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In the past year, two novel diagnoses with similar clinical manifestations have been characterized: E-cigarette, or vaping, product use-associated lung injury (EVALI) and multisystem inflammatory syndrome in children (MIS-C). Throughout Fall 2019, popular media and scientific journals rapidly published articles regarding EVALI as cases were identified across the Unites States. With the acceleration of the COVID-19 pandemic in late Winter and early Spring 2020, popular and scientific focus shifted quickly to disseminating information regarding sequelae of COVID-19, including MIS-C. Changing community disease prevalence, increasing popular media focus, and a high volume of scientific publications all contribute to clinicians readily considering a novel diagnosis. EVALI and MIS-C are novel diagnoses with similar presentations and, though there is substantial cultural focus on the COVID-19 pandemic, when evaluating a pediatric patient with pulmonary or respiratory pathology, clinicians should include both illnesses in their differential diagnosis. This case report outlines the challenge of differentiating between EVALI and MIS-C in the context of the COVID-19 pandemic.
A 17-year-old male was transferred to the pediatric emergency department (ED) from an outside hospital due to fever, shortness of breath, nausea, vomiting and diarrhea.
Four days prior to presentation, the patient accidentally inhaled “a bunch of” motor fumes; he then reported shortness of breath, chest tightness, headache, and subjective fever. His mother noted that he was breathing fast and took his temperature, which was reported to be 101.4 °F. Over the next few days, the patient remained febrile and developed abdominal pain, nausea, vomiting, and diarrhea. The patient and his mother reported that one episode of emesis may have contained blood, but they were unsure.
The patient’s mother contacted his pediatrician, who obtained a chest x-ray, which showed bilateral consolidations. The patient was tested for COVID-19 (negative) and influenza (negative). At the pediatrician’s office, oxygen saturation was reportedly 76% on room air, and he was transferred to a local ED.
In the outside hospital ED, the patient had an oxygen saturation of 88% and was placed on 4L of oxygen via nasal cannula. His D-dimer was significantly elevated, and a chest computed tomography angiography (CTA) was obtained to assess for pulmonary emboli. The CTA showed “no acute pulmonary emboli” and “extensive bilateral airspace disease consistent with severe pneumonia.” Due to the concern for severe pneumonia, the patient was started on empiric antibiotics (ceftriaxone, vancomycin, azithromycin) and transferred to the children’s hospital ED.
In the pediatric ED, the patient was documented as “ill- appearing” on physical exam and required 4L oxygen via nasal cannula to maintain an oxygen saturation of 95%. He temporarily required a non-rebreather mask while in the ED.
Per departmental protocols, ED staff ordered in-house COVID-19 testing (Simplexa COVID-19 Direct Assay), COVID-19 antibody testing, and lab work indicated by the local MIS-C protocol. Laboratory testing showed elevated ESR, CRP, D-Dimer, and fibrinogen. PT and PTT were both elevated. Transferrin was decreased. A white blood cell count was elevated and demonstrated neutrophilia and lymphopenia (Table 1). The chest x-ray obtained in the ED (Figure 1) showed widespread airspace and interstitial opacities, concerning for severe viral or atypical pneumonia.
Past medical history was significant for a seizure disorder, asthma, chronic back pain, anxiety, and attention deficit hyperactivity disorder. Home medications at presentation included escitalopram oxalate, levetiracetam, and tizanidine.
Two and a half months prior to presentation for this acute concern, the patient was also transferred to the pediatric ED from an outside hospital due to fever, shortness of breath, nausea and vomiting. A COVID-19 test and Respiratory Virus Panel (RVP) were both negative at that time. The patient was treated for atypical pneumonia and discharged after 1 day.
Social history was notable for vaping both marijuana and tobacco, cocaine use, and hydrocodone use, but no intravenous drug use.
The patient was admitted to the general pediatrics floor due to respiratory distress and requirement for supplemental oxygen to maintain goal SpO2 >90%. The admitting team ordered a Respiratory Virus Panel, Gastrointestinal Pathogen Panel, blood culture, sputum bacterial culture, sputum fungal culture, and sputum acid fast culture. All were negative or showed no growth.
Infectious Diseases (ID) was consulted to assist in evaluation for possible MIS-C or atypical etiologies of pneumonia.
