03 May 2023: Articles
A 43-Year-Old Brazilian Man with Acute Impairment of Lung Function and Pulmonary Nodules with Features of Electronic Cigarette or Vaping Product Use-Associated Lung Injury (EVALI)
Unusual clinical course, Challenging differential diagnosisLuiz Gustavo De Carvalho Sangalli Lucas 1ACDEF*, Lilian Fátima Miguel Acha2BCD, Valmir Sangalli Lucas 34ABCDE, Domenico Capone 45BCD
Am J Case Rep 2023; 24:e939365
BACKGROUND: Electronic smoking devices were created, and their production industrialized, recently. Since their creation, their use has spread widely. This increase in users led to the appearance of a new lung condition. In 2019, the CDC established the criteria for the diagnosis of electronic cigarette or vaping product use-associated lung injury (EVALI) and the eponym EVALI is now widely recognized. The condition results from the inhalation of heated vapor, which damages the large and small airways and alveoli.
CASE REPORT: This report presents the case of a 43-year-old Brazilian man with acute impairment of lung function, pulmonary nodules on chest computed tomography (CT) and features of EVALI. He was hospitalized after 9 days of respiratory symptoms due to worsening dyspnea, and underwent a bronchoscopy on the same day. His condition evolved into severe hypercapnic respiratory failure that took 3 weeks to improve, and he underwent a surgical lung biopsy that showed an organizing pneumonia pattern. He was discharged after 50 days of hospitalization. Infectious diseases and other lung conditions were ruled out on clinical, laboratory, radiological, epidemiological, and histopathological grounds.
CONCLUSIONS: In conclusion, we report the unusual presentation of EVALI on chest CT showing nodules instead of a ground-glass pattern, as stated in the CDC definitions of a confirmed case. We also report the progression to a critical clinical state and, after treatment, the evolution to complete recovery. We also draw attention to the difficulties in diagnosing and managing the disease, especially at a time when COVID-19 has emerged.
Keywords: E-Cigarette Vapor, Electronic Nicotine Delivery Systems, Lung Injury, Multiple Pulmonary Nodules, Vaping
For centuries, plant products containing nicotine and cannabinoids have been burned and inhaled, but only in the mid-20th century was the smoke of these products as cigarettes associated with chronic lung diseases, cancer, and cardiovascular diseases. More recently, in 2003, a Chinese pharmacist who was a smoker and whose father had died of lung cancer, invented an electronic cigarette with the intention of creating a safe alternative to smoking conventional cigarettes . In the following years, the use of these electronic smoking devices (ESDs), also called e-vaping or e-cigarettes, quickly became frequent with an estimated number of 2.5 million users in the United States of America (USA) between 2010 and 2011 . For fun, or with the intention of reducing harm, this habit has spread particularly among young people. It has spread so much that, at the beginning of the last decade, the American Thoracic Society did not define ESDs as less harmful substitutes for combustion cigarettes, and published a regulation proposal for their commercialization .
The latest edition of the Brazilian National School Health Survey (PeNSE – Pesquisa Nacional de Saúde do Escolar) revealed that, in 2019, 16.8% of school children aged 13–17 years had already tried electronic cigarettes in Brazil . It should be noted that the importation, advertising, and commercialization of ESDs have been prohibited by the Brazilian National Health Surveillance Agency since 2009 .
In recent years, with the uncontrolled increase in the use of ESDs, reports of their toxic effects have accumulated [5–7]. In 2019, the Centers for Disease Control and Prevention of the USA (CDC) officially recognized the condition designated electronic cigarette or vaping product use-associated lung injury (EVALI). In the same year, this institution published recommendations on the disease and confirmed case definitions as follows: (a) use of an e-cigarette or dabbing in 90 days before symptom onset, (b) pulmonary infiltrate, such as opacities, on chest X-ray or ground-glass opacities on chest CT, (c) the absence of pulmonary infection on initial workup, and (d) no evidence in the medical record of a plausible alternative diagnosis [8,9]. These publications considered as probable causal agents vitamin E acetate and tetrahydrocannabinol. As of February 18, 2020, the CDC had already counted 2,807 EVALI-associated cases or deaths .
