Immune Diffuse Alveolar Hemorrhage: A RetrospectiveAssessment of a Diagnostic Scale

Nicolas de Prost • Antoine Parrot • Elise Cuquemelle •

Clement Picard • Jacques Cadranel

Received: 28 March 2013 / Accepted: 24 June 2013

� Springer Science+Business Media New York 2013

Abstract

Background Initiating early steroid treatment in patients

with immune diffuse alveolar hemorrhage (DAH) is a key

aspect of early management. However, steroid initiation is

often delayed until the results of immunological markers

and/or tissue biopsy have been obtained, which could

contribute to poor outcomes. We previously developed a

clinical score allowing for the early diagnosis of DAH of

immune causes. However, this score has not been validated

in an independent cohort of patients. The aim of this study

was to assess the validity of this diagnostic score using an

independent cohort of patients admitted for DAH of

immune and nonimmune causes.

Methods We conducted a retrospective cohort study of

patients admitted between January 2002 and December

2009 for DAH of immune and nonimmune causes.

Results Forty-six patients were included in the study,

with 12 patients having immune DAH and 34 patients with

nonimmune DAH. Application of our previously validated

clinical scale of immune DAH to this independent popu-

lation of patients yielded an area under the ROC curve of

0.95 [0.90–1.01]. A score C4/10 was associated with the

best performances of this scale: sensitivity = 1.00

[0.73–1.00], specificity = 0.88 [0.72–0.97], positive pre-

dictive value = 0.75 [0.48–0.93], and negative predictive

value = 1.00 [0.88–1.00].

Conclusion While immunological tests and tissue biopsy

results are pending, deciding whether to initiate an

immunosuppressive treatment is challenging. The initiation

of early corticosteroid treatment is warranted in patients

with immune DAH and could improve outcomes. This

study confirms that this score allows for a good discrimi-

nation between patients with immune and nonimmune

DAH. Because this series has several limitations, including

its single-center and retrospective nature, the small number

of patients included, and the lack of therapeutic interven-

tion, a prospective evaluation of this score is warranted to

ascertain whether it can improve the adequacy of early

treatment strategies and thus improve the outcomes of

DAH patients.

Keywords Lung diseases � Interstitial � Respiratory

insufficiency � Vasculitis � Heart failure � Renal

insufficiency

Introduction

Diffuse alveolar hemorrhage (DAH) is a rare and life-

threatening syndrome resulting from diffuse bleeding into

the acinar portion of the lung [1]. DAH is a diagnostic

challenge because it may be accompanied by nonspecific

pulmonary manifestations and may be caused by more than

N. de Prost (&)

Service de Reanimation Medicale, Hopital Henri Mondor,

Assistance Publique-Hopitaux de Paris, Universite Paris Est

Creteil, 51 Avenue de Lattre de Tassigny, 94010 Creteil, France

e-mail: nicolas.de-prost@hmn.aphp.fr

A. Parrot

Service de Reanimation, Hopital Tenon, Assistance

Publique-Hopitaux de Paris and Faculte de Medecine

Pierre et Marie Curie, Universite Paris VI, Paris, France

E. Cuquemelle � C. Picard

Service de Pneumologie, Hopital Foch, Suresnes, France

J. Cadranel

Service de Pneumologie and Centre de Competence des

Maladies Rares Pulmonaires, Hopital Tenon, Assistance

Publique-Hopitaux de Paris and Faculte de Medecine

Pierre et Marie Curie, Universite Paris VI, Paris, France

123

Lung

DOI 10.1007/s00408-013-9491-3

100 immune and nonimmune disorders [1, 2]. Prompt

identification of the etiology of DAH and initiation of

appropriate treatment is required to prevent acute respira-

tory failure and often accompanying acute renal failure,

which in turn can lead to chronic renal failure requiring

renal replacement therapy [1, 3]. The initial accepted

treatment of autoimmune disorders is high-dose intrave-

nous corticosteroids [4]. However, corticosteroid initiation

is often delayed until the diagnosis of immune DAH is

deemed definitive, i.e., when specific laboratory tests (e.g.,

immunological markers and/or tissue biopsy) have been

processed, which could contribute to poor outcomes.

Our group previously developed a clinical score that

allows for the early diagnosis of DAH secondary to

immune diseases [5]. Because DAH is a rare syndrome,

this score has not been validated in an independent cohort

of patients. The aim of the current study was to assess the

validity of this diagnostic score using an independent

cohort of patients admitted for DAH of immune and non-

immune causes.

