Progressive Pulmonary Infiltrates in a Man with Mediastinal Lymphoma

Case Vignette

A 48-year-old man with recurrent primary mediastinal diffuse large B-cell lymphoma was evaluated for new right-sided pulmonary infiltrates. Two months earlier, he was diagnosed with a bacterial superinfection of his locally invasive lymphoma due to Haemophilus influenzae with concern for chest wall osteomyelitis (Figure 1). The patient underwent surgical debridement, a chest tube was placed, and he was treated with ceftriaxone plus metronidazole. A large left-sided exudative pleural effusion was thought to be paramalignant. For the patient’s refractory lymphoma, he was started on pembrolizumab every 3 weeks as a planned bridge to autologous hematopoietic stem cell transplantation. One of the past treatment regimens included mediastinal radiation 2 years earlier.

Figure 1.

Timeline of diagnosis, workup, and treatment. The timing of diagnoses is represented by arrows. Timing of chest CT scans is indicated by letters which correspond to the images in Figure 2. CT = computed tomography.

Two months after the diagnosis of the mediastinal infection and while still receiving ceftriaxone and pembrolizumab, a follow-up computed tomographic (CT) scan of the chest demonstrated two new right lower lobe pulmonary nodules (Figure 2A). The patient reported an increasing nonproductive cough and stable dyspnea on exertion but denied fevers. Examination was notable for reduced breath sounds in the left lower lung fields due to the known pleural effusion. Laboratory tests revealed a normal total white blood cell count with mild lymphopenia but were otherwise unremarkable. He had no significant neutropenia before or during this time.

Figure 2.

Chest computed tomographic (CT) scans of two different levels over time (letters refer to chest CT scans in the timeline of Figure 1). (A) New right lower lobe pulmonary nodule (open arrowhead), together with the preexisting mediastinal tumor (×) and left-sided pleural effusion (+). (B) Interval increase in the size and number of multiple ground-glass pulmonary consolidations (open arrow) and nodular consolidation (open arrowhead). (C) Progression of the multiple ground-glass densities in the bilateral lung fields (open arrow) as well as the right lower lobe consolidation (open arrowhead).

The patient’s dyspnea progressed over the next 2 months, necessitating a wheelchair to get to appointments. In the interim, the patient received empiric antifungal therapy with posaconazole for 3 weeks owing to concern for possible fungal pneumonia, transitioned to levofloxacin for the suspected Haemophilus influenzae osteomyelitis, and continued prophylactic acyclovir. Follow-up CT chest scans demonstrated new and progressive ground-glass opacities in addition to increased size and number of nodules (Figures 2B and 2C). Two bronchoalveolar lavages were conducted. Potentially curative hematopoietic cell transplantation was put on hold given his new pulmonary disease.

Questions

• 1. What are the potential etiologies of the pulmonary infiltrates in this patient?

• 2. How would you alter management at this stage in the evaluation?

• 3. Would you perform any additional diagnostic testing?

Clinical Reasoning and Diagnosis

Extensive infectious studies from two bronchoalveolar lavages were all negative, including cultures and stains, fungal polymerase chain reaction (PCR), galactomannan index, direct-fluorescent antibody staining for Pneumoncystis jirovecii, and multiplex PCR for respiratory viruses. Bronchoalveolar lavage exhibited 174 nucleated cells/μL with 79% macrophages, 10% lymphocytes, 11% neutrophils, and a normal CD4 (cluster of differentiation 4)/CD8 ratio of 1.26. The patient’s pulmonary infiltrates worsened despite empiric treatment with posaconazole and ongoing treatment with levofloxacin. Despite initial concerns, there was no evidence for an infectious cause. Pulmonary lymphoma was considered less likely given the clinical context and a negative result for malignant cells of flow cytometric analyses of bronchoalveolar fluid. Radiation pneumonitis was unlikely given that radiotherapy had occurred more than 2 years earlier and had been restricted to the mediastinum. The exudative pleural effusion was present before the development of pulmonary infiltrates and considered to be paramalignant given diagnostic evaluation of pleural fluid indicating an exudative effusion without evidence of infection or malignancy.

