American Journal of Therapeutics 22, e43–e47 (2015)
Pulmonary Drug Toxicity: Presentation of a Case of Recurrent Diffuse Alveolar Damage Caused by Paroxetine Nicolini Antonello, MD,1* Lanata Sergio,2 Tironi Andrea, MD,3 and Barlascini Cornelius4
Pulmonary drug toxicity is being diagnosed more often as a cause of acute and chronic lung disease. Numerous agents including cytotoxic and noncytotoxic drugs have the potential to cause pulmonary toxicity. Recurrent diffuse alveolar damage is a rare manifestation of drug toxicity. We described an extremely rare case of recurrent diffuse alveolar damage caused by the antidepressant drug (paroxetine) resolved by a definitive suspension of the drug, after a recurrent respiratory failure because of inadvertently administering the drug. Keywords: drug toxicity, recurrent diffuse alveolar-damage, severe respiratory failure, antidepressant drug, paroxetine
INTRODUCTION Pulmonary drug toxicity is increasingly being diagnosed as a cause of acute and chronic lung disease. Numerous agents including cytotoxic and noncytotoxic drugs have the potential to cause pulmonary toxicity.1,2 Diffuse alveolar damage (DAD) is a common manifestation of pulmonary drug toxicity and is frequently caused by cytotoxic drugs, especially cyclophosphamide, bleomycin, and carmustine.2 It manifests radiographically as bilateral patchy or homogeneous opacities usually in the mid and lower lungs and on high-resolution computed tomographic scans as scattered or diffuse areas of ground-glass opacity. DAD is a common manifestation of drug-induced lung injury that results from necrosis of type II pneumocytes and alveolar endothelial cells.2,3
1
Respiratory Diseases Unit, Hospital of Sestri Levante, Sestri Levante, Italy; 2Histopathology Unit, Hospital of Sestri Levante, Sestri Levante, Italy; 3Department of Pathology, Ospedali Civili Brescia, Brescia, Italy; and 4Forensic Medicine ASL4, Chiavari, Italy. The authors have no conflicts of interest to declare. *Address for correspondence: Respiratory Diseases Unit, Via Terzi 43, 16039 Sestri Levante, Italy. E-mail: [email protected]
Histopathologically, DAD is divided into an acute exudative phase and a late reparative or proliferative phase.2,3 The exudative phase, which is characterized by alveolar and interstitial edema and hyaline membranes, is most prominent in the first week after lung injury.2–4 The reparative phase, which is characterized by proliferation of type II pneumocytes and interstitial fibrosis, typically occurs after 1 or 2 weeks after the onset of DAD.2–4 Depending on the severity of the injury, fibrosis can improve significantly, remain stable, or progress to honeycomb lung.2,4 Progression to diffuse opacification is not uncommon. With progressive fibrosis, marked architectural distortion can occur.2 The end result may be physiologically useless honeycomb lung tissue. Clinically, DAD produces respiratory failure, and most patients fit into the spectrum of the acute respiratory distress syndrome. Mortality rates approach 50%, but those who survive the acute event usually recover with minimal pulmonary damage.2,3 Patients with DAD present with dyspnea, cough, and occasionally fever. Diffusing capacity for carbon monoxide (DLCO) is characteristically decreased. Recurrent DAD is a rare manifestation of drug toxicity, and sporadic cases have been reported in the literature. We described an extremely rare case of recurrent case of DAD caused by the antidepressant drug (paroxetine) resolved with the suspension of
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Antonello et al
drug. To our knowledge, this is the first case to be reported in the English language medical literature because of paroxetine administration.
