Electrotonic-Cigarette or Vaping Product Use Associated Lung Injury: Diagnosis of Exclusion

Ali A. Mahdi MD, Chris Allahverdian MD, Sharareh Shahangian MD

Dignity Health, St Mary Medical Center, Department of Internal Medicine, Long Beach, California 90813, USA

Abstract

The first reports of lung injury attributable to vaping date back to 2012, but the ongoing outbreak of electrotonic-cigarette or vaping product use associated lung injury (EVALI) began in 2019. It is a diagnosis of exclusion. In this case report, we describe a patient with history of excessive vaping for the last 3 weeks who was admitted to the intensive care unit for acute hypoxic respiratory failure. The patient was diagnosed with EVALI given the history of vaping in the setting of negative infectious work-up and radiographic imaging that showed lung opacities.

Case Presentation 

A 37-year-old man with no significant past medical history initially presented to the emergency department (ED) with “chest pain and trouble breathing.” He reported first feeling chest pain localized to the substernal region 5 days prior to presentation; described it as pleuritic in nature; and rated intensity as severe. The patient stated deep breaths and laying flat aggravated his pain, while leaning forward relieved it. He also reported associated subjective fevers, non-productive cough, nausea and diarrhea but denied any lower extremity swelling, calf pain, prolonged immobilization, or history of congestive heart failure (CHF) or venous thromboembolism (VTE).

The patient denied any past medical or surgical history and reported not being on any medications or over-the-counter supplements. He denied any medication, diet, or environmental allergies. He lives in an apartment (built in the 1990s) with his wife, and does not have any pets. Patient works full-time at a box manufacturing facility where he processes shipping labels, reports drinking approximately 5 to 6 beers a day, denies any history of illicit drug use. He smoked one pack per day for the past ten years, but reported to have quit smoking over the last month. 

Due to his significantly worsening shortness of breath and severe chest pain, he was prompted to present to the ED. Upon presentation, he was febrile (38.9 degrees Celsius), hypoxic (saturating at 88%) in the setting of tachypneic (22 breaths per minute), tachycardic (117 beats per minute), and normotensive (systolic of 105 mmHg). Patient was started on supplemental oxygen, 4 Liters (L) nasal cannula (NC), yet had been noted to continue to desaturate in the mid-80's. Despite being transitioned to 11L non-rebreather mask, he remained tachypneic and hypoxic, and was subsequently started on high flow nasal cannula (HFNC), 50L at 0.50 fraction of inspired oxygen (FiO2).

Physical examination was significant for a man who appeared about the stated age in respiratory distress. He was noted to have scleral icterus, yellow skin discoloration, supraclavicular retraction, increased respiratory exertion, and fine bibasilar crackles. S1 & S2 were heard but no additional heart sounds or friction rubs were noted. His abdomen was soft, nondistended, nontender to superficial or deep palpation, without organomegaly, but with normal bowel sounds. No superficial venous dilation or telangiectasia was noted. Upper and lower extremities were without edema or tenderness. Homan’s sign was negative.

Initial laboratory investigations were significant for leukocytosis (white blood cell count of 12.6 K/uL), normocytic anemia (hemoglobin 8.2 g/dl) with an INR of 1.25, D-dimer 415 ng/ml DDU, troponin 0 ng/ml, hyponatremia (serum sodium 130 mmol/L), potassium 3.8 mmol/L, creatinine 0.79 mg/dL, BUN of 7mg/dL, alanine transaminase 21 IU/L, aspartate transaminase 63 IU/L, alkaline phosphatase 178 IU/L, gamma-glutamine transaminase 224 IU/L, total bilirubin 6.9 mg/dL (direct bilirubin 5.9 mg/dL). His lactic acid was elevated at 3.76 mEq/L. SARS-CoV-2 polymerase chain reaction (PCR) nasal swab was negative. Urine analysis was positive for moderate bilirubin. Urine toxicology was negative. 

Arterial blood gas while on HFNC showed pH 7.45, pCO2 27 mmHg, pO2 68 mmHg and HCO3 21 mEq/L. His PaO2:FiO2 was calculated to be 136, significant for moderate acute respiratory distress syndrome (ARDS).

Electrocardiogram (ECG) showed normal sinus rhythm, rate of 99 beats per minute, no ST segment changes or T wave inversions, without axis devious or conduction abnormalities.

Chest X-Ray (CXR) was significant for extensive patchy bilateral multifocal patchy infiltrates in the mid and lower lobes. Computer tomography (CT) of the chest without contrast (Figure 1) was significant for severe multifocal pneumonia with small bilateral pleural effusions.

Figure 1. Representative images from the computer tomography (CT) of the chest without contrast in (A) lung windows and (B) soft tissue widows. The CT was significant for severe multifocal pneumonia with small bilateral pleural effusions.

CT of the abdomen and pelvis with contrast was significant for hepatomegaly with diffuse fatty infiltrated, moderate gallbladder distention without intra or extra hepatic duct dilatation non-concerning for obstruction. Ultrasound (US) of the gallbladder revealed a distended gallbladder without evidence of stone or wall thickening, but was significant for sludge.

