Sum of the Parts
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《新英格兰医药杂志》
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors' commentary follows.
A 36-year-old Pakistani woman presented to the emergency room with a 10-day history of a nonproductive cough, dyspnea, and fever. She reported having no night sweats and no contact with anyone who was ill, including anyone with known tuberculosis. She had been seen 1 week earlier at a walk-in clinic, where she received a prescription for moxifloxacin for presumed bronchitis, but her symptoms persisted.
This patient's initial presentation with a cough, dyspnea, and fever appears to be most consistent with a community-acquired respiratory tract infection, but the lack of response to treatment with broad-spectrum antibiotics for a week raises the question of whether her pulmonary symptoms are the result of a nonbacterial infection, a more serious systemic infection, or a noninfectious disorder, such as cancer. The dyspnea may be due to respiratory illness but could also reflect other conditions, such as concomitant anemia or heart failure.
The patient said she had no chest pain, orthopnea, or paroxysmal nocturnal dyspnea. A review of her other organ systems was also negative. She had had three uncomplicated pregnancies. She had received no blood transfusions and took no medications other than the antibiotic. Her family history was unremarkable. She said she did not use tobacco, alcohol, or illicit drugs. She had immigrated to the United States 5 years earlier from Pakistan and reported no recent travel. She lived with her husband and children and was not employed outside the home. On examination, she was not in distress. She weighed 55 kg. Her temperature was 39.2°C, pulse 127, respiratory rate 18, blood pressure 149/94 mm Hg, and oxygen saturation 100% while breathing ambient air. Her cardiac examination revealed tachycardia and a soft apical systolic murmur with no radiation. Her lungs were clear. She had scattered petechiae on her legs.
The fact that the patient has not recently traveled to Pakistan makes it unlikely that she acquired an acute illness endemic to the area, unless an arriving traveler exposed her to it. Nonetheless, her symptoms could represent an acute exacerbation of a chronic and previously subclinical illness. Though she reports no exposure to tuberculosis, her residence in Pakistan is associated with an increased risk of prior exposure and subsequent reactivation. Her tachycardia may be related to her fever, a respiratory illness, anemia, or cardiac dysfunction. Her hypertension may have been present but undetected previously or may reflect volume overload resulting from azotemia. Her murmur is nonspecific and may be flow-related, the result of her fever or anemia. The normal oxygen saturation and pulmonary examination do not exclude the possibility of pulmonary disease. Her petechiae are worrisome and suggest a low platelet count or a vasculitis; palpable lesions would be consistent with the latter.
The patient's white cell count was 17,200 per cubic millimeter, with 86% neutrophils, 5% lymphocytes, 8% monocytes, and 1% eosinophils. The hemoglobin level was 7.2 g per deciliter, with a mean corpuscular volume of 74.6 μm3. (The hemoglobin level had been 9.0 g per deciliter 2 months earlier, and she had not returned for follow-up testing.) The platelet count was 130,000 per cubic millimeter. The serum sodium level was 129 mmol per liter, potassium 3.3 mmol per liter, bicarbonate 18 mmol per liter, blood urea nitrogen 46 mg per deciliter (16.4 mmol per liter), and creatinine 3.5 mg per deciliter (309.4 μmol per liter), an increase from 1.0 mg per deciliter (88.4 μmol per liter) 1 year earlier. The serum albumin level was 2.5 g per deciliter. The aspartate aminotransferase level was 47 U per liter (normal range, 16 to 41); the results of other liver function tests were normal. The prothrombin time was normal. A dipstick urinalysis was positive for protein (3+) and blood (3+). Microscopical evaluation showed red cells too numerous to count. A chest radiograph revealed no abnormalities.
The leukocytosis increases my suspicion that this patient has an infectious disease. She has a microcytic anemia, which may represent iron deficiency or an anemia of a chronic disease. The thrombocytopenia in combination with the anemia raises the possibility of microangiopathic hemolysis from thrombotic thrombocytopenic purpura, especially in the setting of petechiae and azotemia. The patient's chemistry panel reveals azotemia, proteinuria, and microscopic hematuria, all suggesting nephritis. Red-cell casts in the urine sediment would provide further evidence of glomerular disease. The hypoalbuminemia is probably due to a hypercatabolic state or glomerular leakage; with a normal prothrombin time, liver synthetic dysfunction is unlikely. The elevated level of aspartate aminotransferase is nonspecific and may be a result of liver disease, hemolysis, or rhabdomyolysis. The normal chest radiograph does not exclude the possibility of parenchymal disease, especially early interstitial disease.
