Microscopic polyangiitis causing diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis Mohamad Hani Lababidi, MD, Chibuzo Odigwe, MD, Chukwuka Okolo, MD, Ahmed Elhassan, MD, and Nkemakolam Iroegbu, MD, MPH

Diffuse alveolar hemorrhage complicating small vessel vasculitis is a life-threatening emergency and should be considered in the differential diagnosis of patients who develop rapidly progressive dyspnea with alveolar opacities on chest imaging. In these patients, the coexistence of pulmonary and renal involvement suggests a multisystem disease. We present a case of a man who presented to our hospital with diffuse alveolar hemorrhage, severe anemia, and rapidly progressive glomerulonephritis.


icroscopic polyangiitis (MPA) is a rare antineutrophil cytoplasmic antibody (ANCA)–associated necrotizing vasculitis, mainly affecting the pulmonary and renal capillaries. One of the so-called pulmonary-renal syndromes, it is characterized by inflammation of the small blood vessels, the absence of granulomas on histopathology, and the presence of circulating ANCAs. The incidence is currently estimated at about 1 in 100,000 per year, with a slight male predominance. Other ANCA-associated vasculitides include granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), and renal-limited vasculitis (1–7). Because of its severe disease manifestations, diffuse alveolar hemorrhage is a cause of significant morbidity and mortality and requires intensive, meticulous, and aggressive care for any chance of a meaningful outcome. Prompt diagnosis is important to permit initiation of therapy that may be both lifesaving and organ sparing. This may be challenging because of the nonspecific clinical features. We report a man who presented to our hospital with severe diffuse alveolar hemorrhage and in whom MPA was subsequently diagnosed. CASE PRESENTATION A 58-year-old Hispanic man with no significant past medical history presented to the emergency department of our hospital with 5 days of exertional dyspnea and nonproductive cough associated with fever and night sweats. He also reported a 12-pound weight loss over the preceding month. He was not on any medications and was a former cigarette smoker with a 20 pack-year history, having quit 1 month prior to presenta-

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tion. He had the sickle cell trait. On admission he was febrile, with a temperature of 101.7°F, a pulse rate of 106 beats per minute, a respiratory rate of 24 breaths per minute, and a blood pressure of 156/80 mm Hg. His initial oxygen saturation was 97% on room air. His conjunctiva was pale, and his mucous membranes were dry. His hemoglobin level was 5.4 g/dL and serum creatinine, 7.2 mg/dL (normal range, 0.6–1.3). A chest radiograph showed bilateral pulmonary infiltrates (Figure 1a). Urinalysis showed large proteinuria and large hematuria. He was transfused with 2 units of packed red blood cells. We excluded the presence of active tuberculosis with a negative Mantoux test and initiated Pneumocystis jiroveci prophylaxis. His HIV test was negative. He rapidly deteriorated, becoming confused and desaturating to 88% oxygen saturation even on 4L nasal cannula supplemental oxygen. A repeat chest radiograph showed worsening of the bilateral infiltrates compared to his prior film on admission (Figure 1b). He was intubated and transferred to the intensive care unit. His chest radiographic findings progressively worsened (Figure 1c). Further evaluation of his anemia with iron studies revealed a pattern consistent with anemia of chronic disease. Other notable laboratory results were a negative hepatitis panel, tuberculosis QuantiFERON, glomerular basement membrane antibody, anti-dsDNA antibody, and PR3-ANCA, but a positive myeloperoxidase (MPO-ANCA). Fiber optic bronchoscopy revealed diffuse blood oozing from all pulmonary segments, consistent with pulmonary hemorrhage, and a percutaneous kidney biopsy showed Pauci-immune crescentic glomerulonephritis, which is typical for MPA. The patient was treated with 1 g intravenous methylprednisolone daily for 3 days and then oral prednisone 60 mg daily, in addition to cyclophosphamide 75 mg twice daily. He was also treated with daily plasmapheresis for 7 days and received atovaquone for pneumocystis prophylaxis. He had some neutropenia following cyclophosphamide treatment and was treated

From the Department of Medicine, St. Joseph Hospital, Chicago, Illinois. Corresponding author: Chibuzo Clement Odigwe, MD, Department of Medicine, St. Joseph Hospital, 2900 North Lake Shore Drive, Chicago, IL 60657 (e-mail: [email protected]). 469





Figure 1. The patient’s chest radiographs. (a) On admission, showing bilateral pulmonary infiltrates. (b and c) Between admission and day 2, showing worsening of the bilateral infiltrates. (d) Improvement after treatment with steroids, immunosuppressant, and plasmapheresis.

with subcutaneous filgrastim with good response (Figure 1d). Persistent severe anemia and hemorrhage was managed with 5 units of packed red blood cells and 20 units of fresh frozen plasma in total. He recovered significantly, was extubated, was discharged to outpatient nephrology and rheumatology followup, and continues to do well. DISCUSSION Pulmonary hemorrhage is a life-threatening condition that often develops acutely on a background of a smoldering process. MPA is one of the most common causes of the pulmonaryrenal syndrome of alveolar hemorrhage and rapidly progressive glomerulonephritis. It has a variable pulmonary presentation, which ranges from fleeting focal infiltrates to massive lung hemorrhage and hemoptysis in the setting of diffuse alveolar hemorrhage. Its peak incidence is between the ages of 30 and 50 years and the incidence has been estimated at between 8 to 10 cases per million per year (1–3). 470

