Acute eosinophilic pneumonia-like syndrome post-initiation of vortioxetine
- Tanya Marie O'Brien
- Pharmacy, Eastern Health, St. John's, Newfoundland and Labrador, Canada
- Correspondence to Tanya Marie O'Brien; tanya.obrien@easternhealth.ca
Abstract
A man in his mid-30s presented to the emergency department with a 1-week history of fatigue, loss of appetite, fever and productive (yellow) cough. This progressed to requiring admission to intensive care needing a oxygen therapy via high-flow nasal cannula for acute hypoxaemic respiratory failure. He had recently started vortioxetine for major depressive disorder, and his acute symptoms correlated with an increase in the dose of vortioxetine. For more than 20 years, rare but consistent reports of serotonergic medications have been implicated in eosinophilic pulmonary conditions. During this same period, serotonergic medications have become a mainstay solution for a wide range of depressive symptoms and disorders. This is the first report of an eosinophilic pneumonia-like syndrome occurring while consuming the novel serotonergic medication vortioxetine.
Background
Eosinophilic pneumonia is a variety of syndromes characterised by pulmonary infiltrates with accumulation of eosinophils in the lung interstitium, alveoli and, usually, peripheral blood eosinophilia. Clinical severity is variable, ranging from simple eosinophilic lung disease (Loeffler’s syndrome) to acute eosinophilic pneumonia (AEP) characterised by fever, rapid onset of respiratory symptoms and patchy, often bilateral, lung infiltrates in the chest roentgenogram, which can lead to a fulminant respiratory failure.1 The defining characteristics needed for the diagnosis of pulmonary eosinophilia include either peripheral blood eosinophilia with radiographically or tomographically identified pulmonary abnormalities, lung tissue eosinophilia demonstrated in transbronchial or open lung biopsies or increased eosinophils in bronchoalveolar lavege (BAL) fluid.2
Vortioxetine is a novel antidepressant drug approved for the treatment of major depressive disorder in adults. Vortioxetine displays a high affinity for the serotonin transporter (SERT) and serotonin 5HT3, 5HT1A and 5HT7 receptors. Functional studies show that vortioxetine acts as a SERT blocker, 5HT3 and 5HT7 receptor antagonist, and a 5HT1A receptor agonist.3 Numerous serotonergic drugs have been associated with AEP.4–8 This is the first case report of AEP-like syndrome occurring while consuming the novel antidepressant vortioxetine.
Case presentation
A patient in his mid-30s presented to the emergency department with a 1-week history of fatigue, loss of appetite, self-reported fever and productive (yellow) cough. The patient’s medical history was significant for depression and anxiety. The patient reported using store-bought nicotine vape products regularly. The patient also reported smoking locally grown cannabis occasionally. There were no changes in either of these habits in the last 6 months. The patient reported having a cat. There were no potential exposures to other chemicals.
Approximately 1 month before admission, vortioxetine 5 mg orally daily was initiated for depression. After 2 weeks, the dose was increased to vortioxetine 10 mg orally daily. A week after the dose was increased, the patient had an isolated episode of vomiting. The subsequent week, the patient experienced a change in bowel habits with loose stool and urgency requiring time off work. A timeline of vortioxetine dosing after initiation and symptoms experienced by the patient leading up to hospital admission is illustrated in table 1.
Timeline of vortioxetine administration and symptoms leading up to hospital admission
| Week 4 preadmission | Week 3 preadmission | Week 2 preadmission | Week 1 preadmission | Admission |
| Started vortioxetine 5 mg daily | ||||
| Vortioxetine increased to 10 mg daily | ||||
| Vomited | ||||
| Bowel habit changes | ||||
| Fatigue | ||||
| Decreased appetite | ||||
| Fever | ||||
| Productive cough | ||||
| Admission | ||||
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Blue highlights vortioxetine 5 mg daily. Green highlights the dose increase to vortioxetine 10 mg daily. Magenta highlights the symptoms experienced by the patient in relation to the dosing of vortioxetine. Red highlights the temporal relationship of the patient’s admission and vortioxetine dosing.
In emergency triage, the patient’s temperature was 37.2°C, blood pressure was 120/58 mm Hg, heart rate was 109 beats per minute and SpO2 was 87% on room air. The patient was subsequently admitted to the intensive care unit (ICU) requiring oxygen therapy via high-flow nasal cannula for acute hypoxaemic respiratory failure.
Investigations
The patient had standard blood work and specific investigations to help diagnose the respiratory illness. Details are illustrated in table 2.