Per ID, the patient was asked about any specific history of exposure to agitated soil (e.g. dirt biking, mud runs, spelunking, excavation), which he did endorse.
Table 1. Laboratory Values as of patient’s initial presentation, especially notable for elevated D-Dimer, ESR, CRP and neutrophil count
Consequently, infection with Histoplasma or Blastomyces were added to the differential diagnosis. Due to the combination of respiratory and gastrointestinal symptoms on presentation, Legionella pneumonia was also considered. Urine antigen tests for Histoplasma, Blastomyces, Legionella, and Streptococcus pneumoniae were sent to an outside lab for evaluation. The patient was empirically treated with vancomycin, azithromycin, and ceftriaxone before ultimately being discharged on oral doxycycline for a 7 day total antibiotic treatment of community acquired atypical pneumonia.
Pulmonology was consulted to evaluate a possible vaping- related lung injury due to the patient’s social history of vaping both nicotine products and marijuana. The consulting pulmonologist agreed that EVALI should be included on the differential. A repeat chest x-ray was recommended if the patient showed worsening clinical status. The consultant also noted that patients with EVALI can deteriorate rapidly, so close monitoring of respiratory function was a critical part to treatment.
Rheumatology was consulted as part of the institutional protocol for evaluation of possible MIS-C. Additionally, there was concern for a potential underlying rheumatologic condition due to the patient’s multisystem involvement and reported chronic back pain. Rheumatology ordered laboratory tests inpatient, and planned to follow up with the patient after discharge regarding results.
Cardiology was not consulted on this case in the context of a noncontributory echocardiogram on the day of admission.
The patient clinically improved both objectively and subjectively over his 4 days in the hospital. This clinical improvement, amidst ongoing concern for possible infectious etiology, was the justification for not treating with steroids, even with his concerning initial presentation. The patient was gradually weaned from supplemental oxygen and was discharged after maintaining an SpO2 > 92% on room air for 24 hours. By discharge, inflammatory markers normalized; neutrophilia and lymphopenia resolved. The patient reported resolution of gastrointestinal symptoms and significant improvement in respiratory symptoms.
All tests for infectious causes were negative, elevating MIS-C and EVALI as the two most likely diagnoses. Due to two negative COVID-19 tests, a negative COVID-19 antibody test, and clinical improvement without MIS-C interventions (e.g. IV Ig, steroids), MIS-C was felt to be less likely. EVALI was the best explanation for the patient’s presentation and hospital course. The patient was counseled by multiple providers on both the general pediatrics and pulmonology teams on the risks of vaping. He was encouraged to quit vaping and informed there was no level of vape use that could be considered safe. Additionally, the patient was offered the option to speak with a psychiatrist, which he declined. The patient was discharged with scheduled follow-up appointments with pulmonology, rheumatology, and his PCP.
EVALI and MIS-C are non-infectious causes of acute lung injury that have been brought to the attention of the medical community in recent months. EVALI is defined as respiratory failure within 90 days of electronic cigarette use with no evidence of infection or alternate causes of respiratory failure.1 Pulmonary infiltrates are noted on chest imaging, and the vast majority of patients (95%) present with cough, chest pain, and shortness of breath.2 Other common symptoms (85%) are fever, chills, and weight loss; slightly less common (77%) are abdominal pain, nausea, vomiting, and diarrhea.2 It is also notable that a significant proportion of patients (86%) reported using electronic cigarettes containing THC.3 In addition to containing THC, these cartridges commonly incorporate vitamin E acetate, an agent that has been linked to EVALI.1,2 Epidemiologically, most patients are white males younger than 35, although most of the deaths (25%, compared to 2% of total cases) occur in patients older than 65.3
The lack of diagnostic criteria for EVALI makes it a diagnosis of exclusion.4 The CDC has created an algorithm that outlines the necessary workup to rule out other causes and make the final diagnosis.4 In summary, the patient needs to have a history of electronic cigarette use, symptoms consistent with those of other EVALI patients, and no apparent infectious etiology present upon evaluation. Infectious workup for suspected EVALI is relatively exhaustive—if a case is severe enough to warrant inpatient admission, the CDC recommends common respiratory evaluations (influenza testing, chest X-rays, etc.) as well as more involved analyses (such as bronchoalveolar lavage or CT scan even with a normal chest X-ray). Bronchoalveolar lavage specimens often show