Diffuse Alveolar Hemorrhage Synergistically Induced by Amiodarone and Rheumatoid Arthritis

Abstract

Diffuse alveolar hemorrhage (DAH) syndrome is characterized by bleeding into the alveolar spaces of the lungs and occurs when there is an injury to the alveolar microcirculation that leads to hemorrhage from the alveolar capillaries. We report a case of an 82-year-old woman who presented with acute respiratory distress. The patient had a history of rheumatoid arthritis (RA) and was on amiodarone for atrial fibrillation therapy. Initial diagnostic workup, including bronchoscopy and imaging studies, revealed diffuse opacities and the bronchoalveolar lavage fluid consistent with DAH. The patient required aggressive management with supportive care and corticosteroids. Laboratory work showed a synergistic effect between amiodarone and RA in inducing DAH. This makes the report unique as no reports in the literature described a synergic effect of amiodarone and RA in inducing DAH. The primary objective of this report is to guide physicians and remind them to keep DAH at the top of their differential diagnosis in the setting of an RA patient taking amiodarone.

Background

Diffuse alveolar hemorrhage (DAH) syndrome is characterized by bleeding into the alveolar spaces of the lungs and occurs when there is an injury to the alveolar microcirculation that leads to hemorrhage from the alveolar capillaries. The cardinal symptom in DAH is hemoptysis. ¹ Diffuse alveolar hemorrhage has been associated with multiple systematic inflammatory diseases and medications.^2-4

Rheumatoid arthritis (RA) is a chronic multisystem autoimmune inflammatory disease with a global prevalence of 0.46%, the highest being in North America, with a prevalence of 0.70%. ⁵

Amiodarone is a class III anti-arrhythmic agent commonly used to manage supraventricular and ventricular arrhythmias. However, it has been implicated with many adverse effects and caution must be used in clinical practice. ⁶

This report describes the case of an 82-year-old patient with RA, who developed DAH shortly after initiating treatment with amiodarone. The extensive literature review revealed few reports that have described amiodarone-induced DAH (Table 1)^7,8 and even fewer had described DAH associated with RA (Table 2).^9-11 Although the previous reports have described DAH because of RA or amiodarone toxicity, no cases have suggested amiodarone augmenting the exacerbation of DAH in an RA patient, which makes our case worth writing about.

Table 1.

Literature Review Showcasing DAH Associated With Amiodarone.