Laboratory investigations
| Investigation | Result | Investigation | Result |
| COVID-19 rapid test | Negative × 2 | Urea | 5.7 mmol/L |
| COVID-19 PCR test | Negative × 2 | Sodium | 140 mmol/L |
| Influenza A and B PCR | Negative | Potassium | 5.0 mmol/L |
| Respiratory syncytial virus PCR | Negative | Chloride | 103 mmol/L |
| Parainfluenza 1, 2 and 3 PCR | Negative | CO₂ | 27 mmol/L |
| Adenovirus PCR | Negative | Creatinine | 112 µmol/L |
| Enterovirus/rhinovirus PCR | Negative | Phosphate | 1.13 mmol/L |
| Human metapneumovirus PCR | Negative | Magnesium | 0.74 mmol/L |
| Cytomegalovirus PCR | Negative | Leucocytes | 16.8×10⁹/L |
| Mycoplasma pneumonia PCR | Negative | Haemoglobin | 159 g/L |
| Good pasture and vasculitis disease panel | Negative | Platelets | 209×10⁹/L |
| Anticellular antibodies panel | Negative | Lymphocytes | 0.9×10⁹/L |
| HIV screen | Non-reactive | Neutrophils | 12.9×10⁹/L (77%) |
| Legionella antigen | Negative | Eosinophils | 2.18×10⁹/L (13%) |
| Drugs of abuse urine assay | Tetrahydrocannabinol (THC) positive | Blood film morphology | Normal |
| C-reactive protein (CRP) high sensitivity | 256.6 mg/L |
The patient had significant serum eosinophilia (13%). Blood cultures were negative. A bronchoscopy or lung biopsy was not performed as the respirologist and intensive care team deemed the patient was not stable enough to tolerate either of these procedures. One of these two procedures is required for a definitive diagnosis of eosinophilic pneumonia. Other noteworthy investigations were leucocytosis, lymphopenia and an elevated CRP high sensitivity, indicating an acute inflammatory response. The patient had a positive THC level on the urine drug screen. The patient was known to occasionally use cannabis, so this would be expected. The patient had a chest X-ray (see figure 1) which exhibited bilateral patchy opacities/areas of consolidation throughout both lungs predominantly in the lower lung fields. Subsequently, the patient’s condition deteriorated, and a chest CT scan was performed (see figure 2). This test demonstrated diffuse bilateral coalescent and patchy opacities in a bronchocentric distribution, sparing the lung apices.
Chest X-ray dual energy. There are bilateral patchy opacities/areas of consolidation throughout both lungs predominantly in the lower lung fields. Cardiomediastinal silhouette is within normal limits. No pleural effusion or pneumothorax.
Chest CT without contrast. Diffuse bilateral coalescent and patchy opacities in a bronchocentric distribution, sparing the lung apices. No bronchiectasis. No bronchial wall thickening.
Differential diagnosis
The patient presented during the COVID-19 pandemic. During this time, excluding COVID-19 as a cause of any respiratory syndrome was necessary. However, with multiple negative rapid and PCR COVID-19 tests, COVID-19 was excluded.
Other viral and bacterial respiratory infections are common in the community. The patient was screened for numerous community-acquired pathogens that could account for the presentation. The results of this screening are detailed in table 2. These investigations were negative.
The patient was also noted to have gastrointestinal symptoms, including vomiting and diarrhoea. These symptoms occurred during the week prior to admission and were not profound. These symptoms are not typical in the presentation of eosinophilic pneumonia. Patients taking serotonergic agents have an elevated risk of experiencing vomiting and diarrhoea. Selective serotonin reuptake inhibitors have a 3%–4% risk of vomiting and a 6%–26% risk of diarrhoea. Vortioxetine has a 3%–6% risk of vomiting and a 7%–10% risk of diarrhoea.9–15 These symptoms, along with fatigue, decreased appetite, fever and productive cough, coincided with a dose increase of vortioxetine. Vortioxetine is a serotonin reuptake transporter (SERT) blocker and prevents the degradation of 5HT. The SERT plays an irreplaceable role in 5HT inactivation by removing 5HT from the interstitial space in the lamina propria into mucosal enterocytes and presynaptic neurons that are responsible for catabolism.16–18 Studies have demonstrated the release of 5HT acting on a series of 5HT receptors initiates secretory reflexes, peristaltic reflexes and, if pronounced, diarrhoea by stimulating intrinsic primary afferent neurons and myenteric interneurons.18–21 This phenomenon could explain the transient gastrointestinal symptoms of the patient. The increased vortioxetine dose could increase SERT blockade. This could lead to an increased concentration of 5HT that could exert adverse effects on the gastrointestinal tract.
