Clinical Findings in Adolescents Hospitalized With EVALI; Novel Report on Coagulopathy

This retrospective cohort study was conducted at 2 major tertiary-care children’s hospitals and was approved by the institutional review board. Participants included 12- to 18-year-old patients who were admitted to the pediatric general inpatient or ICU between January 2019 and June 2021.

Study participants were selected on the basis of diagnosis codes specific to EVALI (International Classification of Diseases, 10th Revision codes: J68, U07), as well as combination codes for pulmonary (J12, 15–18, J98, J93, R09) or GI symptoms (R19, R11) and marijuana or nicotine use or abuse (F19, F12, T40) or urine drug screen positive for THC.

Records were reviewed by 1 of 3 pediatric hospitalists. Inclusion criteria for probable or confirmed EVALI were based on the 2019 CDC case definitions.²²  Exclusion criteria included data from subsequent readmissions within 30 days, suspected EVALI but denial of e-cigarette use, and unrelated hospitalization. Data were collected on demographics, hospitalization metrics, laboratory testing, respiratory support, medication use (antibiotics, corticosteroids, vitamin K), imaging results, and pulmonary function testing (PFT). Statistical analysis was completed using IBM SPSS v27. Two-tailed student t test and χ² statistics were used to determine the statistical difference in reported means between probable and confirmed EVALI cases before combining data. Laboratory values are reported as means and 95% confidence intervals (Cis). PFTs were analyzed by a pediatric pulmonologist and normalized using the global lung function 2012 predictive values. Two-tailed paired and unpaired student t tests were used for PFT analysis.

Using the above-mentioned criteria, 103 patient records were extracted from the electronic health record system. Excluded patients had primary hospitalization diagnoses of cannabinoid hyperemesis syndrome (n = 18), acute intoxication (n = 8), chest pain/syncope (n = 6), asthma exacerbation (n = 4), and other (n = 25).

Forty-four patients (11 probable and 33 confirmed cases of EVALI) met the inclusion criteria for final analysis; 45% of the cases presenting after June 2020 (Fig 1). In the probable EVALI group, viral testing was positive for mycoplasma IgM (n = 2), rhino/enterovirus (n = 3), cytomegalovirus IgM (n = 1), and respiratory syncytial virus (n = 1). None of the viruses were thought to be causative of disease. Remaining probable EVALI patients lacked minimum criteria (ie, respiratory viral testing) to meet the CDC definition of confirmed EVALI. No patients in this study tested positive for severe acute respiratory syndrome coronavirus 2. Statistical analysis was used to compare clinical characteristics and laboratory values between probable and confirmed cases. Except for age, there were no statistical differences. Thus, data are described in aggregate.

Patients with probable EVALI were found to be significantly younger than patients with confirmed EVALI (15.6 vs 16.4 years; P = .04). In aggregate, average age was 16.2 years, and 64% of the patients were males (Table 1). The majority (90%) of patients admitted to using THC-containing products. At the time of admission, vomiting, fever, and cough were most reported. Moreover, 84% and 81% of the patients presented with constitutional and GI symptoms, whereas 72% of the patients presented with respiratory symptoms. Notably, in half of patients, GI symptoms were noted before the development of other symptoms. In 17 of these 44 patients with clear timelines, GI symptoms preceded pulmonary symptoms by 4.7 days [CI, 4.0–5.4]. In addition, 4 patients had weeks-long histories of GI symptoms, and 2 patients had unclear timelines. The average reported weight loss was 12.2 kg [CI, 10.2–14.0] within the last 3 months. Of the 5 EVALI patients with previous asthma history, 4 had mild intermittent asthma with no controller use and 1 had moderate persistent asthma on dual inhaled corticosteroid/long-acting β agonist therapy. Ten patients (23%) had psychiatric diagnoses of depression, anxiety, or attention deficit hyperactivity disorder.

Average length of stay was 6.4 days [CI, 4.0–8.8]. Maximum respiratory support during hospitalization included none (n = 26), nasal cannula (n = 10), oxymask (n = 1), high flow nasal cannula (n = 4), bilevel positive airway pressure (n = 3), and respiratory failure requiring veno–venous extracorporeal membrane oxygenation (n = 1). Eight patients required intensive-level care. All patients were discharged on room air with stable vital signs. There were no readmissions to the hospital system within 7 or 30 days.