PATIENT CASE PRESENTATION A 41-year-old woman suffering from idiopathic alveolar proteinosis (PAP) (biopsy confirmed) (PAP) was referred to intensive care unit because of respiratory failure: PaO2/FiO2 (P/F) ratio 130, severe respiratory acidosis (pH 6.96 and paCO2 112), tachypnea (respiratory rate: 40 breaths per minute), tachycardia (pulse: 130 beats minute), fever (temperature: 38.8°C), and stupor. Before admission, she was given a 7-day course of clarithromycin for an upper respiratory tract infection. In the week before the admission, dyspnea had progressively increased. The patient has been treated with antidepressant drugs for 6 months (paroxetine 20 mg/d). In the month before admission, she complained of dyspnea and mucus expectoration. In the week before admission, dyspnea was present also at rest. Admission chest x-ray showed diffuse bilateral interstitial and alveolar infiltrates (Figure 1A); computed tomography scan of the thorax showed diffuse asymmetric alveolar infiltrates, ground-glass opacities associated with reticulonodular pattern (Figure 1B). Arterial blood gas performed by administering oxygen FiO2 60% by Venturi mask showed a severe acidosis (PaO2 44 mm Hg, PaCO2 121, pH 6.96). Thirty minutes after admission to the intensive care unit, the patient was invasively ventilated by pressure-controlled ventilation: inspiratory positive airway pressure, 28 cm H2O; positive end expiratory pressure (PEEP), 15 cmH20; respiratory rate, 16 per minute; and FiO2, 80% with a tidal volume of 290 mL. Arterial blood gas analysis revealed worsening parameters: pH 6.73, PaCO2 170 mm Hg, and PaO2 112 mm Hg. The ventilation was modified, increasing PEEP to 20 cmH2O. Improved blood gas values were noted 12 hours later (pH 7.23, PaCO2 62.5, PaO2 109 with P/F ratio 234). Twenty-four hours later, a normal pH was achieved (pH 7.35, PaCO2 50, PaO2 112); PEEP was reduced (12 cmH2O). Broadspectrum antibiotics (piperacillin + tazobactam 18 g in continuous infusion + levofloxacin 1000 mg every 24 hours) and antimycotic therapy associated with stress doses of methylprednisolne 250 mg intravenously per 24 hours were initiated during the admission. The white blood cell count was 3800 with 85% polymorphonuclear leukocytes with relative lymphopenia (3.2%); the hematocrit was 42%, hemoglobin 11.8 g/mL, C-reactive protein (CRP) 20.44 mg/L, and lactate dehydrogenase (LDH) 2058 U/L. Urinary antigen tests for Legionella pneumophila and Streptococcus pneumoniae American Journal of Therapeutics (2015) 22(2)
FIGURE 1. (A) Chest x-ray diffuse bilateral interstitial and alveolar opacities. (B) Chest computed tomography: diffuse asymmetric alveolar opacities associated with ground-glass opacities and reticulonodular pattern. (C) Open lung biopsy: focal interstitial fibroplasia with pneumocyte hyperplasia consistent with organizing alveolar damage. E-E 34.
were negative, as were IgM antibodies for Mycoplasma pneumoniae. Polymerase chain reaction for the identification of adenovirus, human coronavirus, metapneumovirus, Chlamydia pneumoniae, Haemphilus influenzae, www.americantherapeutics.com
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Pulmonary Drug Toxicity Caused by Paroxetine
L. pneumophila, M. pneumoniae, and S. pneumoniae were negative. Antigens of Aspergillus and Ziehl–Neelsen stain for acid-fast bacilli and nucleoid acid amplification tests to identify Mycobacterium tuberculosis in blood and broncho–alveolar lavage (BAL) were also negative. BAL cytology showed neutrophilic alveolitis. Granulocytemacrophage colony-stimulating factor auto-antibodies were negative. The radiographic abnormalities gradually cleared; PEEP was progressively reduced. The laboratory data improved (white blood cell 7230, LDH 633 U, and C-RP 0.70). The patient was transferred to the Respiratory Diseases Unit a week later. Pulmonary function tests showed a mild restrictive syndrome: forced vital capacity (FVC) 74.4% of predicted, forced expiratory volume in 1 second (FEV1) 78.5% of predicted, total lung capacity 77.8% of predicted, FEV1/ FVC 90.2%, and a moderate–severe reduction of diffusion capacity for CO (DLCO) (40.5%). The clinical and radiologic picture improved progressively, and the patient was transferred 42 days after admission to the Thoracic Surgical Department to undergo open-lung biopsy. The pathological findings of 3 surgical lung biopsies performed from lower right lobe, the largest being 2.5 3 1 3 0.7 cm were: no gross lesions were identified. On microscopy, lung parenchyma was characterized by the presence of multifocal alveolar septa thickening by edema and fibroplasia associated with reactive pneumocyte hyperplasia. Mild interstitial inflammatory infiltrate and foamy macrophages in airspaces were also seen. Mucus in some bronchiolar lumens and thickening of some arterial wall were additional features. No microorganisms were found. Pulmonary alterations were thought to be the expression of subacute and organizing diffuse alveolar damage of yet-undefined cause (Figure 1C). Three weeks after the discharge from the Thoracic Surgical Departments, the patient following the prescription of a psychiatric consultant again took paroxetine (which was been stopped after intensive care unit admission). Two months later, the patient complained again sudden dyspnea with tachypnea (respiratory rate: 36 breaths per minute) and respiratory discomfort. She was taken to the Emergency Department where a severe respiratory failure was diagnosed (paO2 70 with FiO2 40%, paCO2 31.2, pH 7.49, and paO2/FiO2 ratio 175). Computed chest tomography showed diffuse ground-glass opacities associated with reticulonodular pattern (Figure 2A). The patient was admitted to intensive care unit and treated with noninvasive ventilation –continuous positive airway pressure–(CPAP) delivered by helmet with PEEP 12 cmH20. An hour later, the gas exchange improved (paO2 84 with FiO2 40%, paCO2 34, pH 7.48, paO2/FiO2 ratio 210) and she continued noninvasive ventilation.5 The most www.americantherapeutics.com
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FIGURE 2. (A) Chest computed tomography: diffuse ground-glass opacities associated with reticulo-nodular pattern. (B). Chest computed tomography: nearly complete resolution of radiographic picture 2 years later stopping paroxetine.
