Propylthiouracil (PTU) has recently been observed to be associated with antineutrophil cytoplasmic antibody (ANCA)-positive small vessel vasculitis, resulting in crescentic glomerulonephritis and, infrequently, diffuse alveolar hemorrhage (DAH). We describe a case of a 23-year-old pregnant woman who developed a perinuclear ANCA and antimyeloperoxidase-positive small vessel vasculitis manifesting as DHA and crescentic glomerulonephritis after she began taking PTU. An open lung biopsy was consistent with pulmonary capillaritis. She responded to corticosteroid therapy and discontinuation of PTU. DAH can be caused by pulmonary capillaritis, bland hemorrhage, or diffuse alveolar damage. To our knowledge, this represents the first documentation of an underlying pulmonary capillaritis in a case of PTU-induced DAH. (CHEST 1999; 116:1485-1488)
Key words: antineutrophil cytoplasmic antibody vasculitis; diffuse alveolar hemorrhage; propylthiouracil; pulmonary capillaritis
Abbreviations: ANCA = antineutrophil cytoplasmic antibody; anti-MPO = antimyeloperoxidase antibody; DAH = diffuse alveolar hemorrhage; MPO = myeloperoxidase; p-ANCA = perinuclear antineutrophil cytoplasmic antibody; PTU = propylthiouracil
The syndrome of diffuse alveolar hemorrhage (DAH) is caused by the disruption of alveolar-capillary basement membrane as a consequence of the injury to the arterioles, venules, and alveolar septal capillaries. The three histologic patterns accounting for the majority of DAH are pulmonary capillaritis, bland pulmonary hemorrhage, and diffuse alveolar damage. Davies et al were the first to describe an antineutrophil cytoplasmic antibody (ANCA)-positive small vessel vasculitis, and Dolman et al described the relationship between propylthiouracil (PTU) and small vessel vasculitis for the first time in six patients. We describe a case of PTU-induced ANCA-positive vasculitis in a woman who was in the first month of her pregnancy, resulting in DAH and crescentic glomerulonephritis. To our knowledge, four similar cases[3-6] have been described; however, this is the first one in which an underlying pulmonary capillaritis was documented.
A 23-year-old woman in her first trimester of pregnancy presented with a 4-day history of flu-like symptoms and mild hemoptysis. She had been taking azithromycin as an outpatient. Physical examination findings were normal except for mild thyromegaly and bibasilar inspiratory rales. The chest radiograph revealed bibasilar alveolar and interstitial infiltrates. She had received a diagnosis of hyperthyroidism at age 13 and was taking PTU and methimazole intermittently. She had been untreated for the past 3 years after developing a skin rash attributed to methimazole. However, 2 weeks prior to presentation, PTU therapy was restarted.
On the second day of hospitalization, she deteriorated rapidly after a bout of massive hemoptysis. She was transferred to the ICU, and mechanical ventilatory support was initiated for hypoxemic respiratory failure. Bronchoscopy performed revealed hemorrhagic return from the distal alveoli consistent with DAH. At that point, her hemoglobin dropped to 8.1 g/dL, from the baseline level of 10.5 gm/dL. Other laboratory values showed a WBC count of 6,300 cells/[micro]L; platelets, 146,000/[micro]L; BUN, 25 mg/dL; creatinine, 0.7 mg/dL; erythrocyte sedimentation rate; 30 mm/h; [beta]-human chorionic gonadotropin, 1,445 IU/L (reference range for nonpregnant women, [is less than] 3 IU/L); thyroid stimulating hormone, [is less than] 0.1 mU/L (reference range, 0.4 to 4.6 mU/L; T3U, 34.4% (reference range; 27.8 to 40.7%); free T3, 0.28 nmol/L (reference range, 0.35 to 0.65 nmol/L); T4, 138 nmol/L (reference range, 58 to 154 nmol/L); and a normal coagulation profile. A chest radiograph showed extensive diffuse bilateral alveolar infiltrates. Urinalysis revealed [is greater than] 20 RBCs/high power field and 1+ protein. Serum studies for antiglomerular basement membrane antibodies, antinuclear antibodies, hepatitis serology, HIV, and bacterial and viral titers were negative. The two-dimensional echocardiogram was normal. Indirect immunofluorescence revealed serum perinuclear antineutrophil cytoplasmic antibody (p-ANCA) positivity with a titer of 1:80 (reference laboratory range; positive if [is greater than] 1:40).