Methods

Patients

A retrospective cohort study was performed in the Chest

Department, including an Intensive Care Unit (ICU), of an

800-bed tertiary hospital in France. This observational,

noninterventional analysis of medical records was approved

by the Institutional Review Board of the French Learned

Society for Respiratory Medicine (Societe de Pneumologie

de Langue Francaise). Some of the patients presented in this

article have been included in two previously published series

[2, 6]; however, the information presented in this article is

original.

The score for diagnosing immune DAH was constructed

from a first ‘‘historical’’ cohort of patients admitted

between 1980 and 2002 (Cohort 1; n = 76) [5]. In the

current study, the medical records of consecutive patients

admitted between January 2002 and December 2009 for

suspected DAH were reviewed (Cohort 2; n = 46). All

adult patients with symptomatic DAH were eligible and

underwent a bronchoscopy with bronchoalveolar lavage

(BAL). Symptomatic DAH was defined by the presence of

a compatible clinical and radiological presentation (hem-

optysis and/or new pulmonary infiltrates on chest X-ray

and/or anemia, i.e., the DAH triad [1]) and a macroscopi-

cally bloody BAL fluid, or, alternatively, by the presence

of alveolar siderophages on cytology [7]. Patients with

immunocompromised status (human immunodeficiency

virus infection, hematological malignancies, bone marrow

or solid organ transplantation, immunosuppressive drugs

therapy, cytotoxic chemotherapy or radiotherapy, steroids

at a daily dose higher than 20 mg of prednisone-equivalent

for more than 2 months), hemorrhage of bronchial origin,

or requiring chronic hemodialysis were excluded. The

American College of Rheumatology criteria were used for

defining a necrotizing vasculitis [8–11]. The American

Rheumatism Association criteria were used for defining a

connective tissue disease [12, 13]. The antiglomerular

basement membrane antibody disease (ABMAD) was

diagnosed when the serologic test for antiglomerular

basement membrane antibodies was positive, or, alterna-

tively, when a linear immunofluorescent glomerular

immunoglobulin deposit was present [3]. The diagnostic

criteria for the etiologies of nonimmune DAH (i.e., cardiac,

infectious, toxic, cancer, clotting disorder-related, and

idiopathic DAH) have been published elsewhere [2, 6].

Data Presentation and Statistical Analysis

We tested a previously developed clinical scale for the

diagnosis of immune DAH [5]. A score is calculated by

summing up points associated with the presence of the

following variables upon hospital admission: onset of first

respiratory symptoms C11 days (2 points), constitutional

symptoms (i.e., incapacitating fatigue and/or weight loss

[5 % during the month prior to presentation) (2 points),

arthralgias or arthritis (3 points) and proteinuria C1 g/L

(3 points) [5]. A score C4 was previously determined to be

predictive of a DAH of immune cause. The model was

tested in patients who were not included in the initial

model (Cohort 2) in order to provide an independent

assessment of the scale. The diagnostic performances

(sensitivity, specificity, and negative and positive predic-

tive values) of the scale, as well as their 95 % confidence

intervals, were computed and a receiver operating curve

(ROC) was drawn. Quantitative variables were expressed

as mean ± standard deviation or median (25th–75th

interquartile range) when appropriate. Qualitative variables

were expressed as percentages. Quantitative variables were

compared using Student’s t test when data were normally

distributed or the Mann–Whitney U test in other cases. For

categorical variables, a v2 test or Fisher’s exact test for

small samples was used. A two-sided p \ 0.05 was con-

sidered statically significant. Analyses were carried out

using GraphPad Prism statistical software ver. 5 (Graph-

Pad, San Diego, CA).

Results

Forty-six patients were included in the study (Cohort 2),

including 12 patients with immune DAH and 34 patients

with nonimmune DAH. Cohort 2 did not differ from

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Cohort 1 except for a shorter time from the onset of

respiratory symptoms to hospital admission (Table 1). The

proportion of patients with immune DAH in Cohort 2 was

not significantly different than that in Cohort 1 (26 vs.

42 %; p = 0.27).

In Cohort 2, there were no differences between patients

with immune and nonimmune DAH in terms of demo-

graphics, initial severity score, and need for mechanical

ventilation (Table 1). Patients with immune DAH had a

longer time from the onset of respiratory symptoms to

hospital admission, more frequent urinary sediment

abnormalities, including proteinuria [1 g/L, poorer renal

function, and lower blood hemoglobin levels than patients

with DAH from nonimmune causes. The etiologies of

immune DAH were as follows: ANCA-associated vascu-

litides (n = 9), antiglomerular basement membrane anti-

body disease (n = 2), and systemic lupus erythematosus

(n = 1). Nonimmune DAH included cardiac (n = 19),

miscellaneous (infection, n = 6; clotting disorder, n = 1;

barotrauma, n = 4; and fat embolism, n = 1), and idio-

pathic (n = 3) DAH.