a cell count with neutrophilic predominance, although lipid-laden macrophages and eosinophils have also been seen.1,2 Surgical lung biopsies reveal a wide range of pathologies from mild and nonspecific inflammation to interstitial and peribronchiolar granulomatous pneumonitis.2 Patients who are diagnosed with EVALI tend to have leukocytosis with neutrophilic predominance as well as elevated inflammatory markers, but these are relatively nonspecific findings.1 Radiographic findings are more conclusive, with four discrete radiographic patterns identified in EVALI: acute eosinophilic pneumonia, diffuse alveolar damage, organizing pneumonia, and lipoid pneumonia.1 The most common findings on chest X-ray and CT are bilateral ground-glass infiltrates with basilar predominance and sub-pleural sparing.1 In concordance with the radiographic findings, EVALI’s clinical course involves progressive hypoxemia progressing to acute respiratory distress syndrome (ARDS) in 22% of patients.2 The significance of the histopathological and radiographic findings with respect to disease course and severity has not been ascertained. Consequently, the clinical course has been the most commonly used marker to track patient status. Patients with oxygen saturations greater than 89% on room air are deemed safe to discharge.2 If a patient presents with an oxygen saturation above 95% or minimal respiratory distress, outpatient management of EVALI can be considered.4
Outpatient management of EVALI is largely supportive, with emphasis placed on discontinuation of electronic cigarette use and continued monitoring for infectious etiology. Although all infectious etiologies must be ruled out, patients may be treated with antibiotics before the diagnosis of EVALI is made.2 The influenza vaccine should also be administered if not previously received.4
For patients with a severe disease course, the current proposed treatment for EVALI is respiratory support and administration of systemic glucocorticoids. With this treatment protocol, clinical improvement was documented in 65% of cases.1 No guidelines for dosage or course have been established. Unfortunately, steroids must be used with caution before the diagnosis has been established.4 Steroid treatment can worsen respiratory infections and, in the case of a fungal infection, may cause significant morbidity. For the patient discussed in this case, glucocorticoids were not administered due to ongoing concern for possible infectious etiologies and improvement in the patient’s clinical appearance.
The wide spectrum of EVALI presentation and its relative lack of characterization unfortunately make diagnosis and treatment guidelines difficult to establish. Awareness of the range of clinical, laboratory, and imaging findings are of the utmost importance in assessing and treating patients with suspected EVALI.
MIS-C is even more novel than EVALI, with the diagnosis only recently described during the current SARS-CoV-2 pandemic. Unfortunately, as with EVALI, the diagnostic criteria for MIS-C are poorly characterized. The diagnosis is made based off the following case definition from the Centers for Disease Control and Prevention.5
- An individual aged < 21 years
- Clinical criteria,
- A minimum 24-h history of subjective or objective fever ≥ 38.0 °C, AND
- Severe illness necessitating hospitalization, AND
- Two or more organ systems affected
- Laboratory evidence of inflammation,
- One or more of the following: an elevated CRP, ESR, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, or IL-6; elevated neutrophils or reduced lymphocytes; low albumin
- Laboratory or epidemiologic evidence of SARS-CoV-2 infection,
- Positive SARS-CoV-2 testing by RT-PCR, serology, or antigen OR
- COVID-19 exposure within 4 weeks prior to onset of symptoms
- And, no alternative diagnosis.
Notable parallels have been drawn between MIS-C and Kawasaki disease, but MIS-C can also present as a pneumonitis- like process lacking the hallmark vasculitis features of Kawasaki disease. A study of 186 patients found Kawasaki- like features in 40% of cases and an overall mortality rate of 2%.6 Systems commonly involved were gastrointestinal (92%), cardiovascular (80%), hematologic (76%), mucocutaneous (74%), and respiratory (70%). Although many children with MIS-C have respiratory involvement, a primary concern for these patients is development of cardiac dysfunction during their illness. Pulmonary infiltrates seen on chest X-ray in suspected MIS-C are often consistent with acute left heart failure, although cases of MIS-C-related ARDS have also been reported.5,6 In the series examined by Nakra et al., 50% of patients presented with cardiovascular shock necessitating vasopressor or inotropic support.5 Similar to Kawasaki disease, this disease process raises concern for coronary artery aneurysm, so cardiac monitoring is emphasized for MIS-C patients. In contrast, pulmonary dysfunction is the primary concern with EVALI, so respiratory support and monitoring is more critical to treatment than cardiac monitoring.
