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Case Reports Diffuse Alveolar Hemorrhage with Underlying Pulmonary Capillaritis in the Retinoic Acid Syndrome MARK R. NICOLLS, LANCE S. TERADA, RUBIN M. TUDER, SHEILA A. PRINDIVILLE, and MARVIN I. SCHWARZ Division of Pulmonary Sciences and Critical Care Medicine, Department of Pathology, Division of Hematology and Oncology, and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado

All-trans-retinoic acid (ATRA) can induce a clinical remission in patients with acute promyelocytic leukemia. An adverse condition called “retinoic acid syndrome” limits this therapy. It is characterized by fever and respiratory distress, along with weight gain, pleural or pericardial effusions, peripheral edema, thromboembolic events, and intermittent hypotension. The lung disease has been previously ascribed to an infiltration of leukemic or maturing myeloid cells into lung parenchyma, which is sometimes associated with pleural effusions and diffuse alveolar hemorrhage. We report a case of retinoic acid syndrome in an 18-yr-old woman who developed diffuse alveolar hemorrhage while being treated with ATRA for acute promyelocytic leukemia. An open lung biopsy revealed pulmonary capillaritis. Nicolls MR, Terada LS, Tuder RM, Prindiville SA, Schwarz MI. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. AM J RESPIR CRIT CARE MED 1998;158:1302–1305.

The retinoic acid syndrome was first described in 1991 by Frankel and colleagues (1). The syndrome occurred in 9 of 35 patients treated with all-trans-retinoic acid (ATRA), beginning 2–21 d after treatment began. The primary symptoms were fever and respiratory distress. Other findings included weight gain, lower-extremity edema, pleural or pericardial effusions, diffuse alveolar hemorrhage, cerebral hemorrhage, headache, elevated intracranial pressure, nausea and vomiting, skin reactions, bone pain, tonsillar or cervical lymphadenopathy, pericarditis, intermittent hypotension, and thromboembolism (2–4). Characteristic laboratory findings are leukocytosis and disseminated intravascular coagulation (DIC) in some and hyperbilirubinemia, hypertriglyceridemia, and elevated creatinine in others (4). Chest radiographs indicated bilateral diffuse alveolar or interstitial infiltrates, occasionally with pleural effusions (2). One case of ATRA-associated pneumothorax

(Received in original form September 22, 1997 and in revised form December 4, 1997) Supported by Specialized Centers of Research grant HL27353-04 from the National Heart, Lung, and Blood Institute/National Institutes of Health (NHLBI/ NIH). Dr. Nicolls’ work was supported by NHLBI/NIH training grant 5T32HL07085-23. Correspondence and requests for reprints should be addressed to Marvin I. Schwarz, M.D., The James C. Campbell Professor of Pulmonary Medicine, Head, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Box C272, 4200 East 9th Avenue, Denver, CO 80262. Am J Respir Crit Care Med Vol 158. pp 1302–1305, 1998 Internet address: www.atsjournals.org

has been described (5). The most consistent computed tomographic findings of the lung are small, peripheral nodules and pleural effusions with occasional evidence of ground-glass opacification and reticular shadowing. Often, high-dose corticosteroids reverse this syndrome (2). As experience with ATRA therapy continues and the side-effect profile becomes more extensive, the definition of the retinoic acid syndrome may broaden.

CASE REPORT An 18-yr-old Hispanic female was admitted to the hospital for headaches, bleeding gums, excessive menstrual bleeding, and easy bruisability. Her coagulation studies indicated DIC (Table 1). A bone marrow biopsy demonstrated promyelocytic leukemia (M3) with a 15/17 translocation. A chest radiograph taken at this time was normal. Therapy with ATRA and dexamethasone was initiated. Five days later, her white blood cell count rose to 50,000 and hydroxyurea was started. Four days after that, she developed bilateral knee pain and mild mouth bleeding; laboratory studies showed DIC. She was re-admitted at this time and recovered with corticosteroid therapy. As corticosteroids were being tapered, she developed transient mild hematochezia and vaginal bleeding, which resolved completely over several days. A chest radiograph obtained 10 d after her first admission remained normal. Sixteen days after her original presentation (and 15 d after beginning ATRA), she developed significant hemoptysis. This resulted in respiratory failure, requiring mechanical ventilation. When she was transferred to the intensive care unit (ICU)

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Case Report TABLE 1 LABORATORY AND CLINICAL VALUES ON ADMISSION AND AFTER TREATMENT WITH ALL-TRANS-RETINOIC ACID Variable Hematocrit, % White-cell count, per mm3 Differential, % Neutrophils Band forms Metamyelocytes Promyelocytes Myelocytes Lymphocytes Monocytes Eosinophils Basophils Platelet count, per mm3 Prothrombin time, s Partial thromboplastin time, s Fibrin split products, mg/ml Fibrinogen, mg/dl Thrombin time, s D-dimer, mg/ml Steroid/dose Oxygen saturation