Although MPA is a recognized cause of diffuse alveolar hemorrhage, alveolar hemorrhage is relatively rare as a presenting feature. In a retrospective review of 36 patients, lung involvement was seen in 22% of cases and alveolar hemorrhage in 11% (2–4, 5). Another study by Lane et al found pulmonary involvement in 29% of patients (6). Severe clinical manifestations similar to our index case have also been reported in children (8). The clinical features of MPA present a dilemma in diagnosis on account of their nonspecific and varied clinical presentation. Common clinical features that have been reported include acute or chronic cough, dyspnea, fever, weight loss, myalgia, and arthralgia. Mononeuritis multiplex (60% of cases) and cutaneous vasculitis (>60% cases) have also been reported. Alveolar hemorrhage, in contrast, occurs in only about 20% to 30% of patients, and hemoptysis is sometimes absent due to the ability of the alveoli to absorb a significant amount of blood before it extends to the large airways. In view of the nonspecific nature of the chest x-ray findings, computed tomography scanning is

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said to be more sensitive in terms of distinguishing pulmonary hemorrhage from other causes of alveolar shadowing. Another test of theoretical interest is the measurement of the carbon monoxide transfer coefficient, which may be impractical given the acuity of presentation (1–5). Indeed, a wide variety of pulmonary manifestations of MPA have been reported, including isolated pulmonary hemorrhage, as against the classic pulmonary renal syndrome, as seen in our patient. Chronic alveolar hemorrhage and nonspecific interstitial pneumonia with alveolar hemorrhage preceded by hearing loss have also been seen. Pulmonary fibrosis has been reported in association with the pulmonary complications of MPA, although the mechanism by which this occurs remains unclear (9). A key differential diagnosis is Goodpasture disease, which was excluded in our patient by a negative antiglomerular basement membrane antibody test. Our patient responded to the initial treatment with steroids, immunosuppressant, and plasmapheresis, which is the standard of care (1–8). The combination of oral cyclophosphamide and methylprednisolone induces remission in about 80% to 90% of patients with ANCA-associated vasculitis, with about 75% experiencing complete remission and most remissions occurring between 2 and 6 months. However, there are reports of patients who respond poorly to this regimen, for whom the next option would be recombinant factor VII therapy (2, 10). There are case reports of good clinical response, particularly resolution of diffuse alveolar hemorrhage, in patients in whom recombinant factor VII treatment was instituted. Rituximab is also an option in place of cyclophosphamide, particularly in young patients desiring fertility preservation, although it has not been studied extensively in patients with serum creatinine >4 mg/dL or in patients who require mechanical ventilation (11, 12). Adjunctive plasma exchange is also recommended for patients with significant renal dysfunction without concurrent antiglomerular basement membrane antibody disease or pulmonary hemorrhage in the setting of MPA. Up to seven sessions is recommended over 2 weeks, with 60 mL/kg plasma removal at each session and with albumin or fresh frozen plasma

October 2015

replacement each time depending on the risk of bleeding or the presence of active bleeding (1–5, 7). 1.

Ioachimescu OC, Stoller JK. Diffuse alveolar hemorrhage: diagnosing it and finding the cause. Cleve Clin J Med 2008;75(4):258, 260, 264–265 passim. 2. Buendía-Roldán I, Navarro C, Rojas-Serrano J. Diffuse alveolar hemorrhage: causes and outcomes in a referral center. Reumatol Clin 2010;6(4):196–198. 3. Collins CE, Quismorio FP Jr. Pulmonary involvement in microscopic polyangiitis. Curr Opin Pulm Med 2005;11(5):447–451. 4. Alves dos Santos JW, Michel GT, da Luz Pereira CE, Capelozzi VL, Mileto JN, Florini CA. Microscopic polyangiitis with alveolar hemorrhage. J Brasileiro Pneumologia 2004;30(2):150–153. 5. Mackay J. Rapidly progressive pulmonary haemorrhage in a case of microscopic polyangiitis. BMJ Case Rep 2011 Jul 27;2011. 6. Lane SE, Watts RA, Shepstone L, Scott DG. Primary systemic vasculitis: clinical features and mortality. QJM 2005;98(2):97–111. 7. Hammoudeh F, Perwaiz MK, Patolia S, Schmidt FM, Neupane N, Gulati N, Enriquez D, Quist J, Zahir M, Kennedy E. Diffuse alveolar hemorrhage with ANCA associated vasculitis—review of literature. Br J Med Pract 2011;4(1):a402. Retrieved from http://www.bjmp.org/content/diffusealveolar-haemorrhage-anca-associated-vaculitis-review-literature 8. Blanco Filho F, Ernesto LC, Rosa MA, Stuginski LA, Zlochevsky ER, Blanco F. Rapidly progressive antineutrophil cytoplasm antibodies associated with pulmonary-renal syndrome in a 10-year-old girl. Sao Paulo Med J 2001;119(1):29–32. 9. Huang H, Wang YX, Jiang CG, Liu J, Li J, Xu K, Xu ZJ. A retrospective study of microscopic polyangiitis patients presenting with pulmonary fibrosis in China. BMC Pulm Med 2014;14:8. 10. Mandal SK, Sagar G, Sahoo M, Jasuja S. Recombinant activated factor VII for diffuse alveolar hemorrhage in microscopic polyangiitis. Indian J Nephrol 2012;22(2):130–132. 11. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363(3):221–232. 12. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363(3):211–220.

Microscopic polyangiitis causing diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis


Microscopic polyangiitis causing diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis.

Diffuse alveolar hemorrhage complicating small vessel vasculitis is a life-threatening emergency and should be considered in the differential diagnosi...
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