From Medication to Complication: A Case Report of Acute Eosinophilic Pneumonia Associated With Naltrexone

ABSTRACT

Naltrexone, increasingly used for substance use disorders, can induce acute eosinophilic pneumonia. Prompt recognition through exclusion of other causes and early corticosteroid initiation can ensure rapid improvement and prevent severe complications.

1. Introduction

Acute eosinophilic pneumonia (AEP) is a rare and potentially severe respiratory illness that can result in acute respiratory distress syndrome and death [1]. AEP was first recognized as a distinct clinical condition in 1989 and is marked by symptoms such as acute fever, diffuse pulmonary infiltrates, and respiratory failure [1]. It is characterized by the presence of eosinophils in bronchoalveolar lavage (BAL) fluid and typically responds well to treatment with corticosteroids [2]. Although initially believed to be of unknown origin, AEP can be seen more commonly among deployed military personnel, smokers, or those exposed to environmental hazards including inhaled dust [2, 3, 4, 5]. Notably, it has been linked to a wide range of medications, including antibiotics, antiepileptics, and nonsteroidal anti‐inflammatory drugs (NSAIDs) [1, 6]. However, cases of naltrexone‐induced AEP remain poorly documented in the literature, highlighting the rarity of this specific association. We present the case of a 36‐year‐old female diagnosed with AEP who was receiving intramuscular (IM) naltrexone injections for alcohol use disorder.

2. Case History/Examination

A 36‐year‐old woman with a past medical history of obesity status post sleeve gastrectomy, diverticulitis status post partial colectomy, hyperlipidemia, psoriasis, and alcohol use disorder presented to the emergency department with a 1‐week history of shortness of breath. She had recently recovered from an upper respiratory infection that she attributed to caring for her sick child at home. A few days prior to her presentation, she started experiencing fatigue and shortness of breath, which limited her ability to perform basic tasks, such as walking a few blocks. When symptoms became intolerable, she presented to an urgent care, where she was noted to be tachypneic with use of accessory muscles and had an SpO₂ of 90% on room air. She improved with 3 L of supplemental oxygen via nasal cannula and was sent to the emergency department for further evaluation.

She denied similar prior symptoms and had no history of asthma or chronic lung disease. She had been previously vaccinated against COVID‐19, but neither she nor her daughter had been recently tested for COVID‐19. She reported associated symptoms over the last week, including orthopnea, decreased oral intake, and constipation. Review of systems was otherwise negative for fever, chills, chest pain, nausea, vomiting, diarrhea, hematochezia, hematuria, rash, or syncope.

In terms of her medical and social history, she had started naltrexone IM injections for her alcohol use disorder a month prior and received her second injection a day prior to admission. She had previously been drinking 0.5–1 gal of vodka per day and reported that her last drink was 20 days prior to presentation. Her other medications included atorvastatin, bupropion, fenofibrate, and clonidine. She was previously on apremilast for psoriasis; however, this had been discontinued, and she was using topical treatment only at the time of presentation. Other past surgical history was notable for hernia surgery and cesarean section. The patient lived at home with her 2‐year‐old daughter. She has no history of tobacco or illicit drug use.

Upon presentation to the emergency department, she was afebrile, heart rate 96 beats per minute, BP 119/89, and SpO₂ 98% on 3 L supplemental O₂ via nasal cannula. General exam revealed a young woman in no acute distress. Cardiac examination was significant for tachycardia and a regular rhythm without murmurs. Upon respiratory examination, she was breathing comfortably on 3 L O₂ by nasal cannula, coughing, and in distress with movement with decreased breath sounds in bilateral lung fields. Abdominal exam was significant for an obese abdomen that was soft, nontender, and nondistended. There was no lower extremity edema, and her skin was warm and dry.

3. Differential Diagnosis, Investigations and Treatment

Laboratory testing on admission showed: WBC 20.05/mm³ (7.0% eosinophils), ESR 14.87 mm/h, COVID PCR negative, Anion gap 18 with HCO₃ ⁻ of 16. The patient's lab values on admission to the ED are summarized in Table 1. CT pulmonary angiography, as shown in Figure 1, revealed no pulmonary embolism but did reveal diffuse bilateral ground glass opacities in the upper lobes and lower lobes with subpleural and anterior sparing.