Imaging included 39 chest radiographs and 26 computed tomography (CT) scans (Supplemental Fig 1). Chest radiographs findings include 20% that were interpreted as normal, 26% with viral or reactive airway disease, hyperinflation, or isolated pneumomediastinum or pneumothorax, and 54% with lung field haziness or multifocal opacites. On CT scans, lung parenchymal pathology was identified in 100% of imaging events, and generally included bilateral ground glass opacification with subpleural sparing, with dependent areas of the lungs more affected than upper lobes. Pulmonary complications included small pleural effusions (n = 9), pneumomediastinum (n = 5), and pneumothorax (n = 3). Notably, in 10 cases, abdominal imaging (performed before chest imaging) identified pulmonary changes leading to diagnosis.

Significant laboratory results included elevated white blood cell count of 14.3 k/µL (CI, 13.7–15.0)] with neutrophilic predominance, C-reactive protein (CRP) of 25.2 mg/dL (CI, 22.1–28.2), and erythrocyte sedimentation rate (ESR) of 66.7 mm/hour (CI 26.9–76.4) (Table 2).

Coagulation studies were obtained in 21 patients (18 of 33 patients with confirmed EVALI and 3 of 11 with probable EVALI) (Table 2 and Fig 2). In all 21 patients tested, prothrombin time (PT) and international normalized ratio (INR) were significantly elevated above the reference range. Average PT was 17.7 seconds (CI, 16.4–19.1), and INR was 1.54 (CI, 1.43–1.66). Fibrinogen and d-dimers were also elevated in 14 of 14 and 11 of 12 patients tested respectively. Partial thromboplastin time, platelets, and hepatic function testing were within normal limits. No patients met the criteria for overt disseminated intravascular coagulopathy.²³ 

Three bronchoscopies were delayed because of coagulopathy requiring correction, with 2 advancing to procedure. Two additional bronchoscopies were performed where coagulopathy had either previously been corrected or not checked. Three of 4 BAL samples showed evidence of red blood cells or blood-tinged aspirate. All aspirates showed the presence of lipid-laden macrophages.

PFTs were performed on 14 patients during hospitalization and on 13 patients after hospitalization (within 6 weeks) (Fig 3). Average time to after hospitalization testing was 13.3 days. There was significant improvement in mean percentage predicted forced expiratory volume in 1 second (P < .01) and forced vital capacity (P < .01) between these 2 time points. Significance was maintained in 7 individual patients with paired hospitalization and follow-up testing. Airway obstruction (forced expiratory volume in 1 second/forced vital capacity <85% of predicted value) was seen in 3 out of 14 patients (21%) tested during admission, but in no patients after hospitalization.²⁴ 

Diffusing capacity of the lung for carbon monoxide divided by alveolar volume (DLCO/VA) was collected on 16 patients (predischarge: n = 11; postdischarge: n = 5). In aggregate, 9 of these 16 patients (56%) had abnormal DLCO/VA of either <80% predicted, suggesting evidence of pulmonary vascular disease (predischarge: n = 4 of 11; postdischarge: n = 3 of 5), or >100%, suggesting pulmonary hemorrhage (predischarge: n = 2 of 11).²⁴  There were no paired DLCO/VA samples to examine individual improvement.

Corticosteroids, including methylprednisolone, dexamethasone, and prednisone, were administered to 38 of 44 (86%) patients; the regimen was not standardized, with variable weaning periods. In patients with abnormal coagulation studies, corticosteroids were administered to 21 of 21 patients, and vitamin K was administered to 11 of 21 patients (parenteral: n = 10; oral: n = 1). Coagulation studies improved with either steroids and vitamin K, but lack of standardization and follow-up laboratories limited interpretation of effect size (Supplemental Fig 2).

The presumed diagnosis for several patients in this cohort was initially cannabinoid hyperemesis syndrome (CHS). In our exclusion group, 18 patients were ultimately diagnosed with CHS. Ten of these patients had inflammatory markers. It was noted that inflammatory marker values were significantly different compared with the patients diagnosed with EVALI: CRP 25.2 vs 0.9 mg/dL (P < .01) and ESR 66.7 vs 7 mm/hour (P < .01).

Although the CDC has not reported new case numbers since 2020, EVALI continues to be a significant diagnosis in the adolescent population. In this study, 55% of the cohort was admitted after April 2020. The 2 children’s hospitals involved in this study are in northeast and southeast of the United States, which suggests that this diagnosis continues to be widespread and an important differential diagnosis.