Treatment for MIS-C is also analogous to treatment for Kawasaki disease. The mainstays of treatment for Kawasaki disease are intravenous immunoglobulin (IVIG) therapy and aspirin. MIS-C has demonstrated responsiveness to IVIG therapy, but compared to Kawasaki disease, MIS-C is more likely to require adjunctive steroid therapy.7 In addition to IVIG and steroids, IL-1 and IL-6 antagonists, have reported efficacy in MIS-C treatment.6,7 The hospital course for MIS-C patients tends to be fairly intense, with a median duration of hospitalization at 7 days; in one series of inpatients, 80% received intensive care, 20% required mechanical ventilation, and 48% received vasoactive support.6 Epidemiologically, MIS-C seems to predominantly affect adolescents and children older than 5 years.6 In addition, reports from the UK and France suggest increased incidence in patients of Afro- Caribbean descent, whereas no Kawasaki-like MIS-C cases have been reported from Asian countries as of 4 June 2020.7 This may imply a genetic predisposition to the development and severity of MIS-C, although this hypothesis will require more research before definitive conclusions are drawn.
Of note for this case, MIS-C remained a part of the differential diagnosis even in the context of multiple negative PCR COVID tests. This patient presented relatively early during the COVID-19 pandemic when little was known about the disease course for MIS-C. It was unclear if MIS-C occurred only during active infection that could be detected by PCR, or if it occurred in the absence of PCR detected infection. Consequently, MIS-C was considered in a patient with negative PCR tests.
Clinicians’ relative unfamiliarity with EVALI and MIS-C make diagnosis and treatment challenging, especially as their presentations and patient populations often overlap. In addition, both syndromes are diagnoses of exclusion, requiring extensive workup before either diagnosis is finalized. This case outlined points of differentiation between the two syndromes with an emphasis on the hallmark subjective and objective elements of the clinical course that may inform clinical decision-making.
There is a wide differential for adolescent patients presenting with systemic inflammatory symptoms. The prevalence of SARS-CoV-2 virus should not preclude the consideration of other novel etiologies, notably in this case EVALI. Both MIS-C and EVALI may have overlapping features on presentation including shortness of breath and gastrointestinal symptoms. The course and treatment for MIS-C and EVALI, however, can vary considerably. As such, awareness of the distinguishing factors in each condition as well as thorough history-taking and further workup are necessary to ensure patients are treated appropriately. EVALI and MIS-C, as relatively new phenomena, both require further investigation to establish definitive case criteria and treatment guidelines.
No financial support given. Authors report no conflicts of interest.
- Winnicka L, Shenoy MA. EVALI and the Pulmonary Toxicity of Electronic Cigarettes: A Review. J Gen Intern Med. 2020;35(7):2130- 2135. doi:10.1007/s11606-020-05813-2
- Salzman GA, Alqawasma M, Asad H. Vaping Associated Lung Injury (EVALI): An Explosive United States Epidemic. Mo Med. 2019;116(6):492-496.
- Moritz ED, Zapata LB, Lekiachvili A, et al. Update: Characteristics of Patients in a National Outbreak of E-cigarette, or Vaping, Product Use– Associated Lung Injuries — United States, October 2019. Morb Mortal Wkly Rep. 2019;68(43):985-989. doi:10.15585/mmwr.mm6843e1
- CDC’s Office on Smoking and. What You Need to Know. Centers for Disease Control and Prevention. Published March 17, 2020. Accessed August 7, 2020. https://www.cdc.gov/tobacco/basic_information/e- cigarettes/severe-lung-disease/healthcare-providers/index.html
- Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children. 2020;7(7):69. doi:10.3390/children7070069
- Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N Engl J Med. Published online June 29, 2020. doi:10.1056/NEJMoa2021680
- Galeotti C, Bayry J. Autoimmune and inflammatory diseases following COVID-19. Nat Rev Rheumatol. Published online June 4, 2020:1-2. doi:10.1038/s41584-020-0448-7