Mesalamine-induced eosinophilic pleural effusion

Abstract

A 45-year-old woman with a medical history of ulcerative colitis (UC) presented with difficulty in breathing. The patient was diagnosed with UC a month prior to presentation and was started on mesalamine suppository. Chest x-ray (CXR) on presentation showed bilateral pleural effusion, which was confirmed on CT angiogram of the chest. Diagnostic and therapeutic thoracentesis was performed and 0.7 L of pleural fluid was removed from the left side. The pleural fluid analysis was consistent with exudative pleural effusion with eosinophilia. Symptomatic improvement was noted after thoracentesis. Mesalamine was stopped and repeat CXR was obtained on the follow-up visit, which showed no pleural effusion. The Naranjo score was calculated to be 7, indicating that the eosinophilic pleural effusion was most probably secondary to adverse reaction from mesalamine.

Background

A pleural effusion that contains a minimum of 10% of eosinophils is defined as an eosinophilic pleural effusion (EPE).¹ Malignancy is the most common condition associated with EPE.² Mesalamine use has been reported to be associated with the development of EPE, and the evidence is limited to case reports.^{3 4}

Case presentation

A 45-year-old woman with a medical history of ulcerative colitis (UC) presented to the hospital with difficulty in breathing associated with left-sided pleuritic chest pain. The patient was diagnosed with UC a month prior to presentation, mesalamine suppository was initiated at diagnosis and she had tolerated it well. She had no significant past surgical, social or family history. Her symptoms started 2 weeks prior to presentation. She was evaluated by her primary care physician who diagnosed the patient with pneumonia and started her on oral levofloxacin for 7 days. However, her symptoms continued to worsen despite being on antibiotics. Hence, her primary care physician advised her to come to the emergency department. On presentation to the hospital, her vitals were within normal limits with an SpO₂ of 96% on room air. Pulmonary examination showed decreased breath sounds in the bilateral lower lung fields and dullness to percussion at the bases of both lungs. However, the dullness extended superiorly on the left side up to the midlung level. Chest X-ray (CXR) on presentation showed moderate left-sided pleural effusion and small right-sided pleural effusion.

Investigations

On admission, laboratory workup revealed normal white blood cell count, haemoglobin, electrolytes, procalcitonin and brain natriuretic peptide. PCR was negative when nasopharyngeal specimen was tested for influenza A, influenza B, respiratory syncytial virus and parainfluenza viruses. Histoplasma urine antigen was also negative. Chest X- ray (figure 1) showed moderate left-sided pleural effusion, which was confirmed on CT angiogram of the chest (figure 2). There was no evidence of pulmonary embolism, pneumothorax, mediastinal lymphadenopathy or pulmonary lesions. Diagnostic and therapeutic thoracentesis was performed and 0.7 L of pleural fluid was removed from the left side. Pleura fluid analysis showed an exudative effusion with white blood cell count of 744 with 40% eosinophil predominance, red blood cell count of 1794, lactate dehydrogenase level (LDH) at 97 U/L and total protein at 4.7 g/dL. Serum LDH and total protein were 85 U/L and 5.7 g/dL, respectively. Pleural fluid cytology, gram stain and cultures were negative for bacteria and malignant cells.

Figure 1.

Chest X-ray showing left-side pleural effusion.

Figure 2.

CT angiogram of the chest showing left-side pleural effusion.

Differential diagnosis

The differential diagnosis for exudative EPE is broad. Traumatic aetiologies, including pneumothorax and haemothorax, which were excluded by history, physical exam and imaging, and infectious aetiologies, including bacterial, mycobacterial and fungus, were ruled out by history, parietal fluid’s gram stain, bacterial and fungal cultures; malignancy was ruled out by negative cytology; and pulmonary embolism was ruled by CT angiogram of the chest. Negative autoimmune workup ruled out an autoimmune pathology.