Past studies, primarily those including adults, report that 92% to 98%, 81% to 90%, and 70% to 100% of patients with EVALI presented with respiratory, GI, and constitutional symptoms, respectively.^9,25–28  In 2 smaller case series of adolescents with EVALI, respiratory symptoms at presentation were observed in 75% to 85% of patients.^27–28  Our findings are consistent with fewer respiratory symptoms at presentation but possible development of hypoxia during hospitalization. We hypothesize this delay in presentation in adolescents when compared with adults may be because of better baseline lung function and reserve with shorter histories of inhalation exposure and chronic lung injury.

EVALI remains a diagnosis of exclusion and the differential can be broad. There is significant overlap in the presentation of EVALI, SARS-CoV2 pneumonia, and multisystem inflammatory syndrome in children. The constellation of fever, significant weight loss, and GI or pulmonary symptoms with elevated inflammatory markers should prompt clinicians to obtain unambiguous history regarding vaping. Despite denial of e-cigarette use, in hospitalized patients where there is a high index of suspicion of EVALI, we suggest a drug screen for THC. Although lymphopenia is seen in patients with COVID-19, patients with EVALI seem to present with mild leukocytosis with neutrophilic predominance.²⁹  The mainstay of treatment of EVALI is early administration of steroids. However, in the context of COVID-19, steroids may be delayed until patients are hypoxic, which is potentially detrimental to EVALI patients.³⁰  COVID-19 has been identified to trigger vasculopathy and hypercoagulation. Treatment of COVID-19 may involve early anticoagulation therapy.³¹  Anticoagulation should be approached with caution in a patient with vaping history.

This study demonstrates that coagulopathy is likely a more common finding in EVALI than previously realized. Although coagulation studies were not obtained in all patients (which is a significant study limitation), this is the largest report to date. Other limitations include the lack of direct correlation with bronchoscopy results, lack of further investigation of alternate causes of coagulopathy, and lack of complete follow-up to confirm resolution of coagulopathy. However, it is notable that all 21 patients with coagulation studies showed significant elevation in PT and INR. None of the patients in this cohort met criteria for overt disseminated intravascular coagulopathy, maintaining normal platelet counts and elevated rather than lowered fibrinogen. There was also no evidence of hepatic or renal disease as alternative causes of acquired coagulopathy. Significant isolated abnormality in PT and INR suggests disruption of the extrinsic coagulation pathway, which was improved with the administration of vitamin K or steroids. If diagnosis remains unclear, it is reasonable to administer vitamin K while the patient undergoes further workup. The exact causation for this coagulopathy remains unknown, but this finding should be further studied.

No specific agent has been identified as the causative factor in EVALI. The heterogeneity of e-liquids, which may be both legally or illegally manufactured and distributed, continues to make this investigation difficult. The majority of EVALI cases stem from e-cigarette use with THC-containing e-liquids.⁷  Studies of e-liquids have identified pesticides, thickeners, diluents, acetone, formaldehyde, nitrosonornicotine, nitrosamines, volatile organic compounds, heavy metals, and ultrafine particles.^32–34  Vaping likely alters the primary mechanisms for lung homeostasis with effects on surfactants, microciliary clearance, and phagocytosis of inhaled particles. Although a direct cytotoxic effect of inhaled chemicals on the pulmonary epithelium leading to cellular necrosis and neutrophil inflammation³³  may certainly contribute to the pathogenesis of EVALI, the systemic inflammatory response to inhaled aerosolized compounds may play a greater role suggested by multisystemic involvement and markedly elevated CRP. Currently, the pathogenesis of this significant systemic inflammatory response is unknown but should be further investigated.

