Patients
There were 12 patients with a histopathological diagnosis of OP and concomitant diagnosis of a hematologic malignancy in our database from 1 January 2000 to 1 July 2020. Before OP onset, 7 patients accepted chemotherapy, including 1 patient who accepted SCT, 1 who received targeted therapy (e.g., rituximab) and 3 with ongoing infection. The other 5 patients had OP associated with hematologic malignancies, which were the primary pathologic process without any other related reasons. None of these 5 patients accepted chemotherapy, targeted therapy or SCT. There were 3 female patients, included one with myelodysplastic syndrome (MDS), one with acute myelogenous leukemia (AML, M5), and one with multiple myeloma (MM). One of the 2 male patients had aplastic anemia (AA), and the other T cell lymphoma (TCL). The patients’ ages ranged from 43 to 67 years, and three of them had a smoking history (range from 30 to 80 pack-years).
Clinical Characteristics
The five cases of OP associated with hematologic malignancies presented symptoms similar to those of pulmonary infection, such as fever, cough and dyspnea (Table 1). One patient had a history of hemoptysis, which might have been caused by MDS-induced thrombocytopenia. Two of the patients had a history of productive cough with sputum, but all five patients were observed to have moist inspiratory rales. Consistent with the non-fibrosis on CT scan, none of the patients exhibited Velcro rales.
Table 1
Demographic and clinical characteristics of OP associated with hematologic malignancies
Patients NO. | Age(year)/Gender | Smoking history (pack-year) | Hematologic malignancies | Symptoms | Duration from onset to OP diagnosis | Lung biopsy | Respirator support | Admitted to ICU | Steroid treatment in hospital | Clinical outcome | Follow-up |
1 | 52/F | 0 | Myelodysplastic syndrome (MDS) | Fever, cough, dyspnea, hemoptysis, chest pain | 2 months | Bronchoscopic biopsy | High-flow nasal cannula oxygen therapy and noninvasive mechanical ventilation | 3 weeks | methylprednisolone 40 mg/day (0.8 mg/kg/day), intravenous infusion | Favorable clinical response | Reversed respiratory symptoms after 3 months steroid treatment, surviving, 6 months follow-up |
2 | 43/F | 30 | Acute myelogenous leukemia (AML, M5) | Fever, cough, dyspnea, fatigue, weakness, | 1.5months | Bronchoscopic biopsy | High-flow nasal cannula oxygen therapy | 2 weeks | methylprednisolone 40 mg/day (0.7 mg/kg/day), intravenous infusion | Favorable clinical response | Reversed respiratory symptoms after 2 months steroid treatment, 5 months follow-up |
3 | 67/M | 45 | Aplastic anemia (AA) | Fever, cough, dyspnea, expectoration, chest pain | 6 months | Bronchoscopic biopsy | Noninvasive mechanical ventilation | 2 weeks | methylprednisolone 40 mg/day (0.7 mg/kg/day), intravenous infusion | Favorable clinical response | Reversed respiratory symptoms after 2 months steroid treatment, death caused by AA, 13 months follow-up |
4 | 57/M | 80 | T Cell Lymphoma (TCL) | Fever, cough, dyspnea, expectoration, chest pain | 1 months | 2 times of bronchoscopic biopsy, CT-guided percutaneous lung biopsy | Invasive mechanical ventilation | 3 weeks | methylprednisolone 40 mg/day (0.7 mg/kg/day), intravenous infusion | Favorable clinical response | Reversed respiratory symptoms after 1 month steroid treatment, surviving, 25 months follow-up |
5 | 68/F | 0 | Multiple myeloma (MM) | Fever, cough, dyspnea, | 4 months | Bronchoscopic biopsy | High-flow nasal cannula oxygen therapy | 1 week | methylprednisolone 40 mg/day (0.6 mg/kg/day), intravenous infusion | Favorable clinical response | Reversed respiratory symptoms after 1 month steroid treatment, surviving, 26 months follow-up |
All five OP patients were hospitalized for diagnosis, and all were primarily diagnosed with pulmonary infection. Because of unfavorable responses to antibiotics and immune deficiency, pulmonary aspergillosis were the most frequently considered before the diagnosis of OP. All patients were found to have anemia, and four of them (excluding the patient with TCL) showed hypolymphocytosis in blood routine tests. Interestingly, after the use of steroids, all patients showed improvement of anemia without treatment for the hematologic malignancies. Before the diagnosis of OP, all patients accepted anti-infection treatments for more than 4 weeks, including piperacillin-tazobactam, cefperazone-sulbactam, meropenem, and voriconazole. However, none of them received antiviral treatment, indicating that bacterial and fungal infections were the most considered differential diagnoses in OP associated with hematologic malignancies. Furthermore, all five OP patients were admitted to the intensive care unit (ICU) for respiratory failure (Table 1).