The patient was admitted to the intensive care unit (ICU) with severe sepsis and acute hypoxic respiratory failure likely secondary to presumed viral versus bacterial community acquired pneumonia (CAP) requiring HFNC. Blood cultures were collected, and the patient was started on fluid resuscitation and broad-spectrum antibiotics. Sputum cultures, respiratory viral panel, atypical pneumonia serologies and urine for legionella and pneumococcal antigens were ordered.

His Well’s score was calculated at 1.5 placing him at a low risk for pulmonary embolism (PE) with a D-dimer of 415 ng/ml DDU, likely secondary to septic-inflammatory state. However, given his continued high oxygen requirement, saturating in the high-80s to the low-90s while on HFNC 50L of 60% FiO2, and increased respiratory effort, chest CT chest angiography was ordered but negative for PE or acute aortic pathology. Transthoracic echocardiogram (TTE) demonstrates a preserved left ventricular function with an ejection fraction of 60%, without valvular disease or pericardial effusion.

Repeat CXR showed worsening diffuse multifocal infiltrates concerning for progressive ARDS. He was started on a 5-day course of systemic steroids (dexamethasone) given his worsening oxygen requirements and CXR findings. SARS-CoV2 nasal PCR was repeated as well, which remained negative. Cryptococcus, coccidiomycosis & QuantiFERON-Gold were ordered. His oxygen requirements improved. Labs revealed normalization of lactic acid and bilirubin with down-trending liver enzymes with correlating resolution of patient’s jaundice and icterus. He also reported significant improvement in his gastrointestinal symptoms. Subsequently, he was transferred from the ICU to the telemetry unit.

Infectious work-up (including Streptococcus pneumonia, chlamydia psittaci, chlamydia pneumonia, mycoplasma pneumonia, Legionella pneumonia, cryptococcus, aspergillosis, cryptococcus, histoplasmosis, human immunodeficiency virus, Pneumocystis jiroveci pneumonia (PCP), and tuberculosis), respiratory viral panel and cultures were all negative. Of note, the patient's wife reported that over the course of the last few weeks, the patient had started vaping e-cigarettes. Upon discussion, he that he started vaping a nicotine-containing product in order to quit smoking cigarettes 3-weeks ago, states that he has been “excessive vaping for the last 2-3 weeks.”

Given newfound history of vaping in the setting of negative infectious work-up and CT imaging that showed dense ground glass opacities throughout, differential diagnosis now included E-cigarette, or vaping product, use associated lung injury (EVALI) versus respiratory bronchiolitis associated interstitial lung disease (RB-ILD) secondary to smoking. He was treated with high dose systemic steroids (methylprednisolone) and PCP prophylaxis with trimethoprim-sulfamethoxazole. The broad-spectrum antibiotics were discontinued.

He started to demonstrate significant improvement in his oxygen requirement and in his clinical symptoms, was no longer coughing and was able to ambulate without dyspnea. Repeat CT scan demonstrated interval improvement in pulmonary infiltrates, although radiographic findings on CT were still significant for diffuse pulmonary infiltrates. The patient had near-complete resolution of symptoms, was titrated down to 2L NC, was transitioned to room air, and discharged on hospital day 21 on a steroid taper and PCP prophylaxis.

Discussion 

The first reports of lung injury attributable to vaping date back to 2012, but the ongoing outbreak of electrotonic-cigarette or vaping product use associated lung injury (EVALI) began in 2019 (1). By February 2020, the Center for Disease Control (CDC) documented over 2800 EVALI hospitalizations, amongst which 68 patients died (2). E-cigarettes function to aerosolize various chemicals (including nicotine, tetrahydrocannabinol, favoring and other additives) for inhalation (3). EVALI is a form of acute or subacute lung injury whose pathogenesis is unknown and is thought to be a spectrum of disease, rather than a single process (4,11). The histopathological patterns include acute fibrinous pneumonitis, diffuse alveolar damage and organizing pneumonia, more commonly bronchiolocentric with accompanying bronchiolitis (5). This spectrum of nonspecific acute lung injury commonly presents with cough, dyspnea, gastrointestinal symptoms with accompanying constitutional symptoms (1).

Radiographic findings of EVALI demonstrate a spectrum of nonspecific acute lung injury patterns. Bilateral opacities are typically seen, the majority of chest radiographs demonstrate diffuse hazy or consolidative opacities (6). CT opacities are typically ground glass in density and may spare subpleural spaces. Pleural effusions are less common findings (7). Other radiographic patterns have been noted suggestive of one or more disease processes: diffuse alveolar damage (dependent consolidation, diffuse ground glass and air bronchograms), acute eosinophilic pneumonitis (centrilobular ground glass opacities in the anterior lung fields, confluent ground glass opacities in dependent areas and lobules of mosaic attenuation) and organizing pneumonia (diffuse, multifocal discrete and confluent) (7).

EVALI is a diagnosis of exclusion; thus, pulmonary infectious causes and other etiologies of progressive respiratory insufficiency should be excluded (7). Currently CDC criteria for a confirmed case of EVALI include: (1) Use of e-cigarette or related products in the last 90 days, (2) Lung opacities on CXR or CT, (3) Exclusion of lung infection, including negative influenza polymerase chain reaction (PCR) or rapid test (unless out of season), viral respiratory panel, and if clinically indicated, urine antigen tests for Legionella and Streptococcus pneumonia, blood & sputum cultures, bronchoalveolar lavage and HIV-related opportunistic infections, (4) absence of likely alternative diagnosis including cardiovascular disease, rheumatologic disease and neoplastic (2).