Infectious diseases that might explain such a presentation include endocarditis, viral hepatitis, and human immunodeficiency virus (HIV) infection. A paraproteinemia or vasculitis could present in a similar fashion. Assessment of a peripheral blood smear is warranted immediately to investigate the possibility of microangiopathic hemolysis, with particular concern for thrombotic thrombocytopenic purpura.
The peripheral blood smear revealed less than one schistocyte per high-power field and no other notable findings. The total iron level was 18 μg per deciliter (3.2 μmol per liter), and the total iron-binding capacity 286 μg per deciliter (51.2 μmol per liter). Blood was drawn for cultures; the patient received ceftriaxone in the emergency room and was admitted and placed in a negative-pressure room. Sputum samples for acid-fast bacillus studies were requested. Within a few hours, the patient's respiratory status had rapidly declined. A computed tomographic (CT) scan of the chest revealed diffuse bilateral alveolar infiltrates (Figure 1). Hypoxemic respiratory failure developed, and the patient was intubated. Copious blood was suctioned from the endotracheal tube.
Figure 1. CT Scan of the Chest Obtained without Intravenous Administration of Contrast Material, Showing Diffuse Bilateral Alveolar Infiltrates.
Her acute respiratory decompensation with diffuse alveolar infiltrates and hemoptysis points to the syndrome of alveolar hemorrhage. Possible causes include a bleeding diathesis, diffuse alveolar damage resulting from infection, congestive heart failure, and vasculitis. Given the involvement of multiple organ systems, I am increasingly concerned about a vasculitis. The absence of upper respiratory tract symptoms makes Wegener's granulomatosis unlikely. Goodpasture's syndrome is a possibility, although it is more common in men than in women. I would still test for antineutrophil cytoplasmic antibodies — specifically, antiproteinase 3 and antimyeloperoxidase, which are present in up to 90% of patients with Wegener's granulomatosis; antinuclear antibodies; and anti–glomerular basement membrane antibodies. Given her elevated aspartate aminotransferase level and country of origin, I would also screen for hepatitis B. Ten percent of hepatitis C–infected persons have no apparent risk factor, and I would test for this as well. Both of these viruses may cause a systemic vasculitis (polyarteritis nodosa or cryoglobulinemic vasculitis), which may lead to purpura and a nephritic urine sediment. Measurement of cryoglobulins and complement levels may also be informative; cryoglobulins associated with hepatitis C virus precipitate with IgG and activate complement along the surface of blood vessels, resulting in decreased serum complement — C4 in particular.
The patient was presumed to have a pulmonary–renal syndrome and was treated with methylprednisolone (1 g given intravenously, once a day for 3 days) and one dose of cyclophosphamide (750 mg given intravenously). Plasmapheresis was initiated; 4.5 liters of plasma were removed and completely replaced with equal parts of 5% albumin and fresh-frozen plasma. The pulmonary hemorrhage abated, but the patient became oliguric and her creatinine level rose to 4.6 mg per deciliter (406.6 μmol per liter). Hemodialysis was initiated. Tests for anti–glomerular basement membrane, antimyeloperoxidase, antiproteinase 3, antinuclear antibodies, cryoglobulins, and hepatitis B surface antibody were negative. The serum C3 level was 92 mg per deciliter (normal range, 79 to 152) and the C4 level 23 mg per deciliter (normal range, 16 to 38). The test for hepatitis C antibody was positive, and the viral load was 1,242,487 IU per milliliter. An HIV test was negative.
Extrahepatic manifestations are seen in about 30% of patients with hepatitis C. The virus may bind to B lymphocytes; the resulting autoantibodies may cause vasculitis, leading to membranoproliferative glomerulonephritis and, in rare cases, pulmonary hemorrhage. In many cases, the vasculitis is related to essential mixed cryoglobulinemia, with immune complex deposition in the vessel wall. Cryoglobulin measurements are difficult to perform, and the diagnosis is not ruled out by a single negative result or by serum complement levels in the normal range.
The corticosteroids were tapered over the next 5 weeks to 10 mg of prednisone per day. The plasmapheresis was continued at the same dose for 11 courses approximately every other day, until a spot urine test showed a protein-to-creatinine ratio of zero, the creatinine level was 1.0 mg per deciliter, and the patient's respiratory status improved. Hemodialysis was stopped. When plasmapheresis was stopped, however, pulmonary hemorrhage recurred, the ratio of urinary protein to creatinine rose to 4.7, the C3 level fell to 58 mg per deciliter, and the C4 level fell to 13 mg per deciliter. The creatinine level remained normal. A repeat cryoglobulin measurement was positive. The prednisone dose was then increased to 1 mg per kilogram of body weight per day, and plasmapheresis was resumed.