Here, we report the case of a 43-year-old Brazilian male non-smoker with respiratory symptoms, fever, recent use of ESDs, no history of drug use or suspicious environmental exposure, and negative tests for infectious agents. The imaging scans showed disseminated pulmonary nodules instead of the ground-glass opacities cited in the CDC recommendations for the diagnosis of EVALI [8,9]. The patient developed severe acute respiratory failure and his lung biopsy fragment showed a pattern of organizing pneumonia. With the available data and by exclusion of other possibilities on laboratory, clinical, radiological, epidemiological, and, later, histopathological grounds, the authors concluded that it was a case of EVALI, despite a tomographic presentation that was not exactly aligned with the CDC recommendations.
The presentation of EVALI with nodules on chest CT has also been observed in other publications. Kligerman et al, in a cohort of 160 individuals with this diagnosis, observed that 8.8% of the patients presented with diffuse centrilobular nodules as the main alteration . They concluded that the most common histopathological pattern was organizing pneumonia, which generally manifests on CT scan as ground-glass opacities, consolidation, or both . Landman et al reported a case with tomographic changes very similar to those shown here and concluded that they were due to bronchiolitis obliterans . Pulmonary nodules associated with ground-glass opacities were reported in 1 case in the series presented by Kass et al .
The present report is of a 43-year-old Brazilian man with acute impairment of lung function with features of EVALI. At a time when knowledge about this disease is expanding despite the focus on the COVID-19 pandemic, it seems sensible that cases diverging from the usual presentation are reported. This will contribute to the understanding and expansion of its spectrum of presentation and draw attention to the potential severity of its clinical course.
A male patient, 43 years old, born and living in Rio de Janeiro, pharmacist at a military hospital and previously in good health, visited the emergency department of the Galeão Air Force Hospital with complaints of fever (up to 38°C/100.4°F), chills, coughing up yellowish phlegm, and wheezing for approximately 1 week. These symptoms were followed by bilateral chest pain associated with cough, dyspnea on progressively lower levels of exertion, and diarrheal feces without mucus, pus, or blood.
He denied diabetes mellitus, arthralgias, pulmonary tuberculosis, asthma, cigarette smoking, exposure to drugs, inhalable organic or irritant substances, close contact with birds, and recent travel. He also reported having a myocardial bridge, using bisoprolol for 3 years, and allergic rhinosinusitis under irregular treatment and controlled. He had no report of pulmonary or autoimmune diseases in his family and no known recent contact with people with flu-like symptoms.
On physical examination, he was ruddy, oriented, eupneic at rest, with blood pressure of 130×80 mmHg, heart rate of 81 beats per minute, and respiratory rate of 24 cycles per minute; his axillary temperature was 37°C (98.6°F), and his digital oxygen saturation was 96%. On pulmonary auscultation, fine crackles were heard in the axillary regions. Cardiac auscultation and examination of the abdomen and the limbs were normal.
On that occasion, he tested negative for SARS-CoV-2 in the nasopharyngeal material, and a chest CT scan showed diffuse pulmonary nodules of centrilobular distribution predominantly in the upper lobes, sometimes confluent, and absence of lymph node enlargement or pleural effusion (Figure 1). An expiratory high-resolution CT scan was not obtained. Amoxicillin with sulbactam and azithromycin was prescribed. The diarrhea disappeared, and the cough and the fever improved, but the other respiratory symptoms did not, and he returned to the hospital after 2 days and was hospitalized.
The initial tests showed the following results: 12,100 leukocytes with 2% eosinophils, no neutrophilia, granulations, lymphocytosis, or lymphopenia; normal red blood cells, hemoglobin and platelets; biochemistry, serum proteins, and liver enzymes also normal; calcium: 8.9 mg/dL; c-reactive protein: 1.9 mg/dL; procalcitonin: 0.24 ng/mL; and erythrocyte sedimentation rate: 86 mm in the 1st hour. Two blood samples for hemoculture showed no bacterial growth; serology for cytomegalovirus and HIV were negative; and serology for COVID-19, by immuno-chromatography, was reactive with IgG and non-reactive with IgM, and by ELISA, was non-reactive with IgG and IgA. No other tests for respiratory infectious disease were conducted at this time. An anti-nuclear factor serum test was non-reactive, the rheumatoid factor assay was less than 20 IU/mL, and the treponemal test for syphilis was negative. C3 complement dosage was 43.4 mg/dL and C4 was 3.3 mg/dL. Tests for antigens and antibodies for hepatitis in serum and for alcohol-acid-resistant bacilli in spontaneous sputum were negative. A chest X-ray was also performed, and this showed diffusely distributed pulmonary micronodules (Figure 1).
