Diffuse Alveolar Hemorrhage in Acute Myeloid Leukemia Sowmya Nanjappa, MBBS, MD, Daniel K

Case Series

Diffuse Alveolar Hemorrhage in Acute Myeloid Leukemia Sowmya Nanjappa, MBBS, MD, Daniel K. Jeong, MD, Manjunath Muddaraju, MD, Katherine Jeong, MD, Eboné D. Hill, MD, and John N. Greene, MD

Summary: Diffuse alveolar hemorrhage is a potentially fatal pulmonary disease syndrome that affects individuals with hematological and nonhematological malignancies. The range of inciting factors is wide for this syndrome and includes thrombocytopenia, underlying infection, coagulopathy, and the frequent use of anticoagulants, given the high incidence of venous thrombosis in this population. Dyspnea, fever, and cough are commonly presenting symptoms. However, clinical manifestations can be variable. Obvious bleeding (hemoptysis) is not always present and can pose a potential diagnostic challenge. Without prompt treatment, hypoxia that rapidly progresses to respiratory failure can occur. Diagnosis is primarily based on radiological and bronchoscopic findings. This syndrome is especially common in patients with hematological malignancies, given an even greater propensity for thrombocytopenia as a result of bone marrow suppression as well as the often prolonged immunosuppression in this patient population. The syndrome also has an increased incidence in individuals with hematological malignancies who have received a bone marrow transplant. We present a case series of 5 patients with acute myeloid leukemia presenting with diffuse alveolar hemorrhage at our institution. A comparison of clinical manifestations, radiographic findings, treatment course, and outcomes are described. A review of the literature and general overview of the diagnostic evaluation, differential diagnoses, pathophysiology, and treatment of this syndrome are discussed.

Introduction 5 patients. The median patient age was 57 years (range, Diffuse alveolar hemorrhage (DAH) is a potentially fa- 51–70 years). Three (60%) patients were women. No tal pulmonary disease that affects individuals with can- congruity was observed on the AML subtype diag- cer and hematological/nonhematological malignan- nosed by pathology. Two (40%) patients had received cies. Clinicians caring for patients with acute myeloid allogeneic hematopoietic stem cell transplantation leukemia (AML) must maintain a high index of sus- (HSCT) with matched unrelated donors in the year picion for DAH, because these patients are immuno- prior to developing DAH, whereas the other 3 patients compromised by their underlying disease process and were receiving induction chemotherapy (7 days stan- subsequently at increased risk because they typically dard-dose cytarabine plus 3 days of daunorubicin). receive treatment with immunosuppressive agents and The 2 patients who received HSCT had prior pulmo- stem cell transplantation. Here we present a case series nary function tests available, with results revealing de- of 5 patients with AML who developed DAH. We also creased diffusing lung capacity for carbon monoxide review the clinical presentation, diagnostic evaluation, of below 80%. Three patients had a history of a prior differential diagnosis, and therapeutic management of or underlying pulmonary disorder, including 1 patient this potentially life-threatening clinical syndrome. with a history of left lower lobe resection, 1 patient with a history of chronic obstructive pulmonary dis- Case Series ease, and 2 patients with a history of cryptogenic-or- Table 1 summarizes the clinical characteristics for the ganizing pneumonia. One patient had a history of an unknown autoimmune disorder affecting his ear. Each patient’s clinical presentation was different. From the Departments of Internal Medicine (SN, KJ, EDH), Radi- One patient presented with fever at the time of diag- ology (DKJ), and Infectious Diseases (JNG), H. Lee Moffitt Cancer Center & Research Institute, Department of Oncologic Sciences nosis of DAH (by bronchoscopy). Four patients devel- (SN, DKJ, EDH), University of South Florida Morsani College of oped hypoxia with increasing oxygen requirements Medicine, Tampa, Florida, and the Department of Critical Care and dyspnea. Three patients complained of cough, and Medicine (MM), SSM St Mary’s Health Center, St Louis, Missouri. 2 patients presented with bleeding at other sites in the Address correspondence to Sowmya Nanjappa, MBBS, MD, and John N. Greene, MD, Moffitt Cancer Center, 12902 Magnolia Drive, form of epistaxis. One patient had hemoptysis and that Tampa, FL 33612. E-mails: [email protected] and patient was neither hypoxic nor dyspneic at the time. [email protected] All patients were thrombocytopenic and anemic. Submitted February 17, 2016; accepted March 4, 2016. On radiological imaging, all 5 patients had bilateral, No significant relationships exist between the authors and the com- panies/organizations whose products or services may be referenced ground-glass pulmonary opacities on computed tomog- in this article. raphy (CT). In 3 patients, the findings of bronchoalveo-

