Enhancing the response to interferon-alpha.

BACKGROUND: Though initially recognized as antiviral agents, it was soon demonstrated that certain neoplasms were particularly sensitive to interferon-alpha (IFN-alpha). Indeed, the initial success of systemic IFN-alpha treatment in AIDS-associated Kaposi's sarcoma (AIDS-KS) occurred before identification of the human immunodeficiency virus (HIV) and in the absence of any coherent view of KS pathogenesis. With a more comprehensive understanding how KS develops and which circumstances provide an increased virulence of this neoplasm in HIV-infected persons, a more subtle rationale for IFN-alpha treatment arose regarding the disorder of the endogenous IFN-system in HIV-positive individuals. Until recently IFN-alpha was the only therapy available for patients with chronic hepatitis C (CHC). However, no more than 30% of these patients show a sustained virological response. Initial therapy with a combination therapy of IFN-alpha and ribavirin turned out to be more effective than treatment with IFN-alpha alone. To ameliorate response rates in antiviral IFN-therapy a profound understanding of viral dynamics, as well as immunological conditions associated with viral persistence, seems to be essential. Within a conference of the European Society of Clinical Virology (ESCV), which took place in Hamburg from August 30 to September 2, 1998, and was entitled 'Progress in Clinical Virology IV', a satellite symposium was organized to evaluate the clinical results of special antiviral treatment options with IFN-alpha, to analyze treatment failures with this cytokine and to ameliorate future strategies of IFN-alpha therapy. It focussed on HIV-related complications as coinfection with hepatitis C virus (HCV) and AIDS-KS, respectively. METHODS: A kinetic model of HCV infection based on principles established in studying HIV-1 infection was presented which is predictive for the outcome of IFN-alpha treatment. It involves different rates of velocity and compares the rates of acute clearance after different dosages of IFN-alpha application. Using the hypothesis to fit the changes in serum HCV RNA measured in a set of patients, it was found that 5 mIU daily dosing on average blocks 81% of HCV production/release, whereas 10 or 15 mIU blocks about 95% of HCV production/release. RESULTS: Only recently clinical data revealed a greater benefit of combination therapy with IFN-alpha and ribavirin compared to IFN-alpha alone in patients with chronic hepatitis C. In 345 CHC patients relapsing after pretreatment with IFN-alpha monotherapy, sustained response was achieved in a 10-fold higher degree with a combination of IFN and ribavirin compared to patients retreated with IFN alone. In 1775 treatment-naive patients with CHC, response rates to the combination therapy was significantly higher in all patient groups with more than 60% of sustained virological response in patients with genotype 2 and 3, while patients with genotype 1 (poorer prognosis) benefit from extended combination treatment duration from 24 to 48 weeks (17 versus 29% of sustained virological response), respectively. CONCLUSIONS: As viral dynamics on one side and host immune response on the other feature as two landmarks on which the manifestation of viral persistence and chronic viral infections is established, some similarities of HCV and HIV disease are striking. An unusual endogenous IFN-alpha system is associated with both infections and is a negative prognostic factor to response to treatment with IFN-alpha in CHC as well as AIDS-KS. The consequences for treatment options with IFN are a combination with ribavirin in CHC and a graduated systemic treatment schedule in AIDS-KS starting with IFN-treatment in early disease followed by chemotherapy in advanced stages of KS.     

Minimal change disease in a patient receiving IFN-alpha therapy for chronic hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is associated with several extrahepatic syndromes. The principal types of renal disorders associated with chronic HCV infection are cryoglobulinemia or noncryoglobulinemic membranoproliferative glomerulonephritis (MPGN). Interferon-alpha (IFN-alpha) may precipitate or exacerbate the occurrence of MPGN. Our patient was a 32-year-old man who tested positive for HCV in July 1997. The patient was treated with IFN-alpha in another medical center for 6 months because his liver biopsy showed chronic active hepatitis. In December 1998, he applied to our clinic for a follow-up examination. The level of aspartate aminotransferase (AST) was 44 U/L, and that of alanine aminotransferase (ALT) was 69 U/L. HCV RNA was positive in serum, and chronic HCV infection was detected by liver biopsy. IFN-alpha therapy (5 million U/day) was administered for 6 months longer. In May 1999, the patient came to our polyclinic with edema of the feet and legs. We detected proteinuria, serum cholesterol of 269 mg/dl, AST of 50 U/L, ALT of 41 U/L, serum total protein of 3.4 g/dl, serum albumin of 1.2 g/dl, positive cryoglobulin, and urine protein of 9.84 g/day. Cryoglobulinemic MPGN was suspected and kidney biopsy was performed, resulting in a diagnosis of minimal change disease (MCD).     

Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature.

BACKGROUND: Granulomatous disease resembling sarcoidosis is a well-described condition associated with common variable immunodeficiency (CVID). Its treatment remains problematic, and new therapeutic options are needed. OBJECTIVES: To report the efficacy of treatment with infliximab, a chimeric anti-tumor necrosis factor alpha monoclonal antibody, in a patient with granulomatous CVID and to review the literature on the treatment of patients with granulomatous CVID. METHODS: A 22-year-old white man with CVID developed acute multiorgan failure, with granulomatous inflammation on lung and liver biopsy specimens. He was initially treated with antibiotics, intravenous immunoglobulin, and corticosteroids for 5 weeks without improvement. High-dose infliximab was then infused weekly for 6 weeks and then monthly for 9 months. The response to infliximab was determined by changes on clinical examination, imaging studies, and histologic studies. RESULTS: The patient's condition dramatically improved after 1 dose of infliximab infusion, with decreasing hepatosplenomegaly, ventilatory support requirements, and pulmonary infiltrates. Ventilatory support was successfully discontinued within 3 weeks. The corticosteroid dose was tapered without reactivation of the disease. After 9 months of therapy, follow-up imaging studies showed resolution of pulmonary infiltrates, no hepatosplenomegaly, and no portal hypertension, and a percutaneous liver biopsy revealed no granulomas; then, infliximab use was discontinued. The patient remains free of granulomatous disease after 18 months of follow-up. CONCLUSIONS: To our knowledge, this is the first report of severe visceral granulomatous CVID successfully treated with infliximab. Infliximab may be an effective therapy for granulomas in CVID. Further studies of infliximab and other tumor necrosis factor a antagonist therapies in granulomatous CVID are warranted.     

Renal insufficiency in sarcoidosis. A clinical and pathologic study

The relationship of sarcoidosis to renal insufficiency is not widely known by pathologists or clinicians. During an 8-year period beginning in 1980, we observed six patients with sarcoidosis and clinically significant renal insufficiency (serum creatinine, greater than 260 mumol/L). In one of these patients with long-standing sarcoidosis, renal insufficiency was attributed to unrelated primary renal disease until renal biopsy specimen showed interstitial noncaseating granulomas. The four patients with renal insufficiency at presentation differed from the typical patient with sarcoidosis because they were white men who lacked the usual clinical constellation of skin, eye, and pulmonary involvement. All four had noncaseating granulomas on their initial biopsy (bone marrow [3 patients], and lymph node [1 patient]), suggesting each had sarcoidosis, yet each had two or more follow-up biopsies before the diagnosis of sarcoidosis was accepted and appropriate therapy initiated. One of these four patients underwent long-term antifungal and antituberculous therapy. The major causes of renal insufficiency in these six patients were complications of hypercalcemia and interstitial granulomatous nephritis. Except in one patient with nephrocalcinosis, prednisone therapy resulted in a dramatic fall in serum creatinine level with resolution of hypercalcemia. Sarcoidosis is a rare, but treatable, cause of renal insufficiency. Early recognition by clinicians and pathologists may spare patients from undergoing unnecessary biopsies and result in more timely initiation of therapy.     