Supportive care initially focuses on management of hypoxia with supplemental oxygen at a goal saturation of 88 to 92% (3). Empiric antibiotics should also be initiated to cover likely pathogens for CAP. Although the optimal treatment of EVALI is not yet known, systemic glucocorticoids have been used in the majority of patients with varying efficacy (9). Given the postential efficacy and low incidence of adverse effects, systemic glucocorticoids should be considered in EVALI cases with progressively worsening symptoms and hypoxemia (7,10). Flexible bronchoscopy may be utilized in excluding other causes of non-resolving or progressive pneumonitis; however, bronchoscopy is generally reserved for patients with progressive or severe symptoms despite treatment.

Our patient’s initial complaint of chest pain upon presentation raised concerns for cardiovascular disease. ECG without any signs of acute ischemia in the setting of a troponin of 0.000 ng/ml was not indicative of acute coronary syndrome. Marginally elevated D-dimer in the setting of worsening hypoxemia and tachycardia was concerning for PE, but CTA was non-significant for any PE or aortic pathology. TTE without pericardial effusion and ECG without PR segment depression or ST segment elevations, ruled out pericarditis. The initial chest CT raised concerns for multifocal pneumonia; however, infectious, and autoimmune workup were negative. Given the patient's history of vaping within the last 90 days, diffuse dense ground glass opacities on CT, absence of infectious etiology and absence of alternative diagnosis, the patient met the CDC Criteria for EVALI and started on treatment. Given the patient's clinical improvement and reduced oxygen requirements while on systemic steroids, flexible bronchoscopy was deferred.

Conclusion

While alternative causes of respiratory illness may be more prevalent, it is important to consider and assess for pulmonary illness associated with vaping, particularly in patients where no other cause can be clearly identified. Patients reporting respiratory complaints as well as gastrointestinal symptoms should be questioned about any recent e-cigarette to assess for possible EVALI given the appropriate clinical scenario, radiographic findings, and absence of pulmonary infectious etiologies and other causes progressive respiratory insufficiency.

References

1. Jonas AM, Raj R. Vaping-Related Acute Parenchymal Lung Injury: A Systematic Review. Chest. 2020 Oct;158(4):1555-1565. [CrossRef] [PubMed]
2. Centers for Disease Control and Prevention (CDC). Outbreak of Lung Injury Associated with the Use of E-Cigarette, or Vaping, Products. https://www.cdc.gov/tobacco/basic_information/e-cigarettes/severe-lung-disease.html#latest-information (Accessed on May 06, 2020).
3. Schier JG, Meiman JG, Layden J, et al. Severe Pulmonary Disease Associated with Electronic-Cigarette-Product Use - Interim Guidance. MMWR Morb Mortal Wkly Rep. 2019 Sep 13;68(36):787-790. [CrossRef] [PubMed]
4. Thota D, Latham E. Case report of electronic cigarettes possibly associated with eosinophilic pneumonitis in a previously healthy active-duty sailor. J Emerg Med. 2014 Jul;47(1):15-7. [CrossRef] [PubMed]
5. Butt YM, Smith ML, Tazelaar HD, et al. Pathology of Vaping-Associated Lung Injury. N Engl J Med. 2019 Oct 31;381(18):1780-1781. [CrossRef] [PubMed]
6. Aberegg SK, Cirulis MM, Maddock SD, Freeman A, Keenan LM, Pirozzi CS, Raman SM, Schroeder J, Mann H, Callahan SJ. Clinical, Bronchoscopic, and Imaging Findings of e-Cigarette, or Vaping, Product Use-Associated Lung Injury Among Patients Treated at an Academic Medical Center. JAMA Netw Open. 2020 Nov 2;3(11):e2019176. [CrossRef] [PubMed]
7. Layden JE, Ghinai I, Pray I, et al. Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin - Final Report. N Engl J Med. 2020 Mar 5;382(10):903-916. [CrossRef] [PubMed]
8. Maddock SD, Cirulis MM, Callahan SJ, Keenan LM, Pirozzi CS, Raman SM, Aberegg SK. Pulmonary Lipid-Laden Macrophages and Vaping. N Engl J Med. 2019 Oct 10;381(15):1488-1489. [CrossRef] [PubMed]
9. Davidson K, Brancato A, Heetderks P, Mansour W, Matheis E, Nario M, Rajagopalan S, Underhill B, Wininger J, Fox D. Outbreak of Electronic-Cigarette-Associated Acute Lipoid Pneumonia - North Carolina, July-August 2019. MMWR Morb Mortal Wkly Rep. 2019 Sep 13;68(36):784-786. [CrossRef] [PubMed]
10. Josef V, Tu G. Case report: the importance of screening for EVALI. Southwest J Pulm Crit Care. 2020;20(3)87-94. [CrossRef]

Cite as: Mahdi AA, Allahverdian C, Shahangian S. Electrotonic-Cigarette or Vaping Product Use Associated Lung Injury: Diagnosis of Exclusion. Southwest J Pulm Crit Care Sleep. 2022;24:96-100. doi: https://doi.org/10.13175/swjpccs026-22 PDF 