272 Cancer Control July 2016, Vol. 23, No. 3 lar lavage (BAL) on bronchoscopy confirmed the diag- tor VII. Three patients died due to hypoxic respiratory nosis of DAH by retrieving progressively bloody effluent failure within 30 days of confirming the DAH diagno- on BAL. DAH was suspected in 1 patient by her clinical sis by bronchoscopy. The other 2 patients did not re- syndrome and pinkish effluent on BAL, and 1 patient quire intubation and were weaned off supplemental had suspected DAH based on documentation of bloody oxygen and discharged home in stable condition. secretions noted from bronchoscopy performed at a different institution. Although none of the cultures taken Discussion during bronchoscopy in the 5 patients revealed an un- DAH is a clinical syndrome defined by a disturbance of derlying infectious process, all patients were being em- the alveolar-capillary basement membrane that causes pirically given broad-spectrum antibiotics. bleeding into the pulmonary alveoli.1 It is a final, com- All 5 patients were treated with high-dose steroids mon pathway for a variety of underlying issues affect- and 1 patient also received aminocaproic acid and fac- ing the lungs, including autoimmune vasculitides, drug

Table 1. — Select Clinical Characteristics of Study Patients Patient Sex Age, Malignancy Oncological Pulmonary Exposure Symptoms Bleeding at Available Vitals WBC, Hemo- Platelet y Therapy Disease to Antico- Other Sites on Presentation 103/ globin, Count, at DAH History agulants mcL g/dL 103/mcL Diagnosis 1 M 63 AML 7 + 3 induction COP No Cough Epistaxis BP: 124/78 mm Hg 3.74 7.4 14 (FAB, M5a) LLL resection Dyspnea HR: 102 beats/ Unknown Fever minute autoimmune Hypoxia RR: 20 breaths/ disorder minute Temp: 98.8 °F 2 F 51 AML MUD COP Prophy- Cough Epistaxis BP: 121/80 mm Hg 0.02 8.1 35 (FAB, M1 Allogenic COPD lactic Fever Hemoptysis HR: 109 beats/ in relapse) HSCT dalteparin minute Rhinovirus (5000 U) Hemoptysis RR: 20 breaths/ minute

O2 saturation: 96% on room air Temp: 98.7 °F

3 M 70 ALL Reinduction Nodular No Dyspnea No BP: 99/51 mm Hg 0.03 7.4 5 (WHO, MEC pneumonia Hypoxia HR: 76 beats/ therapy- Suspected minute related sleep apnea myeloid RR: 17 breaths/ neoplasms) minute Temp: 97.7 °F 4 F 57 AML MUD None No Dyspnea No BP: 127/71 mm Hg 0.30 9.8 15 (WHO, with Allogenic Hypoxia HR: 78 beats/ myelodys- HSCT minute plasia-related Left chest changes) wall pain RR: 30 breaths/ minute

O2 saturation: 97% on room air Temp: 97.8 °F 5 F 56 AML 7 + 3 induction None No Cough No BP: 139/88 mm Hg 95.10 7.1 20 (FAB, M4) Dyspnea HR: 109 beats/ Hypoxia minute RR: 22 breaths/ minute