A bronchoscopy was performed on the day of hospital admission and showed a normal result. A transbronchial biopsy was not performed due to the drop in arterial oxygen saturation observed during the endoscopy. After this procedure, the patient developed hypoxemia and was admitted to the Intensive Care Unit (ICU). At this time, intravenous antibiotics for resistant bacteria, antituberculosis therapy, amphotericin B, and corticosteroids were started. The patient’s condition became worse over the next few hours, with the onset of respiratory failure requiring orotracheal intubation and mechanical ventilation with high oxygen concentration and progressively higher levels of positive end-expiratory pressure. A search for acid-alcohol resistant bacilli and fungi, a galactomannan test, and an automated molecular test for
At the followup, 20 days after discharge, he complained of tiredness when walking quickly on flat ground, fine rales were maintained in the lower thirds of the hemi-thoraces and chest CT revealed faint nodular opacities in the lungs; the functional tests showed indirect signs of airway obstruction and normal carbon monoxide diffusing capacity. These changes disappeared at the 7th month of followup (Figure 3). The tomographic alterations also disappeared 9 months after discharge (Figure 4).
The significance of the case presented here is the unusual finding of an initial tomographic presentation that diverged from the case definition of EVALI published by the CDC in 2019 [8,9]. The laboratory investigation of respiratory infectious disease was not completely comprehensive, but some possibilities could be considered unlikely (influenza and
Although described in 2014, EVALI was only recognized as a specific disease, under the name of EVALI, and as a public health problem, in 2019 by the CDC, which published the definition of a confirmed case . In this document, the diagnostic criteria for imaging tests were infiltrates on chest radiography or ground-glass opacities on CT. More recently, Kligerman et al showed that, in a cohort of 160 individuals diagnosed with EVALI, the most common chest CT presentation was a ground-glass image and assigned this pattern to organizing pneumonia, which generally manifests on CT scan as ground-glass opacities, consolidation, or both. They also observed that 8.8% of the patients presented diffuse centrilobular nodules as the main tomographic alteration . The authors attributed these nodules with little or no ground-glass opacity to the injury being primarily centered in the small airways. In the case reported, in which the surgical biopsy also showed organizing pneumonia, the initial chest CT scan, unlike the most frequently seen patterns mentioned above, did not show ground-glass opacities. Instead, it showed diffusely distributed pulmonary nodules sparing the subpleural spaces – a centrilobular pattern – likely reflecting the bronchiolocentric distribution of the lesion that may have the same explanation given by Kligerman et al. This pattern is nonspecific and the most likely causes for this form of injury presentation are airway-centered organizing pneumonia foci, pulmonary hemorrhage, and hypersensitivity reactions (the last 2 were not observed in this case) . These authors also observed a direct ratio between the frequency of ESD use and the severity of the disease manifestations, and an inverse ratio between this severity and the time between the beginning of the habit and the symptoms, with a cut-off point at 6 months . The patient, although he mentioned the use of an ESD 2 times a day in the last 9 months, presented with bilateral consolidations, severe respiratory failure, and near death, which is in conflict with his assertion of ESD use at this level.
The tomographic changes documented in these pages are very similar to those shown in the EVALI report published by Landman et al . However, unlike in our case, they conclude – based on the findings of chest CT and transbronchial biopsy – that these changes were due to bronchiolitis obliterans, despite the difficulty of establishing this histopathological diagnosis in the tiny fragments usually obtained by this endoscopic method. In parallel with the report of Landman et al, the disease presented here evolved with severe hypercapnia that was refractory to conventional ventilatory methods, reflecting the involvement of the airways, which was later confirmed in the examination of the biopsy specimen. Improvement with steroid treatment was also observed. Likewise, in the first month after discharge, there was exercise intolerance and signs of airway obstruction on pulmonary function tests. However, differently from Landman et al`s report, the complaints disappeared and the pulmonary functional tests normalized after 7 months. Diffusion to carbon monoxide remained at the normal level and CT scan after 11 months showed only the scar from the surgical procedure.