The finding of cryoglobulins makes sense in the setting of this patient's presentation; the fall in the complement levels, which was concurrent with the other manifestations, further supports the hypothesis that this illness is due to cryoglobulinemic vasculitis. Hepatitis C is most likely driving the vasculopathy, and treatment may be warranted. The clinical and serologic manifestations of vasculopathy in patients with hepatitis C often diminish with antiviral therapy. However, pulmonary hemorrhage is a rare manifestation, and the response is unpredictable. Before exposing this patient to the toxicities of antiviral medications, I would seek further evidence that the vasculitis is related to hepatitis C. Given her tenuous respiratory status, I would obtain tissue from a nonpulmonary site. Membranoproliferative glomerulonephritis is the most common manifestation of nephropathy associated with hepatitis C. Although this finding would not absolutely rule out other causes of the patient's vasculitis, it would support the hypothesis that hepatitis C is the underlying cause of her clinical presentation.
A percutaneous renal biopsy revealed membranoproliferative glomerulonephritis (Figure 2). No cryoglobulins were identified on electron microscopy. A second measurement of the hepatitis C viral load showed 4,001,000 IU per milliliter.
Figure 2. Renal Biopsy Specimen Showing Membranoproliferative Glomerulonephritis (Periodic Acid–Schiff Stain).
Panel A shows infiltration of the renal parenchyma and glomeruli with lymphocytes (arrow) at low-power magnification. Panel B shows mesangial proliferation (arrows) and a thickened Bowman's capsule (arrowheads) at higher-power magnification. Electron microscopy confirmed the presence of type 1 membranoproliferative glomerulonephritis.
The results of the renal biopsy are consistent with hepatitis C–associated nephropathy, and my clinical diagnosis is multisystem disease (lung, kidney, and skin) related to hepatitis C–associated mixed cryoglobulinemia. The absence of cryoglobulins on microscopy does not rule out this diagnosis. Her increased viral load is consistent with immunosuppression. Higher viral loads correlate with a poorer response to antiviral therapy. There is little published literature to guide the treatment of such a patient, but I would favor continued treatment with corticosteroids and plasmapheresis and the addition of antiviral treatment for hepatitis C, using pegylated interferon and ribavirin. A genotype should be checked; longer therapy is recommended for genotype 1 than for genotype 2 or 3.
Plasmapheresis was stopped after seven courses every other day, and immediately thereafter treatment with peginterferon alfa-2b (1.5 mg per kilogram of ideal body weight) and ribavirin (1000 mg) was begun. Testing revealed hepatitis C, genotype 3a. The pulmonary hemorrhage resolved completely. The patient was discharged to a rehabilitation facility 3 months after her initial presentation. She completed a 6-month course of antiviral therapy, at which time the ratio of urinary protein to creatinine was 0.17, indicating almost complete resolution of the nephropathy. The viral load was undetectable 6 months after completion of the antiviral therapy, indicating a sustained viral response. She returned home and has resumed the level of functioning she had before becoming ill.
Commentary
This patient presented with petechiae, pulmonary hemorrhage, azotemia, proteinuria, and hematuria. Among the possible diagnoses discussed, vasculitis is an uncommon one, but it was rapidly recognized as a possible explanation for the involvement of multiple organ systems.
This combination of pulmonary hemorrhage and suspected glomerulonephritis suggested a pulmonary–renal syndrome, a manifestation of small-vessel vasculitis. Although Goodpasture's syndrome was the first such syndrome to be described, it is now recognized that the pulmonary–renal syndrome may be caused by a heterogeneous group of systemic vasculitides, including Goodpasture's syndrome, antineutrophil cytoplasmic antibody–associated vasculitides (including Wegener's granulomatosis and microscopic polyangiitis), lupus-associated small-vessel vasculitis, and cryoglobulinemia vasculitis.1
The serologic studies for hepatitis C were requested because the patient had an elevated aspartate aminotransferase level, and the positive result posed a challenge: Is infection with hepatitis C virus directly related to the patient's current presentation? Recognizing that infection with this virus might explain all the manifestations of her illness was critical to identifying effective therapy.
