What are the likely causes of wheezing and dyspnea in a patient with Hodgkin lymphoma who currently has severe neutropenia and moderate‑severe anemia?

Causes of Wheezing and Dyspnea in Hodgkin Lymphoma with Severe Neutropenia and Anemia

In a patient with Hodgkin lymphoma presenting with wheezing, dyspnea, severe neutropenia (WBC 1.52), and moderate-severe anemia (Hgb 7.9), the most critical immediate concern is opportunistic infection—particularly Pneumocystis jiroveci pneumonia (PJP) in the setting of severe immunosuppression—followed by consideration of bleomycin-induced pulmonary toxicity, lymphomatous pulmonary involvement, and anemia-related dyspnea. 1

Primary Infectious Etiologies (Most Urgent)

Opportunistic Infections in Severe Neutropenia

• Patients with severe neutropenia and low CD4+ counts (<200 cells/μL) are at high risk for PJP and gram-negative bacterial pneumonia, which commonly present with dyspnea and can produce wheezing. 1
• The NCCN guidelines explicitly recommend prophylactic antibiotics for gram-negative bacteria and PJP when CD4+ T-cell count is <200 cells/μL in Hodgkin lymphoma patients. 1
• Neutropenic fever occurs in 11-12% of ABVD-treated patients, and respiratory symptoms in this context warrant immediate evaluation for bacterial pneumonia, fungal infections, and PJP. 2

Critical Pitfall

• B symptoms (fever, night sweats, weight loss) in Hodgkin lymphoma patients should always prompt investigation of opportunistic infection rather than being automatically attributed to lymphoma. 1

Chemotherapy-Related Pulmonary Toxicity

Bleomycin-Induced Pneumonitis

• Bleomycin causes pulmonary toxicity in 10% of treated patients, with approximately 1% progressing to pulmonary fibrosis and death. 3
• The FDA label warns that patients with compromised pulmonary function are at extreme risk, and pulmonary toxicity is unpredictable despite being age and dose-related. 3
• For ABVD in advanced-stage Hodgkin lymphoma, patients with symptoms of pulmonary compromise or fall in DLCO should consider dropping bleomycin after 2 cycles, particularly with complete response on PET/CT. 1
• Bleomycin toxicity presents with dyspnea and can produce wheezing due to bronchospasm, though the classic presentation is pneumonitis. 1, 3

Drug-Induced Bronchospasm

• Chemotherapeutic agents can cause bronchospasm with or without cough, which may explain the wheezing component. 1

Lymphoma-Related Pulmonary Involvement

Direct Pulmonary Parenchymal Disease

• Pulmonary parenchymal involvement occurs in 38% of Hodgkin's disease patients, and in untreated disease is invariably associated with mediastinal lymphadenopathy. 4
• Three radiological patterns exist: nodular, bronchovascular-lymphangitic, and pneumonic-alveolar, any of which can cause dyspnea and wheezing. 4

Pleural Effusion

• Pleural effusion occurs in 16% of lymphoma patients and is the chief symptom in 63% of patients with lymphomatous pleural effusions, presenting as progressive dyspnea. 5, 6, 4
• Hodgkin's disease effusions primarily result from obstruction of lymphatic drainage by enlarged mediastinal lymph nodes. 5, 6
• Dyspnea is described as progressive shortness of breath beginning with exertion and advancing to breathlessness at rest, often with chest heaviness or tightness. 7

Mediastinal Mass Effect

• Mediastinal lesions may impinge on adjacent airways and lead to chronic cough and wheezing, though cough as the main symptom is often overlooked. 1

Anemia-Related Dyspnea

Severe Anemia Contribution

• With hemoglobin of 7.9 g/dL, anemia of chronic disease is contributing significantly to dyspnea, as this represents moderate-severe anemia. 8
• Anemia in Hodgkin lymphoma is usually due to abnormalities in iron metabolism mediated by IL-6 and hepcidin elevation, displaying characteristics of anemia of chronic disease. 8
• Anemia at diagnosis can be aggravated by intensive chemotherapy, and this patient's severe anemia likely reflects both disease and treatment effects. 8

Thromboembolic Disease

Pulmonary Embolism

• The incidence of thrombosis in hematological malignancies varies between 2-58%, and pulmonary embolism must be considered with sudden onset dyspnea. 9
• In pulmonary embolism with effusion, approximately 75% report pleuritic pain, and dyspnea is characteristically out of proportion to effusion size. 7

Diagnostic Algorithm

Immediate Evaluation Required

1. Chest imaging (CT chest) to evaluate for:

   • Pulmonary infiltrates suggesting infection or bleomycin toxicity
   • Pleural effusion
   • Mediastinal lymphadenopathy with airway compression
   • Pulmonary parenchymal lymphoma involvement 1

2. If CD4+ count available and <200 cells/μL, empiric PJP prophylaxis or treatment should be strongly considered. 1

3. Pulmonary function tests including DLCO to assess for bleomycin toxicity if patient has received bleomycin. 1

4. Blood cultures and sputum studies given severe neutropenia and risk of bacterial/fungal infection. 1

5. If pleural effusion present, diagnostic thoracentesis with cytology, though cytologic yield is poor in lymphoma (31-55%), with flow cytometry improving diagnostic accuracy. 5, 6

Treatment Considerations

• Growth factor support may be required in the setting of prolonged severe neutropenia, despite concerns about bleomycin interaction, as the risk-benefit favors CSF use in severe immunosuppression. 1
• Dose reductions may be appropriate with severe and prolonged cytopenias, contrary to standard ABVD guidelines. 1
• Transfusion support for severe anemia to improve oxygen-carrying capacity and reduce dyspnea. 8