The patient was known to habitually use nicotine vape products. Vaping has been increasingly associated with lung injury, also known as E-cigarette or vaping, product use associated lung injury (EVALI).22 The patient reported using store-bought nicotine vape products, with no changes in nicotine products or vape devices in the last 6 months or longer. The vape product company confirmed there was no alpha-tocopheryl acetate in any of their vape products. Alpha-tocopheryl acetate is a compound that has been associated with EVALI.23 The lack of recent changes in smoking habits reduces the probability that AEP could be associated with vaping/smoking. A case series was published in Ref. 24 involving 33 patients for whom cigarette smoking was deemed to be the causative agent of AEP. These data suggest that recent alterations in smoking habits, not only beginning to smoke but also restarting to smoke or increasing daily smoking doses, are associated with the development of AEP. The patient has vaped cannabis products since his admission to the hospital without any consequences. These details make EVALI less likely.
Pulmonary embolism usually presents with abrupt onset of shortness of breath. However, given the negative CT pulmonary angiography, this was ruled out.
The patient did not have a history of exposure to chemicals; therefore, diseases like asbestosis and hypersensitivity pneumonitis were low on the differential.
The patient was young, and therefore, diseases that would result in cardiogenic pulmonary oedema were low on the differential. Aside from mild tachycardia, there were no signs of cardiac abnormalities. Non-cardiogenic pulmonary oedema, on the other hand, encompasses numerous diseases that could present like the patient with diffuse bilateral coalescent ground glass opacities on CT. Vasculitis tests were negative. Acute respiratory distress syndrome was a possibility, but given the quick resolution with steroids, this diagnosis was less likely. Drug reactions have the potential to cause non-cardiogenic pulmonary oedema. These reactions are usually immune-mediated responses. The lack of eosinophilia on bronchoscopy or lung biopsy precludes a definitive diagnosis of eosinophilic pneumonia. Using the WHO-Uppsala Monitoring Centre scale25, vortioxetine as a cause for the patient’s AEP-like condition was probable. The respiratory abnormality had a reasonable time relationship to vortioxetine consumption. Although vaping can cause EVALI, the lack of recent changes in this habit makes it unlikely the patient’s respiratory illness could be attributed to vaping. There was a clinically reasonable response to withdrawal of vortioxetine, and rechallenge was not required as vortioxetine was discontinued.
Treatment
The patient was initially treated with 75 % oxygen therapy via high-flow nasal cannula. Moxifloxacin 400 mg intravenously daily was initiated for community-acquired pneumonia. Rabeprazole 20 mg orally daily was started for stress ulcer prophylaxis, and enoxaparin 40 mg subcutaneously daily was initiated for venothromboembolism prophylaxis. On the evening of admission, the patient was started on dexamethasone and given a dose of dexamethasone 6 mg intravenously once. The following day, the patient’s oxygen requirements increased to 85%. Dexamethasone was changed to methylprednisolone 125 mg intravenously every six hours and antibiotics were escalated to piperacillin-tazobactam 4.5 g intravenously every six hours. Three days after admission and 2 days after receiving high-dose steroids, the patient’s status improved. The patient was switched to 4 L of oxygen via nasal prongs. Six days after admission, the patient was switched to room air and discharged from the hospital with a tapering dose of oral prednisone. The patient completed their course of prednisone at 6 weeks from their admission date.
Outcome and follow-up
The patient has made a complete recovery with a return to all activities prior to the onset of illness. At follow-up 10 weeks post-admission, the CT was completely resolved with residual mucous plugging being the only finding.
Discussion
Eosinophils play a prominent proinflammatory role in airway allergic inflammation, including the pathogenesis of asthma. In a study by Boehme et al, eosinophils purified from human peripheral blood of allergic donors were exposed to 5HT. 5HT alone was found to induce the migration of human eosinophils in a dose-dependent manner.26 The effects of 5HT on inflammatory cells are largely mediated by one or more of the following receptors (5HT1A, 5HT2A, 5HT3, 5HT4 and 5HT7). Human eosinophils express 5HT1A, 5HT1B, 5HT1E, 5HT2A, 5HT2B and 5HT6 receptors with 5HT2A being the most predominantly expressed, although at variable levels among different donors.27 Functional studies show that vortioxetine acts as a SERT blocker, a 5HT3 and 5HT7 receptor antagonist, and a 5HT1A receptor agonist.3 It is logical to conclude that a drug causing changes in serotonin equilibrium may cause excess or deficient levels of serotonin at various stages in the inflammatory cascade with the potential to be pathologic. During the last couple of decades, there have been rare but consistent occurrences of eosinophilic respiratory diseases associated with serotonergic drugs. Table 3 references a timeline of reported cases of eosinophilic pulmonary diseases associated with serotonergic drugs.