Hepatitis C affects at least 1.8% of Americans and is underdiagnosed; up to 10% of patients have no known risk factors for the infection.2 It is associated with many autoimmune disorders, particularly in patients who have an associated mixed cryoglobulinemia.3 Few cases of massive pulmonary hemorrhage with chronic hepatitis C have been reported; such cases have also been associated with glomerulonephritis and cryoglobulinemia.4,5
Cryoglobulins are immunoglobulins that precipitate in cool temperatures and are associated with chronic infections (especially hepatitis C and HIV infection), autoimmune disorders, and hematologic cancers.6 False negative results of cryoglobulin tests are not uncommon,7 and careful handling is required to obtain an accurate measurement. While the patient is in a fasting state (since lipids may interfere with the test), at least 20 ml of blood should be drawn into a tube that has not been treated with anticoagulant. The specimen should be transported and centrifuged at 37°C. The serum should then be kept for more than 72 hours at 4°C to allow for precipitation of cryoglobulins. Cryoglobulinemia can take many forms, including a small-vessel vasculitis caused by deposition of complexes of antigen, cryoglobulin, and complement.6 In this patient, the initial cryoglobulin test, given the apparent vasculitic nature of her illness and the later positive test, yielded a false negative result. By recognizing the limitations of this laboratory test, the discussant did not prematurely reject the diagnosis of cryoglobulinemia.
Cryoglobulinemia is present in 40% of patients with chronic hepatitis C; however, vasculitic sequelae are seen in only 2 to 3% of these patients.3 These sequelae consist of skin involvement (palpable purpura) in 80% of cases, nerve involvement in 50%, and renal involvement (typically type I membranoproliferative glomerulonephritis) in 30%.8
Managing an autoimmune manifestation of an infectious disease is complex. Although immunosuppressive agents may be needed to control potentially life-threatening autoimmune complications, there is a risk that these agents will worsen the infection. In the case of hepatitis C, short courses of corticosteroids do not seem to affect the histologic progression of liver disease9; however, chronic immunosuppression, as seen in transplant recipients and patients with the acquired immunodeficiency syndrome, may hasten disease progression.10,11 Because this patient had a relapse after initial immunosuppressive therapy, a decision was made to treat the underlying hepatitis C. Many small studies have suggested a benefit of interferon alfa and ribavirin therapy in patients with hepatitis C–associated membranoproliferative glomerulonephritis, demonstrating that control of the viremia may result in resolution of cryoglobulinemia and renal dysfunction.12,13,14,15 A reasonable approach, as used in this case, is first to control the acute autoimmune manifestations of disease with immunosuppressive therapy and then to treat the underlying infection to prevent relapse; however, data supporting this approach are limited.
This case represents an uncommon presentation of a common disease. Recognizing that the parts of this patient's complicated presentation summed up to hepatitis C ultimately led to the correct diagnosis and to effective therapy.
Dr. Buller reports receiving consulting and lecturing fees from Pfizer and Novartis. No other potential conflict of interest relevant to this article was reported.
We thank Drs. James Boyer, Thomas Duffy, and Jerome Kassirer for reviewing the manuscript, and Dr. Bhupinder Lyall for caring for the patient and sharing the clinical information with us.
Source Information
From the Department of Internal Medicine, Yale University School of Medicine, New Haven (M.P., G.K.B., C.I.M., A.N.S.); and the Department of Internal Medicine, St. Mary's Hospital, Waterbury (G.K.B.) — both in Connecticut.
Address reprint requests to Dr. Prasad at 1500 Locust St., Apt. 2518, Philadelphia, PA 19102, or at meeta@alumni.princeton.edu.
References
Bosch X, Font J. The pulmonary-renal syndrome: a poorly understood clinicopathologic condition. Lupus 1999;8:258-262.
Recommendations for the prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm Rep 1998;47:1-39.
Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 1999;42:2204-2212.
Roithinger FX, Allinger S, Kirchgatterer A, et al. A lethal course of chronic hepatitis C, glomerulonephritis, and pulmonary vasculitis unresponsive to interferon treatment. Am J Gastroenterol 1995;90:1006-1008.
Gomez-Tello V, Onoro-Canaveral JJ, de la Casa Monje RM, et al. Diffuse recidivant alveolar hemorrhage in a patient with hepatitis C virus-related mixed cryoglobulinemia. Intensive Care Med 1999;25:319-322.
Cacoub P, Costedoat-Chalumeau N, Lidove O, Alric L. Cryoglobulinemia vasculitis. Curr Opin Rheumatol 2002;14:29-35.
Musset L, Diemert MC, Taibi F, et al. Characterization of cryoglobulins by immunoblotting. Clin Chem 1992;38:798-802.