June 2022 Pulmonary Case of the Month: A Hard Nut to Crack

Daniel Gergen MD¹

Anne Reihman MD¹

Carolyn Welsh MD^1,2

¹Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Colorado, Aurora, Colorado USA

²Eastern Colorado Veterans Affairs Medical Center, Aurora, Colorado USA

History of Present Illness: A 54-year-old man presented to clinic with chronic cough, dyspnea on exertion, unintentional weight loss, and night sweats. Seven months before, he developed dyspnea on exertion and symptoms did not improve with inhalers. Four months prior to presentation, he was treated for presumed community-acquired pneumonia of the right lower lobe. Neither symptoms nor chest radiograph improved with multiple courses of antibiotics. In the four weeks prior to presentation his symptoms progressed to the point that he was unable to walk in his house without significant dyspnea.

Review of systems: 10-pound unintentional weight loss and six weeks of night sweats.

Past Medical History, Social History and Family History: The patient had a 15-pack-year smoking history and quit 15 years prior to presentation. He had no other past medical history, surgical history, family history, nor medications.

Physical Examination: Vital signs were normal on presentation. Physical exam showed faint wheezing and decreased breath sounds over the right posterior lung fields.

Radiography: Chest radiograph demonstrated dense opacification in the superior segment of the right lower lobe (Figure 1).

Figure 1. Initial chest radiography. A: PA view. B: Lateral view.

What are diagnostic possibilities at this time?

1. Lung abscess
2. Lung cancer
3. Foreign body with post-obstructive pneumonia
4. Tuberculosis
5. 1 and 3
6. All the above

Cite as: Gergen D, Reihman A, Welsh C. June 2022 Pulmonary Case of the Month: A Hard Nut to Crack. Southwest J Pulm Crit Care Sleep. 2022;24(6):89-92. doi: https://doi.org/10.13175/swjpccs024-22 PDF

March 2022 Pulmonary Case of the Month: A Sore Back Leading to Sore Lungs

Lewis J. Wesselius MD¹

Brandon T. Larsen MD PhD²

Departments of ¹Pulmonary Medicine and ²Pathology

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

An 82-year-old woman from Colorado was referred because of progressive shortness of breath over the past year. Her primary care physician had prescribed Trelegy® which did not improve her dyspnea. An outside pulmonologist noted abnormal findings on her thoracic CT scan and a bronchoscopy with bronchoalveolar lavage (BAL) was preformed which was positive for Mycobacterium Avium Complex (MAC). She was treated with a 3-drug regimen (azithromycin, rifampin, ethambutol) for 6 months with mild improvement. After the treatment was stopped, she noted more dyspnea and required supplemental oxygen. She underwent a fundoplication and initially improved but a month later her shortness of breath seemed to worsen. She was started on prednisone which was tapered to 10 mg/day. She was referred to the Mayo Clinic for possible VATS lung biopsy.

Past Medical History (PMH), Social History (SH), Family History (FH)

PMH

• Hiatal Hernia/GERD
• Ulcerative Colitis
• Hypertension
• Chronic Back pain
• Prior breast implants

SH

• Former smoker (24 pack-years, quit 1988)
• Social use of alcohol, no drug use
• No exposure to birds or down
• No occupational dust exposures
• Home humidifier
• Has indoor hot tub used frequently for back pain

FH

• Unremarkable

 Medications

• Prednisone 10 mg daily
• Pantoprazole 40 mg bid
• Pregabalin 25 mg at bedtime
• Oxycodone 5 mg q 6 hours prn pain
• Ondansetron 4 mg tablet q 8hhours prn nausea

Physical examination

• BMI 31.9
• Oxygen saturation at rest 95% on 4 lpm, 88% on RA
• Chest: scattered crackles
• Cardiovascular: regular rate without murmur
• Extremities: no clubbing or edema

Which of the following should be done next? (Click on the correct answer to be directed to the second of seven pages.)

1. Pulmonary function testing
2. Open surgical lung biopsy
3. Review thoracic CT scan
4. 1 and 3
5. All of the above

Cite as: Wesselius LJ, Larsen BT. March 2022 Pulmonary Case of the Month: A Sore Back Leading to Sore Lungs. Southwest J Pulm Crit Care Sleep. 2022;24(3):36-39. doi: https://doi.org/10.13175/swjpccs011-22 PDF 

Diagnostic Challenges of Acute Eosinophilic Pneumonia Post Naltrexone Injection Presenting During The COVID-19 Pandemic

Michelle Breuer

Abdulmonam Ali, MD

SSM Health

Mount Vernon, IL USA

Introduction

Acute eosinophilic pneumonia (AEP) is a rare respiratory illness that may present with nonspecific symptoms ranging in severity from cough and dyspnea to potentially fatal acute respiratory distress syndrome. Although the exact etiology of AEP is unknown, it is thought to be a hypersensitivity reaction that can be idiopathic or caused by various infections, inhalation exposures, and medications (1).  Here we present a rare case of AEP secondary to injectable naltrexone.