significant laboratory data were the red cell count being 3,880,000, white cell count 21,850 (neutrophils 80.5% and lymphocytes 13.4%), platelets 521000, Creactive protein 16.47 mg/dL, and LDH 878 U/L. Urinary antigen tests for L. pneumophila and S. pneumoniae were negative, as were IgM antibodies for M. pneumoniae. The patients were treated with broad-spectrum antibiotics and high dose of corticosteroids (methylprednisolone 250 mg per 24 hours). In few days, the clinical picture improved as respiratory exchanges (paO2 103 with FiO2 24%, paCO2 38.3, pH 7.43, PaO2/FiO2 ratio 431) normalized. The noninvasive ventilation was stopped and she was transferred to the Respiratory Diseases Unit. The spirometric values at admission of the patient were: FVC 72.0%, FEV1 77.2%, FEV1/FVC 91.3%, total lung capacity 78.5%, residual volume (RV) 86.9%, and DLCO 60.5%. The patient underwent flexible bronchoscopy American Journal of Therapeutics (2015) 22(2)
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Antonello et al
and BAL. BAL cytology showed neutrophilic alveolitis. In consideration of the clinical history of the patient and the BAL findings, paroxetine was definitively discontinued.1,6 After 6 months, functional respiratory values returned to the range of normality, and the radiological finding progressively improved. The patient was followed for more than 2 years and did not present further episodes of acute respiratory failure. The computed tomography of the chest performed 2 years later after the second discharge shows a nearly complete resolution (Figure 2B). Naranjo algorithm for determining the likelihood of adverse drug reaction assigned a score of 9 (definite adverse drug reaction). The definitive diagnosis was drug-induced (paroxetine) recurrent DAD. The patient gave consent for publication of her case report.
DISCUSSION The clinical and radiological manifestations of this drug-mediated “collateral damage” generally reflect histopathological changes (Table 1). These alterations include DAD, nonspecific interstitial pneumonia, organizing pneumonia, eosinophilic pneumonia, and obliterative bronchiolitis, and also pulmonary hemorrhage, edema, hypertension, or veno-occlusive disease.1,7,8 Diffuse alveolar damage is the classic histological manifestation of acute respiratory distress syndrome. Clinically, patients present with severe hypoxemia and typically require mechanical ventilation. The histological findings will vary depending on when a biopsy is obtained during the course of the disease. The damage to the capillary endothelium and alveolar epithelium results in exudation of edema fluid and cellular
breakdown products, with subsequent pneumocyte hyperplasia and fibroblastic proliferation as the lung attempts to repair the damage. The entire process is propagated by a complex and ever-expanding collection of cytokines and other cellular factors. Response to corticosteroid therapy in patients with drug-induced DAD is variable and may depend on the inciting drug, severity of the reaction, and promptness of the therapeutic intervention.6–9 Histopathologically, DAD is typically divided into 2 phases: the acute/exudative phase and the organizing/proliferative phase. The acute phase generally occurs during the first week after pulmonary insult, with the organizing phase occurring after the first week after pulmonary insult with the organizing phase occurring after the first week; however, the processes actually represent a continuum and overlapping features may be encountered, particularly late in the first week. Some authors additionally include a final fibrotic stage. The acute/exudative phase is usually easily recognizable. The findings are generally diffuse and relatively uniform, but may occasionally be more focal. Although the earliest changes may be seen only ultrastructurally, by day intraalveolar edema and interstitial widening are apparent.7,9 Hyaline membranes may be seen at this point and may reach a peak 4–5 days after the initial insult. Hyaline membranes are composed of cellular and proteinaceous debris and appear as dense glassy eosinophilic membranes lining the alveolar ducts and alveolar spaces. The hyaline membranes characteristic of the acute phase gradually disappear as they become incorporated into the alveolar septa; however, residual hyaline membranes may be identifiable depending on the timing of the biopsy in the course of disease. The fibrosis in DAD tends to be loose, and myxoid and will appear bluishgray on hematoxylin–eosin sections, in contrast to the
Table 1. Principal histopathologic manifestations of pulmonary drug toxicity. Mechanism of injury Diffuse alveolar damage (DAD)
Nonspecific interstitial pneumonia Organizing pneumonia (OP)
Eosinophilic pneumonia Pulmonary hemorrhage