In terms of in-hospital outcomes, there were no differ-

ences between patients with immune and nonimmune DAH

regarding ICU admission, mechanical ventilation, and

hospital mortality (Table 2). In contrast, renal replacement

therapy was required more frequently in patients with

immune than nonimmune DAH and the former received

corticosteroids, cyclophosphamide, and plasmaphereses

more frequently than the latter (Table 2).

Application of our previously built clinical scale of

immune DAH [5] to this independent population of

patients yielded an area under the ROC curve of 0.95

[0.90–1.01] (Fig. 1). A score C4/10 was associated with

the best performances of this scale: sensitivity = 1.00

[0.73–1.00], specificity = 0.88 [0.72–0.97], positive pre-

dictive value = 0.75 [0.48–0.93], and negative predictive

value = 1.00 [0.88–1.00]. For patients with immune DAH,

corticosteroids were administered after a median delay of 1

Table 1 Demographic and clinical characteristics of patients with diffuse alveolar hemorrhage (DAH) upon hospital admission

Cohort 1 Cohort 2 pb

All (n = 75) All (n = 46) Immune DAH

(n = 12)

Non immune DAH

(n = 34)

pa

Age (years) 50 ± 18 52 ± 21 48 ± 22 54 ± 21 0.40 0.61

Male 50 (66.7) 32 (69.5) 5 (41.7) 27 (79.4) 0.41 0.88

Weight loss [5 % 22 (29.3) 22 (47.8) 10 (83.3) 12 (35.3) 0.10 0.21

First symptom-admission (days) 11 (4–30) 5 (2–19) 19 (2–30) 4 (1–11) 0.046 0.02

Arthritis 15 (20.0) 3 (6.5) 1 (8.3) 2 (5.9) 0.99 0.11

Proteinuria [1 g/Lc 24 (35.8) 11 (23.9) 7 (58.3) 4 (11.8) 0.035 0.43

Diagnostic score – 2 (0–4) 5 (4–5) 2 (0–3) \0.0001 –

Extrapulmonary symptoms

Cutaneous 25 (33.3) 9 (19.6) 5 (41.7) 4 (11.8) 0.11 0.23

Gastrointestinal 10 (13.3) 4 (8.7) 1 (8.3) 3 (8.8) 0.99 0.57

Neurological 13 (17.3) 11 (23.9) 3 (25.0) 8 (23.5) 0.99 0.49

Nose-ear-throat 8 (10.7) 2 (4.3) 2 (16.7) 0 (0.0) 0.074 0.32

Ocular 10 (13.3) 1 (2.2) 0 (0.0) 1 (2.9) 0.99 0.10

Urinalysis reagent strip

Hematuria 19 (25.3) 11 (23.9) 9 (75.0) 2 (5.9) 0.0008 [0.99

Proteinuria 22 (29.3) 13 (28.3) 8 (66.7) 5 (14.7) 0.02 [0.99

GFRd (mL/min) 64 (33–103) 50 (28–100) 28 (6–82) 51 (35–100) 0.13 0.18

Pulmonary-renal syndrome 14 (18.7) 7 (15.2) 6 (50.0) 1 (2.9) 0.003 0.81

Hemoglobin (g/dL) 8.0 (10.0–12.0) 9.7 (7.2–12.8) 6.9 (5.9–8.4) 10.9 (7.9–13.5) 0.0002 0.45

Mechanical ventilation 11 (14.7) 11 (23.9) 2 (16.7) 9 (26.5) 0.71 0.35

SAPS IIe 25 ± 17 28 ± 18 27 ± 23 28 ± 16 0.94 0.33

a p values for comparisons between immune and nonimmune DAH of Cohort 2b p values for comparisons between Cohort 1 and Cohort 2c n = 67 patients available in Cohort 1d Glomerular filtration ratee Simplified Acute Physiology Score II [16]

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(range = 0–1) day after admission, including three patients

(25 %) for whom corticosteroid administration was

delayed more than 48 h following hospital admission. In

contrast, 11 (32 %) patients with nonimmune DAH

received early corticosteroid infusions inappropriately.

Applying our scale upon hospital admission to Cohort 2

would have led to treating all patients with immune DAH

and only three patients with nonimmune DAH.

Discussion

The reported prognosis of DAH is poor, with in-hospital

mortality ranging from 20 to over 50 % [6, 14, 15]. While

immunological tests and tissue biopsy results are pending,

deciding whether to initiate an immunosuppressive treat-

ment is challenging. The initiation of early corticosteroid

treatment is warranted in patients with immune DAH and

could improve outcomes [3, 4]; however, corticosteroids

could be deleterious for patients with nonimmune DAH.