Case Presentation

A 45-year-old Caucasian male with a history of alcohol use disorder presented to the emergency room with a 3-day history of progressively worsening dyspnea and dry cough. The patient was a lifelong non-smoker with an unremarkable past medical history aside from alcohol abuse and obesity (BMI 41.64 kg/m²). He denied fever or chills, orthopnea, chest pain, or symptoms suggestive of paroxysmal nocturnal dyspnea. He also denied any recent sick contacts, including exposure to COVID-19. Relevant history includes alcohol cessation 1 month before presentation. After 2 weeks of cessation, he received his first injection of naltrexone (Vivitrol®) as part of alcohol relapse prevention. Physical exam was notable for an initial SpO₂ of 69% on room air, sinus tachycardia at a rate of 121 bpm, and obesity. Chest examination exhibited decreased air entry with bilateral fine crackles on auscultation. No skin rashes or peripheral edema were appreciated, and the remaining physical exam was within normal limits. The patient was started on supplemental oxygen (6 liters/minute nasal cannula to maintain SpO2 above 90%).

Workup was performed and chest x-ray showed diffuse bilateral pulmonary infiltrates (Figure 1), hence, the patient was started on empiric antibiotic and steroid therapy.

Figure 1. Chest X-ray showing bilateral ground-glass opacities.

SARS-CoV-2 PCR testing was performed twice due to high clinical suspicion of COVID-19 infection (the patient was seen during the Coronavirus pandemic). Both SARS-CoV-2 tests were negative as well as the rest of the respiratory viral panel. CBC was significant for leukocytosis with an absolute peripheral eosinophil count of 0.49 x 10⁹ cells/L. Bloodwork also revealed mildly elevated troponin, d-dimer, and LDH. However, electrocardiogram showed no significant ST changes and Computerized Tomography (CT) angiography chest showed no evidence of pulmonary embolism but confirmed the chest x-ray findings of diffuse bilateral ground-glass opacities with anterolateral subpleural parenchymal sparing (Figure 2).

Figure 2. CTA chest (axial view, lung window) showing diffuse ground-glass opacities.

An echocardiogram showed an ejection fraction of 60% and normal left ventricular diastolic function. Moderate right ventricular (RV) dilation with reduced systolic function was reported and the peak RV pressure was estimated at 39 mmHg. Extensive blood testing for connective tissue disease was negative for ANCA, CCP, ANA, and cryoglobulins. Immunoglobulin E (IgE) level was within normal limits at 14KU/L (reference range < 214 KU/L).  Infectious disease serology was negative for mycoplasma, strongyloides, coccidioides, and aspergillus. HIV and hepatitis screening were also negative. Bronchoscopy with bronchoalveolar lavage (BAL) was performed and was significant for 27% eosinophils, 42% lymphocytes, 25% monocytes, 6% neutrophils (Figure 3).

Figure 3. Bronchoalveolar lavage (BAL) showing increased numbers of eosinophils.

BAL culture remained negative including mycobacterial and fungal cultures. BAL testing for Pneumocystis Jirovecii was negative as well. BAL cytology showed benign bronchial epithelial cells and inflammatory cells. No parasites were seen in BAL and fungal staining was negative.

The constellation of the above clinical, radiological, and laboratory findings was highly suggestive of acute eosinophilic pneumonia diagnosis. The patient’s methylprednisolone dose was increased to 125mg every 8 hours. Due to high FiO2 requirements and poor pulmonary reserve, the patient remained intubated after his bronchoscopy procedure. Over the following 48 hours, FiO₂ requirements improved significantly and his repeat chest x-ray showed almost complete resolution of the pulmonary infiltrates. The patient was successfully extubated to 2 liters of oxygen via nasal cannula on the third day.  Supplemental oxygen was eventually weaned off to room air. There wasn’t significant desaturation observed with the exercise trial. He was discharged home on a gradually tapering dose of oral steroids over 6 weeks. The patient was later seen at the pulmonary clinic for a follow-up visit. He was doing well and denied any significant respiratory symptoms. A follow-up chest x-ray was within normal limits (Figure 4).

Figure 4. Chest x-ray upon follow-up.

Discussion 

Acute eosinophilic pneumonia (AEP) is defined by rapid eosinophilic infiltration of the lung tissue, resulting in impaired gas exchange. Presenting symptoms are nonspecific and may include cough, progressive dyspnea, chest pain, and fever (2). Chest imaging of patients with AEP shows diffuse bilateral parenchymal infiltrates. Diagnosis can be made in the appropriate clinical and radiological context, with BAL showing at least 25% eosinophils on the fluid differential, and with no other identifiable causes (1).

The pathogenesis of AEP is not completely understood; however, it is hypothesized to involve a hypersensitivity reaction in patients with genetic susceptibility (3,4). AEP can be associated with many identifiable causes including cigarette smoke most notably, as well as other inhalants, infections, and medications. Although antibiotics and nonsteroidal anti-inflammatory drugs are among the more common inciting medications, injectable naltrexone has been implicated in several case reports (3,5,6,7).

The clinical presentations of AEP can mimic SARS-CoV-2 pneumonia, community-acquired pneumonia, or ARDS; hence, a high index of clinical suspicion is essential to avoid delay in therapy. A confident diagnosis of AEP can usually be made without a lung biopsy in patients who meet the following criteria (8):

1) acute onset of febrile respiratory manifestations (≤ 1-month duration before consultation).

2) bilateral diffuse opacities on chest radiography.

