Diffuse alveolar hemorrhage secondary to sarcoidosis

Abstract

Diffuse alveolar hemorrhage (DAH) is a pulmonary condition that can be caused by autoimmune disorders such as lupus, small vessel vasculitis, and antiphospholipid syndrome. Sarcoidosis as a cause of DAH has been reported; however, the literature remains limited. We performed a chart review for patients with a diagnosis of both sarcoidosis and DAH. Seven patients met inclusion criteria. Mean (range) patient age was 54 years (39–72), and 3 patients had a history of tobacco use. Diagnosis of DAH and sarcoidosis were concurrent for 3 patients. Corticosteroids were used for treatment of DAH in all patients; 2 (including 1 with refractory DAH) were successfully treated with rituximab. We believe sarcoidosis-associated DAH is more common than previously reported. It is essential to consider sarcoidosis in the differential diagnosis of immune-mediated DAH.

Key Points • Sarcoidosis can cause diffuse alveolar hemorrhage (DAH); more extensive studies are needed to estimate this condition’s prevalence. • BMI of 25 or higher appears to be a risk factor for the development of sarcoidosis-associated DAH.

Introduction

Diffuse alveolar hemorrhage (DAH) is a pulmonary condition that presents with hemoptysis, cough, and dyspnea. DAH can be mediated by immune and nonimmune causes. Causes of immune-mediated DAH include lupus, small vessel vasculitis, and antiphospholipid syndrome [1–3]. Sarcoidosis as a cause of immune-mediated DAH has been reported; however, the literature remains limited [4, 5]. Due to the high rate of complications associated with DAH, it is essential to identify whether more cases related to sarcoidosis exist. The aim of our study was to identify patients at our institution with DAH secondary to sarcoidosis.

Methods

We performed a retrospective cross-sectional study of patients with a history of DAH and sarcoidosis seen at Mayo Clinic between January 1, 2000, and June 30, 2022. We searched the electronic health records using the terms, “alveolar hemorrhage” and “sarcoidosis”. The diagnosis of DAH was based on clinical criteria, such as hemoptysis, cough, dyspnea, hypoxemia, or low hemoglobin level; imaging, such as patchy or diffuse alveolar opacities on chest radiography or computed tomography; or histopathologic findings, such as hemosiderin-laden macrophages on bronchioalveolar lavage. The diagnosis of sarcoidosis was based on characteristic imaging, positive pathology results, and negative testing for tuberculosis and fungal disease. Patients were excluded if they were on anticoagulation at the time of DAH or had an infectious process, positive antineutrophil cytoplasmic antibodies, positive antiphospholipid antibodies, or history of a bleeding disorder. Patients with DAH in the setting of recent thoracic surgery were also excluded. After identifying patients who met the criteria, we collected patient demographics, including age, sex, ethnicity, and body mass index (BMI). Date of sarcoidosis diagnosis, date of DAH diagnosis, smoking history, symptoms, need for supplemental oxygen at the time of DAH, treatments received following DAH, and outcomes were also recorded. Comparison of clinical features and findings was performed using descriptive statistics. The Mayo Clinic Institutional Review Board approved the protocol and did not require informed consent due to the retrospective nature of the study.

Results

Of the 142 patients identified by our search, 7 met inclusion criteria (Fig. 1 and Table 1). Five patients were women and 2 were men; 2 were African American/Black and 5 were White. The mean (range) age was 54 years (39–72). Three patients had a history of tobacco use, 1 of whom also had a history of marijuana use. All patients had a BMI of 25 or higher; 3 had BMIs between 25 and 29 (overweight), 3 between 30 and 39 (obese), and 1 higher than 40 (morbidly obese). All patients had pulmonary sarcoidosis; 1 patient had renal sarcoidosis, and another presented with cutaneous sarcoidosis. All patients presented with dyspnea, 5 with cough, 4 with hemoptysis, and 2 with supplemental oxygen dependence. Laboratory results showed anemia in 6 patients (hemoglobin level not reported for 1); angiotensin-converting enzyme level elevation (< 40 µg/L) in 5 patients (not reported for other 2); and hypercalcemia in 1 patient.

Fig. 1.

Inclusion and exclusion criteria of patients with DAH secondary to sarcoidosis. DAH indicates diffuse alveolar hemorrhage

Table 1.