Vassilopoulos D, Calabrese LH. Hepatitis C virus infection and vasculitis: implications of antiviral and immunosuppressive therapies. Arthritis Rheum 2002;46:585-597.
Calleja JL, Albillos A, Cacho G, Iborra J, Abreu L, Escartin P. Interferon and prednisone therapy in chronic hepatitis C with non-organ-specific antibodies. J Hepatol 1996;24:308-312.
Mathurin P, Mouquet C, Poynard T, et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999;29:257-263.
Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology 1999;30:1054-1058.
Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330:751-756.
Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kidney Dis 2004;43:617-623.
Bruchfeld A, Lindahl K, Stahle L, Soderberg M, Schvarcz R. Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and renal insufficiency. Nephrol Dial Transplant 2003;18:1573-1580.
Sabry AA, Sobh MA, Sheaashaa HA, et al. Effect of combination therapy (ribavirin and interferon) in HCV-related glomerulopathy. Nephrol Dial Transplant 2002;17:1924-1930.(Meeta Prasad, M.D., Grego)
A 36-year-old Pakistani woman presented to the emergency room with a 10-day history of a nonproductive cough, dyspnea, and fever. She reported having no night sweats and no contact with anyone who was ill, including anyone with known tuberculosis. She had been seen 1 week earlier at a walk-in clinic, where she received a prescription for moxifloxacin for presumed bronchitis, but her symptoms persisted.
This patient's initial presentation with a cough, dyspnea, and fever appears to be most consistent with a community-acquired respiratory tract infection, but the lack of response to treatment with broad-spectrum antibiotics for a week raises the question of whether her pulmonary symptoms are the result of a nonbacterial infection, a more serious systemic infection, or a noninfectious disorder, such as cancer. The dyspnea may be due to respiratory illness but could also reflect other conditions, such as concomitant anemia or heart failure.
The patient said she had no chest pain, orthopnea, or paroxysmal nocturnal dyspnea. A review of her other organ systems was also negative. She had had three uncomplicated pregnancies. She had received no blood transfusions and took no medications other than the antibiotic. Her family history was unremarkable. She said she did not use tobacco, alcohol, or illicit drugs. She had immigrated to the United States 5 years earlier from Pakistan and reported no recent travel. She lived with her husband and children and was not employed outside the home. On examination, she was not in distress. She weighed 55 kg. Her temperature was 39.2°C, pulse 127, respiratory rate 18, blood pressure 149/94 mm Hg, and oxygen saturation 100% while breathing ambient air. Her cardiac examination revealed tachycardia and a soft apical systolic murmur with no radiation. Her lungs were clear. She had scattered petechiae on her legs.
The fact that the patient has not recently traveled to Pakistan makes it unlikely that she acquired an acute illness endemic to the area, unless an arriving traveler exposed her to it. Nonetheless, her symptoms could represent an acute exacerbation of a chronic and previously subclinical illness. Though she reports no exposure to tuberculosis, her residence in Pakistan is associated with an increased risk of prior exposure and subsequent reactivation. Her tachycardia may be related to her fever, a respiratory illness, anemia, or cardiac dysfunction. Her hypertension may have been present but undetected previously or may reflect volume overload resulting from azotemia. Her murmur is nonspecific and may be flow-related, the result of her fever or anemia. The normal oxygen saturation and pulmonary examination do not exclude the possibility of pulmonary disease. Her petechiae are worrisome and suggest a low platelet count or a vasculitis; palpable lesions would be consistent with the latter.
The patient's white cell count was 17,200 per cubic millimeter, with 86% neutrophils, 5% lymphocytes, 8% monocytes, and 1% eosinophils. The hemoglobin level was 7.2 g per deciliter, with a mean corpuscular volume of 74.6 μm3. (The hemoglobin level had been 9.0 g per deciliter 2 months earlier, and she had not returned for follow-up testing.) The platelet count was 130,000 per cubic millimeter. The serum sodium level was 129 mmol per liter, potassium 3.3 mmol per liter, bicarbonate 18 mmol per liter, blood urea nitrogen 46 mg per deciliter (16.4 mmol per liter), and creatinine 3.5 mg per deciliter (309.4 μmol per liter), an increase from 1.0 mg per deciliter (88.4 μmol per liter) 1 year earlier. The serum albumin level was 2.5 g per deciliter. The aspartate aminotransferase level was 47 U per liter (normal range, 16 to 41); the results of other liver function tests were normal. The prothrombin time was normal. A dipstick urinalysis was positive for protein (3+) and blood (3+). Microscopical evaluation showed red cells too numerous to count. A chest radiograph revealed no abnormalities.