3) hypoxemia, with PaO₂ on room air<60 mm Hg, and/or PaO₂/FiO₂≤300 mm Hg, and/or oxygen saturation on room air<90%.4) lung eosinophilia, with >25% eosinophils on BAL differential cell count (or eosinophilic pneumonia at lung biopsy).

5) absence of known causes of AEP, including drugs, infections, asthma, or atopic disease.

In our case, the patient has met most of the suggested criteria for diagnosing AEP in addition to the presence of a triggering factor (a clear temporal relationship between the development of symptoms and the recent naltrexone injection). However, we met with a few obstacles before making the diagnosis of AEP.  During these unprecedented times, any patient presenting with acute hypoxic respiratory failure, and/or ground-glass opacities (both are classic for SARS-CoV-2 pneumonia as well as AEP) must go through an additional screening process to rule out COVID-19, including contact and airborne infection isolation precautions in addition to the standard precautions and SARS-CoV-2 PCR testing.  

On the other hand, several recent reports of AEP presumably triggered by SARS-CoV-2 infection had been described (9-10), which was another factor that contributed to making the diagnosis of AEP more challenging in his case and kept COVID-19 high on the differential diagnosis list. Furthermore, our patient received steroids on the initial presentation which likely affected the accuracy of the total eosinophilic counts in the BAL.

AEP has a higher likelihood than chronic eosinophil pneumonia of presenting with more severe symptoms and has a greater potential of rapid progression to respiratory failure. One review study reported 30-80% of AEP patients required intensive care unit admission and another case review noted 20% of AEP patients required mechanical ventilation (4,11). Treatment includes supportive care, recognition and avoidance of identifiable triggers, and systemic corticosteroids. Most patients rapidly improve with prompt corticosteroid treatment and experience complete recovery (1,3). Relapse of AEP rarely occurs (4).

Numerous conditions can cause pulmonary eosinophilia that needs to be differentiated from AEP. Different classifications have been suggested, but we will list the broad categories and most common etiologies including chronic eosinophilic pneumonia, eosinophilic granulomatosis with polyangiitis (EGPA, previously known as Churg-Strauss), drug and toxin-induced eosinophilic lung disease, helminthic, and fungal infection-related eosinophilic lung diseases, idiopathic hypereosinophilic syndrome, neoplasms, interstitial lung disease, coccidioidomycosis, tuberculosis, and allergic bronchopulmonary aspergillosis.

In addition to AEP, several conditions are associated with elevated BAL eosinophils greater than 25%.  These conditions include chronic eosinophilic pneumonia, EGPA, tropical pulmonary eosinophilia.  Other conditions causing BAL eosinophilia, but less than 25%, include connective tissue disease, drug-induced pneumonitis, fungal pneumonia, idiopathic pulmonary fibrosis, pulmonary Langerhans cell histiocytosis, sarcoidosis.

Finally, multiple medications are implicated in drug-induced AEP, however, naltrexone is still not well recognized as a potential cause.  In a recent retrospective review, naltrexone was not included in the medication list compiled (11).

Conclusion

Injectable naltrexone, a long-acting opioid antagonist, is used for the treatment of opioid and alcohol dependence. Although rare, the use of injectable naltrexone is associated with the potentially fatal side effect of AEP. Since AEP shares many clinical attributes with other causes of acute lung injury, including community-acquired pneumonia and SARS-CoV-2 pneumonia, it can be easily overlooked. Therefore, having an accurate history and an appropriate index of suspicion is important for early detection and proper management (3).

References

1. De Giacomi F, Vassallo R, Yi ES, Ryu JH. Acute Eosinophilic Pneumonia. Causes, Diagnosis, and Management. Am J Respir Crit Care Med. 2018 Mar 15;197(6):728-736. [CrossRef] [PubMed]
2. Katz U, Shoenfeld Y. Pulmonary eosinophilia. Clin Rev Allergy Immunol. 2008 Jun;34(3):367-71. [CrossRef] [PubMed]
3. Mears M, McCoy K, Qiao X. Eosinophilic Pneumonia and Extended-Release Injectable Naltrexone. Chest. 2021;160(4): A1676 [Abstract]. [CrossRef]
4. Suzuki Y, Suda T. Eosinophilic pneumonia: A review of the previous literature, causes, diagnosis, and management. Allergol Int. 2019 Oct;68(4):413-419. [CrossRef] [PubMed]
5. Horsley R, Wesselius LJ. June 2107 Pulmonary Case of the Month. Southwest J Pulm Crit Care. 2017;14(6):255-61. [CrossRef]  
6. Esposito A, Lau B. Saved by the BAL: A Case of Acute Eosinophilic Pneumonia After Methyl-Naltrexone Injection. Chest. 2019;156(4):A2210 [Abstract]. [CrossRef]
7. Korpole PR, Al-Bacha S, Hamadeh S. A Case for Biopsy: Injectable Naltrexone-Induced Acute Eosinophilic Pneumonia. Cureus. 2020 Sep 3;12(9):e10221. [CrossRef] [PubMed]
8. Philit F, Etienne-Mastroïanni B, Parrot A, Guérin C, Robert D, Cordier JF. Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med. 2002 Nov 1;166(9):1235-9. [CrossRef] [PubMed]
9. Araújo M, Correia S, Lima AL, Costa M, Neves I. SARS-CoV-2 as a trigger of eosinophilic pneumonia. Pulmonology. 2022 Jan-Feb;28(1):62-64. [CrossRef] [PubMed]
10. Murao K, Saito A, Kuronuma K, Fujiya Y, Takahashi S, Chiba H. Acute eosinophilic pneumonia accompanied with COVID-19: a case report. Respirol Case Rep. 2020 Nov 16;8(9):e00683. [CrossRef] [PubMed]
11. Bartal C, Sagy I, Barski L. Drug-induced eosinophilic pneumonia: A review of 196 case reports. Medicine (Baltimore). 2018 Jan;97(4):e9688. [CrossRef] [PubMed]
12. Salahuddin M, Anjum F, Cherian SV. Pulmonary Eosinophilia. 2021 Dec 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. [PubMed]