Drugs Bleomycin, busulfan, carmustine, cyclophosphamide mitomycin, melphalan, gold salts, morphine, codeine, cisapride, lansoprazole, lorazepam, methadone, sertraline, paroxetine, fluoxetine, venlafaxine, hydroxizine, alprazolam, temazepam, and gabapentin Amiodarone, methotrexate, carmustine, and chlorambucil Bleomycin, gold salts, methotrexate, amiodarone, nitrofurantoin, penicillamine, sulfasalazine, cyclophosphamide methadone, lorazepam, zolpidem, and omeprazole Penicillamine, sulfasalazine, nitrofurantoin, para-aminosalicylic acid, and nonsteroidal antiinflammatory drugs Anticoagulants, amphotericin B, cytarabine (ara-C), penicillamine, and cyclophosphamide
American Journal of Therapeutics (2015) 22(2)
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Pulmonary Drug Toxicity Caused by Paroxetine
collagenous fibrosis typically seen in other disorders such as nonspecific interstitial pneumonia and usual interstitial pneumonia. Organizing fibroblastic tissue may be observed in airspaces, particularly the alveolar ducts (alveolar duct fibrosis). After the organizing phase, some cases of DAD will gradually resolve, whereas others may develop continued interstitial fibrosis with architectural remodeling and progressive respiratory compromise.6–9 The histological findings of DAD may result from a large number of potential etiologies that include numerous infectious agents, drug reactions, collagen vascular/immune-mediated diseases, ingestant/ inhalant exposure, shock, sepsis, and numerous other agents.7,10–12 DAD is one of the many histopathological patterns seen in drug-induced lung disease and has been associated with many pharmacologic agents, most commonly chemotherapy drugs such as bleomycin. Response to corticosteroid therapy in patients with drug-induced DAD is variable and may depend on the inciting drug, severity of the reaction, and promptness of the therapeutic intervention.10 It is well known that DAD is often associated with antineoplastic drugs, amiodarone, and drugs of abuse.7,10 Rarely it has been related to psychotropic drugs.6,12,13 Several types of antidepressant have been implicated6: amitriptyline,6 venlafaxina,6,9 sertraline,9,12 fluoxetine.9 The last 2 are selective serotonin uptake inhibitors as is paroxetine. Other psycho-active drugs such as lithium,6 promethazine, zolpidem and the benzodiazepines lorazepam, alprazolam, and temazepam have been implicated.9 Sporadic cases are reported in literature; however, the most of the described cases were not established by applying a probability scale,6,9,12 but only with simple temporal or/and causal relationship. Only Torok et al13 described a case with drug dechallenge and rechallenge in support to radiological and histopathological findings. The largest case report of recurrent DAD was published by Savici and Katzenstein,12 who reported 6 cases of recurrent DAD. In 3 of the 6 cases, antidepressant drugs were involved.
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CONCLUSIONS This case demonstrates the relation of a common antidepressant drug causing severe lung disease, after excluding other causes, in support of radiological and histopathological picture of drug-induced lung injury.
REFERENCES 1. Cooper JA Jr. Drug-induced lung disease. Adv Intern Med. 1997;42:231–268. 2. Rossi SE, Erasmus JJ, McAdams HP, et al. Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics. 2000;20:1245–1259. 3. Pietra GG. Pathologic mechanisms of drug-induced lung disorders. J Thorac Imaging. 1991;6:1–7. 4. Smith GJ. The histopathology of pulmonary reactions to drugs. Clin Chest Med. 1990;11:95–117. 5. Antonelli M, Conti G, Esquinas A, et al. A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med. 2007;35;18–25. 6. Piciucchi S, Romagnoli M, Chilosi M, et al. Prospective evaluation of drug-induced lung toxicity with high-resolution CT and transbronchial biopsy. Radiol med. 2011;116:246–263. 7. Poletti V, Casoni A, Cancellieri A, et al. Diffuse alveolar damage. Pathologica. 2010;102:453–463. 8. Rice AJ, Wells AU, Bouros D, et al. Terminal diffuse alveolar damage in relation to interstitial pneumonias. An autopsy study. Am J Clin Pathol. 2003;119:709–714. 9. Parambil JG, Myers TL, Aubry MC, et al. Causes and prognosis of diffuse alveolar damage diagnosed on surgical lung biopsy. Chest. 2007;132:50–57. 10. Takatani K, Miyazaki E, Nureki S, et al. High-resolution computed tomography patterns and immunopathogentic findings in drug-induced pneumonitis. Respir Med. 2008; 102:892–898. 11. Matsuno O. Drug-induced interstitial lung diasese: mechanisms and best diagnostic approaches. Respir Res. 2012;13:39. 12. Savici D, Katzenstein AL. Diffuse alveolar damage and recurrent respiratory failure: report of 6 cases. Hum Pathol. 2001;32:1398–1402. 13. Torok NI, Donaldson BL, Taji J, et al. Diffuse alveolar damage and recurrent respiratory failure secondary to sertraline. Am J Ther. 2012;19:e132–e135.