Case number	Case	Age/sex	Presentation	Duration on amiodarone	Imaging	Bronchoscopy/biopsy	Treatment	outcome
1	Dean et al	76/M	Dyspnea, cough, and fever	350 days	Interstitial infiltrates	Intra-alveolar hemorrhages, fibrin deposition, and foam cells	Steroids	Died
2	Dean et al	70/M	Dyspnea, fever	198 days	Interstitial infiltrates	Intra-alveolar hemorrhages, fibrin deposition, and foam cells	Steroids	Died
3	Dean et al	70/M	Dyspnea, cough, and fever	274 days	Interstitial infiltrates	Intra-alveolar hemorrhages, fibrin deposition, and foam cells	Steroids	Died
4	Dean et al	37/M	Dyspnea, cough, and fever	91 days	Interstitial infiltrates	Intra-alveolar hemorrhages, fibrin deposition, and foam cells	Steroids	Died
5	Dean et al	63/F	Cough, fever	236 days	Alveolar infiltrates	Intra-alveolar hemorrhages, fibrin deposition, and foam cells	Steroids	Died
6	Dean et al	74/M	Cough	465 days	Interstitial infiltrates	Intra-alveolar hemorrhages, fibrin deposition, and foam cells	Steroids	Died
7	Vizioli and Cho	80/M	Dyspnea, cough	1 month	Bilateral alveolar and interstitial infiltrates	Bloody respiratory secretions, on microscopy, had fresh blood and hemosiderin-laden and foamy macrophages	Steroids	Recovered, restarted on low-dose amiodarone
8	Goldstein et al	70/M	Dyspnea, cough, and fever	15 days	Bilateral alveolar and interstitial infiltrates	Foamy macrophages	High-dose steroids	Recovered
9	Ravishanker et al	58/M	Hemoptysis	10 days	Bilateral infiltrates	Blood, hemosiderin-laden and foamy macrophages	High-dose steroids, heart transplant	Recovered
10	Iskander et al	59/M	Hemoptysis, orthodeoxia, and platpynea	18 days	Pulmonary infiltrates	Hemosiderin-laden macrophages	High-dose steroid	Recovered
11	Camus et al	69/M	Dyspnea, cough, and fever	240 days	Alveolar and interstitial infiltrates	Blood and hemosiderin-laden macrophages	Steroids	Recovered
12	Iskandar	69/M	Dyspnea, cough	8 months	Bilateral upper lobe infiltrates	Blood and hemosiderin-laden macrophages	High-dose steroids, tapered over 6 months	Recovered
13	Tanawuttiwat et al	46/M	Acute hypoxic respiratory failure, bloody secretions in aspirate	18 days	Severe diffuse bilateral perihilar infiltrates	Blood-stained BAL fluid, hemosiderin-laden and foamy macrophages	High-dose corticosteroids	Died
14	Border et al	NA/M	Dyspnea, pleuritic chest pain	1 day	Bilateral alveolar infiltrates	Blood-stained effluent, blood cells and foamy macrophages on microphage	Methyl prednisone 1 g daily	Died
15	Blasco et al	74/M	Dyspnea, trepopnea, hemoptysis, and anemia	5 months	Bilateral interstitial infiltrates	Exudate alveolar hemorrhage	Prednisone 30 mg × 3 months	Recovered
16	Pendyal et al	66/M	Acute hypoxic respiratory failure	NA	Bilateral patchy opacities	Blood-stained fluid	NA	Recovered
17	Papanikolaou et al	70/F	Pulmonary hypertension and hypoxemia	5 months	Bilateral ground-glass opacities	58% hemosiderin-laden macrophages	Prednisone 32 mg × 3 months	Recovered
18	Papanikolaou et al	54/M	Hemoptysis and shortness of breath	3 weeks	Bilateral hazy opacities with ground-glass attenuation and increased interstitial markings at the lung periphery	Macroscopically hemorrhagic and showed 100% hemosiderin-laden macrophages	Methyl-prednisolone 600 mg/day for 5 days and then switched to prednisone 48 mg/day	Recovered
19	Saeed et al	73/F	Hemoptysis and shortness of breath	4 days	Bilateral diffuse interstitial infiltrates and multifocal pulmonary consolidations	Hemorrhagic fluid with hemosiderin-laden macrophages	High-dose steroids	Recovered

Abbreviations: DAH, diffuse alveolar hemorrhage; BAL, bronchioalveolar lavage; NA, not applicable.

Table 2.

Literature Review Showcasing DAH Associated With RA.

Case number	Case	Age/sex	Presentation	Duration	Imaging	Bronchoscopy/biopsy	Treatment	outcome
1	Schwarz et al	56/M	Dyspnea, cough	40 years	NA	Hemorrhagic smears and cultures of the BAL and serology for viral, bacterial including Legionella species, and fungal organisms were negative.	Steroids	Recovered
2	Schwarz et al	64/M	Dyspnea, cough, and hemoptysis	20 years	NA	Hemorrhagic smears and cultures of the BAL and serology for viral, bacterial including Legionella species, and fungal organisms were negative.	Steroids	Died
3	Schwarz et al	25/F	Dyspnea, cough, hemoptysis, and fever	2 years	NA	Hemorrhagic smears and cultures of the BAL and serology for viral, bacterial including Legionella species, and fungal organisms were negative.	Steroids	Recovered
4	Schwarz et al	45/F	Dyspnea, cough, and hemoptysis	3 years	NA	Hemorrhagic smears and cultures of the BAL and serology for viral, bacterial including Legionella species, and fungal organisms were negative.	Steroids	Recovered
5	Osman et al	36/F	Dyspnea, cough, and hemoptysis	20 years	Perihilar consolidations and ground-glass opacities	Increasingly sanguineous return and red blood cells too numerous to count on the cell analysis	Steroids	Recovered
6	Nakashima et al	89/F	Dyspnea	2 months	Interstitial infiltrates	Intra-alveolar hemorrhages	Steroids	Died
7	Dua et al	45/F	Dyspnea, cough	1-2 years	Interstitial infiltrates	Intra-alveolar hemorrhages	Steroids	Recovered

Abbreviations: DAH, diffuse alveolar hemorrhage; RA, rheumatoid arthritis; NA, not applicable; BAL, bronchioalveolar lavage.