O2 saturation: 95% on room air Temp: 99.3 °F continued on the next page

July 2016, Vol. 23, No. 3 Cancer Control 273 Table 1. — Select Clinical Characteristics of Study Patients, continued Patient Pro- BAL CMV Cultures Medical Antibiotic Treatment Intubation Mortality Length calcitonin, Appearance PCR Treatment of ng/mL Respiratory Sputum Blood for DAH Given on Duration Hospital Admission Stay, d 1 NR Bloody Negative Negative No Negative Steroids None NA Yes Deceased 15 results 2 NR Bloody Negative Negative No VRE Aminocaproic Yes 41 d Yes Deceased 41 results Candida acid Received for glabrata Factor VII prolonged Steroids neutropenia, treatment of bacteremia 3 NR Bloody No Negative No Strepto- Steroids Yes 32 d No Alive 32 results results coccus Empiric mitis antibiotics for Strepto- neutropenia, coccus treatment of oralis bacteremia 4 0.23 Bloody No Negative No Negative Steroids Yes 10 d No Deceased 12 results results Empiric antibiotics for neutropenia 5 1.21 Pinkish No Negative No Negative Steroids Yes 22 d No Alive 22 results results Initially started for treatment of pneumonia Continued for prophy- laxis after prolonged neutropenia 7 + 3 = 7 days standard-dose cytarabine plus 3 days of daunorubicin, ALL = acute lymphocytic leukemia, AML = acute myeloid leukemia, BAL = bronchoal- veolar lavage, BP = blood pressure, CMV = cytomegalovirus, COP = cryptogenic organizing pneumonia, COPD = chronic obstructive pulmonary disease, DAH = diffuse alveolar hemorrhage, F = female, FAB = French American British classification, HR = heart rate, HSCT = hematopoietic stem cell transplantation, LLL = left lower lobe, M = male, MEC = mitoxantrone/etoposide/intermediate-dose cytarabine, MUD = matched unrelated donor, NR = not reported, PCR = polymerase chain reaction, RR = respiratory rate, Temp = temperature, VRE = vancomycin-resistant enterococci, WBC = white blood count, WHO = World Health Organization classification. toxicities, infections, organ transplantation, and radio- anticoagulants.2,7 Diffuse alveolar damage with edema therapy.1,2 Among patients with leukemia, DAH is one of of the alveolar septa without signs of lung inflammation the most common, noninfectious complications related or direct extravasation of red blood cells characterizes a to thrombocytopenia.2 In particular, DAH has been as- third pattern of DAH, with hyaline membranes forming sociated with patients following HSCT, with a reported along the alveolar spaces.7 Infections, transplantation, incidence of 3% to 20% in patients following HSCT and a including HSCT, and radiotherapy have all been associ- mortality rate that ranges from 50% to 80%.3 Early recog- ated with this pattern of DAH.7 nition and management is crucial given the potential for rapid progression and the high rate of mortality. Clinical Presentation DAH can be divided into 3 characteristic patterns In accordance with the patients in our case series, the on histological examination, thus reflecting different clinical signs and symptoms of DAH may vary. The pathophysiological mechanisms. The most common onset of symptoms is typically acute and nonspecific; presentation described is associated with pulmonary fever, cough, dyspnea, and chest pain are among the vasculitis or capillaritis and involves neutrophilic infil- most commonly presenting symptoms.1 tration and destruction of the pulmonary interstitium.2,7 Although hemoptysis may occur in up to This pattern of DAH is often caused by systemic auto- two-thirds of individuals with DAH, our case series immune vasculitides. Another characteristic pattern in- demonstrates that hemoptysis is often absent.1 A de- volves extravasation of red blood cells into the alveoli crease in hematocrit level should alert the clinician to without signs of vasculitis or inflammation, and it may possible DAH. Another report has underscored the ab- be seen with infections and a variety of drugs, including sence of hemoptysis in patients with DAH, so hemopty-

274 Cancer Control July 2016, Vol. 23, No. 3 sis alone is not a reliable indicator for diagnosing DAH.4 However, bleeding from other sites may support clinical suspicion for DAH.5 Our patients exhibited epistaxis, but other signs or symptoms of coagulopathy such as purpura may be present. Acute respiratory failure with hypoxia and an increasing oxygen requirement is also often seen as a presenting symptom.2 Findings on a pulmonary examination are typically nonspecific and may reveal tachypnea, crackles, or bronchial breath sounds. Although the underlying pathophysiology that leads to DAH following HSCT is not well understood, patients who have received stem cell transplants are often at greatest risk for DAH within the first 30 days following transplantation.1,3 DAH occurs in approximate- ly 5% of allogenic and autologous recipients and has a mortality rate that ranges from 50% to 100%.12 Other risk factors for DAH following HSCT include advanced age, myeloablative chemotherapy prior to transplantation, radiotherapy, and severe acute graft-vs-host 2 disease. Our 2 patients who received stem cell trans- Fig 1. — Posteroanterior radiograph of the chest demonstrates bilateral, plants did not have DAH in the early post-transplant multifocal opacities. period, but it is worth noting that patients with leukemia remain at risk given their underlying immunosuppression and hematological disorder. A