The patient continued to deteriorate and had significant pulmonary hemorrhage requiring 10 U of packed RBCs. She was treated with IV corticosteroids (methylprednisolone 250 mg every 6 h) and plasmapheresis. The latter was discontinued when the antiglomerular basement membrane antibody test was negative. An open lung biopsy showed alveolar wall disruption with acute intra-alveolar hemorrhage, intra-alveolar fibrin tufts, hemosiderin-laden macrophages, type II pneumocyte hyperplasia, and foci of interstitial polymorphonuclear infiltrates with fragmentation and nuclear dust, especially around the small blood vessels (Fig 1). Immunofluorescent microscopy showed no evidence of Ig deposition, and serum viral studies were negative. After initiation of corticosteroid therapy, the patient's alveolar hemorrhage stabilized, and she rapidly improved and was extubated. PTU therapy was also discontinued at the same time, and the patient continued to improve despite weaning of corticosteroids. She was discharged after several days. An outpatient renal biopsy revealed focal crescentic glomerulonephritis (Fig 2). The corticosteroid dosage was tapered down over a period of 5 months. The patient remains in clinical remission 18 months later. A repeat p-ANCA test at 11 months was negative, and a test for antimyeloperoxidase (anti-MPO) was positive with a titer of 10 U/mL (reference laboratory range: positive if [is greater than] 7U/mL).
[Figures 1-2 ILLUSTRATION OMITTED]
This patient developed a PTU-induced p-ANCA-positive vasculitic syndrome resulting in DAH and crescentic glomerulonephritis. DAH can result from pulmonary capillaritis, bland hemorrhage, or diffuse alveolar damage. In this case, DAH was associated with pulmonary capillaritis.
PTU is responsible for ANCA-positive syndrome, and several reports documenting crescentic glomerulonephritis have been described.[7-11] Choi et al described a patient in whom Wegener's granulomatosis was initially diagnosed. This was associated with cytoplasmic ANCA and antiproteinase 3 antibodies. The patient developed hyperthyroidism and PTU therapy was started, followed by the return of vasculitic symptoms and the antibody type changed to p-ANCA and anti-MPO. His ANCA type reverted back to antiproteinase 3 with a cytoplasmic ANCA immunofluorescence pattern after stopping PTU. There are four case reports of PTU-associated ANCA-positive syndrome with DAH in the English literature. D'Cruz et al described a 62-year-old man who developed DAH after taking PTU for 11 months. The p-ANCA and anti-MPO antibodies were positive. Romans et al, Ohtsuka et al, and Harper et al each reported a case of DAH in young women, who took PTU for periods ranging from 7 to 36 months. In each case, serum ANCA was detected. All of these patients had a preceding influenza-like prodrome, and all improved with discontinuation of PTU. Two of them required immunosuppressive therapy with corticosteroids and cyclophosphamide. Transbronchial biopsies were performed in three patients and indicated hemosiderin-laden macrophages, but no evidence of vasculitis was reported. Two patients had renal biopsies revealing focal crescentic glomerulonephritis.
The present patient is the youngest of the reported cases of DAH associated with PTU. She developed symptoms 2 weeks after the initiation of PTU, whereas the other patients had taken PTU for 7 to 36 months. However, she had used PTU on and off for the last 13 years and could have developed some sensitization to it. Hers is the only case of PTU-induced DAH in which the DAH caused life-threatening hypoxemia requiring mechanical ventilatory support, but the patient still responded to discontinuation of PTU and initiation of corticosteroid therapy. In this report, we describe for the first time the documentation of underlying pulmonary capillarities in PTU-induced DAH.