Historical case reports of eosinophilic pulmonary disease associated with serotonergic drugs
| 1999 | Clomipramine | Barnés et al 1 |
| 2000 | Fluoxetine | Behnia et al4 |
| 2000 | Venlafaxine | Fleisch et al 5 |
| 2007 | Duloxetine | Espeleta et al 6 |
| 2011 | Fluoxetine | Alagha et al 28 |
| 2011 | Venlafaxine | Tsigkaropoulou et al 7 |
| 2011 | Venlafaxine | Paparrigopoulous et al 29 |
| 2012 | Clomipramine | Gallego et al 30 |
| 2012 | Paroxetine | Yasui-Furukori et al 31 |
| 2013 | Risperidone | Rizos et al 2 |
| 2015 | Paroxetine | Maia et al 32 |
| 2018 | Olanzapine | Huang et al 33 |
| 2018 | Sertraline | Muftah et al 8 |
| 2021 | Sertraline | Brancaleone et al 34 |
Patient’s perspective
First-hand account by the patient 1 week post discharge
The first signs that something was wrong was probably the evening a week and a half prior to admission. I was cleaning out my old car in preparation to trade it in for a new one, and part way through I spontaneously vomited. I could never determine a reason this may have happened other than nerves/excitement of getting a new car. Throughout the rest of that week, I had some gastrointestinal problems. Not necessarily diarrhoea, but loose, more often, and in some cases an urgency that resulted in me leaving work early.
By the end of the week, my energy levels were depleting. On Saturday (5 days later) I felt pretty good, I helped one of my friends move a wood stove into his house, and most of that day I was fine, maybe with some lower energy than I would normally feel. I also filled my first 10 mg Trintellix (vortioxetine) prescription after completing 4 weeks of samples (2 weeks of 5 mg, 2 weeks of 10 mg). On Sunday my energy was definitely lower, and I had a nap in the evening which is highly unusual for me. That evening I developed a minor fever. I believe the reading was approximately 38.5 degrees (Celsius). I also didn’t have much of an appetite that day.
Monday I bought two rapid tests and had a PCR test scheduled for that evening. The rapid tests and PCR test all came back negative, the PCR results came in on Tuesday morning. Tuesday evening I was still low energy, had little to no appetite and had a bit of a cough, which is when I decided to go to the ER, where my oxygen levels were measured at 86%.
Since discharge, I haven’t had much in the way of nicotine cravings, so I have been able to avoid vaping. I don’t think I’ve felt any withdrawal from the lack of Trintellix (vortioxetine). I have yet to set up an appointment with my doctor to discuss alternatives. I tried going to the gym tonight, but I found it fairly difficult to do very much, but I guess as long as I keep trying it will get back to normal.
Learning points
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Serotonergic medications are among the known causes of eosinophilic pneumonia. Vortioxetine, a novel antidepressant involving serotonin modulation, might theoretically cause eosinophilic pneumonia through similar mechanisms, and this should be considered in patients taking this medication who present with eosinophilic pneumonia.
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Patients with eosinophilic pneumonia usually present with a complex clinical history that includes numerous potential causes of eosinophilic pneumonia. When trying to isolate a diagnosis, investigating the timeline of events is one of the most important tasks of the clinician.
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Historically, changes in a patient’s routine of nicotine use have been observed in most patients who present with eosinophilic pneumonia associated with nicotine products. Gathering information about a patient’s smoking habits, products used and time relationships are important in the management of otherwise healthy patients with acute eosinophilic pneumonia.
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The lack of eosinophilia on bronchoscopy or lung biopsy precludes a definitive diagnosis of eosinophilic pneumonia. Long-term pharmacovigilance and large-scale research would be needed to identify a true association.
Ethics statements
Patient consent for publication
Footnotes
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Twitter @o_brien_tanya
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Contributors TMO is the sole contributor of this paper.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.
References
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