American Journal of Therapeutics (2015) 22(2)
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Pulmonary Drug Toxicity: Presentation of a Case of Recurrent Diffuse Alveolar Damage Caused by Paroxetine Nicolini Antonello, MD,1* Lanata Sergio,2 Tironi Andrea, MD,3 and Barlascini Cornelius4
Pulmonary drug toxicity is being diagnosed more often as a cause of acute and chronic lung disease. Numerous agents including cytotoxic and noncytotoxic drugs have the potential to cause pulmonary toxicity. Recurrent diffuse alveolar damage is a rare manifestation of drug toxicity. We described an extremely rare case of recurrent diffuse alveolar damage caused by the antidepressant drug (paroxetine) resolved by a definitive suspension of the drug, after a recurrent respiratory failure because of inadvertently administering the drug. Keywords: drug toxicity, recurrent diffuse alveolar-damage, severe respiratory failure, antidepressant drug, paroxetine
INTRODUCTION Pulmonary drug toxicity is increasingly being diagnosed as a cause of acute and chronic lung disease. Numerous agents including cytotoxic and noncytotoxic drugs have the potential to cause pulmonary toxicity.1,2 Diffuse alveolar damage (DAD) is a common manifestation of pulmonary drug toxicity and is frequently caused by cytotoxic drugs, especially cyclophosphamide, bleomycin, and carmustine.2 It manifests radiographically as bilateral patchy or homogeneous opacities usually in the mid and lower lungs and on high-resolution computed tomographic scans as scattered or diffuse areas of ground-glass opacity. DAD is a common manifestation of drug-induced lung injury that results from necrosis of type II pneumocytes and alveolar endothelial cells.2,3
1
Respiratory Diseases Unit, Hospital of Sestri Levante, Sestri Levante, Italy; 2Histopathology Unit, Hospital of Sestri Levante, Sestri Levante, Italy; 3Department of Pathology, Ospedali Civili Brescia, Brescia, Italy; and 4Forensic Medicine ASL4, Chiavari, Italy. The authors have no conflicts of interest to declare. *Address for correspondence: Respiratory Diseases Unit, Via Terzi 43, 16039 Sestri Levante, Italy. E-mail: [email protected]
Histopathologically, DAD is divided into an acute exudative phase and a late reparative or proliferative phase.2,3 The exudative phase, which is characterized by alveolar and interstitial edema and hyaline membranes, is most prominent in the first week after lung injury.2–4 The reparative phase, which is characterized by proliferation of type II pneumocytes and interstitial fibrosis, typically occurs after 1 or 2 weeks after the onset of DAD.2–4 Depending on the severity of the injury, fibrosis can improve significantly, remain stable, or progress to honeycomb lung.2,4 Progression to diffuse opacification is not uncommon. With progressive fibrosis, marked architectural distortion can occur.2 The end result may be physiologically useless honeycomb lung tissue. Clinically, DAD produces respiratory failure, and most patients fit into the spectrum of the acute respiratory distress syndrome. Mortality rates approach 50%, but those who survive the acute event usually recover with minimal pulmonary damage.2,3 Patients with DAD present with dyspnea, cough, and occasionally fever. Diffusing capacity for carbon monoxide (DLCO) is characteristically decreased. Recurrent DAD is a rare manifestation of drug toxicity, and sporadic cases have been reported in the literature. We described an extremely rare case of recurrent case of DAD caused by the antidepressant drug (paroxetine) resolved with the suspension of
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www.americantherapeutics.com
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e44
Antonello et al
drug. To our knowledge, this is the first case to be reported in the English language medical literature because of paroxetine administration.
