What are the manifestations and management of lung involvement in acute leukemia?

Lung Involvement in Acute Leukemia: Manifestations and Management

Overview

Pulmonary infiltrates in acute leukemia represent a life-threatening emergency requiring immediate diagnostic workup and empiric treatment, with mortality rates reaching 30-50% depending on etiology and timing. 1, 2

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Clinical Manifestations

Leukemia-Specific Pulmonary Syndromes

Lung involvement in acute leukemia presents through three distinct leukemia-specific mechanisms, accounting for approximately 60% of respiratory events in the early phase: 2, 3

Leukostasis

• Occurs with hyperleukocytosis (WBC >100,000/μL), causing pulmonary infiltrates, retinal hemorrhages, and altered mental status 4
• Presents with acute respiratory distress and requires immediate cytoreduction 3
• Associated with 41% mortality at day 28 3

Pulmonary Leukemic Infiltration (PLI)

• Can occur even without hyperleukocytosis and with low blast counts 5
• Presents with diffuse alveolar, interstitial, mixed, or peribronchial/perivascular patterns on HRCT 5
• Standard chest radiography may be negative while HRCT shows infiltrates 5
• Associated with 23% mortality at day 28 3

Acute Lysis Pneumopathy (ALP)

• Develops after initiation of chemotherapy due to massive tumor lysis in the lungs 3, 6
• Presents as new or worsening pulmonary infiltrates with hypoxemia despite initial improvement 6
• Associated with 31% mortality at day 28 3

Infectious Causes

Early Phase (First 2 Weeks)

• Bacterial pneumonia predominates, requiring broad-spectrum β-lactam with antipseudomonal activity 4, 1
• Focal infiltrates suggest bacterial etiology 1

Late Phase (After 2 Weeks)

• Invasive fungal infections (Aspergillus) become primary concern 4, 1
• Pneumocystis jirovecii pneumonia in ALL patients 4, 1
• Viral pneumonias (CMV, respiratory viruses) 1

Other Non-Infectious Causes

• Pulmonary hemorrhage and edema 1
• Diffuse alveolar damage 1
• Transfusion-related acute lung injury (TRALI) - rare 1
• Differentiation syndrome 1

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Diagnostic Approach

Initial Assessment at Diagnosis

Before starting chemotherapy, all patients should undergo: 4

• Chest CT scan to identify infectious foci and establish baseline, particularly if infection is suspected 4
• Clinical examination for signs of leukostasis (respiratory distress, altered mental status, visual changes) 4
• Assessment of WBC count and blast percentage 3

Diagnostic Workup for Pulmonary Infiltrates

First-line diagnostic approach includes: 4

• Chest CT scan (more sensitive than X-ray; HRCT preferred for pattern recognition) 4, 5
• Inflammatory markers: CRP and procalcitonin 4
• Blood cultures (two sets) 4
• Urinary antigens for Legionella and Pneumococcus 4
• Nasopharyngeal swab for respiratory viruses including SARS-CoV-2 4
• Serum galactomannan (threshold 0.5) and beta-D-glucan 4
• Sputum culture if available 4

Second-line approach (if no etiology identified or lack of response): 4

• Bronchoalveolar lavage (BAL) with comprehensive microbiological testing 4
• BAL galactomannan (cutoff ≥1.0) 4
• Quantitative P. jirovecii PCR (>1,450 copies/mL diagnostic) 4
• Molecular analysis for atypical bacteria, CMV-DNA, and fungi 4
• Consider open lung biopsy if diagnosis remains elusive and patient stable enough 5, 6

Key diagnostic patterns: 1, 5

• Focal infiltrates → bacterial infection (early) or fungal (late)
• Diffuse infiltrates + early timing → consider leukostasis, PLI, pulmonary hemorrhage, or viral pneumonia
• Diffuse infiltrates + late timing → fungal infection, PCP, or immune reconstitution