The leukocytosis increases my suspicion that this patient has an infectious disease. She has a microcytic anemia, which may represent iron deficiency or an anemia of a chronic disease. The thrombocytopenia in combination with the anemia raises the possibility of microangiopathic hemolysis from thrombotic thrombocytopenic purpura, especially in the setting of petechiae and azotemia. The patient's chemistry panel reveals azotemia, proteinuria, and microscopic hematuria, all suggesting nephritis. Red-cell casts in the urine sediment would provide further evidence of glomerular disease. The hypoalbuminemia is probably due to a hypercatabolic state or glomerular leakage; with a normal prothrombin time, liver synthetic dysfunction is unlikely. The elevated level of aspartate aminotransferase is nonspecific and may be a result of liver disease, hemolysis, or rhabdomyolysis. The normal chest radiograph does not exclude the possibility of parenchymal disease, especially early interstitial disease.
Infectious diseases that might explain such a presentation include endocarditis, viral hepatitis, and human immunodeficiency virus (HIV) infection. A paraproteinemia or vasculitis could present in a similar fashion. Assessment of a peripheral blood smear is warranted immediately to investigate the possibility of microangiopathic hemolysis, with particular concern for thrombotic thrombocytopenic purpura.
The peripheral blood smear revealed less than one schistocyte per high-power field and no other notable findings. The total iron level was 18 μg per deciliter (3.2 μmol per liter), and the total iron-binding capacity 286 μg per deciliter (51.2 μmol per liter). Blood was drawn for cultures; the patient received ceftriaxone in the emergency room and was admitted and placed in a negative-pressure room. Sputum samples for acid-fast bacillus studies were requested. Within a few hours, the patient's respiratory status had rapidly declined. A computed tomographic (CT) scan of the chest revealed diffuse bilateral alveolar infiltrates (Figure 1). Hypoxemic respiratory failure developed, and the patient was intubated. Copious blood was suctioned from the endotracheal tube.
Figure 1. CT Scan of the Chest Obtained without Intravenous Administration of Contrast Material, Showing Diffuse Bilateral Alveolar Infiltrates.
Her acute respiratory decompensation with diffuse alveolar infiltrates and hemoptysis points to the syndrome of alveolar hemorrhage. Possible causes include a bleeding diathesis, diffuse alveolar damage resulting from infection, congestive heart failure, and vasculitis. Given the involvement of multiple organ systems, I am increasingly concerned about a vasculitis. The absence of upper respiratory tract symptoms makes Wegener's granulomatosis unlikely. Goodpasture's syndrome is a possibility, although it is more common in men than in women. I would still test for antineutrophil cytoplasmic antibodies — specifically, antiproteinase 3 and antimyeloperoxidase, which are present in up to 90% of patients with Wegener's granulomatosis; antinuclear antibodies; and anti–glomerular basement membrane antibodies. Given her elevated aspartate aminotransferase level and country of origin, I would also screen for hepatitis B. Ten percent of hepatitis C–infected persons have no apparent risk factor, and I would test for this as well. Both of these viruses may cause a systemic vasculitis (polyarteritis nodosa or cryoglobulinemic vasculitis), which may lead to purpura and a nephritic urine sediment. Measurement of cryoglobulins and complement levels may also be informative; cryoglobulins associated with hepatitis C virus precipitate with IgG and activate complement along the surface of blood vessels, resulting in decreased serum complement — C4 in particular.
The patient was presumed to have a pulmonary–renal syndrome and was treated with methylprednisolone (1 g given intravenously, once a day for 3 days) and one dose of cyclophosphamide (750 mg given intravenously). Plasmapheresis was initiated; 4.5 liters of plasma were removed and completely replaced with equal parts of 5% albumin and fresh-frozen plasma. The pulmonary hemorrhage abated, but the patient became oliguric and her creatinine level rose to 4.6 mg per deciliter (406.6 μmol per liter). Hemodialysis was initiated. Tests for anti–glomerular basement membrane, antimyeloperoxidase, antiproteinase 3, antinuclear antibodies, cryoglobulins, and hepatitis B surface antibody were negative. The serum C3 level was 92 mg per deciliter (normal range, 79 to 152) and the C4 level 23 mg per deciliter (normal range, 16 to 38). The test for hepatitis C antibody was positive, and the viral load was 1,242,487 IU per milliliter. An HIV test was negative.