Pulmonary capillaritis is characterized by neutrophilic infiltration of the alveolar interstitium with fibrinoid necrosis and capillary thrombosis. There is a loss of integrity in the alveolar capillary basement membrane with leakage of RBCs into the alveolar space resulting in DAH. Pulmonary capillaritis has also been described in the setting of microscopic polyangiitis, Wegener's granulomatosis, systemic lupus erythematosus, Goodpasture's syndrome, progressive systemic sclerosis, rheumatoid arthritis, mixed connective tissue disease, and other disorders.[13,14]
Elevated ANCA levels have been reported to be induced by other drugs such as hydralazine, antithyroid medications (propylthiouracil, methimazole, carbimazole), penicillamine, minocycline, and clozapine.[3,15-25] A similar picture to that described in our patient (ie, DAH or glomerulonephritis) has been seen in cases of ANCA-positive vasculitis induced by penicillamine, hydralazine, and carbimazole.
The mechanism of PTU-induced ANCA-positive vasculitis is unknown. Jiang et al proposed that activated neutrophils in the presence of hydrogen peroxide release myeloperoxidase (MPO) from its granules, which converts PTU into cytotoxic products. Von Schmiedeberg et al speculated that, in the presence of MPO, PTU gets converted to PTU sulfonate, which is immunogenic for T cells, and these T cells in turn activate B cells, which mediate the vascular injury. Lee et al suggested that PTU interacts with MPO to change the heme structure of the enzyme, which may then act as a hapten. Patients who have been taking PTU for years can develop the vasculitis at any time, and most have a preceding flu-like illness. It is possible that the etiology of PTU-induced ANCA-positive vasculitis may be multifactorial and a viral infection triggers the cascade of events that ultimately result in vascular injury.
This patient developed vasculitis and DAH after several courses of PTU treatment. From the information provided by the patient and her pharmacy, all the PTU was from the same drug company. The dramatic improvement of the clinical status of patients after stopping PTU definitely points toward PTU as the etiologic factor. PTU is also known to cause immunologic reactions such as drug-induced lupus. As pointed out by Jiang et al, neutrophils have to be primed in order to convert PTU intocytotoxic products. It is possible that an individual who receives multiple courses of PTU may develop vasculitis only when the neutrophils are appropriately primed by a viral infection. In several case reports, a flu-like illness precedes PTU-induced vasculitis.[2-9]
It is possible that pregnancy might have a contributory role in this case. The immunologic alterations in pregnancy are complex and not completely understood. It remains unknown how the maternal immune system adjusts to the presence of an antigenically foreign fetus. There are increases in maternal suppressor T Cells and a decrease in helper T cells, accompanied by an increase in serum IgG. Remissions of rheumatoid arthritis and decreases in the relapse rate of ulcerative colitis occur during pregnancy.[30,31] Five cases of Wegener's granulomatosis and several cases of Churg-Strauss syndrome and polyarteritis nodosa have developed during pregnancy. To our knowledge, the present case is the first of PTU-induced ANCA vasculitis in pregnancy. It does, however, remain unclear as to the effect of pregnancy on the development of the PTU-induced vasculitic syndrome.
DAH and crescentic glomerulonephritis due to an ANCA-positive vasculitis associated with PTU is an unusual but important syndrome to recognize because the discontinuation of PTU combined with the initiation of corticosteroids and sometimes cyclophosphamide results in recovery.
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(*) From the Saint Elizabeth Helath Center (Drs. Dhillon, Singh, Doe, Qadri, and Ricciardi), Youngstown, OH; and the Division of Pulmonary and Critical Care (Dr. Schwarz), University of Colorado Health Sciences Center, Denver, CO.
Financial assistance provided by St. Elizabeth Health Center, Youngstown, OH.
Manuscript received November 1, 1998; revision accepted June 16, 1999.
Correspondence to: Samjot Singh Dhillon, MD, Department of Internal Medicine, St. Elizabeth Health Center, 1044 Belmont Ave, Youngstown, OH 44501-1970; e-mail: firstname.lastname@example.org
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