TABLE 1.

Admission laboratory results of the patient.

Lab	Value	Normal range
Sodium	137 mmol/L	136–145 mmol/L
Potassium	4.0 mmol/L	3.5–5.1 mmol/L
Chloride	101 mmol/L	98–107 mmol/L
Bicarbonate	18 mmol/L	22–29 mmol/L
BUN	11 mg/dL	10–20 mg/dL
Creatinine	0.83 mg/dL	0.3–1.5 mg/dL
Glucose	115 mg/dL	82–115 mg/dL
AST	39 U/L	5–34 U/L
ALT	43 U/L	0–55 U/L
ALP	48 U/L	40–150 U/L
Magnesium	1.7 mg/dL	1.6–2.6 mg/dL
Phosphorus	3.1 mg/dL	2.3–4.7 mg/dL
WBC	17.03 × 103/μL	4–11 × 103/μL
Hemoglobin	17.6 g/dL	12–15.5 g/dL
Hematocrit	49.5%	36%–46%
MCV	87.8 fL	80–100 fL
Platelets	356 × 103/μL	135–430 × 103/μL
Neutrophils	11.67 × 103/μL	2.00–7.00 × 103/μL
Lymphocytes	2.32 × 103/μL	1.5–4.00 × 103/μL
Monocytes	1.35 × 103/μL	0.20–0.80 × 103/μL
Basophils	0.05 × 103/μL	0.00–0.20 × 103/μL
Eosinophils absolute	1.50 × 103/μL	0–0.5 × 103/μL
Immature granulocytes	0.14 × 103/μL	0.01–0.03 × 103/μL
ESR	17	0–20
CRP	14.87	< 0.50

FIGURE 1.

Patient CT chest scan revealing bilateral infiltrates in lungs.

The patient was admitted to the internal medicine service for workup of acute hypoxic respiratory failure. The differential diagnosis for her respiratory failure initially included multifocal or atypical pneumonia, autoimmune pneumonitis, aspergillus pneumonia, endemic mycoses, parasitic infection, and drug‐induced lung injury. She was initially treated with a 5‐day course of ceftriaxone and azithromycin for presumed community‐acquired pneumonia. Infectious and autoimmune workup, including blood cultures, sputum cultures, respiratory viral panel, ANA, and ANCA, were negative. CBC with differential was trended, which showed her absolute eosinophil count increased from 1.50 to 2.52 (normal range 0–0.50) over the first three days of admission. Pulmonology was consulted, and she underwent bronchoscopy. BAL was performed on the right lung upper lobe and was sent to cytopathology. ThinPrep with Papanicolaou stain and cell block with H&E stain revealed many eosinophils present in a background of macrophages and neutrophils (Figure 2). Grocott's methenamine silver stain was negative for Pneumocystis jirovecii organisms. Immunohistochemical stain for herpes simplex virus was also negative. Her peripheral eosinophilia and BAL results were most consistent with AEP thought to be secondary to naltrexone or an autoimmune process. On hospital Day 6, she was started on a prednisone taper beginning with 40 mg daily for 7 days, followed by 30 mg daily for 7 days, 20 mg daily for 7 days, and finally, 10 mg daily for 7 days for AEP.

FIGURE 2.

Lung right upper lobe bronchoalveolar lavage (BAL) specimen. ThinPrep with Papanicolaou stain (A) and cell block with H&E stain (B) of BAL show eosinophils (arrows) present in a background of macrophages, neutrophils, and benign bronchial epithelial cells. Magnification, 600×.

4. Conclusion and Results

After being treated with prednisone for 2 days, her symptoms had significantly improved, and she was able to be weaned off supplemental oxygen. Addiction medicine was consulted during admission, and naltrexone was discontinued. She was then started on acamprosate 666 mg three times daily for her alcohol use disorder. She was discharged home on hospital Day 8 and told to continue tapering down her steroids by 10 mg weekly for the subsequent 4 weeks. A repeat CT of the chest was ordered for after completion of the steroid taper. Unfortunately, the patient was lost to follow up, and the CT chest was not obtained.