Extrahepatic manifestations are seen in about 30% of patients with hepatitis C. The virus may bind to B lymphocytes; the resulting autoantibodies may cause vasculitis, leading to membranoproliferative glomerulonephritis and, in rare cases, pulmonary hemorrhage. In many cases, the vasculitis is related to essential mixed cryoglobulinemia, with immune complex deposition in the vessel wall. Cryoglobulin measurements are difficult to perform, and the diagnosis is not ruled out by a single negative result or by serum complement levels in the normal range.
The corticosteroids were tapered over the next 5 weeks to 10 mg of prednisone per day. The plasmapheresis was continued at the same dose for 11 courses approximately every other day, until a spot urine test showed a protein-to-creatinine ratio of zero, the creatinine level was 1.0 mg per deciliter, and the patient's respiratory status improved. Hemodialysis was stopped. When plasmapheresis was stopped, however, pulmonary hemorrhage recurred, the ratio of urinary protein to creatinine rose to 4.7, the C3 level fell to 58 mg per deciliter, and the C4 level fell to 13 mg per deciliter. The creatinine level remained normal. A repeat cryoglobulin measurement was positive. The prednisone dose was then increased to 1 mg per kilogram of body weight per day, and plasmapheresis was resumed.
The finding of cryoglobulins makes sense in the setting of this patient's presentation; the fall in the complement levels, which was concurrent with the other manifestations, further supports the hypothesis that this illness is due to cryoglobulinemic vasculitis. Hepatitis C is most likely driving the vasculopathy, and treatment may be warranted. The clinical and serologic manifestations of vasculopathy in patients with hepatitis C often diminish with antiviral therapy. However, pulmonary hemorrhage is a rare manifestation, and the response is unpredictable. Before exposing this patient to the toxicities of antiviral medications, I would seek further evidence that the vasculitis is related to hepatitis C. Given her tenuous respiratory status, I would obtain tissue from a nonpulmonary site. Membranoproliferative glomerulonephritis is the most common manifestation of nephropathy associated with hepatitis C. Although this finding would not absolutely rule out other causes of the patient's vasculitis, it would support the hypothesis that hepatitis C is the underlying cause of her clinical presentation.
A percutaneous renal biopsy revealed membranoproliferative glomerulonephritis (Figure 2). No cryoglobulins were identified on electron microscopy. A second measurement of the hepatitis C viral load showed 4,001,000 IU per milliliter.
Figure 2. Renal Biopsy Specimen Showing Membranoproliferative Glomerulonephritis (Periodic Acid–Schiff Stain).
Panel A shows infiltration of the renal parenchyma and glomeruli with lymphocytes (arrow) at low-power magnification. Panel B shows mesangial proliferation (arrows) and a thickened Bowman's capsule (arrowheads) at higher-power magnification. Electron microscopy confirmed the presence of type 1 membranoproliferative glomerulonephritis.
The results of the renal biopsy are consistent with hepatitis C–associated nephropathy, and my clinical diagnosis is multisystem disease (lung, kidney, and skin) related to hepatitis C–associated mixed cryoglobulinemia. The absence of cryoglobulins on microscopy does not rule out this diagnosis. Her increased viral load is consistent with immunosuppression. Higher viral loads correlate with a poorer response to antiviral therapy. There is little published literature to guide the treatment of such a patient, but I would favor continued treatment with corticosteroids and plasmapheresis and the addition of antiviral treatment for hepatitis C, using pegylated interferon and ribavirin. A genotype should be checked; longer therapy is recommended for genotype 1 than for genotype 2 or 3.
Plasmapheresis was stopped after seven courses every other day, and immediately thereafter treatment with peginterferon alfa-2b (1.5 mg per kilogram of ideal body weight) and ribavirin (1000 mg) was begun. Testing revealed hepatitis C, genotype 3a. The pulmonary hemorrhage resolved completely. The patient was discharged to a rehabilitation facility 3 months after her initial presentation. She completed a 6-month course of antiviral therapy, at which time the ratio of urinary protein to creatinine was 0.17, indicating almost complete resolution of the nephropathy. The viral load was undetectable 6 months after completion of the antiviral therapy, indicating a sustained viral response. She returned home and has resumed the level of functioning she had before becoming ill.
Commentary
This patient presented with petechiae, pulmonary hemorrhage, azotemia, proteinuria, and hematuria. Among the possible diagnoses discussed, vasculitis is an uncommon one, but it was rapidly recognized as a possible explanation for the involvement of multiple organ systems.