In another report, Kass et al, in a series of 10 patients with suspected or confirmed EVALI, observed pulmonary nodules on CT scan in only 1 case, but even this was in association with ground-glass opacities . From these observations, it can be concluded that pulmonary nodules as the main tomographic alteration of EVALI remain a rare and noteworthy manifestation.
The mechanism underlying the development of EVALI is not fully understood. It is speculated from studies in human cell culture and in rats that the inhalation of the heated vapor produced by the ESDs alters the permeability of the epithelial surface of the airways and increases the exposure of parenchymal cells to the toxic components contained therein, leading to injury, inflammation, and induction of a systemic pro-inflammatory state .
The pathology of EVALI is variable and nonspecific, most often showing 1 or more features of acute lung injury [15,16]. This heterogeneity may in part be due to the presence of different agents in ESDs, their combination, dose, and inhalation technique determining the site of their deposition, whether in the airways or in the alveoli [15,16]. The finding of organizing pneumonia, either isolated or associated with other alterations, is the most frequent histopathological pattern in most series, and was observed in the case described here [15,16]. The initial radiological presentation with disseminated bilateral nodules and a centrilobular pattern, however, differed from CDC definitions and proved to be challenging for differential diagnosis, in particular with conditions showing similar patterns to those of infectious diseases, aspiration, bronchiolitis of other causes, hypersensitivity pneumonitis, and diffuse alveolar hemorrhage [1,11]. An additional challenge was the fact that the patient, like many, initially omitted information about the use of ESDs due to forgetfulness or ignorance of the illnesses associated with it. It should be noted that the patient fell ill in the midst of the COVID-19 pandemic, which represented an additional difficulty, given the incipient knowledge about this disease at that time.
Another aspect to be considered is the potential for severity in the evolution of EVALI, reaching near death as documented here. Although infrequent, a fatal outcome was described in 1.25% of cases in the series by Kligerman et al . These findings direct attention to the possibility of severe acute complications from the use of ESDs, to which the unknown risk of developing late-onset chronic disease, such as those observed in conventional cigarette use, must be added.
The authors report a case with the diagnosis of EVALI with a chest CT presentation different from the most frequent pattern described in the literature, thus requiring a greater exercise of differential diagnosis, particularly with respect to infectious diseases, hypersensitivity, aspiration, and diffuse alveolar hemorrhage. Two additional difficulties were (1) that the information on the use of an ESD was only brought by the family after at least 2 weeks of hospitalization, and (2) the fact that the patient fell ill amid the COVID-19 pandemic. The severity of the evolution of the illness guided the expansion of the initial antibiotic treatment until infectious causes could be safely ruled out, and it motivated the option of performing a surgical lung biopsy, given the impression of the urgency of obtaining a specimen with a greater possibility of leading to a diagnosis. The disease followed an almost fatal course, which is not commonly reported, but did not leave lasting pulmonary functional sequelae. Finally, this report bears witness to a serious toxic effect of ESDs, with the possibility of death. At a time when people, especially young people, are so influenced by electronic means of communication, it seems imperative that such reports gain space and warn about the risk of using a device whose harm is often minimized or omitted.
FiguresFigure 1.. Imaging studies: (A) Chest X-ray at admission with diffusely distributed nodules in both lungs; (B–D) Chest CT 2 days before admission showing small 5–10 mm nodules diffusely distributed, sparing subpleural spaces (centrilobular pattern), some with ramifications that indicate airway involvement, and small consolidations in the vascular trajectory, particularly in the upper right lobe (arrow). CT – computed tomography. Figure 2.. Histopathological findings and CT image: (A) Histological sections showing lung tissue with light-colored interstitial nodules of fibroblast proliferation immersed in an extracellular edematous matrix, some of them occupying the alveolar lumen (arrows); (B) Injury to the epithelium of the terminal bronchiole with interstitial fibroblastic proliferation nodule partially occluding its lumen (plugs) (arrow); (C) Multiple light-colored fibroblastic nodules distending the septal interstitium and occupying the air spaces with atelectasis of adjacent pulmonary tissue; (D) Tomographic image obtained 2 weeks before the biopsy showing multiple centrilobular pulmonary nodules and a dense triangular elongated band based on parietal pleura assigned to atelectasis (arrow). The histological findings characterize an organizing pneumonia pattern; no infectious organisms or viral cytopathic changes were identified. CT – computed tomography. Figure 3.. Pulmonary function tests: (A) Parameters 20 days after discharge showing normal values of dynamic and static volumes of capacities, a negative bronchodilator test (red in the charts), an increase in residual volume (RV) absolute and relative to total lung capacity (TLC), suggesting airway obstruction not observed in spirometry, and a normal carbon monoxide (CO) diffusing capacity; (B) Prebronchodilator values 7 months after discharge with normalization of RV and a normal CO diffusing capacity. FVC – forced vital capacity; FEV1 – forced expiratory volume in 1 second. Figure 4.. Late chest CT: (A, B) CT 9 months after discharge showing disappearance of the lesions previously described. CT – computed tomography.
