically develop slowly and progressively over months to years [4,5]. While the mean age at presentation is 40 years, Asian panbronchiolitis occasionally develops in childhood [5,6]. Chronic sinusitis was found in at least 75% of Japanese patients, often preceding chest symptoms by years [5]. With negative histories for chronic sinusitis and an acute disease onset, the diagnosis was not supported in any case [6]. Due to the lack of histological specimens and lung biopsy being infeasible during respiratory decompensation, the working diagnosis of acute diffuse panbronchiolitis was made upon clinical presentation and typical radiographic findings.

Unfortunately, our diagnostic work-up of the two initial patients was challenged by various factors: external presentation and late transfer of patients to our care, or incomplete, perhaps unreliable, patient histories with respect to the brands and providers of the novel hazardous compounds consumed by the adolescents. We immediately and visually diagnosed the recent third case, although he plausibly denied smoking habits at first. Follow-up CT imaging showed centrilobular nodular hazy densities with upper lobe predominance suspect for respiratory bronchiolitis for Patient 2 after 35 months (Figure 3B), resembling persistent exposure to inhaled noxae, while reporting smoking one cigarette daily and no illicit drug use. The follow-up CT for Patients 1 and 3 showed nearly complete resolution after 6 months and significant improvement after 2 months, respectively (Figure 3A,C). Given the more recent manifestation in Patient 4, no follow-up CT was available at the time of submission.

The emergence of new smoking systems, particularly e-cigarettes, has been followed by e-cigarette, or vaping, product-use-associated lung injury (EVALI), particularly among adolescents and young adults [7]. In addition to nicotine, e-cigarettes may be used to deliver tetrahydrocannabinol (THC) or cannabidiol (CBD) and numerous flavoring or supporting ingredients, which are not strongly regulated. Blount et al. recently identified vitamin E acetate as a possible causative agent of EVALI [8]. Only seven cases of EVALI with one fatal outcome have been reported outside of the U.S. so far [9,10,11,12,13,14]. Between the fall of 2019, when EVALI was first reported, and 18 February 2020 (the last date of data collection), there were 2807 confirmed cases in the United States requiring hospital admission and 68 deaths [15]. The use of e-cigarettes or other vaping products could not be proven in three of the four patients, excluding the diagnosis of EVALI according to Layden et al. [7]. Furthermore, EVALI typically manifests with bilateral pulmonary infiltrates on a chest X-ray, not seen in our patients [7]. Respiratory bronchiolitis must be differentiated as another inhaled drug-/smoke-induced lung injury pattern. Memorizing this pattern helps in the differential diagnostic work-up. Generally, we categorize the acute diffuse panbronchiolitis as an exposure related, non-infectious diffuse parenchymal disorder [16]. In addition to the respiratory bronchioles, the pulmonary interstitial space with the adjacent alveolar ducts and alveoli are affected.

After reviewing the literature, we identified one similar case of a 17-year-old patient with severe bronchiolitis following Mycoplasma pneumoniae infection [17]. However, the right-sided predominance of disease manifestation clearly visible on chest radiograph, absence of severe respiratory distress, and positive infectious correlation were key distinctions from our patients. The chest radiographic findings with comparable signs of bronchiolitis in a series of four cases after inhalation of synthetic marijuana fit the histories and clinical courses of our Patients 2 and 4 [18]. Alhadi et al. reported the clinical course of a patient who presented with diffuse pulmonary infiltrates related to chronic inhalation of multiple synthetic-cannabinoid-containing products [19]. As in our cases, the patient was treated with antibiotics and steroids. Given the rapid resolution of radiographic and clinical derangements after the administration of corticosteroids, the authors considered the differential diagnosis of hypersensitivity pneumonitis (HP), also known as exogenous allergic alveolitis (EAA). HP typically presents with a restrictive pulmonary process resulting from the patient´s hypersensitivity to bio-aerosols, whereas our patients clearly had an obstructive lung function impairment and no exposure history (Figure 1B [20]. The use of waterpipes was reported by three of four patients, another popular smoking system among adolescents, often falsely considered less dangerous through the supposed filtering effects of water [21].

A combination of yet unknown precipitating factors, such as undetected infection or toxins, may have been causative in our patients. To assist colleagues facing similar cases, we recommend the following diagnostic work-up:

• An adequate medical history is the key to proper diagnosis and therapy. Therefore, a thorough history must be taken in a calm, trust-building environment to obtain honest answers to sensitive questions regarding drug use.
• Early CT scans should be taken to identify BD in adolescents with potential inhalation hazards and progressive pulmonary symptoms.
• Broad infectious work-up including sputum, serum (blood cultures, titers, and PCR), and BAL analysis should be performed.
• Lung biopsy (video-assisted thoracic surgery or trans-bronchial biopsy) should be performed if clinically feasible for histological diagnosis and if uncertain about diagnosis.
• Initial urine and blood specimens should be taken for toxicological analysis (e.g., immunoassays, gas, or liquid-chromatography mass spectrometry). Consider that novel drugs may not be included in standard diagnostic panels.