Day 1 First Admission*

Day 10 Second Admission

Day 12

Day 14

Day 17 ICU Admission

Day 18

22.8 7.7

35.6 71.2

35.1 50.8

28.6 16.0

24.4 6.4

24 10.2

4.0 4.0

16 14 18 1 24 38 6 0 0 37 45.6 47.4 80 44 21.6 8.0 dexamethasone/ 10 mg i.v. bid 96% (RA)

20 8 10 5 1 7 49 0 0 32 20.2 45.3 160 139 43.1 8.0 dexamethasone/ 10 mg i.v. bid 94% (RA)

58 32 2

12 15.8 20 . 80 124 12.5 dexamethasone/ 10 mg i.v. bid 98% (RA)

38 22 9 2

74 6 1

21 2 0 0 36 16.2 33.6 80 172 20.0

47 13.8 31 80 225 11.7

dexamethasone/ 10 mg i.v. qd 96% (RA)

dexamethasone/ 10 mg i.v. qd 71% (RA)

14 5 0 0 100 14.2 34 20 454 13.3 2.0 dexamethasone/ 10 mg i.v. bid 98% intubated FIO2 5 0.80

Definition of abbreviations: RA 5 room air; i.v. 5 intravenous; bid 5 twice a day; qd 5 once a day. * Therapy with ATRA and dexamethasone was started.

on Day 17, the patient was receiving dexamethasone (10 mg a day given intravenously), ATRA, hydroxyurea, and allopurinol. There was no family history of malignancy or a theumatologic condition. She was a student with no known history of alcohol, tobacco, or drug abuse. Examination revealed an intubated young Hispanic woman with bright red endotracheal secretions. Her temperature was 39.18 C; blood pressure, 140/ 70 mm Hg; and pulse, 118. Her examination was remarkable for thigh ecchymoses, blood oral secretions, and diffuse rhonchi. Laboratory values from the time of the ward admission to the time of transfer to the ICU showed resolving DIC (Table 1). Her chest radiograph showed bilateral alveolar infiltrates (Figure 1). Blood cultures subsequently became positive for streptococcus anginous. Urine culture grew more than 100,000/ ml enterococcus. The patient was started on antibiotics, and all subsequent cultures were negative. A bronchoscopy was performed, and bronchoalveolar lavage revealed a sequential hemorrhagic return consistent with diffuse alveolar hemorrhage. Two days after admission to the ICU, the DIC had resolved, but the patient continued to have significant pulmonary hemorrhage requiring transfusion with a total of 10 U of packed red blood cells and 40 U of platelets. There were no other sites of blood loss. In order to exclude a viral or autoimmune process, an open-lung biopsy was performed. The lung biopsy showed diffuse interstitial neutrophilic infiltration, and many of these cells were fragmented. There were also interstitial fibrinoid necrosis and diffuse alveolar hemorrhage (Figure 2). These findings are consistent with pulmonary capillaritis. Special stains for acid-fast bacilli, fungi, cytomegalovirus, and herpes simplex virus were all negative. Immunostains were performed on frozen tissue by the direct immunofluorescence technique employing polyclonal antibodies to immunoglobulin (Ig)G, IgA, IgM, C3, C1q, and fibrinogen. There was no evidence of immune complex deposition by fluorescence microscopy. Serology for antinuclear antibody, rheumatoid factor, and antinuclear cytoplasmic antibody was also negative.

The patient was given 1 g methylprednisolone intravenously, daily for 3 d. In succeeding days, she recovered enough to be taken off the ventilator, and within 11 d, she no longer needed supplemental oxygen. She was discharged from the hospital on a prednisone taper and ATRA. The patient completed a full 45-d course of ATRA. The corticosteroids were tapered off as she finished this course (3–4 wk after suffering pulmonary capillaritis). Sixteen months later, the patient was in complete remission after having received consolidation che-

Figure 1. Chest radiograph demonstrating diffuse alveolar filling and dense consolidation on the right.

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Figure 2. Lung parenchyma showing infiltration of alveolar septa by neutrophils (thin arrow) associated with fibrinoid fragmentation of the alveolar septal wall (thick arrow) and alveolar hemorrhage (hematoxylin and eosin, original magnification: 3200).

motherapy with cytosine arabinoside (AraC) and daunorubicin. As of late 1997, she had no pulmonary complaints, and her chest radiograph was normal.