Interdisciplinary discussions between the pulmonary, oncology, infectious disease, and radiology specialists lead to a final diagnosis of a PD-1 (programmed cell death protein 1) inhibitor–induced pneumonitis caused by pembrolizumab. The diagnosis was made based on the progression of symptoms and radiologic findings after starting this immune checkpoint inhibitor (ICI) and no identified infection after extensive testing. This diagnosis was supported by the patient’s excellent clinical and radiographic response to discontinuation of pembrolizumab therapy and treatment with high-dose corticosteroids.

The patient was initially treated with 1 week of prednisone 40 mg daily (0.5 mg/kg/d), with a rapid taper over a second week because of competing concerns for assessing response to a salvage chemotherapy regimen (Figure 3). The patient had immediate symptomatic improvement allowing him to walk without dyspnea within a few days. A CT scan of the chest 2 weeks later showed improvement (Figure 4A). Given an incomplete radiographic response, the patient was restarted on high-dose prednisone (1 mg/kg daily) with a taper over 4 weeks as per the American Society of Clinical Oncology guidelines (1). This resulted in a near-complete radiographic resolution of the pulmonary infiltrates within another 3 weeks, with concurrent improvement in the pleural effusion (Figure 4B). Because of the initiation of high-dose prednisone, trimethoprim-sulfamethoxazole was started for Pneumocystis jirovecii prophylaxis.

Figure 3.

Timeline of treatment and radiographic resolution. Timing of chest CT scans is indicated by letters which correspond to the images in Figure 4. CT = computed tomography.

Figure 4.

Chest computed tomographic (CT) scans of two different levels over time (referring to chest CT scans in the timeline of Figure 3). (A) After a short course of corticosteroids, the previously demonstrated ground-glass opacities coalesced into consolidations in the right upper and lower lobes with scattered surrounding ground-glass opacities (open arrow). (B) After a second 3-week course of high-dose corticosteroids, there was near-complete resolution of the parenchymal infiltrates and concomitant substantial improvement in the left pleural effusion.

Discussion

In patients treated with ICIs, there should be a high level of suspicion for immune-related adverse events (irAEs). Pembrolizumab is a fully humanized IgG4 monoclonal antibody that binds to and blocks PD-1 on the surface of cytotoxic T-cells. This results in augmented T-cell–mediated killing of malignant cells, which upregulate expression of proteins that bind to PD-1 to blunt T-cell responses. This can also lead to irAEs affecting any organ system, with common manifestations including rashes and colitis.

Recognition of noninfectious causes of pulmonary infiltrates in immunocompromised patients is critically important to guide appropriate interventions but can be challenging. The recent successful implementation of ICIs in patients with refractory or relapsed lymphoma (2) will likely expand the use of PD-1 inhibitors. This adds complexity to the management of patients with lymphoma given that irAEs can mimic a variety of infectious syndromes (3, 4). However, ICIs do not appear to independently increase infection risk (3).

Pneumonitis can be a severe irAE in patients treated with ICIs such as pembrolizumab and has been described in approximately 3–7% of patients (1, 4–7), although our understanding of irAEs related to ICIs continues to evolve. The severity grading system includes symptoms and radiographic findings. Grade 1 is asymptomatic disease confined to one lobe or less than 25% lung parenchyma involvement. Grade 2 is symptomatic disease involving 25–50% of lung parenchyma. Grade 3 is defined by severe symptoms requiring hospitalization, and Grade 4 pneumonitis is life-threatening (1).

Symptom onset 1 month after the first dose of pembrolizumab, as in our patient, is early but not atypical. The median time to onset is 3 months (1) but has a wide range from a few weeks to several months (4, 8, 9). Cough and dyspnea are the most common symptoms at presentation (1, 8, 10). Fever is a less common finding and has been reported in approximately 10–30% of patients with ICI-associated pneumonitis (5, 10). Thus, absence of fever may raise suspicion for a noninfectious cause of lung disease in this context.