PATIENT CASE PRESENTATION A 41-year-old woman suffering from idiopathic alveolar proteinosis (PAP) (biopsy confirmed) (PAP) was referred to intensive care unit because of respiratory failure: PaO2/FiO2 (P/F) ratio 130, severe respiratory acidosis (pH 6.96 and paCO2 112), tachypnea (respiratory rate: 40 breaths per minute), tachycardia (pulse: 130 beats minute), fever (temperature: 38.8°C), and stupor. Before admission, she was given a 7-day course of clarithromycin for an upper respiratory tract infection. In the week before the admission, dyspnea had progressively increased. The patient has been treated with antidepressant drugs for 6 months (paroxetine 20 mg/d). In the month before admission, she complained of dyspnea and mucus expectoration. In the week before admission, dyspnea was present also at rest. Admission chest x-ray showed diffuse bilateral interstitial and alveolar infiltrates (Figure 1A); computed tomography scan of the thorax showed diffuse asymmetric alveolar infiltrates, ground-glass opacities associated with reticulonodular pattern (Figure 1B). Arterial blood gas performed by administering oxygen FiO2 60% by Venturi mask showed a severe acidosis (PaO2 44 mm Hg, PaCO2 121, pH 6.96). Thirty minutes after admission to the intensive care unit, the patient was invasively ventilated by pressure-controlled ventilation: inspiratory positive airway pressure, 28 cm H2O; positive end expiratory pressure (PEEP), 15 cmH20; respiratory rate, 16 per minute; and FiO2, 80% with a tidal volume of 290 mL. Arterial blood gas analysis revealed worsening parameters: pH 6.73, PaCO2 170 mm Hg, and PaO2 112 mm Hg. The ventilation was modified, increasing PEEP to 20 cmH2O. Improved blood gas values were noted 12 hours later (pH 7.23, PaCO2 62.5, PaO2 109 with P/F ratio 234). Twenty-four hours later, a normal pH was achieved (pH 7.35, PaCO2 50, PaO2 112); PEEP was reduced (12 cmH2O). Broadspectrum antibiotics (piperacillin + tazobactam 18 g in continuous infusion + levofloxacin 1000 mg every 24 hours) and antimycotic therapy associated with stress doses of methylprednisolne 250 mg intravenously per 24 hours were initiated during the admission. The white blood cell count was 3800 with 85% polymorphonuclear leukocytes with relative lymphopenia (3.2%); the hematocrit was 42%, hemoglobin 11.8 g/mL, C-reactive protein (CRP) 20.44 mg/L, and lactate dehydrogenase (LDH) 2058 U/L. Urinary antigen tests for Legionella pneumophila and Streptococcus pneumoniae American Journal of Therapeutics (2015) 22(2)
FIGURE 1. (A) Chest x-ray diffuse bilateral interstitial and alveolar opacities. (B) Chest computed tomography: diffuse asymmetric alveolar opacities associated with ground-glass opacities and reticulonodular pattern. (C) Open lung biopsy: focal interstitial fibroplasia with pneumocyte hyperplasia consistent with organizing alveolar damage. E-E 34.
were negative, as were IgM antibodies for Mycoplasma pneumoniae. Polymerase chain reaction for the identification of adenovirus, human coronavirus, metapneumovirus, Chlamydia pneumoniae, Haemphilus influenzae, www.americantherapeutics.com
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Pulmonary Drug Toxicity Caused by Paroxetine
L. pneumophila, M. pneumoniae, and S. pneumoniae were negative. Antigens of Aspergillus and Ziehl–Neelsen stain for acid-fast bacilli and nucleoid acid amplification tests to identify Mycobacterium tuberculosis in blood and broncho–alveolar lavage (BAL) were also negative. BAL cytology showed neutrophilic alveolitis. Granulocytemacrophage colony-stimulating factor auto-antibodies were negative. The radiographic abnormalities gradually cleared; PEEP was progressively reduced. The laboratory data improved (white blood cell 7230, LDH 633 U, and C-RP 0.70). The patient was transferred to the Respiratory Diseases Unit a week later. Pulmonary function tests showed a mild restrictive syndrome: forced vital capacity (FVC) 74.4% of predicted, forced expiratory volume in 1 second (FEV1) 78.5% of predicted, total lung capacity 77.8% of predicted, FEV1/ FVC 90.2%, and a