Diffuse pulmonary infiltrates in an old man with chronic lymphocytic leukemia.

An 82-year-old man known case of chronic lymphocytic leukemia (CLL) presented with fever and weakness. He had never received any treatment for his CLL in the past. On admission he was found to be in mild respiratory distress with bilateral crackles and had markedly elevated white blood count (WBC) (137 K/uL with 93% lymphocytes). His respiratory status deteriorated necessitating non-invasive ventilatory support. Chest computed tomography (CT) scan revealed bilateral diffuse ground glass opacities, so broad spectrum antibiotic therapy was initiated. Despite that, he remained febrile and cultures were all negative. Chest x-rays showed progressive worsening of diffuse alveolar opacities. Bronchoalveolar lavage (BAL) was negative for infectious etiologies, however flow cytometry of the fluid was consistent with CLL. Chemotherapy with chlorambucil was started. Although most of the pulmonary infiltrates in CLL patients are due to infectious causes, leukemic cells infiltration should be considered as well in CLL patients with respiratory symptoms who do not respond appropriately to standard antimicrobial regimen.

Case Report

The patient is an 82-year-old white man with a history of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) diagnosed 2 years ago. He had remained asymptomatic and did not require any treatment during this time. His past medical history also included chronic obstructive pulmonary disease (COPD), atrial fibrillation, diastolic heart failure, myelodysplastic syndrome and chronic kidney disease. He was a former 3-pack-day smoker for 20 years who had quit a few years prior. Over the past six months, his condition deteriorated with a progressive rise in white blood count (WBC) to approximately 120–130 K/uL and worsening anemia requiring blood transfusions on a regular basis. Due to progression of CLL, a decision was made to begin chemotherapy. However, a hospital admission one month prior due to pneumonia precluded start of therapy. He returned on the day of his latest admission with a fever of 102°F, malaise, fatigue and weakness.

On admission he found to be an ill-looking old man, tired and in mild respiratory distress. His vital signs were as follows: temperature 100.5°f, pulse 67 beats/min, respiratory rate 26/min, and oxygen saturation 99% on nasal cannula 3 L/min and blood pressure 110/40 mmHg. Physical examinations were significant for bilateral crackles without wheezing or rhonchi, irregularly irregular heart rate with a grade II/VI unchanged systolic murmur at the LSB, and trace pedal edema without clubbing or cyanosis. The rest of his examination was unremarkable.

Complete blood count (CBC) showed leukocytosis (WBC 137 K/uL with 93% lymphocytes), hematocrit of 23.5% and a platelet count of 79 K/uL. Chemistry panel was significant for blood urea nitrogen (BUN) of 101 mg/dL and creatinine of 2.9 mg/dL. Lactate dehydrogenase and uric acid were both elevated (589 IU/L and 13.9 mg/dL respectively). He became hypoxic and tachypneic requiring non-invasive ventilatory support. Broad spectrum antibiotic therapy with a combination of cefepime and vancomycin was started for newly found bilateral diffuse ground glass opacities and infiltrates on chest computed tomography (CT) scan (Figures 1, 2). He remained febrile with a productive cough for yellowish sputum. Microbiology studies including blood, urine and sputum cultures were all negative. A bronchoscopy revealed copious amounts of thick, greenish, dark tannish secretions. Bronchoalveolar lavage (BAL) of right middle lobe was negative for pneumocystis jirovecii, legionella, nocardia, fungal, acid-fast bacilli (AFB), bacterial and respiratory viral panel. Cytomegalovirus serology and polymerase chain reaction (PCR) were negative. Follow up chest x-rays showed progressive worsening of diffuse alveolar opacities. Flow cytometry of BAL fluid showed lambda restricted B cells with dim CD20 and coexpression of CD5 and CD23 consistent with CLL (Figure 3A, 3B).

Figure 1

Computed tomography scan of chest on admission.

Figure 2

Chest x-ray on admission.

