ICU ROUNDS Pulmonary leukostasis as a complication of leukemia Pantaree Aswanetmanee MD, Hawa Edriss MD, Chok Limsuwat MD ABSTRACT Multiple acute pulmonary complications occur in patients with hematologic malignan- cies. They might be associated with the disease itself, with complications from treatment, or with the consequences of an impaired immune status. Pulmonary leukostasis is one of the most common life-threatening complications in patients with hyperleukocytosis. The risk of this condition is higher in myeloid leukemia with white blood cell counts greater than 100,000 /µL. Leukostasis is a diagnostic challenge for clinicians due to non-specific symptoms and radiographic presentation. Definitive treatment of pulmonary leukostasis is still controversial; however, early detection and treatment by cytoreduction may im- prove outcomes. Key words: leukemia, hyperleukocytosis, leukostasis, respiratory complications INTRODUCTION Hyperleukocytosis is often defined as a white more frequently in AML, especially in the microgranu- blood cell (WBC) count > 100,000/μL and is associated lar variant of acute promyelocytic (FAB-M3) leukemia, with increased morbidity and mortality. It can induce myelomonocytic (FAB-M4) leukemia, and monocytic leukostasis, tumor lysis syndrome, and disseminated (FAB-M5) leukemia, and in chronic myelogenous intravascular coagulopathy (DIC). Hyperleukocyto- leukemia (CML) in blast crisis.4 In ALL hyperleuko- sis is present in 10-20% of patients with newly diag- cytosis occurs more frequently in patients with cyto- nosed acute myelocytic leukemia (AML) and 10-30% genetic subtype t (4, 11) and t (9:22).2 A WBC count of patients with acute lymphoblastic leukemia (ALL).1, >10,000/μL is considered in the hyperleukocytosis 2 However, the importance of the absolute number range in acute promyelocytic leukemia.3 Leukostasis depends on the underlying hematological disorder. is a serious manifestation of hyperleukocytosis be- Most patients with chronic lymphocytic leukemia or cause vascular occlusion by leukemic blasts causes ALL remain asymptomatic even with WBC counts > tissue hypoxia.3The respiratory and central nervous 500,000/μL, while in AML a WBC count ≥ 50,000/µL systems are the most frequently affected systems by can cause severe symptoms.3 Leukostasis occurs leukostasis. This review focuses on pulmonary leukostasis Corresponding author: Chok Limsuwat , MD in hyperleukocytosis and describes the pathophysiol- Contact Information: [email protected] ogy, clinical presentation, differential diagnosis, and DOI: 10.12746/swrccc2015.0310.028 management of this condition. The Southwest Respiratory and Critical Care Chronicles 2015;3(10) 17 Pantaree Aswanetmanee, et al. Pulmonary leukostasis as a complication of leukemia PATHOPHYSIOLOGY CLINICAL PRESENTATION AND DIAGNOSIS The pathophysiology of hyperleukocytosis and The clinical presentation of leukostasis is usu- leukostasis is not well established. The pathogenesis ally nonspecific. The respiratory and nervous systems likely involves both changes in blood viscosity and are often involved, and this can result in death.2, 4, 13 the deformability of leukemic cells (the ability of the The differential diagnosis of pulmonary opacities in cells to change shape when passing through blood patients with hematological malignancies is broad and vessels). Marked elevations in WBCs lead to an in- includes pneumonia, pulmonary hemorrhage, edema, creased fractional volume of leukocytes (leukocrit), and leukostasis (Table). Infection is the most common and this leads to an increased blood viscosity. In ad- pulmonary complication in acute leukemia, and most dition, blast cells are less deformable than normal patients with respiratory infections have either bac- mature WBCs, and these rigid blast cells cause oc- terial pneumonia or fungal pneumonia. Pulmonary clusion of the microvasculature and decrease blood leukostasis and leukemic infiltration are uncommon flow resulting in tissue hypoxia.5 but should be considered in the differential diagnosis in these patients. Rare drug complications also occur The viscosity of leukocyte suspensions in vitro and include tyrosine kinase inhibitor induced pulmo- increases dramatically when the leukocrit exceeds 12- nary complications, retinoic acid syndrome, and he- 15 ml/dL.5 But the leukemic blast concentrations nec- mophagocytic lymphohistiocytosis.14 essary to reach a leukocrit of 12-15 mL/dL (300,000- 450,000/μL for AML and 6,000,000-8,000,000/ μL for Pulmonary complications, including leukosta- ALL) are rarely seen.5 Leukostasis has also been sis, occur in up to 80% of all leukemia patients and are described with blast counts of less than 50,000/µL.6 a major cause of death in these patients.16 Pulmonary This indicates that