Cite as: Breuer M, Ali A. Diagnostic Challenges of Acute Eosinophilic Pneumonia Post Naltrexone Injection Presenting During The COVID-19 Pandemic. Southwest J Pulm Crit Care Sleep. 2022;24(2):26-31. doi: https://doi.org/10.13175/swjpccs002-22 PDF 

Symptomatic Improvement in Cicatricial Pemphigoid of the Trachea Achieved with Laser Ablation Bronchoscopy

Elizabeth Benge MD¹, Vincent Tran MD², Nazanin Sheikhan MD¹, Sapna Bhatia MD³, Yi McWhorter DO⁴, John Collier MD³, Arnold Chung MD⁵

Departments of ¹Internal Medicine, ²Surgery, ³Pulmonology, ⁴Anesthesiology/Critical Care Medicine, and ⁵MountainView Cardiovascular and Thoracic Surgery Associates

HCA Healthcare MountainView Hospital 

Las Vegas, NV, USA 

Abstract

Cicatricial pemphigoid (CP) with tracheal involvement is a rare and potentially deadly condition. Here, we report the first case in which Nd:YAG laser (1064nm) laser ablation bronchoscopy was used to treat CP with tracheal involvement. Our patient is a 71-year-old male with a history of CP refractory to medical therapy affecting his trachea who presented to the emergency department with dyspnea. He ultimately underwent bronchoscopy with Nd: YAG laser (1064nm) laser ablation, which resulted in a temporary alleviation of his respiratory symptoms. A repeat laser ablation was planned in hopes of prolonging the patient’s remission, but due to interval changes in the patient’s airway anatomy, it was deemed unsafe. While our patient’s uniquely advanced disease was not amenable to further laser-mediated intervention, it is possible that patients with less advanced disease may experience better outcomes with similar therapy. This case shows the promise laser ablation could hold for patients with tracheal cicatricial pemphigoid.

Introduction

Cicatricial pemphigoid (CP) is a diverse group of subepithelial blistering disorders of the skin and mucous membranes (1,2). Tracheal involvement is a rare and deadly sequela of this disease class (3). We report the first case in which Nd:YAG laser (1064nm) laser ablation bronchoscopy was used as a treatment for CP with tracheal involvement. Of note, the terms cicatricial pemphigoid and mucous membrane pemphigoid are synonymous and are used interchangeably throughout this report.

Case Presentation

Our patient is a 71-year-old man with a history of CP affecting his left eye and trachea who presented to the emergency department with progressively worsening dyspnea.

The patient has a history of multiple bronchoscopies; the most recent one showed tracheal pemphigoid lesions partially obstructing his airway. His diagnosis of cicatricial pemphigoid had been made over fifteen years prior to the current presentation via biopsy and subsequent immunofluorescence staining. On admission, his respiratory rate was 21 breaths/min and his oxygen saturation was 97% on 50% Bipap: 14/8. He was admitted to the intensive care unit for evaluation and management of his acute hypoxic respiratory failure.

Initially, a fiberoptic bronchoscopy was performed under laryngeal mask airway (LMA) general anesthesia. Dense, dark-colored lesions were noted to be occluding most of the trachea, consistent with the patient’s history of tracheal CP (Figure 1).

Figure 1. Patient’s trachea demonstrating heavy burden of cicatricial pemphigoid lesions prior to any intervention

They were partially removed in a piecemeal manner with forceps instrumentation. After this procedure, the patient still required supplemental oxygen, oscillating between BiPAP and nasal cannula. Two days later, he was started on rituximab, which he had also received during previous relapses.

On hospital day four, our cardiothoracic surgery team performed bronchoscopy with laser ablation under LMA general anesthesia. After the procedure, the patient’s tracheal lesions had markedly decreased in size (Figure 2).

Figure 2. Patient’s trachea with reduced lesions status-post bronchoscopy with laser ablation.

He was also entirely weaned off supplemental oxygen.

In the following weeks, the patient’s symptom burden was significantly decreased. He reported an improvement in his quality of life and satisfaction with the procedure. A subsequent repeat laser ablation was planned at the three-month mark. This procedure was more technically challenging due to airway-narrowing caused by an increase in scar tissue from the initial laser ablation. Due to the risks imposed by the interval changes in the patient’s anatomy, we decided against further laser therapy. In the absence of laser treatments, the patient’s tracheal pemphigoid recurred and symptoms returned to their prior state. He currently receives interval fiberoptic bronchoscopies to partially remove his lesions when they threaten his airway.