moderate–severe reduction of diffusion capacity for CO (DLCO) (40.5%). The clinical and radiologic picture improved progressively, and the patient was transferred 42 days after admission to the Thoracic Surgical Department to undergo open-lung biopsy. The pathological findings of 3 surgical lung biopsies performed from lower right lobe, the largest being 2.5 3 1 3 0.7 cm were: no gross lesions were identified. On microscopy, lung parenchyma was characterized by the presence of multifocal alveolar septa thickening by edema and fibroplasia associated with reactive pneumocyte hyperplasia. Mild interstitial inflammatory infiltrate and foamy macrophages in airspaces were also seen. Mucus in some bronchiolar lumens and thickening of some arterial wall were additional features. No microorganisms were found. Pulmonary alterations were thought to be the expression of subacute and organizing diffuse alveolar damage of yet-undefined cause (Figure 1C). Three weeks after the discharge from the Thoracic Surgical Departments, the patient following the prescription of a psychiatric consultant again took paroxetine (which was been stopped after intensive care unit admission). Two months later, the patient complained again sudden dyspnea with tachypnea (respiratory rate: 36 breaths per minute) and respiratory discomfort. She was taken to the Emergency Department where a severe respiratory failure was diagnosed (paO2 70 with FiO2 40%, paCO2 31.2, pH 7.49, and paO2/FiO2 ratio 175). Computed chest tomography showed diffuse ground-glass opacities associated with reticulonodular pattern (Figure 2A). The patient was admitted to intensive care unit and treated with noninvasive ventilation –continuous positive airway pressure–(CPAP) delivered by helmet with PEEP 12 cmH20. An hour later, the gas exchange improved (paO2 84 with FiO2 40%, paCO2 34, pH 7.48, paO2/FiO2 ratio 210) and she continued noninvasive ventilation.5 The most www.americantherapeutics.com
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FIGURE 2. (A) Chest computed tomography: diffuse ground-glass opacities associated with reticulo-nodular pattern. (B). Chest computed tomography: nearly complete resolution of radiographic picture 2 years later stopping paroxetine.
significant laboratory data were the red cell count being 3,880,000, white cell count 21,850 (neutrophils 80.5% and lymphocytes 13.4%), platelets 521000, Creactive protein 16.47 mg/dL, and LDH 878 U/L. Urinary antigen tests for L. pneumophila and S. pneumoniae were negative, as were IgM antibodies for M. pneumoniae. The patients were treated with broad-spectrum antibiotics and high dose of corticosteroids (methylprednisolone 250 mg per 24 hours). In few days, the clinical picture improved as respiratory exchanges (paO2 103 with FiO2 24%, paCO2 38.3, pH 7.43, PaO2/FiO2 ratio 431) normalized. The noninvasive ventilation was stopped and she was transferred to the Respiratory Diseases Unit. The spirometric values at admission of the patient were: FVC 72.0%, FEV1 77.2%, FEV1/FVC 91.3%, total lung capacity 78.5%, residual volume (RV) 86.9%, and DLCO 60.5%. The patient underwent flexible bronchoscopy American Journal of Therapeutics (2015) 22(2)
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Antonello et al
and BAL. BAL cytology showed neutrophilic alveolitis. In consideration of the clinical history of the patient and the BAL findings, paroxetine was definitively discontinued.1,6 After 6 months, functional respiratory values returned to the range of normality, and the radiological finding progressively improved. The patient was followed for more than 2 years and did not present further episodes of acute respiratory failure. The computed tomography of the chest performed 2 years later after the second discharge shows a nearly complete resolution (Figure 2B). Naranjo algorithm for determining the likelihood of adverse drug reaction assigned a score of 9 (definite adverse drug reaction). The definitive diagnosis was drug-induced (paroxetine) recurrent DAD. The patient gave consent for publication of her case report.