DISCUSSION All-trans-retinoic acid is an emerging therapy for the acute treatment of promyelocytic leukemia because it promotes terminal differentiation of myeloid precursors (6–8). Although ATRA induces an effective hematologic remission, it is limited by the development of retinoid resistance, leukocytosis, and the retinoic acid syndrome. This syndrome refers to a constellation of findings including unexplained fever, fluid retention, multiple sites of hemorrhage, organ failure, and thrombotic events (4, 9). Pulmonary complications have been described as (1) respiratory distress, pleural effusions, and diffuse alveolar hemorrhage associated with interstitial infiltration of maturing myeloid or leukemic cells (2, 5); (2) a sterile infiltration of neutrophilic granulocytes into the lung as a manifestation of Sweet’s Syndrome, which was described in two ATRA-treated patients who developed infiltration of skin and internal organs by neutrophilic granulocytes, leading to fever, painful erythematous cutaneous plaques, myositis, fasciitis, and proteinuria (10); (3) pulmonary leukostasis in the absence of significant leukocytosis, which was described in one patient (11); and (4) pneumothorax, which has been described in one patient (5). In this report, we describe for the first time the occurrence of pulmonary capillaritis following ATRA therapy. Pulmo-

nary capillaritis developed 2 wk after ATRA treatment started, timing similar to development of retinoic acid syndrome. Pulmonary capillaritis is distinguished by a neutrophilic invasion of the alveolar interstitium with fibrinoid necrosis and capillary thrombosis. The neutrophils fragment and there is a subsequent loss of integrity in the alveolar capillary basement membrane, with leakage of red blood cells in the alveolar space (12, 13). By contrast, a biopsy from a previously described case of retinoic acid syndrome (2) showed maturing myeloid cells invading lung parenchyma without pulmonary capillaritis. None of the conditions known to be associated with pulmonary capillaritis, such as systemic vasculitis or a collagen vascular disease, were present in this patient. In addition, isolated, severe pulmonary bleeding occurred while the patient’s DIC was resolving, suggesting that the diffuse alveolar hemorrhage was not the result of coagulopathy. This is, therefore, the first documented case of ATRA-associated pulmonary capillaritis. It is possible that pulmonary capillaritis represents one end of a spectrum of alveolar involvement in the retinoic acid syndrome, with the previously described leukemic or myeloid cell invasion at the other end. Accordingly, neutrophils, presumably derived from normal hematopoiesis, appear 15 d after the initiation of therapy (14), approximately the time this patient developed fever and respiratory distress due to diffuse alveolar hemorrhage with underlying pulmonary capillaritis. The decision to continue ATRA in the face of pulmonary hemorrhage was a difficult one. Initially, there was debate

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whether pulmonary capillaritis in this patient was indeed a manifestation of the retinoic acid syndrome. There was also some delay in ruling out other causes of pulmonary capillaritis. Frankel and colleagues (2) presented two illustrative case reports of the syndrome. In the first case, ATRA was discontinued, and the patient eventually died of multiple organ failure. In the second, ATRA was continued; the patient was treated with corticosteroids and survived. A review (9) included the statement that, for retinoic acid syndrome, discontinuation of the drug is probably not effective. This patient appeared to respond quickly to high-dose methylprednisolone because her oxygenation significantly improved within 12 h of treatment, despite ongoing ATRA therapy. The standard treatment for retinoic acid syndrome is 10 mg of dexamethasone intravenously every 12 h for at least 3 d (2). This patient received a longer course, given the severity of her presentation, in spite of continued ATRA therapy. There are several possible explanations for the development of pulmonary capillaritis from ATRA. The drug increases expression of the adherence ligands VLA4, lymphocyte function–associated antigen 1, and macrophage antigen 1 on the surface of leukemic myeloid cells, increasing their attachment to endothelial cells (15). It also induces endothelial cell expression of intercellular adhesion molecule-1, which facilitates neutrophil attachment and activation. These and other adhesion molecules collectively regulate trafficking of leukocytes into various organs (16). In addition, ATRA increases the chemotactic response of leukemic cells to interleukin-8 in vitro and increases actin polymerization in cytokinestimulated neutrophils, which may increase their entrapment in the pulmonary vascular bed (17, 18). Thus, ATRA promotes various cellular processes that could potentially promote influx of neutrophils into the lung parenchyma, causing pulmonary capillaritis. Because the histologic features of this care are indistinguishable from cases of pulmonary capillaritis due to other causes, it strengthens the notion that pulmonary capillaritis is a syndrome marked by the abnormal retention of neutrophils in the lung and their subsequent activation in the vascular and interstitial spaces. The specific factors leading to neutrophil activation may vary in pulmonary capillaritis depending on the underlying disease state. It is also notable that, in the present case, diffuse alveolar hemorrhage occurred as corticosteroids were being tapered, then remitted after high-dose treatment was resumed. In addition to known corticosteroid effects on immune function, dexamethasone diminishes the concentration of cellular retinol binding protein I and cellular retinoic acid receptor-b mRNA (19). This effect may, in part, explain the therapeutic role of corticosteroids in this syndrome. All-trans-retinoic acid and its related retinoid compounds have other applications in the lung. Retinoids have been demonstrated as necessary for the regulation of embryologic, fetal, and adult pulmonary development (20). Elastase-induced emphysema in rats was reversed after ATRA treatment (21). Finally, retinoids are currently being evaluated in lung cancer chemoprevention trials (22). Such a wide spectrum of activity for this class of compounds underscores the importance of further evaluating its properties in disease and nondisease states. Acknowledgment : The authors thank Raymond P. Warrell, Jr., M.D., for generously providing the latter pathological specimen cited in the DISCUSSION section of this article.

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