Diagnostic Evaluation Abnormal blood cell counts, including those resulting in anemia and leukocytosis, and elevated inflammatory markers are typical in the setting of DAH.1 However, in patients with AML, these laboratory abnormalities are often ubiquitous and, thus, are limited in offering diagnostic clues. Furthermore, prior research in patients receiving HSCTs has found that the initial degree of thrombocytopenia does not correlate with the develop- ment of DAH.2,6 Findings on pulmonary function tests in the setting of DAH are typically characterized by an increased diffusing lung capacity for carbon monoxide and decreased levels of exhaled nitric oxide.1 The pa- B tients in our case series had normal findings on pulmonary function testing, but these tests were performed prior to the onset of clinical symptoms of DAH. With the rapid progression and severity of DAH, patients are often unable to complete pulmonary function testing at the time of symptoms and diagnosis.6 Findings on chest radiography may appear normal or may show nonspecific, diffuse opacities reflec- tive of diffuse lung disease (Fig 1).2 CT of the chest will characteristically show diffuse or patchy, bilateral ground-glass opacities, as were seen in all 5 of our case patients (Fig 2).1 These opacities are often more centrally located and at the bases; they typically spare the periphery.3 In addition, interlobular septal thicken- ing may develop.2 Findings on CT are likely to rapidly Fig 2A–B. — (A) Axial CT of the chest demonstrates bilateral, multifocal 2 ground-glass opacities with a geographical distribution compatible with progress in conjunction with disease progression. Al- alveolar hemorrhage. (B) These opacities were acutely increased from though DAH is a clinical syndrome drawing together findings on CT obtained 5 days prior. clinical symptoms, laboratory abnormalities, and find- CT = computed tomography.