Discussion 

In a study involving subjects with aggressive ocular CP, 81% of patients achieved clinical remission with rituximab therapy (4). Medical therapy had repeatedly failed to reduce our patient’s symptoms, making his case unique in both its rarity and refractory nature. With no other options, our team developed an innovative treatment modality in an attempt to offer our patient some symptomatic relief.

Previous case reports have shown the utility of low-level laser therapy in mucous membranous lesions (5-7). One study showed successful resection of an obstructive mass caused by CP and restoration of airway patency using a Holmium LASER (2100nm) (8-9). We decided to ablate/resect the inflammatory tissue using an Nd:YAG LASER (1064nm) given its medium penetration length (1-4mm), coagulopathic ability (high heme absorption), and decreased tissue destruction when compared to the Ho:YAG laser; which has a higher laser absorption coefficient with water.

To our knowledge, this is the first case report of successful treatment of cicatricial pemphigoid with Nd:YAG laser (1064nm) ablation therapy. This procedure resulted in immediate, although ultimately impermanent, improvement in our patient’s respiratory insufficiency. Our patient also reported an improved quality of life during the period of time the laser ablation therapy offered him symptomatic relief. He was able to attend his grandchildren’s’ soccer games and walk to the end of his driveway to get his newspaper, activities he had not be able to participate in for years.

While our patient’s improvement was temporary, his disease process was uniquely advanced. It is possible that patients with less advanced disease may experience longer periods of remission with laser-mediated therapy, or may be able to tolerate repeated laser ablation procedures. Importantly, our patient’s case demonstrates that laser therapy can significantly reduce the burden of pemphigoid lesions, and can lead to a better quality of life for a disease process with few alternative treatment modalities.

Conclusion 

Therapeutic fiberoptic bronchoscopy with laser ablation is a promising treatment for patients suffering from CP of the trachea. Future investigations should focus on optimizing the laser ablation technique to achieve safe and sustained results.

References

1. Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am Acad Dermatol. 2000 Oct;43(4):571-91. [CrossRef] [PubMed]
2. Minaie A, Surani SR. Mucous Membrane Pemphigoid with Tracheal Involvement. Case Rep Pulmonol. 2016;2016:5749784. [CrossRef] [PubMed]
3. Kato K, Moriyama Y, Saito H, Koga H, Hashimoto T. A case of mucous membrane pemphigoid involving the trachea and bronchus with autoantibodies to β3 subunit of laminin-332. Acta Derm Venereol. 2014 Mar;94(2):237-8. [CrossRef] [PubMed]
4. You C, Lamba N, Lasave AF, Ma L, Diaz MH, Foster CS. Rituximab in the treatment of ocular cicatricial pemphigoid: a retrospective cohort study. Graefes Arch Clin Exp Ophthalmol. 2017 Jun;255(6):1221-1228. [CrossRef] [PubMed]
5. Oliveira PC, Reis Junior JA, Lacerda JA, Silveira NT, Santos JM, Vitale MC, Pinheiro AL. Laser light may improve the symptoms of oral lesions of cicatricial pemphigoid: a case report. Photomed Laser Surg. 2009 Oct;27(5):825-8. [CrossRef] [PubMed]
6. Yilmaz HG, Kusakci-Seker B, Bayindir H, Tözüm TF. Low-level laser therapy in the treatment of mucous membrane pemphigoid: a promising procedure. J Periodontol. 2010 Aug;81(8):1226-30. [CrossRef] [PubMed]
7. Minicucci EM, Miot HA, Barraviera SR, Almeida-Lopes L. Low-level laser therapy on the treatment of oral and cutaneous pemphigus vulgaris: case report. Lasers Med Sci. 2012 Sep;27(5):1103-6. [CrossRef] [PubMed]
8. Jalil BA, Abdou YG, Rosen SA, Dammad T. Mucous Membrane Pemphigoid Causing Central Airway Obstruction. J Bronchology Interv Pulmonol. 2017 Oct;24(4):334-338. [CrossRef] [PubMed]
9. Benge E, Yamaguchi L, Tran V, Sheikhan N, Bhatia S, Mcwhorter Y, Collier J, Chung A. Successful Treatment of Cicatricial Pemphigoid of the Trachea with Laser Ablation Bronchoscopy. Chest. 2021 Oct 1;160(4):A1999-2000 [Abstract]. [CrossRef]

Abbreviations

• Bipap: bilevel positive airway pressure
• CP: cicatricial pemphigoid
• Ho:YAG: holmium-doped yttrium aluminum garnet
• Laser: light amplification by stimulated emission of radiation
• LMA: laryngeal mask airway
• Nd:YAG: neodymium-doped yttrium aluminum garnet

Disclosures

Conflicts of Interest: The above listed authors have no conflicts of interest to declare.
Funding: This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.
This case was presented at the CHEST Annual Meeting that took place from Oct 17, 2021 – Oct 20, 2021 in a virtual format.

Cite as: Benge E, Tran V, Sheikhan N, Bhatia S, McWhorter Y, Collier J, Chung A. Symptomatic Improvement in Cicatricial Pemphigoid of the Trachea Achieved with Laser Ablation Bronchoscopy. Southwest J Pulm Crit Care. 2022;24(1):8-11. doi: https://doi.org/10.13175/swjpcc058-21 PDF