Diffuse alveolar hemorrhage caused by IgA deposition associated with multiple myeloma

Key Clinical Message We report a man with diffuse alveolar hemorrhage caused by multiple myeloma who was diagnosed with the aid of bronchoalveolar lavage and transbronchial lung biopsy. Multiple myeloma should be considered as an important differential diagnosis in patients with diffuse alveolar hemorrhage, and bronchoscopy may help to differentiate the cause.


| INTRODUCTION
Many different diseases cause diffuse alveolar hemorrhage (DAH), 1 and it needs to be accurately diagnosed early in its course. The available reports on patients with multiple myeloma (MM) and DAH state that the causes are pulmonary-renal syndromes (PRS), [2][3][4] immunoglobulin A (IgA) deposition in the alveolar wall, 5,6 certain drugs, [7][8][9][10][11] postautologous stem cell transplantation, 12 and uncertain origin. 13 DAH was the initial symptom in three cases of PRS and in two cases of IgA deposition in the alveolar wall, and in other reports, DAH occurred during the course of MM treatment. Here, we report the third known case of DAH in a 77-yearold man with undiagnosed MM who was admitted to our hospital for treatment of DAH caused by deposition of IgA.
After the patient's respiratory condition improved, bronchoalveolar lavage fluid (BALF) was obtained from the left B5 by bronchoscopy. We instilled 150 mL of 0.9% NaCl and aspirated 70 mL of bloody fluid containing 93.2% macrophages, 4.7% lymphocytes, 2.1% neutrophils, with a CD4/8 ratio of 0.5, and 25% hemosiderin-laden macrophages. A transbronchial lung biopsy (TBLB) showed interstitial fibrosis but was negative for plasma cells. We found no amyloid deposition in the lung by direct fast scarlet staining. However, deposition of IgA was revealed on a blood vessel wall by immunofluorescence staining, but no deposition of IgG was present ( Figure 4). We thus thought that the patient had DAH caused by IgA deposition due to MM of Durie/ Salmon stage IIA and International Staging System stage II. We reduced the corticosteroid dose due to the diagnosis of MM, and he was discharged from our hospital on the 55th hospital day. Nine days later, treatment with lenalidomide and corticosteroid was started by the Department of Hematology in another hospital. His serum IgA and κ/λ ratio decreased, and the DAH improved after two courses of the treatment; however, the tumor in the left ilium did not improve.

| DISCUSSION
This case showed that IgA deposition due to MM might cause DAH. We used the diagnostic criteria of the International Myeloma Working Group 14 to diagnose MM in this patient based on the serum M protein level, extramedullary plasmacytoma, and presence of the iliac lesion. Other main conditions associated with MM, that is, renal disorder, hypercalcemia, and anemia, were not identified in this patient.
de Prost et al 1 reported that one-third of all occurrences of DAH were caused by immune diseases, especially vasculitis and antiglomerular basement membrane antibody syndrome, and connective tissue diseases. Among the non-immune-mediated etiologies, systolic or diastolic cardiac dysfunction of the left ventricle and valvular heart disease were the main causes, followed by infection and drug-induced DAH. Cancer was identified in 4% of patients. 2 In the present case, DAH was diagnosed on the basis of the clinical course and BALF and TBLB findings. Antibodies related to connective tissue diseases, including MPO-ANCA and PR3-ANCA, were all negative. Serum levels of IgA and IgA-κ-type M protein, the sFLC κ/λ ratio, and the iliac lesion helped us to diagnose MM. F I G U R E 3 Histology of the left iliac tumor showed abnormal cells stained with hematoxylin and eosin. Immunostaining of the biopsied specimen showed the cells to be negative for CD20 but positive for CD79a and CD138, indicating that the abnormal cells were plasma cells F I G U R E 4 Transbronchial lung biopsy showed interstitial fibrosis negative for plasma cells by hematoxylin and eosin staining. We found no amyloid deposition in the lungs by direct fast scarlet stain. Immunofluorescence staining revealed deposition of IgA on a blood vessel wall, but no deposition of IgG was found Among five diagnosed cases of MM due to DAH, three were caused by PRS 2-4 and two by IgA deposition in the alveolar wall, 5,6 in which IgA-κ-type M proteins were detected. Schreiber et al. reported that immunohistochemistry revealed dense pericapillary and perivascular deposits of IgA. 6 In both cases, the treatment for MM affected the DAH. As in the present patient, immunofluorescence of a TBLB specimen from these two patients also showed deposition of IgA on a blood vessel wall. We thought perivascular deposits of IgA might have caused collapse of these vessel walls that led to DAH.
After treatment for MM was initiated in our patient, his serum IgA level and sFLC κ/λ ratio decreased, and his DAH and respiratory condition improved, although his iliac lesion remained unchanged. We are continuing to follow this patient to determine whether his MM has improved.
In conclusion, we reported a case of DAH caused by IgA deposition associated with MM. In this patient, TBLB revealed deposition of IgA in the alveolar wall. MM should be considered as one possible cause of DAH as the initial symptom of MM might well be DAH. IgA deposition in the alveolar wall should also be considered as a potential cause of DAH in the absence of PRS.