Because DAH is a rare syndrome that can reveal a life- and

function-threatening underlying immune process [1], most

patients with the onset of a previously unknown immune

disease presenting with DAH are going to be taken care of

by nonexpert physicians (i.e., in the Emergency Room or in

the ICU) in the acute setting. To provide a noninvasive tool

that would distinguish between immune and nonimmune

DAH during the early phase of management would cer-

tainly be helpful. The differences in the clinical presenta-

tion of patients with immune and nonimmune DAH

allowed for the development of a predictive clinical scale

to help clinicians identify patients with immune DAH [5].

This scale yielded the best performances for diagnosing

immune DAH when at least two of the following symp-

toms were present: onset of first respiratory symptoms

C11 days, fatigue and/or weight loss during the month

prior to presentation, arthralgias or arthritis, and proteinuria

C1 g/L. Importantly, proteinuria was measured in less than

1 h on fresh urine collected upon admission using a dye-

binding colorimetric method.

The current study shows that the application of this scale

to 46 patients who were not included in the initial cohort

allowed for good discrimination between patients with

immune and nonimmune DAH. The area under the ROC

curve was 0.95, with best performances for a score of C4

(i.e., corresponding to the presence of two of the four items

of the score), consistent with the findings of the initial

study [5]. Compared to pulmonary-renal syndrome, this

scale exhibited much better sensitivity (41 vs. 96 %) and

comparable specificity (96 vs. 88 %) for the diagnosis of

immune DAH. Importantly, application of this score upon

admission to the current cohort of patients not only would

have led to reducing the delay of corticosteroid adminis-

tration to patients with immune DAH, it would have also

reduced the proportion of inappropriate corticosteroid

administration to patients with nonimmune DAH.

This series certainly has several limitations, i.e., its

single-center and retrospective nature, the small number of

patients included, and the lack of therapeutic intervention.

Table 2 Hospital course of patients with immune and nonimmune diffuse alveolar hemorrhage (DAH)

All (n = 46) Immune DAH

(n = 12)

Nonimmune DAH

(n = 34)

p

Hospital length of stay (days) 8 (5–19) 12 (3–27) 8 (5–17) 0.51

ICU admission 39 (84.8) 9 (75.0) 30 (88.2) 0.35

Mechanical ventilation 12 (26.1) 2 (16.7) 10 (29.4) 0.47

Hemodialysis 6 (13.0) 5 (41.7) 1 (2.9) 0.003

Steroids 23 (50.1) 12 (100.0) 11 (32.3) \0.0001

Cyclophosphamide 10 (21.7) 8 (66.7) 2 (5.9) \0.0001

Plasmapheresis 3 (6.5) 3 (25.0) 0 (0.0) 0.014

Hospital mortality 12 (26.1) 1 (8.3) 11 (32.3) 0.14

0.0 0.2 0.4 0.6 0.8 1.00.0

0.2

0.4

0.6

0.8

1.0 0234

5

6, 7

8

10

1-specificity

Sens

itiv

ity

Scale 4

AUC=0.95

Fig. 1 Receiver operating characteristic curve showing the perfor-

mance of a previously derived clinical scale5 for the diagnosis of

immune diffuse alveolar hemorrhage in an independent cohort of 46

patients (annotated numbers on the curve are the result of the scale).

The area under the curve (AUC) was 0.95 [0.90–1.01]

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Moreover, one has to acknowledge that, except for the

variable ‘‘proteinuria [1 g/L,’’ the assessment of the

presence of the other variables compounding the score

could be somewhat subjective and could be impacted by

the experience and the specialty of the attending physician

as well as by the intrinsic variability of medical interviews.

One additional factor limiting the generalizability of our

findings is that our center has a 24 h emergency bron-

choscopy service available at bedside, allowing for a

timely diagnosis of DAH. Delayed access to bronchoscopy

and BAL would further delay the diagnosis of DAH and

thus that of its etiology. A multicenter prospective evalu-

ation of this score is warranted to ascertain whether it can

improve the adequacy of early treatment strategies and thus

improve outcomes of DAH patients.

In conclusion, the current study confirms the good dis-

crimination performance of a previously developed score

for diagnosing immune DAH based on variables immedi-

ately available upon hospital admission. Applying this

score not only might help reduce the delay of steroid

administration to patients with immune DAH and thus

improve their prognosis, it might also limit the overtreat-

ment of patients with nonimmune DAH.

Conflict of interest None of the authors has a conflict of interest to

disclose.

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