Intrahepatic MxA and PKR protein expression in chronic hepatitis C virus infection

The therapeutic effect of interferon-alpha and ribavirin in the treatment of chronic hepatitis C viral infection is limited. To identify patient characteristics that may predict responsiveness to treatment, the intrahepatic protein expression of two directly induced IFN-alpha effector proteins, MxA and PKR, were studied. Forty liver biopsy samples from patients with a variety of chronic liver diseases were stained for MxA and PKR protein using immunohistochemical techniques. In a HCV patient cohort, 30 liver biopsies were stained for MxA and PKR protein prior to treatment with IFN-alpha and ribavirin. PKR protein expression was not upregulated in viral liver disease. In contrast, MxA protein expression was significantly upregulated in viral liver disease (P = 0.005). In chronic HCV liver disease, moderate to strong cytoplasmic expression of MxA protein was observed in hepatocytes and monocytes, indicating endogenous hepatocellular IFN-alpha pathway activation. In the HCV patient cohort treated with combination therapy, strong pre-treatment MxA hepatocyte expression was predictive of a non-response to treatment (odds ratio 9.33; P = 0.01; 95% confidence interval 1.63-53.2). This effect was independent of HCV genotype and viral load. It is concluded that pretreatment hepatocellular MxA expression may become a useful predictor of response to combination treatment with IFN-alpha and ribavirin.     

Pernicious anemia during IFN-alpha treatment for chronic hepatitis C.

Some latent diseases, such as immune disorders, can appear during interferon-alpha (IFN-alpha) therapy. These disorders are difficult to predict because of their low prevalence in the general population. We describe a case of pernicious anemia (PA) in a patient affected by chronic hepatitis C and macrocytosis during IFN-alpha therapy. Hemoglobin (Hb) concentration reached 7.3 g/dl. Anti-intrinsic factor (IF) antibodies were present, but not antiparietal cell antibodies (APCA). Suspension of IFN-alpha and administration of vitamin B(12) resulted in normal Hb concentrations. This case is the first instance of early PA (at the second month of IFN therapy) in a patient affected by chronic hepatitis C. The only other case of PA in a patient affected by hepatitis C virus (HCV) infection occurred during the second year of maintenance IFN therapy. We recommend that particular attention be paid to such clinical and laboratory conditions as macrocytosis in administering IFN-alpha therapy for chronic hepatitis C.     

Necrotizing sarcoid granulomatosis mimicking an intracranial neoplasm: clinicopathologic features and review of the literature.

We present a unique case of biopsy-proven necrotizing sarcoidosis involving the central nervous system (CNS) in a 52-year-old woman. The patient presented with a 3-month history of left-sided headache and sharp, shooting pains on the left side of her face. She also has a previous history of sarcoidosis, histopathologically confirmed on parotid gland biopsy 24 years before. Imaging studies of the present lesion revealed a 1.8 x 1.4-cm mass in the left temporal lobe with signal intensity suggestive of meningioma or low-grade glial neoplasm. Surgical resection was initiated, and intraoperative consultation with frozen sections revealed granulomata. The lesion was biopsied, and surgical intervention was terminated. Permanent sections failed to reveal bacteria, mycobacteria, fungi, or foreign bodies. A diagnosis of necrotizing neurosarcoidosis was rendered. The patient was administered steroid therapy and clinically responded favorably. At the most recent follow-up almost 2 years later, there was no evidence of recurrence or progression. Necrotizing sarcoidosis has been reported most commonly in the lungs and rarely in other organ systems. We report the first histologically proven case involving the CNS as well as a rare example of sarcoidosis and necrotizing sarcoid granulomatosis in the same patient. Sarcoidosis and its necrotizing variant should be considered in the differential diagnosis of a granulomatous mass lesion involving the CNS, particularly in the context of a history of systemic disease.     

Liver cirrhosis after prolonged therapy with IFN-alpha plus interleukin-2 in a metastatic renal cancer long-term survivor.

