Clear and Bright: An Elusive Cause of Hypoxemia.

A 54-year-old previously healthy woman was hospitalized with progressive shortness of breath and hypoxemia. Six months prior to admission, the patient first presented to her primary care physician with arthralgias, morning stiffness, and fatigue. Initially, joint pain and stiffness affected her fingers and toes and persisted throughout the day. Over the next month, her wrists and knees were additively involved, causing difficulty in activities of daily living. At that time, she reported no dry eyes, dry mouth, joint swelling, rashes, respiratory symptoms, or muscle weakness. She was a lifelong nonsmoker without occupational or environmental exposures. She had 2 long-term house dogs. Although originally from Japan, she did not have any recent foreign travel, insect bites, or known sick contacts. The patient was referred to a rheumatologist. Serologic tests for antinuclear antibody, rheumatoid factor, cyclic citrullinated peptide, and antineutrophil cytoplasmic autoantibody were negative. Levels of C3 and C4 complement were also within the normal ranges. The erythrocyte sedimentation rate was normal at 6 mm/h (ref <30 mm/h), whereas C-reactive protein was elevated at 13 mg/L (reference <5 mg/L). Her initial examination was notable for tenderness of the proximal interphalangeal joints bilaterally, as well as right knee and left hip tenderness. The lungs were clear. There were no rashes or joint swelling noted. She was initiated on oral prednisone 15 mg daily, followed by a taper of 2.5 mg every week, with improvement in her joint pain. Shortly after tapering off prednisone, the patient developed chest tightness and dyspnea on minimal exertion, as well as subjective fever and chills. Her primary care physician noted that her oxygen saturation was 81% while climbing stairs, and by the end of the month, she required 2 liters of supplemental oxygen at rest and 6 liters with mild exertion. Notably, she remained free of arthralgias at this time. An evaluation for the cause of her hypoxemia commenced. Computed tomography of the chest showed faint, diffuse ground-glass opacities and subtle mosaicism within the lung parenchyma (Figure 1). Pulmonary function tests showed low diffusing capacity for carbon monoxide at 53% predicted, without obstructive or restrictive ventilatory defects. Right heart catheterization revealed mild, precapillary pulmonary hypertension with a mean pulmonary artery pressure of 27 mm Hg (ref <21 mm Hg). Laboratory studies showed a white blood cell count of 3,600 cells/mm3 (neutrophils 67%, lymphocytes 17%, monocytes 13%, eosinophils 2%, basophils 1%), hemoglobin 13.5 g/dL, platelet count 142,000/mm3, creatinine 0.8 mg/dL, an elevated aspartate aminotransferase (AST) to 102 U/L (ref <35 U/L), with protein of 6.6 g/dL and albumin of 4.1 g/dL. The peripheral blood smear showed mild leukopenia with a mixed cell population without overt cytologic atypia or circulating blasts. She was diagnosed with an interstitial lung disease (ILD) of uncertain etiology and started on prednisone 60 mg daily. After 1 month without improvement and with progressive functional decline, she was admitted to the Johns Hopkins Hospital. Her continued fatigue, progressive shortness of breath, and hypoxemia were disconcerting, and her lack of sustained response to escalating doses of prednisone raised concern for an infectious or malignant process with prominent lung involvement. A priority was to collect bronchoalveolar lavage samples to investigate for occult infection. On presentation to our hospital, the patient's temperature was 37°C, heart rate 72 beats per min, respiratory rate 18 breaths/min, and oxygen saturation 99% on 3 liters supplemental oxygen. She was tired appearing, but her breathing was not labored. Her lungs were clear except for faint crackles in the posterior left lower lung field. Cardiovascular examination showed regular rhythm and normal quality S1 and S2, without murmurs, rubs, or gallops. Skin and joint examination revealed no cyanosis, clubbing, or rash, and no synovitis. Abdominal and neurological examinations were unremarkable. There was no cervical, submandibular, or axillary lymphadenopathy. Diagnostic data while on oral prednisone 20 mg daily showed white blood cell count 6,870 cells/mm3 (neutrophils 78%, lymphocytes 13%, monocytes 7%), hemoglobin 11.9 g/dL, platelet count 209,000/mm3, creatinine 0.7 mg/dL, and normal liver chemistries. Serum lactate dehydrogenase was elevated to 720 U/L (ref 122-220 U/L). A ventilation-perfusion scan showed normal ventilation and decreased perfusion in a subsegmental pattern in the lateral aspect of the anterior segment of the left upper lobe. Bronchoalveolar lavage was performed, which showed lymphocytosis with nondiagnostic flow cytometry and cytopathology. She was seen in clinic 3 weeks after discharge, at which time cultures from bronchoalveolar lavage remained negative. Given her constellation of findings of mosaic ground-glass opacities on computed tomography imaging, mild pulmonary hypertension on right heart catheterization, isolated low diffusing capacity for carbon monoxide without restrictive or obstructive ventilatory abnormalities, and heterogeneous blood