hyperleukocytosis itself is not leukostasis has been identified as the single worst enough to cause leukostasis, and other factors, like prognostic factor in patients presenting with hyper- the presence of circulating blasts or the attachment leukocytosis with either AML or CML in myeloid blast of the blast cells to the endothelium, may contribute.7 crisis.13 Patients with pulmonary leukostasis present The expression and function of adhesion receptors in with fever, dyspnea, tachypnea, and hypoxia; symp- leukemic cells and the up and down regulation of ad- toms range from mild shortness of breath to acute hesive molecules are important causes of leukosta- respiratory failure and death. Chest radiographic find- sis.8 Myeloblasts are larger than lymphoblasts and ings usually include varying degrees of alveolar and lymphocytes. Hence, leukostasis is more common interstitial infiltration. However, the chest x-ray can be in AML than in ALL. Thornton, et al.9 demonstrated normal, even in patients with severe respiratory dis- that genetic mutations, such as the FLT3 mutation in tress.17 Computed tomography of the chest may dem- AML, could be associated with hyperleukocytosis and onstrate thickening of the bronchovascular bundles, leukostasis. Differences in expression of these adhe- prominence of the peripheral pulmonary arteries, and sive molecules on myeloblast and lymphoblast cell ground glass opacities. The arterial blood gas should surfaces may explain leukostasis without hyperleu- be interpreted skeptically as the PaO2 can be falsely kocytosis and the higher incidence of leukostasis in decreased (pseudohypoxemia) in patients with hy- AML than in ALL.10-12 Sturki and coworkers suggested perleukocytosis due to rapid oxygen consumption by that cytokines, including ILβ and TNF-α, produced by the high number of WBCs. Complete assessment of blast cells cause activation of endothelial cells and patients, searching for other signs and symptoms of this blast-endothelial cells interaction is enhanced by leukostasis, and close frequent monitoring are criti- adhesion molecules, like selectins and vascular ad- cal and can help to differentiate between pseudo and hesion molecules.11 true hypoxemia. In addition, monitoring pulse oxime- try can more accurately assess oxygenation status.18 Clinicians should identify patients with pulmonary leu- 18 The Southwest Respiratory and Critical Care Chronicles 2015;3(10) Pantaree Aswanetmanee, et al. Pulmonary leukostasis as a complication of leukemia Table Pulmonary complications in patients with hematologic malignancies Pulmonary complication Clinical setting Finding Infectious Bacterial pneumonia Fever, cough, sputum, and/or neutro- Segmental or lobar consoli- penia dation Fungal pneumonia Post chemotherapy with neutropenia, Halo sign, segmental or fever, hemoptysis subsegmental pleura-based consolidation, cavitation- centrilobular nodules, fungal ball, peribronchial or peri- bronchiolar consolidations Pneumocystis jiroveci Impaired cellular immunity, usually Bilateral perihilar ground pneumonia post hematopoietic stem cell trans- glass opacities plant (PJP) CMV-induced pneumonia Same as PJP Ground glass opacities, micronodules, or airspace consolidation Non-infectious Leukostasis Hyperleukocytosis with AML or ALL Varying degrees of intersti- tial and/or alveolar opacities. Ground glass opacities Pulmonary hemorrhage Thrombocytopenia, sudden onset of Rapid progression of diffuse pulmonary symptoms, rare hemop- ground glass opacities and/ tysis or consolidation Pulmonary edema History of positive fluid intake, mul- Cardiomegaly, redistribu- tiple transfusion, cardiotoxic medica- tion of blood flow toward tion, and renal failure. Edema and the upper lobes, increase in high jugular venous pressure. vasculature, ground glass opacities and/or consolida- tion, increased interstitial markings Retinoic acid syndrome History of treatment with ATRA for Diffuse ground glass opaci- acute pro- myelocytic leukemia (AML ties and/or consolidation subtype M3) Effects of tyrosine kinase History of imatinib therapy with a Varying degree of interstitial inhibitor therapy median duration of 49 days (range, pneumonia, ground glass 10–282 days), interstitial pneumonia opacities, nodular, or reticu- lar infiltration AML-acute myeloid leukemia, ALL-acute lymphocytic leukemia, ATRA- all-trans–retinoic acid, PJP- Pneumocystis jiroveci pneumonia The Southwest Respiratory and Critical Care Chronicles 2015;3(10) 19 Pantaree Aswanetmanee, et al. Pulmonary leukostasis as a complication of leukemia kostasis as quickly as possible since early diagnosis anticoagulant is citrate, this requires the administra- and treatment should improve outcomes. tion of calcium, which may cause calcium-phosphate precipitation and worsen