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Management

Emergency Management of Hyperleukocytosis with Leukostasis

Immediate interventions required: 4

• Hydroxyurea 50-60 mg/kg/day until WBC <10-20 × 10⁹/L 4
• Leukapheresis may be considered but has no proven impact on long-term outcomes 4
• Aggressive hydration to prevent tumor lysis syndrome 4
• Allopurinol or rasburicase for uric acid control 4
• Avoid excessive RBC transfusions until WBC reduced (increases blood viscosity) 4

Treatment of Leukemia-Specific Lung Involvement

For suspected PLI or leukostasis: 3

• Dexamethasone therapy is protective and should be initiated (multivariate analysis showed OR 0.26 for mortality) 3
• Immediate initiation of induction chemotherapy once diagnostic samples obtained 4
• Standard "3+7" regimen (anthracycline + cytarabine) 4

For acute lysis pneumopathy: 6

• Aggressive pulmonary support 6
• Continue chemotherapy as tumor lysis indicates treatment response 6
• Monitor closely for deterioration 6

Empiric Antimicrobial Therapy

For febrile neutropenic patients with pulmonary infiltrates not typical for PCP or lobar pneumonia: 4

• Broad-spectrum β-lactam with antipseudomonal activity (as for fever of unknown origin) 4
• Add mold-active antifungal therapy with voriconazole or liposomal amphotericin B at treatment doses (not prophylactic doses) 4
• If already on voriconazole or posaconazole prophylaxis, switch to liposomal amphotericin B 4

For suspected Pneumocystis pneumonia (PCP): 4

• Start treatment before bronchoscopy if pattern suggests PCP (diffuse infiltrates + elevated LDH) 4
• High-dose trimethoprim-sulfamethoxazole is first-line 4
• Alternative: clindamycin plus primaquine if TMP/SMX intolerant 4
• Adjunctive corticosteroids NOT generally recommended in non-HIV patients (only consider in individual cases with critical respiratory insufficiency) 4
• Initiate secondary prophylaxis after successful treatment 4

Re-assessment strategy: 4

• If no response after 7 days, repeat chest CT and consider bronchoscopy with BAL 4

Prophylaxis Considerations

PCP prophylaxis: 4

• NOT routinely recommended for BTK or BCL-2 inhibitor monotherapy 4
• Required if concurrent high-dose corticosteroids, purine analogues, or idelalisib 4

Antibiotic prophylaxis: 4

• NOT routinely recommended 4
• Fluoroquinolones only considered in recurrent infections (ESMO) or neutropenia (NCCN) 4
• Beware drug-drug interactions with targeted therapies 4

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Prognostic Factors and Outcomes

Independent risk factors for mortality in AML patients with respiratory events: 3

• Age >50 years (OR 13) 3
• ECOG performance status ≥2 (OR 5.4) 3
• Need for invasive mechanical ventilation (OR 19) 3

Protective factor: 3

• Dexamethasone therapy (OR 0.26) 3

Overall mortality: 2, 3

• Day-28 mortality: 34.5% for leukemia-specific respiratory events 3
• Day-28 mortality: 48.6% for other respiratory events 3
• Quarter of AML patients require ICU admission during disease course 2

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Critical Pitfalls to Avoid

• Do not delay treatment waiting for definitive diagnosis in unstable patients—empiric therapy based on most likely etiology is mandatory 1
• Do not assume infection is the only cause of pulmonary infiltrates; leukemia-specific involvement accounts for 60% of early respiratory events 2, 3
• Do not rely on standard chest X-ray alone; HRCT is essential and may show infiltrates when X-ray is negative 5
• Do not overlook leukemic infiltration in patients without hyperleukocytosis—PLI can occur with low blast counts 5
• Do not transfuse RBCs aggressively in hyperleukocytosis before cytoreduction (increases viscosity) 4
• Do not use prophylactic doses of antifungals for empiric treatment—use full treatment doses 4