flow on ventilation-perfusion scanning, a pulmonary microvascular process was posited to explain her course. Her systemic symptoms and elevated lactate dehydrogenase raised suspicion for an occult lymphoproliferative disorder. She was readmitted for further evaluation. Upon rehospitalization, she was unable to bathe herself due to profound fatigue. Fluorine-18-fluorodeoxyglucose-positron emission tomography showed diffuse, bilateral uptake of the right and left lung fields (Figure 2), which was heterogeneous in the apical and basilar regions (Figure 2B-F). Whole blood flow cytometry showed a small population of phenotypically abnormal B cells, which accounted for 1% of total cells. These showed monoclonal expression of kappa light chain with dimmer CD9, CD20, dim CD38, CD10, partial CD5, and partial CD20 expression. An ultrasound-guided, transbronchial lung biopsy was nondiagnostic. Given the "clear and bright" pattern of fluorodeoxyglucose uptake on positron emission tomography imaging, suspicion for a neoplastic process remained high. Random skin biopsies were performed from the right thigh, abdomen and left forearm, revealing atypical cells infiltrating small vessels within the mid-to-deep dermis (Figure 3).2Ferreri AJ Campo E Seymour JF et al.Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'.Br J Haematol. 2004; 127: 173-183Crossref PubMed Scopus (497) Google Scholar On immunohistochemistry, the cells were positive for CD20, MUM1, BCL-2, partially positive for CD5 and BCL-6, and negative for CD3, CD10, and CD30, with Ki-67 proliferation index exceeding 90% (Figure 3C). Staining for Epstein-Barr virus by in-situ hybridization was negative. These findings confirmed an underlying diagnosis of intravascular large B-cell lymphoma (IVBCL), supporting involvement of the pulmonary vasculature by IVBCL as the cause of her dyspnea and hypoxemia. IVBCL is a rare subtype of non-Hodgkin lymphoma characterized by proliferation of a clonal population of lymphoid cells within the lumen of blood vessels. The classical variant of disease often presents with constitutional symptoms, including fever of unknown origin, and may involve the central nervous system (CNS) and skin. A pronounced decline in performance status is often described.3Ponzoni M Ferreri AJM Campo E et al.Definition, diagnosis, and management of intravascular large B-cell lymphoma: proposals and perspectives from an international consensus meeting.J Clin Oncol. 2007; 25: 3168-3173Crossref PubMed Scopus (350) Google Scholar Of note, pulmonary involvement may be present in up to one-third of patients, with dyspnea, hypoxemia, and lung infiltrates commonly reported. A subset manifests isolated cutaneous involvement, which is notably frequent among women in western countries and presents with single or multiple skin lesions.2Ferreri AJ Campo E Seymour JF et al.Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'.Br J Haematol. 2004; 127: 173-183Crossref PubMed Scopus (497) Google Scholar A hemophagocytic syndrome-associated variant is characterized by bone marrow involvement, fever, hepatosplenomegaly, and thrombocytopenia.1Ponzoni M Campo E Nakamura S. Intravascular large B-cell lymphoma: a chameleon with multiple faces and many masks.Blood. 2018; 132: 1561-1567Crossref PubMed Scopus (105) Google Scholar Our patient had laboratory evidence of mild leukopenia and thrombocytopenia when she first sought medical care. Establishing a diagnosis of IVBCL is challenging because clinical symptoms are often nonspecific, and biopsies may be nondiagnostic (as in our patient's transbronchial biopsy). Clinicians often have limited familiarity with the condition, and prognosis is poor in part due to frequent delay in diagnosis.1Ponzoni M Campo E Nakamura S. Intravascular large B-cell lymphoma: a chameleon with multiple faces and many masks.Blood. 2018; 132: 1561-1567Crossref PubMed Scopus (105) Google Scholar Given the extent of involvement, patients with IVBCL are considered to have disseminated disease at diagnosis and should receive anthracycline-based combination chemotherapy. Our patient was treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine (Oncovin), and prednisone (R-CHOP)4Coiffier B Lepage E Briere J et al.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 235-242Crossref PubMed Scopus (4537) Google Scholar with intrathecal prophylaxis followed by high-dose methotrexate.4Coiffier B Lepage E Briere J et al.CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med. 2002; 346: 235-242Crossref PubMed Scopus (4537) Google Scholar After the first cycle of her chemotherapy regimen, her symptoms of dyspnea, chest tightness, and fever resolved, and her energy and activity level meaningfully improved. Remarkably, by hospital discharge, she no longer required supplemental oxygen therapy. In this report, we present the case of a 54-year-old woman with a months-long illness of arthralgias, constitutional symptoms, and ultimately hypoxemic respiratory failure due to the elusive diagnosis of IVBCL. Her narrative demonstrates the importance of high clinical suspicion and the benefit of timely initiation of chemotherapy, as reflected by the complete resolution of her presenting symptoms and marked functional recovery.