July 2016, Vol. 23, No. 3 Cancer Control 275 ings on imaging, bronchoscopy with BAL showing pro- It is important that clinicians remember that DAH gressively bloody effluent is usually diagnostic.7 When can disguise itself in areas of infection as well as in- it is performed, Prussian blue staining of the BAL fluid farction.2 As reflected in our case series, it seems rea- will characteristically reveal hemosiderin-laden mac- sonable to consider empirical antibiotic coverage while rophages or siderophages.3 Prussian blue staining was establishing a diagnosis. Furthermore, pulmonary ede- not performed in our case series. However, previous ma and prior injury from radiotherapy can complicate reports have attempted to define alveolar hemorrhage or obscure the diagnosis and should be worked-up and by the presence of at least 20% of siderophages on ex- treated if necessary.2 amination of BAL fluid samples to aid in the diagnosis In patients who have received HSCT, idiopathic when BAL findings are equivocal.6 pneumonia syndrome and engraftment syndrome should also be considered in the differential diagno- Differential Diagnosis sis.2 Engraftment syndrome is usually characterized Although it is essential to maintain a high index of sus- by noninfectious fever following HSCT, skin rash or picion for DAH, clinicians must also consider a broad erythroderma, and increased capillary permeability differential of alternative diagnoses. In addition, con- leading to pulmonary edema with similar radiologi- sideration should be given to the potential etiologies cal appearances to DAH.2 Engraftment syndrome oc- instigating DAH. Patients with leukemia may develop curs in 30% to 40% of patients following bone marrow DAH related to thrombocytopenia or another coagu- transplant, and it is thought to be related to cytokine lopathy triggered by the malignancy. These patients production during engraftment.3 Idiopathic pneumo- also often require treatment with anticoagulants given nia syndrome has been described in patients follow- their propensity for venous thrombosis. Other treat- ing HSCT, typically within the first 6 months after ments can place patients at risk for developing DAH transplantation.2,8 This syndrome is associated with through bone marrow suppression. Use of cytarabine symptoms and signs of pneumonia and widespread al- and all-transretinoic acid are among several immuno- veolar injury despite the absence of infection, cardiac suppressive agents associated with DAH.2 dysfunction, renal failure, or iatrogenic fluid.2,8 Indeed, When considering alternative diagnoses to DAH, this expansive definition encompasses a variety of localized pulmonary hemorrhage caused by bronchi- disorders, and DAH following HCST and engraftment ectasis, tumor, or infection should be distinguished syndrome have both been considered subset classifica- from DAH.1 Pulmonary infections, acute eosinophilic tions of idiopathic pneumonia syndrome.8 pneumonia, aspiration pneumonitis, and acute respiratory distress syndrome can all present with similar Treatment clinical and radiographic findings. Diffuse leukemic Standard treatment strategies for DAH are typically di- infiltration of the lungs may be a manifestation of ma- rected toward the underlying etiology. Supportive-care lignancy and can be confused with DAH.5 Viral pneu- measures, including hemodynamic support and inva- monias, Pneumocystis jiroveci infection, Mycoplasma sive or noninvasive oxygen supplementation, the dis- pneumoniae infection, and toxoplasmosis, among oth- continuation of any offending agents, and reversal of er atypical infections, can often present with diffuse coagulopathy are basic first-line therapies. In cases of pulmonary infiltrates comparable with CT findings for DAH with an etiology suspected to be attributable to DAH.2 Table 2 lists the infectious causes of DAH.9-20 autoimmune vasculitides, immunosuppressive therapies and plasmapheresis have been used. Systemic high-dose steroids are typically recommended for non- Table 2. — Infectious Causes of Diffuse Alveolar Hemorrhage infectious cases of DAH to combat the inflammation Category Agent/Disease precipitated by the underlying disease process.9 How- Bacterial Legionella13 ever, research has not shown significant differences in Leptospirosis10 rates of mortality between patients with DAH receiving 9 Mycobacterium tuberculosis11 low-, medium-, or high-dose steroids. Mycoplasma pneumoniae12 Use of platelet transfusions to treat thrombocyto- Stenotrophomonas maltophilia9 penia in the setting of hemorrhage is widely accepted, but further research is necessary for the use of other Fungal Invasive aspergillosis18 Mucormycosis19 treatments such as aminocaproic acid and activated factor VII. Although initial study results have suggest- 20 Parasitic Strongyloides stercoralis ed a benefit to using aminocaproic acid in addition to Viral Cytomegalovirus15 steroids to treat DAH in patients who had received al- 14 Dengue logeneic HSCT, subsequent research has showed no Influenza H1N116 benefit.9 Prior case reports and research have shown Hantavirus17 that use of factor VII can control bleeding in the set-

276 Cancer Control July 2016, Vol. 23, No. 3 ting of DAH, but the cost can be restrictive in patients 17. Hong YM, Moon JC, Yang HC, et al. Hemorrhagic fever with renal 10 syndrome and coexisting hantavirus pulmonary syndrome. Kidney Res whose underlying disease remains grim. Use of factor Clin Pract. 2012;31(2):118-120. VII must also be weighed against the risk of thrombo- 18. Wah TM, Moss HA, Robertson RJ, et al. Pulmonary complications following bone marrow transplantation. Br J Radiol. 2003;76(906):373-379. sis, and clinicians should use it with caution or avoid it 19. Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical altogether in patients who have had recent surgery or manifestations of mucormycosis. Clin Infect Dis. 2012;54(suppl 1):S23-S34. 20. Steinhaus D, Gainor J, Vernovsky I, et al. Survival in a case of dif- have a history of thrombosis, liver disease, myocardial fuse alveolar hemorrhage due to Strongyloides stercoralis hyperinfection. infarction, or stroke.10 The patients in our case series Respir Med Case Rep. 2012;5:4-5. 21. Panoskaltsis-Mortari A, Griese M, Madtes DK, et al; American all received high-dose steroids in accordance with cur- Thoracic Society Committee on Idiopathic Pneumonia Syndrome. An rent recommendations; 1 patient received aminocapro- official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia ic acid and factor VII without success. syndrome. Am J Respir Crit Care Med. 2011;183(9):1262-1279. 22. Rathi NK, Tanner AR, Dinh A, et al. Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT Conclusions patients with diffuse alveolar hemorrhage. Bone Marrow Transplant. Early recognition and prompt diagnosis of diffuse alve- 2015;50(3):420-426. 23. Pathak V, Kuhn J, Gabriel D, et al. Use of activated factor VII in olar hemorrhage (DAH) in patients with acute myeloid patients with diffuse alveolar hemorrhage: a 10 years institutional experience. leukemia can be a challenging but decisive step toward Lung. 2015;193(3):375-379. decreasing the high mortality rate associated with this life-threatening syndrome. Our case series highlights the combination of clinical signs and diagnostic evi- dence that can help distinguish DAH from alternative diagnoses. Further research may help elucidate the underlying pathophysiological mechanisms of DAH, par- ticularly following hematopoietic stem cell transplantation, and unlock prospects for improved diagnosis and treatment.

