Diffuse alveolar hemorrhage caused by IgA deposition associated with multiple myeloma

Abstract

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.

Full text

Clin Case Rep. 2019;7:1049–1052.
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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 pulmo-
nary‐renal syndromes (PRS),2-4 immunoglobulin A (IgA)
deposition in the alveolar wall,5,6 certain drugs,7-11 postau-
tologous 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‐year‐
old man with undiagnosed MM who was admitted to our hos-
pital for treatment of DAH caused by deposition of IgA.
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CASE REPORT
A 77‐year‐old man was admitted to our hospital with hem-
optysis and slight fever of two weeks’ duration. He had
been treated and followed for an old myocardial infarction
and was taking clopidogrel and aspirin. On admission, his
blood pressure was 111/55 mm Hg, pulse rate was 72/min,
and body temperature was 37.2°C. His arterial oxygen satu-
ration was 91% on O2 at 2 L/min via nasal canula, and arte-
rial blood gas analysis showed a PaO2 of 61.9 Torr, PaCO2
of 30.3 Torr, and pH of 7.46. Chest X‐ray and computed
tomography (CT) showed bilateral ground‐glass opacities
(Figure 1). Blood tests revealed a white blood cell count of
10 900/µL (normal, 3900‐9800) (neutrophils 82.9%, lympho-
cytes 9.0%, eosinophils 2.3%, monocytes 5.7%), hemoglobin
10.7 g/dL (normal, 13.5‐17.6), platelets 202 000/µL (normal,
130 000‐369 000), prothrombin time 13.9 seconds (normal,
10.7‐12.9), activated partial thromboplastin time 49.4 sec-
onds (normal, 24.0‐39.0), C‐reactive protein 14.3 mg/dL
(normal, <0.3), LDH 386 IU/L (normal, 119‐229), total
protein 7.4 g/dL (normal, 6.6‐8.4), serum albumin 3.2 g/
dL (normal, 3.8‐5.2), serum creatinine 0.8 mg/dL (normal,
0.6‐1.1), blood urea nitrogen 16 mg/dL (normal, 8‐20), cal-
cium 8.2 mg/dL (normal, 8.8‐10.5), IgA 946 mg/dL (normal,
110‐410), immunoglobulin G (IgG) 964 mg/dL (normal,
870‐1700), and immunoglobulin M (IgM) 37 mg/dL (nor-
mal, 35‐220). Urinalysis showed protein of 223 mg/dL
Received: 30 November 2018
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Revised: 15 March 2019
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Accepted: 29 March 2019
DOI: 10.1002/ccr3.2151
CASE REPORT
Diffuse alveolar hemorrhage caused by IgA deposition associated
with multiple myeloma
AtsukiFurube1
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NahoKagiyama1
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TakashiIshiguro1
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YotaroTakaku1
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KazuyoshiKurashima1
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YoshihikoShimizu2
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NoboruTakayanagi1
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
1Department of Respiratory
Medicine,Saitama Cardiovascular and
Respiratory Center, Saitama, Japan
2Department of Diagnostic
Pathology,Saitama Cardiovascular and
Respiratory Center, Saitama, Japan
Correspondence
Atsuki Furube, Department of Respiratory
Medicine, Saitama Cardiovascular and
Respiratory Center, Saitama, Japan.
Email: atsukifurube@gmail.com
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 diagno-
sis in patients with diffuse alveolar hemorrhage, and bronchoscopy may help to
differentiate the cause.
KEYWORDS
bronchoalveolar lavage, diffuse alveolar hemorrhage, multiple myeloma, transbronchial lung biopsy

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FURUBE Et al.
(normal, <19) and was negative for occult blood. We ini-
tially suspected bacterial pneumonia, with antiplatelet agents
as the cause of the DAH. Although we started antibiotics
and stopped the antiplatelet agents, his pulmonary lesions
gradually worsened, and hemoptysis continued on the 2nd
hospital day. He required the administration of oxygen at an
FiO2 of 80% to maintain an O2 saturation above 90%, which
precluded the performance of bronchoscopy. We also con-
sidered systemic vasculitis and started a 3‐day course of in-
travenous methylprednisolone (1000 mg/d) followed by oral
prednisolone at 40 mg/d. However, the corticosteroid therapy
was not effective: the inflammatory reaction increased, and
his respiratory function continued to deteriorate. Therefore,
we began another 3‐day course of intravenous methylpred-
nisolone on the 9th hospital day. Tests for antibodies associ-
ated with connective tissue diseases, including MPO‐ANCA,
PR3‐ANCA, and anti‐GBM antibody, were all negative.
Although his IgA value was high, his IgG and IgM values
were normal. Serum electrophoresis showed no M protein,
but serum immunoelectrophoresis revealed the presence of
IgA‐κ‐type M protein. Serum free light chain (sFLC) assay
showed a κ/λ ratio of 21.4 (normal, 0.2‐1.8). The patient’s
β2‐microblobulin was 1.6 mg/L (normal, 0.9‐1.9), and he
was negative for urine Bence Jones protein. An abdominal
CT performed to search for MM revealed a left iliac tumor
(Figure 2). A CT‐guided needle biopsy of this tumor was
performed that revealed abnormal cells on hematoxylin and
eosin staining. Immunostaining of the biopsied specimen
showed the cells to be positive for CD79a and CD138, in-
dicating that the abnormal cells were plasma cells (Figure
3). Moreover, immunostaining of these cells was positive for
IgA and kappa light chain, and thus we diagnosed the patient
as having IgA‐κ‐type MM.
After the patient’s respiratory condition improved, bron-
choalveolar 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% macro-
phages, 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 fi-
brosis but was negative for plasma cells. We found no am-
yloid 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 lenalid-
omide 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.
3
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DISCUSSION
This case showed that IgA deposition due to MM might
cause DAH. We used the diagnostic criteria of the
FIGURE 1 Chest X‐ray and
computed tomography images showed
bilateral ground‐glass opacities
FIGURE 2 Abdominal computed tomography showed a left iliac
tumor

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FURUBE Et al.
International Myeloma Working Group14 to diagnose
MM in this patient based on the serum M protein level,
extramedullary plasmacytoma, and presence of the iliac le-
sion. Other main conditions associated with MM, that is,
renal disorder, hypercalcemia, and anemia, were not identi-
fied in this patient.
de Prost et al1 reported that one‐third of all occurrences
of DAH were caused by immune diseases, especially vas-
culitis and antiglomerular basement membrane antibody
syndrome, and connective tissue diseases. Among the
non‐immune‐mediated etiologies, systolic or diastolic car-
diac 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 re-
lated 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.
FIGURE 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
FIGURE 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

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Among five diagnosed cases of MM due to DAH, three
were caused by PRS2-4 and two by IgA deposition in the al-
veolar 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 pres-
ent 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 re-
vealed 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.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
AF: is the guarantor of the paper, taking responsibility for the
integrity of the work as a whole, from inception to published
article. NK, TI, YT, KK, YS, and NT: aggregated the data
and helped draft the discussion of the manuscript.
ORCID
Atsuki Furube https://orcid.org/0000-0002-4342-5098
Takashi Ishiguro https://orcid.org/0000-0001-6004-1769
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How to cite this article: Furube A, Kagiyama N,
Ishiguro T, et al. Diffuse alveolar hemorrhage caused by
IgA deposition associated with multiple myeloma. Clin
Case Rep. 2019;7:1049–1052. https://doi.org/10.1002/
ccr3.2151