This combination of pulmonary hemorrhage and suspected glomerulonephritis suggested a pulmonary–renal syndrome, a manifestation of small-vessel vasculitis. Although Goodpasture's syndrome was the first such syndrome to be described, it is now recognized that the pulmonary–renal syndrome may be caused by a heterogeneous group of systemic vasculitides, including Goodpasture's syndrome, antineutrophil cytoplasmic antibody–associated vasculitides (including Wegener's granulomatosis and microscopic polyangiitis), lupus-associated small-vessel vasculitis, and cryoglobulinemia vasculitis.1
The serologic studies for hepatitis C were requested because the patient had an elevated aspartate aminotransferase level, and the positive result posed a challenge: Is infection with hepatitis C virus directly related to the patient's current presentation? Recognizing that infection with this virus might explain all the manifestations of her illness was critical to identifying effective therapy.
Hepatitis C affects at least 1.8% of Americans and is underdiagnosed; up to 10% of patients have no known risk factors for the infection.2 It is associated with many autoimmune disorders, particularly in patients who have an associated mixed cryoglobulinemia.3 Few cases of massive pulmonary hemorrhage with chronic hepatitis C have been reported; such cases have also been associated with glomerulonephritis and cryoglobulinemia.4,5
Cryoglobulins are immunoglobulins that precipitate in cool temperatures and are associated with chronic infections (especially hepatitis C and HIV infection), autoimmune disorders, and hematologic cancers.6 False negative results of cryoglobulin tests are not uncommon,7 and careful handling is required to obtain an accurate measurement. While the patient is in a fasting state (since lipids may interfere with the test), at least 20 ml of blood should be drawn into a tube that has not been treated with anticoagulant. The specimen should be transported and centrifuged at 37°C. The serum should then be kept for more than 72 hours at 4°C to allow for precipitation of cryoglobulins. Cryoglobulinemia can take many forms, including a small-vessel vasculitis caused by deposition of complexes of antigen, cryoglobulin, and complement.6 In this patient, the initial cryoglobulin test, given the apparent vasculitic nature of her illness and the later positive test, yielded a false negative result. By recognizing the limitations of this laboratory test, the discussant did not prematurely reject the diagnosis of cryoglobulinemia.
Cryoglobulinemia is present in 40% of patients with chronic hepatitis C; however, vasculitic sequelae are seen in only 2 to 3% of these patients.3 These sequelae consist of skin involvement (palpable purpura) in 80% of cases, nerve involvement in 50%, and renal involvement (typically type I membranoproliferative glomerulonephritis) in 30%.8
Managing an autoimmune manifestation of an infectious disease is complex. Although immunosuppressive agents may be needed to control potentially life-threatening autoimmune complications, there is a risk that these agents will worsen the infection. In the case of hepatitis C, short courses of corticosteroids do not seem to affect the histologic progression of liver disease9; however, chronic immunosuppression, as seen in transplant recipients and patients with the acquired immunodeficiency syndrome, may hasten disease progression.10,11 Because this patient had a relapse after initial immunosuppressive therapy, a decision was made to treat the underlying hepatitis C. Many small studies have suggested a benefit of interferon alfa and ribavirin therapy in patients with hepatitis C–associated membranoproliferative glomerulonephritis, demonstrating that control of the viremia may result in resolution of cryoglobulinemia and renal dysfunction.12,13,14,15 A reasonable approach, as used in this case, is first to control the acute autoimmune manifestations of disease with immunosuppressive therapy and then to treat the underlying infection to prevent relapse; however, data supporting this approach are limited.
This case represents an uncommon presentation of a common disease. Recognizing that the parts of this patient's complicated presentation summed up to hepatitis C ultimately led to the correct diagnosis and to effective therapy.
Dr. Buller reports receiving consulting and lecturing fees from Pfizer and Novartis. No other potential conflict of interest relevant to this article was reported.
We thank Drs. James Boyer, Thomas Duffy, and Jerome Kassirer for reviewing the manuscript, and Dr. Bhupinder Lyall for caring for the patient and sharing the clinical information with us.
Source Information
From the Department of Internal Medicine, Yale University School of Medicine, New Haven (M.P., G.K.B., C.I.M., A.N.S.); and the Department of Internal Medicine, St. Mary's Hospital, Waterbury (G.K.B.) — both in Connecticut.
Address reprint requests to Dr. Prasad at 1500 Locust St., Apt. 2518, Philadelphia, PA 19102, or at meeta@alumni.princeton.edu.
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