ICI-associated pneumonitis is a diagnosis of exclusion. Combinations of ICIs and certain tumor types have been identified as risk factors (7). Withholding pembrolizumab was delayed in this case because of ongoing concerns for infection based in part on the airway-centric findings. For Grade 2 pneumonitis as in this case, the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines recommend repeat chest CT imaging and an infectious workup including testing of the nasopharynx, sputum, blood, and urine with consideration for a bronchoalveolar lavage to rule out infection or malignant lung infiltration (1, 11). If no infection is identified and there is no response to antimicrobial therapy, a diagnosis of ICI-associated pneumonitis should be considered. A bronchoalveolar lavage lymphocyte count greater than 15–20% may be more common but is not specific to ICI-associated pneumonitis, and the role of biopsy remains unclear (5).

The radiographic findings in this case consisted of ground-glass opacities and nodular consolidations representing an organizing pneumonia subtype of pneumonitis. Although there are no pathognomonic radiographic features of ICI-associated pneumonitis, ground-glass opacities are the most frequent findings, and organizing pneumonia with patchy or confluent consolidations with or without air bronchograms is the most common pattern (4, 5, 8, 10). The differential diagnosis for these radiographic findings is broad and includes infectious causes and noninfectious causes. Pleural effusion has been described as an irAE (1). However, in our patient, the effusion was present before initiation of pembrolizumab, although it may have increased in size after pembrolizumab was started.

Treatment recommendations for Grade 1 pneumonitis include holding the ICI with the addition of oral corticosteroids (prednisone 1–2 mg/kg/d) for Grade 2 pneumonitis. For Grades 3 and 4 pneumonitis, hospitalization and intravenous corticosteroids are advised. In refractory cases, additional immunosuppressants (e.g., infliximab) should be considered (1, 11). Rechallenging with an ICI can be considered for Grades 1 and 2 pneumonitis that respond well to treatment but not for Grades 3 and 4 pneumonitis (11). Concomitant empiric antimicrobial therapy should be considered depending on the clinical context. Treatment duration depends on grading and response to treatment but is typically given for several weeks (1). Most cases of pneumonitis respond well to withholding the offending drug and/or immunosuppression, but fatal cases have been described (10, 12).

Answers

1. What are the potential etiologies of the pulmonary infiltrates in this patient?

In this patient with refractory mediastinal lymphoma and recent initiation of pembrolizumab, the differential diagnosis remains broad and consists of atypical infection, ICI-associated pneumonitis, and lymphomatous involvement of the lungs.

2. How would you alter management at this stage in the evaluation?

Given the possibility of ICI-associated pneumonitis, pembrolizumab should be held and corticosteroids should be administered if there is no evidence for an infectious or malignant etiology on the basis of the diagnostic evaluation.

3. Would you perform any additional diagnostic testing?

Repeat chest CT imaging should be performed to evaluate for a response, and transbronchial biopsy is generally considered unnecessary when the clinical presentation is consistent with ICI-associated pneumonitis.

Follow-up

The pulmonary infiltrates did not recur. Due to lymphoma progression, the patient was not rechallenged with pembrolizumab and transitioned to a salvage chemotherapeutic regimen. Curative treatment with autologous hematopoietic cell transplantation was initially reconsidered but then deferred given refractory disease. The patient subsequently died of sepsis.

This case highlights the importance of a high index of suspicion for ICI-associated irAEs to facilitate timely interventions and avoid delays in potentially curative oncologic treatments.

Insights

• •The indications for treatment with ICIs are rapidly expanding, together with increased numbers of patients at risk for irAEs.
• •There are no pathognomonic radiographic features of ICI-associated pneumonitis, but ground-glass opacities with a pattern of organizing pneumonia is the most frequent finding.
• •In patients with possible ICI-associated pneumonitis, evaluation for infections and other causes of lower respiratory tract disease should be performed but should not significantly delay definitive therapy for an irAE in the appropriate clinical context.
• •Treatment for ICI-associated pneumonitis consists of withholding the causative agent, and systemic corticosteroids or other antiinflammatory agents may be indicated depending on the severity.