5. Discussion

AEP cases have been reported worldwide; however, the exact pathophysiology remains unknown. Some suggest it is related to an acute hypersensitivity reaction to an unidentified inhaled antigen in an otherwise healthy individual [1]. Cases have been reported of patients inhaling irritants, including a firefighter involved in the World Trade Center collapse, a young smoker after consecutive exposure to fireworks, patients with recent cigarette smoking, electronic cigarette, or water pipe use, and military personnel exposed to sand and dust [3, 4, 5]. Cases have also been described in patients with HIV following the use of inhaled cocaine or heroin, as well as cases possibly triggered by COVID‐19 infection [7, 8, 9, 10].

Several medications have also been demonstrated to induce AEP. While NSAIDs and antibiotics have traditionally been implicated in drug‐induced AEP, injectable naltrexone has been described in several instances [11, 12, 13, 14, 15]. IM naltrexone is an extended release opioid antagonist used to treat opiate and alcohol dependence. Since AEP has several of the same clinical presentations as other acute lung injuries, such as community‐acquired and COVID‐19 pneumonia, the diagnosis can be routinely missed. Accordingly, given the increasing use of naltrexone, obtaining a detailed history is paramount for recognizing the noninfectious etiology of AEP. In patients with AEP who underwent lung biopsies, histopathology revealed abnormalities in over 75% of the surface area of the lung tissue, including acute and organizing diffuse alveolar damage, hyaline membranes with interstitial widening, and interstitial alveolar eosinophils [16].

The clinical presentation is generally an acute illness, with the most common symptoms being a nonproductive cough, dyspnea, and fever in almost every patient. Other associated symptoms often include malaise, myalgias, night sweats, chills, and pleuritic chest pain. Lab values are generally significant for neutrophilic leukocytosis with an initially normal eosinophil count. ESR, CRP, and IgE are generally elevated. Initial steps in evaluation should include a thorough medication reconciliation to assess for offending agents associated with AEP. Evaluation should also assess for previous irradiation of the chest, travel, or exposure to parasites or fungi.

This case underscores the importance of sustaining a wide diagnostic lens, particularly when medications potentially underpin acute lung injury. The initial differential diagnosis was broad, including infectious, autoimmune, and iatrogenic causes. Additionally, because our patient did not improve with the use of antibiotics, we had to keep more rare noninfectious etiologies in mind. With a negative autoimmune and infectious workup, medication induced AEP was highest on the differential. Pulmonology ultimately concluded that naltrexone was the most likely associated factor due to her recent injection of this medication just prior to her symptoms. While this was mostly a diagnosis of exclusion, AEP does have specific diagnosis criteria [1, 2]. These include the following:

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 mmHg, and/or PaO2/FiO2 ≤ 300 mmHg, 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 infection or of other known causes of eosinophilic lung disease (especially exposure to a drug susceptible to induce pulmonary eosinophilia).

Our patient displayed three out of five of the above criteria, as she did not present with a fever, and her oxygen saturation on room air was equal to 90% rather than being below 90%. While she did not have a fever on presentation to the emergency department, it is possible she had an unrecognized fever in the days prior to admission. This is important to consider, as not all patients will present immediately upon onset of symptoms. While the patient's delay in seeking medical attention is unclear, it may have been due to attributing her symptoms to an unresolved upper respiratory infection. Additionally, barriers to care, such as being a single mother with significant time constraints from work, could have played a role. She ultimately sought care at an urgent care facility only when her symptoms became intolerable. This underscores the importance of patient education on the early recognition of symptoms that warrant prompt medical evaluation. Regardless, after her extensive inpatient hospital workup, she was diagnosed with AEP based on fulfilling the majority of the above criteria. Given its clinical overlap with other acute lung injuries, obtaining a detailed history becomes pivotal for recognizing the noninfectious etiology of AEP, particularly in the context of the escalating use of naltrexone.

Author Contributions

Amir Davoodi: conceptualization, investigation, writing – original draft, writing – review and editing. Amy Bordogna: investigation, writing – review and editing. Jenna Guma: conceptualization, investigation, writing – review and editing. Shuyue Ren: investigation, writing – review and editing. Kathryn Haroldson: supervision, writing – review and editing.

Consent

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.