DISCUSSION The clinical and radiological manifestations of this drug-mediated “collateral damage” generally reflect histopathological changes (Table 1). These alterations include DAD, nonspecific interstitial pneumonia, organizing pneumonia, eosinophilic pneumonia, and obliterative bronchiolitis, and also pulmonary hemorrhage, edema, hypertension, or veno-occlusive disease.1,7,8 Diffuse alveolar damage is the classic histological manifestation of acute respiratory distress syndrome. Clinically, patients present with severe hypoxemia and typically require mechanical ventilation. The histological findings will vary depending on when a biopsy is obtained during the course of the disease. The damage to the capillary endothelium and alveolar epithelium results in exudation of edema fluid and cellular
breakdown products, with subsequent pneumocyte hyperplasia and fibroblastic proliferation as the lung attempts to repair the damage. The entire process is propagated by a complex and ever-expanding collection of cytokines and other cellular factors. Response to corticosteroid therapy in patients with drug-induced DAD is variable and may depend on the inciting drug, severity of the reaction, and promptness of the therapeutic intervention.6–9 Histopathologically, DAD is typically divided into 2 phases: the acute/exudative phase and the organizing/proliferative phase. The acute phase generally occurs during the first week after pulmonary insult, with the organizing phase occurring after the first week after pulmonary insult with the organizing phase occurring after the first week; however, the processes actually represent a continuum and overlapping features may be encountered, particularly late in the first week. Some authors additionally include a final fibrotic stage. The acute/exudative phase is usually easily recognizable. The findings are generally diffuse and relatively uniform, but may occasionally be more focal. Although the earliest changes may be seen only ultrastructurally, by day intraalveolar edema and interstitial widening are apparent.7,9 Hyaline membranes may be seen at this point and may reach a peak 4–5 days after the initial insult. Hyaline membranes are composed of cellular and proteinaceous debris and appear as dense glassy eosinophilic membranes lining the alveolar ducts and alveolar spaces. The hyaline membranes characteristic of the acute phase gradually disappear as they become incorporated into the alveolar septa; however, residual hyaline membranes may be identifiable depending on the timing of the biopsy in the course of disease. The fibrosis in DAD tends to be loose, and myxoid and will appear bluishgray on hematoxylin–eosin sections, in contrast to the
Table 1. Principal histopathologic manifestations of pulmonary drug toxicity. Mechanism of injury Diffuse alveolar damage (DAD)
Nonspecific interstitial pneumonia Organizing pneumonia (OP)
Eosinophilic pneumonia Pulmonary hemorrhage
Drugs Bleomycin, busulfan, carmustine, cyclophosphamide mitomycin, melphalan, gold salts, morphine, codeine, cisapride, lansoprazole, lorazepam, methadone, sertraline, paroxetine, fluoxetine, venlafaxine, hydroxizine, alprazolam, temazepam, and gabapentin Amiodarone, methotrexate, carmustine, and chlorambucil Bleomycin, gold salts, methotrexate, amiodarone, nitrofurantoin, penicillamine, sulfasalazine, cyclophosphamide methadone, lorazepam, zolpidem, and omeprazole Penicillamine, sulfasalazine, nitrofurantoin, para-aminosalicylic acid, and nonsteroidal antiinflammatory drugs Anticoagulants, amphotericin B, cytarabine (ara-C), penicillamine, and cyclophosphamide
American Journal of Therapeutics (2015) 22(2)
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Pulmonary Drug Toxicity Caused by Paroxetine
collagenous fibrosis typically seen in other disorders such as nonspecific interstitial pneumonia and usual interstitial pneumonia. Organizing fibroblastic tissue may be observed in airspaces, particularly the alveolar ducts (alveolar duct fibrosis). After the organizing phase, some cases of DAD will gradually resolve, whereas others may develop continued interstitial fibrosis with architectural remodeling and progressive respiratory compromise.6–9 The histological findings of DAD may result from a large number of potential etiologies that include numerous infectious agents, drug reactions, collagen vascular/immune-mediated diseases, ingestant/ inhalant exposure, shock, sepsis, and numerous other agents.7,10–12 DAD is one of the many histopathological patterns seen in drug-induced lung disease and has been associated with many pharmacologic agents, most commonly chemotherapy drugs such as bleomycin. Response to corticosteroid therapy in patients with drug-induced DAD is variable and may depend on the inciting drug, severity of the reaction, and promptness of the therapeutic intervention.10 It is well known that DAD is often associated with antineoplastic drugs, amiodarone, and drugs of abuse.7,10 Rarely it has been related to psychotropic drugs.6,12,13 Several types of antidepressant have been implicated6: amitriptyline,6 venlafaxina,6,9 sertraline,9,12 fluoxetine.9 The last 2 are selective serotonin uptake inhibitors as is paroxetine. Other psycho-active drugs such as lithium,6 promethazine, zolpidem and the benzodiazepines lorazepam, alprazolam, and temazepam have been implicated.9 Sporadic cases are reported in literature; however, the most of the described cases were not established by applying a probability scale,6,9,12 but only with simple temporal or/and causal relationship. Only Torok et al13 described a case with drug dechallenge and rechallenge in support to radiological and histopathological findings. The largest case report of recurrent DAD was published by Savici and Katzenstein,12 who reported 6 cases of recurrent DAD. In 3 of the 6 cases, antidepressant drugs were involved.
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CONCLUSIONS This case demonstrates the relation of a common antidepressant drug causing severe lung disease, after excluding other causes, in support of radiological and histopathological picture of drug-induced lung injury.
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American Journal of Therapeutics (2015) 22(2)
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