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 

March 2021 Pulmonary Case of the Month: Transfer for ECMO Evaluation

Nicholas G. Blackstone, MD

April Olson, MD

Angela Gibbs, MD

Bhupinder Natt, MD

Janet Campion, MD

University of Arizona College of Medicine – Tucson

Tucson, AZ USA

History of present illness

A 31-year-old male fire fighter with a history of recurrent “atypical pneumonia”, environmental and drug allergies, nasal polyps, asthma, and Crohns disease (not on immunosuppressants) was transferred from an outside hospital for management of acute hypoxic respiratory failure with peripheral eosinophilia. Prior to admission he reported a 2-week history of worsening dyspnea, productive cough and wheezing, prompting an urgent care visit where he was prescribed amoxicillin-clavulanate for suspected community acquired pneumonia. Despite multiple days on this medication, his symptoms significantly worsened until he was unable to lie flat without coughing or wheezing. He was ultimately admitted to an outside hospital where his labs were notable for a leukocytosis to 22,000 and peripheral eosinophilia with an absolute eosinophil count of 9700 cells/microL. His blood cultures and urine cultures were negative, and a radiograph of the chest demonstrated bilateral nodular infiltrates. With these imaging findings combined with the peripheral eosinophilia there was a concern for Coccidioidomycosis infection and he was subsequentially started on empirical fluconazole in addition to ceftriaxone and azithromycin. Bronchoalveolar lavage (BAL) was performed revealing 80% eosinophils, 14% polymorphic nuclear cells (PMNs), 4% monocytes and 2% lymphocytes, no pathogens were identified. The patient’s clinical status continued to decline despite antimicrobial therapy, and he was intubated for refractory hypoxia. At this point, the patient was transferred to our hospital for further care.

What is the most likely diagnosis in this patient? (Click on the correct answer to be directed to the second of four pages.)

1. Acute asthma exacerbation
2. Bacterial pneumonia
3. Coccidioidomycosis pneumonia
4. Eosinophilic pneumonia
5. Rocky Mountain Spotted Fever

Cite as: Blackstone NG, Olson A, Gibbs A, Natt B, Campion J. March 2021 Pulmonary Case of the Month: Transfer for ECMO Evaluation. Southwest J Pulm Crit Care. 2021;22(3):69-75. doi: https://doi.org/10.13175/swjpcc069-20 PDF

June 2017 Pulmonary Case of the Month

Robert Horsley, MD

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ USA

History of Present Illness

A 61-year-old woman presented to the emergency department for 3 days of fevers up to 102º F, malaise, and progressive shortness of breath. Her symptoms started immediately after he last naltrexone injection for alcohol use disorder.

Past Medical History, Social History and Family History

• Alcohol use disorder
• Treated with monthly naltrexone injections, received 3 doses total, and gabapentin
• No other previous medical issues
• Nonsmoker

Physical Examination

• Vital signs: Pulse 100, BP 108/90, respiratory rate 34, SpO2 93% 10L non-rebreathing mask
• Cyanotic on room air
• Lungs clear

Radiography

A portable chest x-ray was performed in the emergency department (Figure 1).

Figure 1. AP chest radiograph taken in the emergency department.

A thoracic CT scan was performed (Figure 2).

Figure 2. Representative images from thoracic CT in lung windows.

Laboratory

• CBC showed a white blood cell count of 12,000 cells/mcL.
• The differential showed a left shift.
• Lactate was 5.2 mmol/L

Which of the following is (are) true? (Click on the correct answer to proceed to the second of five pages)

1. A lactate level of 5.2 can be a normal finding in a critically ill patient
2. Her symptoms are likely an allergic reaction to naltrexone
3. The most likely diagnosis is an atypical pneumonia
4. 1 and 3
5. All of the above

Cite as: Horsley R, Wesselius LJ. June 2107 pulmonary case of the month. Southwest J Pulm Crit Care. 2017;14(6):255-61. doi: https://doi.org/10.13175/swjpcc063-17 PDF

August 2012 Pulmonary Case of the Month

All Eosinophilia Is Not Asthma

Lewis J. Wesselius, MD

Departments of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 73 year old man was seen with a one month history of shortness of breath. He dated this to an emergency room visit for an arm injury for which he had a DPT vaccination. Previously, he had been able to swim regularly, but he is now unable to swim due to worsening dyspnea. He also had some cough that was nonproductive.

PMH, SH and FH

He has a past medical history of coronary artery disease with prior stenting of his right and left anterior descending artery in 2010. He also has a history of hypertension, dysplipidemia, a carotid endarterectomy and a single seizure after a corneal transplant.

His present medications include:

• Atorvastatin
• Lisinopril
• Metoprolol
• Warfarin

He has a minimal smoking history and denied use of alcohol, drugs or unusual exposures. 

Physical Examination

His vitals signs were normal and he was afebrile but he was receiving supplemental oxygen at 3 lpm.

Chest examination revealed bilateral crackles but no wheezes.

Cardiovascular examination showed a regular rhythm with a Grade 2/6 systolic ejection murmur.

He had no clubbing or edema.

The remainder of the physical examination was either normal or noncontributory.

Chest X-ray

His admission chest x-ray is shown in Figure 1.

 Figure 1. Admission chest x-ray showing the PA (Panel A) and lateral (Panel B).

Which of the following are possible causes of the patient’s clinical picture?

1. Coccidioidomycosis (Valley Fever)
2. Allergic reaction to the DPT vaccination
3. Pulmonary edema
4. A + C
5. All of the above

Reference as: Wesselius LJ. August 2012 pulmonary case of the month: all eosinophilia is not asthma. Southwest J Pulm Crit Care 2012;5:58-64. (Click here for a PDF version of the case presentation)