References

1. Lichtenberger JP III, Digumarthy SR, Abbott GF, et al. Diffuse pulmonary hemorrhage: clues to the diagnosis. Curr Probl Diagn Radiol. 2014;43(3):128-139. 2. Escuissato DL, Warszawiak D, Marchiori E. Differential diagnosis of diffuse alveolar haemorrhage in immunocompromised patients. Curr Opin Infect Dis. 2015;28(4):337-342. 3. Sharma SK, Kumar S, Singh AK, et al. Diffuse alveolar hemorrhage following allogeneic peripheral blood stem cell transplantation: a case report and a short review. Indian J Hematol Blood Transfus. 2014;30(1):41-44. 4. Lara AR, Schwarz MI. Diffuse alveolar hemorrhage. Chest. 2010;137(5):1164-1171. 5. Rabe C, Appenrodt B, Hoff C, et al. Severe respiratory failure due to diffuse alveolar hemorrhage: clinical characteristics and outcome of intensive care. J Crit Care. 2010;25(2):230-235. 6. Schwarz MI, Whitcomb ME, Goldman AL. The spectrum of diffuse pulmonary infiltration in malignant disease. Chest. 1973;64(1):88-93. 7. Lewis ID, DeFor T, Weisdorf DJ. Increasing incidence of diffuse alveolar hemorrhage following allogenic bone marrow transplantation. Bone Marrow Transplant. 2000;26(5):539-543. 8. Lassence AD, Fleury-feith J, Escudier E, et al. Alveolar hemorrhage: diagnostic criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med. 1995;151(1):157-163. 9. Tada K, Kurosawa S, Hiramoto N, et al. Stenotrophomonas maltophilia infection in hematopoietic SCT recipients: high mortality due to pulmonary hemorrhage. Bone Marrow Transplant. 2013;48(1):74-79. 10. Gulati S, Gulati A. Pulmonary manifestations of leptospirosis. Lung India. 2012;29(4):347-353. 11. Marruchella A, Corpolongo A, Tommasi C, et al. A case of pulmonary tuberculosis presenting as diffuse alveolar haemorrhage: is there a role for anticardiolipin antibodies? BMC Infect Dis. 2010;10:33. 12. Kong MX, Newman K, Goldenberg R, et al. Fatal mycoplasma pneumoniae infection: case report and review of the literature. N A J Med Sci. 2012;5(2):126-130. 13. Sundar KM, Pearce MJ. Diffuse alveolar hemorrhage due to Legio- nella pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2004;21(2):158-159. 14. Gulati S, Maheshwari A. Atypical manifestations of dengue. Trop Med Int Health. 2007;12(9):1087-1095. 15. Gasparetto EL, Ono SE, Escuissato D, et al. Cytomegalovirus pneumonia after bone marrow transplantation: high resolution CT findings. Br J Radiol. 2004;77(921):724-727. 16. Kennedy ED, Roy M, Norris J, et al; 2009 Pandemic H1N1 Influen- za-Associated Lower Respiratory Tract Hemorrhage Working Group. Low- er respiratory tract hemorrhage associated with 2009 pandemic influenza A (HINI) virus infection. Influenza Other Respir Viruses. 2013;7(5):761-765.

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