Case Presentation

An 82-year-old woman presented with a past medical history significant for atrial fibrillation, congestive heart failure, RA, iron deficiency anemia, asthma, liver cirrhosis, type 2 diabetes mellitus, gastroesophageal reflux disease, and deep vein thrombosis status post–inferior vena cava (IVC) filter placement. The patient was diagnosed with RA in 2019 and was managed effectively using hydroxychloroquine.

One month prior to the current admission, the patient was admitted due to chest pain and shortness of breath. The patient underwent esophagogastroduodenoscopy (EGD) in which no bleeding was noted and there was only mild gastritis; a colonoscopy the following day showed no active bleeding. In addition, both chest computed tomography (CT) and chest X-ray were negative for signs of consolidation. The patient was diagnosed with atrial fibrillation with a rapid ventricular response and was placed on amiodarone 200 mg twice daily to be doubled.

This patient’s admission was related to fatigue, dizziness, and multiple falls upon standing up; the patient’s blood pressure was 129/54 mm Hg, a pulse of 81 bpm with an irregularly irregular rhythm, respiratory rate of 24 breaths/min, SpO2 of 89%, and temperature of 98.6 °F. She also complained of having dark brown stools with positive fecal occult blood. Anemia workup showed low Hgb with iron deficiency. The patient was noticed to have an increased oxygen requirement and was transferred to the intensive care unit.

Imaging showed bilateral diffuse pulmonary infiltrates on chest X-ray and extensive ground-glass opacity and crazy paving pattern were noted bilaterally on chest CT angiogram with and without intravenous (IV) contrast, as shown in Figures 1 and 2.

Figure 1.

Chest computed tomography angiogram showing extensive ground-glass opacity and crazy paving pattern noted bilaterally: (A) Sagittal view, (B) coronal view, and (C) axial view.

Figure 2.

Chest X-Ray showing bilateral diffuse pulmonary infiltrates.

Based on the laboratory findings and imaging, bronchoscopy was performed to rule out the concerns of DAH. Serial bronchioalveolar lavage (BAL) was progressively bloody, consistent with alveolar hemorrhage. Analysis of the fluid showed 3471 red blood cells (RBCs), cultures were found negative, and cytology showed alveolar macrophages and inflammatory cells. Malignancy was ruled out.

The autoimmune panel showed anti-nuclear antibody 1:640 (positive), cyclic citrulline peptide antibody 76 units (positive), and rheumatoid factor 49.1 IU/mL (positive). The antineutrophil cytoplasmic antibody (C-ANCA and P-ANCA), glomerular basement membrane antibody, myeloperoxidase antibody, Serine proteinase 3, and anti-Smith antibodies were all negative. The C3 and C4 complement levels were within normal ranges.

The patient’s coagulation profile was abnormal, with elevated PT at 18.9 and elevated INR at 1.61, which were attributed to secondary to synthetic liver dysfunction in NASH cirrhosis.

Discussion

The patient likely experienced DAH secondary to amiodarone-induced pulmonary toxicity due to the recent initiation of amiodarone. Amiodarone was discontinued and replaced with sotalol to manage atrial fibrillation. In addition, the patient was placed on high-dose methylprednisolone, starting with 1000 mg daily, with a slow taper 5 days later. Our patient’s clinical history was unique, given that she was diagnosed with RA in 2019 with rheumatoid factor (RF) titers of 36.8 IU/mL. After a thorough review of the patient’s previous hospital records, it was noticed that her anti-nucleotide antibodies (ANAs) titers were negative during her first admission. During her most recent admission, the patient’s ANA titers became positive with a value of 1:640, and the RF titers rose to 49.1 IU/mL. This elevation in inflammatory markers suggests that the patient was experiencing an acute RA flare. This concurrent flare in the setting of recent anti-arrhythmic initiation indicates a likely synergistic effect of both amiodarone and RA in developing DAH.

Our recommendation from this case report is that clinicians maintain DAH high on their differential in RA patients on amiodarone presenting with respiratory distress. Further studies should be done on the effect of amiodarone on RA pulmonary manifestations as a likely synergistic relationship exists.