Figure 3

A–B. Flow cytometry of bronchoalveolar lavage fluid showed lambda restricted B cells with dim CD20 and coexpression of CD5 and CD23.

A decision was made to initiate therapy with chlorambucil. Initially, he responded to treatment resulting in significant drop in WBC and improvement in both respiratory status and lung infiltrates (Figure 4). Unfortunately, his improvement was short lived and he developed worsening of respiratory failure. He and his family opted for hospice care and he passed away shortly thereafter.

Figure 4

Chest x-ray after chemotherapy.

Discussion

Pulmonary complications are a major cause of morbidity and mortality in patients with CLL, the most common type of adult leukemia. These are include but not limited to pulmonary infiltrates, pleural effusion, hilar and mediastinal adenopathy. Pulmonary infiltrates are usually caused by infectious etiologies in the majority of patients with CLL. However, they can be seen due to parenchymal infiltration by leukemic cells, pulmonary leukostasis, alveolar hemorrhage, pulmonary embolism and secondary malignancy including lung cancer. Drug-induced pulmonary injury should also be considered in differential diagnosis of a new pulmonary infiltrate in known cases of CLL. Chlorambucil, fludarabine and rituximab, which are the most common chemotherapic agents for CLL treatment, are known to cause lung toxicity.[1-3] Pulmonary involvement by the leukemic cells occurs more commonly in CLL than in other types of leukemia and has been reported in up to 40% of patients in autopsy studies. However, most of the patients do not have clinical features or radiological evidences suggesting of leukemic cell infiltrates. These infiltrates are accounted for only 10% of radiographic infiltrates noted in patients with CLL.[2-4] In a study of all CLL patients who were admitted to a tertiary care hospital with a respiratory disease between 1993 and 2001, pulmonary complications were noted mostly in patients with end-stage disease who had a history of prior therapy for CLL. In that study, pneumonia accounted for the highest percentage of pulmonary diagnoses (75%) followed by malignant pleural effusion (7%) and upper respiratory infection/bronchitis (4%). Leukemic pulmonary infiltrates due to CLL was only identified in three individual (2%): one patient had bilateral infiltration, and two patients had single lobe involvement.[5]

Although direct pulmonary involvement by leukemia is most commonly seen in patient with advanced disease present with blast crisis, interestingly, CLL can present as pulmonary infiltration in the absence of extrapulmonary manifestation. Also, low-grade CLL may evolve to an aggressive large-cell lymphoma characterized by rapid clinical deterioration, fever, progressive adenopathy, and involvement of extranodal sites including the lung. This process may occur in patients who have had no previous chemotherapy and prognosis is usually poor.[3,4]

Common presenting symptoms in leukemic infiltration of pulmonary parenchyma are dry cough, persistent low-grade fever and progressive dyspnea.[1,4] Chest radiograph shows either localized or diffuse infiltrates which may have a pattern similar to that of pulmonary edema. Pleural effusions and intrathoracic adenopathy can also be seen though not very common.[2] Exclusion of infectious etiologies together with a tissue diagnosis, either by transbronchial/open lung biopsy or BAL, is required to establish the diagnosis.[1,3,4] Pulmonary involvement due to leukemic cells infiltration in CLL is potentially reversible and long-term remissions have been reported in patients who were treated aggressively with chemotherapic agents.[3,4]

Conclusions

Pulmonary complications of CLL include pulmonary infiltrates, pleural effusion, hilar and mediastinal adenopathy. Most of the pulmonary infiltrates in CLL patients are caused by infectious etiologies. However they can be seen due to leukemic cells infiltration, pulmonary leukostasis, alveolar hemorrhage, pulmonary embolism, drug-induced and secondary malignancy including lung cancer. Diffuse pulmonary infiltrates in CLL can have a pattern similar to pulmonary edema and can be diagnosed by open lung biopsy, transbronchial biopsy or BAL. CLL-induced pulmonary infiltrates can be treated effectively with standard chemotherapic regimen.