Treatment

The patient finished a 7-day course of levofloxacin prior to admission. Initially, the patient was started on ceftriaxone and azithromycin empirically for community-acquired pneumonia. Diagnostic and therapeutic thoracentesis was performed and 0.7 L of pleural fluid was removed from the left side. Antibiotics were stopped according to pleural fluid analysis, and in the absence of an alternate explanation, pleural effusion was attributed to mesalamine, which was stopped. This resulted in resolution of her pleural effusions on subsequent follow-ups.

Outcome and follow-up

The patient was followed up as an outpatient with her primary care physician for 3 months. Electronic medical record review confirmed complete resolution of pleural effusion on a repeat CXR (figure 3) 1 month after stopping mesalamine, with no recurrent episodes of pleural effusion.

Figure 3.

Follow-up chest X-ray showing complete resolution of the pleural effusion.

Discussion

EPE also known as pleural fluid eosinophilia^{3 4} accounts for 5%–16% of exudative pleural effusions. It is precipitated by multiple aetiologies, including malignancy, infections, trauma, autoimmune diseases, parasitic infestations and multiple other less common aetiologies. Lung cancer is the most common malignancy associated with EPE.² Fourteen per cent to 25% of EPE remains idiopathic despite detailed and extensive workup.⁵ The pathogenesis of EPE remains unclear, but reports have suggested involvement of interleukin-5 as an inducer of eosinophilic production and differentiation.⁶ Multiple medications have been associated with the development of EPE, including mesalamine, warfarin,⁷ dantrolene,⁸ valproic acid,⁹ carbimazole,¹⁰ methimazole,¹¹ olanzapine¹² and multiple other medications.

Mesalamine is a 5-aminosalycic acid compound and is the active component of sulfasalazine.^{13 14} It is also known as mesalazine, and 5-amino-2-hydroxybenzoic acid. The mechanism of action of mesalamine is unclear, but it appears to include local anti-inflammatory effect.^10–15 It is used for the treatment of UC and Crohn’s disease.^10–15 It is a well-tolerated medication with a benign side-effect profile that includes but is not limited to abdominal pain, headache, nausea and vomiting.^{14 16}

Mesalamine-induced EPE has been reported in the literature but limited to case reports (table 1). Onset of EPE was similar between the cases, up to 3 months after the initiation of mesalamine. Treatment consists mainly of stopping mesalamine and monitoring the patient. Mesalamine has also been associated with pulmonary infiltrates, as well as EPE.^{3 4 17}

Table 1.

Reported cases of mesalamine-induced EPE

Cases	Age/sex	Indication	Daily dose (mg)	Time period to first episode of EPE	Episodes (n)	Lung infiltrates	Treatment
Sesin et al3	73/F	UC	2400	2–3 months	2	Yes	Discontinued
Trisolini et al4	38/M	None	2400	2–4 weeks	1	Yes	Discontinued and steroids
Kim et al19	30/F	UC	1000	3 weeks	1	Yes	Discontinued
Lalani et al20	61/M	UC	3200	Not available	1	No	Discontinued
This study	45/F	UC	1000	1 month	1	No	Discontinued

EPE, eosinophilic pleural effusion; F, female; M, male; UC, ulcerative colitis.

Management of mesalamine-induced EPE involved stopping the medication and monitoring response. Trisolini et al stopped mesalamine and started corticosteroids at the same time.⁴ Corticosteroids have been suggested as a treatment of EPE due to the possible underlying immunological pathophysiology of the disease.4 6 17 18 Kim et al stopped the mesalamine and started the patient on intravenous methylprednisolone 500 mg for 3 days followed by oral prednisone 30 mg per day; the patient completely recovered in 3 months.¹⁹

Patient’s perspective.

I was terrified because I thought I had a bad pneumonia, and the antibiotics were not working. I am happy and bumped that all of this is because of the medication, because this means I have to try something else now.

Learning points.

• Mesalamine is a first-line treatment of ulcerative colitis (UC) with a relatively benign adverse effect profile.

• Mesalamine has been associated with eosinophilic pleural effusion (EPE), with the association limited to case reports.

• Discontinuing mesalamine may be enough to prevent recurrence of EPE.

• Alternative therapies for UC can be substituted for mesalamine in patients with EPE.