Patient demographics and clinical characteristics

Characteristic	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7
BMI	45	31	32	27	34	27	25
Smoking/drug use	No	Yes	Yesa	Yesb	No	No	No
Symptoms	Dyspnea, hemoptysis	Dyspnea, cough, hemoptysis	Dyspnea, cough, hemoptysis	Dyspnea, cough	Dyspnea, cough	Dyspnea, hemoptysis	Dyspnea, cough
Time between sarcoidosis/ DAH	2 years	Concomitant	10 years	4 years	Concomitant	Concomitant	2 years
Ground-glass on CT	Yes	Yes	Yes	Yes	No	Yes	Yes
Noncaseating granulomas	Positive	Positive	Positive	Positive	Positive	Positive	Positive
Extrapulmonary sarcoidosis	Yes (renal)	No	No	No	Yes (cutaneous)	No	No
ACE levels, µg/Lc	80	68	Not reported	66	Not reported	42	46
Hemoglobin, g/dLd	7.6	6.6	11.3	11.0	12.9	10.4	Not reported
Treatment	Prednisone	Prednisone, leflunomide, infliximab, methotrexate, rituximab	Prednisone, rituximab	Prednisone	Prednisone	Methylprednisolone, prednisone	Prednisone

ACE, angiotensin converting enzyme; BMI, body mass index; DAH, diffuse alveolar hemorrhage

^a Quit 20 years prior to study

^b Marijuana

^c Normal < 40 µg/L

^d Normal: 13.5–17.5 g/dL

Computed tomography (CT) performed at the time of DAH revealed patchy areas of ground-glass opacities in 6 patients, mediastinal and hilar lymphadenopathy in 5, and pulmonary nodules in 4. One patient did not present with ground glass opacities on CT-scan; however, findings of alveolar hemorrhage and epithelial granuloma were found during on tissue biopsy during bronchoscopy. Three patients had concomitant diagnosis of DAH and sarcoidosis, while diagnosis of sarcoidosis preceded that of DAH for 4 patients. All patients had hemosiderin-laden macrophages reported on bronchioalveolar lavage.

All patients received corticosteroids as therapy for DAH. Four improved and remained without symptoms, 1 experienced persistent dyspnea, and 1 had a fluctuating course. Two patients received rituximab; 1 in addition to concomitant corticosteroids and the other after recurrence of DAH despite treatment with prednisone, leflunomide, infliximab, and methotrexate. The latter patient remained stable for 2 years; however, due to COVID-19, the patient discontinued rituximab and returned with recurrence of DAH. The patient’s condition stabilized after reinitiation of rituximab.

Discussion

We report on 7 patients with sarcoidosis-associated DAH, a rarely reported entity. To our knowledge, this is the largest group of patients with this association in the English literature. Previous studies reported that tobacco use could trigger the development of this condition [4, 5]; however, tobacco use was not as prevalent in our study. Interestingly, every patient in our study presented with a high BMI independent of previous corticosteroid use, suggesting that BMI of 25 or higher may be a factor related to sarcoidosis-associated DAH. The literature shows that obesity can cause a proinflammatory state and increase vascular permeability [6]. Other studies have indicated that those with a higher BMI may also have a higher incidence of sarcoidosis [7, 8]. Additional research is necessary to define the interplay between obesity and sarcoidosis, whether it affects sarcoidosis severity or correlates with development of DAH.

All patients in our study received corticosteroids, and most recovered well. We found it interesting that treatment with rituximab was successful for the patient with refractory DAH after multiple therapies had been unsuccessful.

In 3 patients, diagnosis of DAH and sarcoidosis was made concurrently, suggesting that high disease activity may contribute to DAH. Of the 4 patients in whom DAH manifested years after diagnosis of sarcoidosis, 3 had discontinued sarcoidosis treatment (1 methotrexate, 2 corticosteroids); DAH occurred between 1 and 3 months after discontinuation of treatment. It is possible that effective sarcoidosis management may lower the risk of DAH.

The main limitation of our study is its retrospective nature. Further research is necessary to clarify the frequency of sarcoidosis-associated DAH and contributing factors. Our retrospective review suggests that this entity is more common than previously reported; therefore, it is essential to consider sarcoidosis in the differential diagnosis of immune-mediated DAH.

Author contributions

M.D-M. contributed to conception and design; collection, analysis, and interpretation of data; drafting and critical revision of the manuscript; and generation of tables/figures. M.M.S. conception and design, analysis and interpretation of data, drafting and critical revision of the manuscript, and generation of tables/figures. R. R.B. contributed to drafting and critical revision of the manuscript. A.A., V.M., and B.W. contributed to critical revision of the manuscript. F.B. contributed to conception and design, analysis and interpretation of data, critical revision of the manuscript, and generation of tables/figures. All authors gave final approval of the article.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Declarations

IRB or IACUC approval

Approved by the Mayo Clinic IRB.

Patient consent (or statement on welfare of animals)

Per Mayo Clinic IRB, informed consent was not required due to the retrospective nature of the study.

Disclosures

The authors declare that they have no relevant conflicts of interest.