Radiologic findings
All patients underwent high-resolution computed tomography (HRCT) before OP diagnosis, and one of them even completed positron emission tomography-computed tomography (PET-CT). As in previous studies[10–12], there were patchy consolidative opacities and airspace consolidation along the bronchovascular bundle or in the subpleural area on HRCT (Fig. 1). However, some uncommonly described findings on HRCT were observed in these cases. One MDS case and one AML case were showing multiple nodules along the bronchovascular bundle with ground-glass opacity (GGO). The HRCT scan of the MDS case even showed a halo of GGO as a typical early sign of pulmonary fungal infection (Fig. 2A). Additionally, the AML case exhibited interlobular septal thickening and a reticulonodular pattern (Fig. 2B). Interestingly, both cases progressed rapidly and developed extensive bilateral opacity on HRCT in less than two weeks (Fig. 2C, D).
PET-CT was conducted on the TCL patient, and showed a high standardized uptake value (SUV) max of the lung and pleura (range from 2.5–3.5). On the other hand, PET-CT showed a higher SUV max of the retroperitoneal and intraperitoneal lymph nodes (greater than 7.5), indicating that pulmonary lesion may be different from lymphadenopathy.
Diagnosis
Since OP is a rare disease and is defined by a special pathological pattern, it takes a long time to diagnose this condition[2]. The duration from onset to OP diagnosis was extensive, ranging from 1 to 6 months in the 5 OP cases. OP was frequently diagnosed by lung biopsy, including bronchoscopic and CT guide percutaneous biopsy. All 5 patients underwent bronchoscopic biopsy. Due to the subpleural lesion and limitation of the biopsy sample, a TCL patient failed to obtain a proper diagnosis for lung lesions even after 2 bronchoscopic biopsies. Finally, the OP diagnosis was confirmed in via CT guide percutaneous biopsy.
Cytological detection was conducted in BALF from the five patients, and no malignant cells were found. Four of them had differential cell counts and T cell subsets in BALF, except for the MM case. The ratios of lymphocyte ranged from 15–30%, and the ratios of the CD4+/CD8 + T cells ranged from 1.5 to 3.0. However, the neutrophil ratios were under 15% in all 4 cases. In addition, malignant cells were not observed in the alveolar space or wall from the biopsy sample.
Although bronchoscopy revealed purulent sputum in the TCL patient with OP, the pathogen-detection results were negative in sputum and BALF. Bronchoscopy of the other 4 patients revealed only a few secretions without edema and congestive mucosa in the airways. To detect possible pathogens, next-generation sequencing (NGS) technology was conducted in blood and BALF from the MDS and AML cases. The sequence analysis did not identify causative pathogens for the two cases.
Treatment And Outcome
Once the five patients were diagnosed with OP, all were treated with intravenous steroids (methylprednisolone, 40 mg/day) for more than 1 week. Fever and cough were the earliest and most frequently improved symptoms after steroid treatment. The five patients have underwent steroid (intravenous and oral) treatment for 3 to 6 months. During follow-up, we have found that the respiratory symptoms and radiological abnormalities were completely reversed after 1–3 months of steroid use (Table 1). One patient died due to AA at the 13th month of follow-up, and the other four patients survived during follow-up.
Due to agranulocytosis, the AML patient was treated with voriconazole and cefoperazone-sulbactam after OP diagnosis. The other four OP patients discontinued anti-fungus treatment after no evidence of fungal infection was found. Because of mild neutropenia, the AA and TCL patients received piperacillin-tazobactam treatment after their OP diagnosis.