A review of the present literature identified several proposed mechanisms of inflammation and coagulopathy because of vaping substances. Muthumalage et al showed that exposure to aerosolized vaping compounds (vitamin E acetate and medium-chain fatty acids) induced a significant increase in interleukin (IL)-6, eotaxin, and granulocyte colony-stimulating factor in BAL samples and eicosanoid inflammatory mediators in mouse and human serum.³⁵  Other studies before the EVALI outbreak have demonstrated elevation in IL-4, IL-6, IL-8, and IL-10, which are all proinflammatory cytokines and play roles in immune suppression.^35–38  Khanijo et al hypothesized imbalance in the inflammation-coagulation axis in acute lung injury may lead to impaired factor VII-mediated alveolar fibrin turnover by macrophages.^39–40  Additionally, increased vitamin E from oral supplementation, also a concerning substance in e-liquids, is known to act as an antagonist to vitamin K, leading to a disruption of the clotting cascade.⁴¹  Ramirez et al showed that 2-week exposure in mice to JUUL can cause a 10-fold decrease in median bleeding occlusion and hemostasis time, along with increased platelet activation.⁴²  Despite studies of vaping increasing short-term platelet activation,^43–44  there has only been 1 case report of arteriovenous thrombosis during acute hospitalization for EVALI.⁴⁵ 

There are, however, multiple reports of alveolar hemorrhage and hemoptysis associated with EVALI.^13–21  Although this study included limited bronchoscopies, we demonstrate the presence of red blood cells and blood-tinged secretions, even after correction of coagulopathy. The PFT findings in our cohort were consistent with the few reports in the literature with variable spirometry findings of minimal airway obstruction and significantly reduced DLCO/VA values.^46–49  Widespread damage to the pulmonary small vessels leading to blood collecting in the alveoli is exacerbated by abnormal coagulation, which may lead to diffuse alveolar hemorrhage. If enough alveoli are affected, gas exchange (ie, DLCO/VA) is decreased (<80%).⁵⁰  Low DLCO/VA values without significant obstruction are observed in interstitial lung disease and vasculitis.²⁴  The elevated PT may cause mild pulmonary bleeding but then significant interstitial inflammation, which decreases DLCO/VA. If enough bleeding occurs, DLCO/VA (>100%) is elevated because of the uptake of carbon monoxide by hemoglobin. Correction of coagulopathy in patients with increased DLCO/VA may help to decrease pulmonary hemorrhage. Interestingly, although our sample size is limited, we found continued decreased DLCO/VA despite improvement in other PFTs within 6-week follow-up, suggesting persistent pulmonary vascular disease, although this did not reach significance. To date, no previous study has described this finding. We suggest further investigation in association of coagulopathy and abnormal DLCO/VA measurements.

In this study, a fourth of the patients had sufficiently severe enough GI symptoms to require abdominal imaging leading to the identification of lung findings. Approximately 46% of initial chest radiographs were interpreted as no pathology or minimal findings that could lead to a misdiagnosis. CT chest imaging showed 100% sensitivity in the detection of small distal airway pathology with universal findings of bilateral ground glass opacities, subpleural sparing, and lobar consolidation.^51–53  This emphasizes the importance of obtaining a CT scan when there is a high suspicion of EVALI. CT in EVALI may show subpleural sparing distinct from COVID-19.⁵⁴ 

Several patients were initially thought to have CHS before developing respiratory symptoms. One marked difference between EVALI and CHS is the level of inflammation; CRP and ESR are significantly elevated in EVALI but are normal in CHS. This suggests that inflammatory markers may be used for early differentiation between these 2 diseases and emphasizes the role of inflammation in EVALI.

Twenty-three percent of adolescents in our population had preexisting depression or anxiety consistent with other studies on adolescent EVALI patients.⁵⁵  This is compared with the 8.4% of the general population of children aged 6 to 17 years having “ever been diagnosed with either anxiety or depression” in 2012.⁵⁶  Discharge planning should include providing resources on cessation (psychological and pharmaceutical), as well as appropriate referrals to adolescent medicine, addiction, or psychological services.

EVALI continues to be a relevant differential diagnosis. Naming this disease “E-cigarette/vaping-associated lung injury” misses the bigger picture of systemic inflammation and multisystem involvement. In this study, adolescents were more likely to be admitted with GI and constitutional symptoms than with pulmonary problems. To date, EVALI-associated coagulopathy is not reported in the literature nor mentioned in the CDC diagnosis algorithm.⁷  The novel finding of coagulopathy among adolescents with EVALI in this cohort reveals an opportunity to detect comorbid-clotting deficiencies and initiate therapy early to possibly avoid development of alveolar hemorrhage and further lung damage. We strongly recommend that coagulation studies be performed routinely, and certainly before an invasive procedure such as bronchoscopy, to avoid preventable complications.

We thank Kathleen Rooney-Otero, MD, Ramamoorthy Nagasubramanian, MD, and Eileen Antico for their contributions to this study.