1.. Kligerman S, Raptis C, Larsen B, Radiologic, pathologic, clinical, and physiologic findings of electronic cigarette or vaping product use-associated lung injury (EVALI): Evolving knowledge and remaining questions: Radiology, 2020; 294(3); 491-505
2.. King BA, Alam S, Promoff G, Awareness and ever-use of electronic cigarettes among U.S. adults, 2010–2011: Nicotine Tob Res, 2013; 15(9); 1623-27
3.. Leone FT, Douglas IS, The emergence of e-cigarettes: A triumph of wishful thinking over science (editorial): Annals ATS, 2014; 11(2); 216-19
4.. : Analysis of comparable indicators on students in the 9th grade of primary school – capital municipalities, 2009–2019, Rio de Janeiro, Brazilian National Institute of Geography and Statistics (IBGE) Available: [Published 2022]https://biblioteca.ibge.gov.br/visualizacao/livros/liv101955.pdf
5.. Flower M, Nandakumar L, Singh M, Respiratory bronchiolitis-associated interstitial lung disease secondary to electronic nicotine delivery system use confirmed with open lung biopsy: Respirol Case Rep, 2017; 5(3); e00230 [Erratum in Respirol Case Rep. 2017;5(4): e00242]
6.. Atkins G, Drescher F, Acute inhalational lung injury related to the use of electronic nicotine delivery system (ENDS): Chest, 2015; 148(4); 83A
7.. Polosa R, Campagna D, Tashkin D, Subacute bronchial toxicity induced by an electronic cigarette: take home message: Thorax, 2014; 69(6); 588
8.. Jatlaoui TC, Wiltz JL, Kabbani S, Update: Interim guidance for health care providers for managing patients with suspected e-cigarette, or vaping, product use – associated lung injury – United States, November 2019: Morb Mortal Wkly Rep, 2019; 68; 1081-86
9.. , 2019 Lung Injury Surveillance Primary Case Definitions Available: [Published 2019]https://www.cdc.gov/tobacco/basic_information/e-cigarettes/assets/2019-Lung-Injury-Surveil-lance-Case-Definition-508.pdf
10.. , Outbreak of lung injury associated with the use of e-cigarette, or vaping, products – electronic cigarettes, smoking & tobacco use: Cent Dis Control Prev, 2020; 1-4 Available: [Accessed October 12, 2022]https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html
11.. Kligerman SJ, Kay FU, Raptis CA, CT findings and patterns of e-cigarette or vaping product use-associated lung injury: a multicenter cohort of 160 cases: Chest, 2021; 160(4); 1492-511
12.. Landman ST, Dhaliwal I, Mackenzie CA, Life-threatening bronchiolitis related to electronic cigarette use in a Canadian youth: CMAJ, 2019; 191(48); E1321-31
13.. Kass AP, Overbeek DL, Chiel LE, Case series: Adolescent victims of the vaping public health crisis with pulmonary complications: Pediatr Pulmonol, 2020; 55(5); 1224-36
14.. Crotty Alexander LE, Drummond CA, Hepokoski M, Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice: Am J Physiol Regul Integr Comp Physiol, 2018; 314(6); R834-47
15.. Mukhopadhyay S, Mehrad M, Dammert P, Lung biopsy findings in severe pulmonary illness associated with e-cigarette use (vaping): Am J Clin Pathol, 2020; 153(1); 30-39
16.. Butt YM, Smith ML, Tazelaar HD, Pathology of vaping-associated lung injury: N Engl J Med, 2019; 381(18); 1780-81
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