Interleukin-2 (IL-2) therapy is associated with serious toxic effects on the cardiopulmonary system. Less frequent toxicity is described in liver and the gastrointestinal system. A case of severe liver toxicity is described in a patient who underwent long-term immunotherapy with IL-2 (4.5 MU/m(2) s.c. daily, 5 days per week for 6 weeks, with 4 weeks of interval) plus interferon-alpha (IFN-alpha) (3 MU s.c. t.i.w., also covering the intervals between IL-2 cycles) for a metastatic renal carcinoma. A review of the literature is provided. The patient tolerated well the immunotherapy scheduled with apparently only a World Health Organization (WHO) G3 anemia and a G2 asthenia and is still alive, with a disease-free survival of 28 months. Notwithstanding a complete absence of liver function test abnormality during all scheduled clinical controls, the patient developed portal hypertension due to liver cirrhosis, which was histologically demonstrated. All common etiologic viral and toxic agents were ruled out. Long-term IL-2 therapy can induce liver cirrhosis. The appearance of liver and spleen enlargement during IL-2 therapy can be considered an indicator of liver damage. Thus, in this setting, closer monitoring is warranted despite normal liver function tests.     

Case report: a case of light chain deposition disease involving liver and stomach with chronic hepatitis C virus infection and hepatocellular carcinoma

Light chain deposition disease (LCDD) is a rare, plasma cell proliferative disorder characterized by mainly abnormal light chain deposition in various organs. Hepatitis C virus (HCV) is a hepatotrophic and lymphotrophic virus and significantly related to B-cell proliferation. This is a case report of systemic LCDD involving liver, stomach, bone marrow, and probably kidney, in a patient with HCV-related hepatocellular carcinoma (HCC). A 62-year-old man with chronic HCV infection who presented with a small HCC in segment 8 of the liver and nephrotic syndrome showed kappa typed immunoglobulin light chain depositions in biopsy specimens of bone marrow, stomach, and non-tumorous liver parenchyma. After treatment of the HCC with transarterial chemoembolization, antiviral therapy for chronic hepatitis C was started. The patient showed early virologic response at 12 weeks of treatment; however, antiviral therapy was discontinued due to adverse effects and he was lost to follow-up. This is the first case of LCDD involving the liver and stomach in a patient with chronic HCV infection and HCC, which may represent LCDD as a rare HCV-associated B cell proliferative disease.     

Efficacy and long-term follow up of combination therapy with interferon alpha and ribavirin for chronic hepatitis C in Korea

Combination therapy with interferon alpha (IFN-alpha) and ribavirin for 24 or 48 weeks according to HCV genotype has improved the overall sustained virological response (SVR) rates to approximately 40%. The aim of this study was to investigate the long-term efficacy of combination therapy with IFN-alpha and ribavirin for chronic hepatitis C in Koreans. One hundred thirty-eight patients with chronic hepatitis C who received this combination therapy between 1995 and 2003 were analyzed retrospectively. All patients were treated with IFN-alpha 3-6 million units three times weekly in combination with 900-1200 mg/day of ribavirin for 24 weeks. The overall SVR rate was 41.3%. Patients were followed up for a median of 41 months (range, 12-105 months) after completion of therapy. In all of the SVR patients (57 patients), SVR was conserved during the follow-up period. None of the patients progressed to decompensated liver disease or hepatocellular carcinoma (HCC). However, 5 of the 81 non-SVR patients (6.2%) progressed to decompensated liver disease or HCC. In conclusion, combination therapy with IFN-alpha and ribavirin shows good long-term efficacy in patients with chronic hepatitis C in Korea, one of the highest endemic areas of hepatitis B virus (HBV) infection.     

Sarcoidosis with selective involvement of a second liver allograft: report of a case and review of the literature.

A case of sarcoidosis recurrent in a patient's second liver allograft is described. There was no granulomatous disease seen in the patient's first liver allograft. After the second orthotopic liver transplantation (OLT), the patient was successfully treated for acute rejection, aspergillus infection, and cytomegalovirus viremia. Approximately 2 months after the second OLT, the patient was treated with long-term interferon-alpha for recurrent hepatitis C. Five years after the operation, he experienced liver failure secondary to recurrent hepatitis and underwent a third OLT. This is only the second reported case of sarcoidosis recurrent in the liver parenchyma of a transplanted organ and the first in which interferon-alpha might have played a role.     

Multiple myeloma in association with sarcoidosis

The association of sarcoidosis with Hodgkin disease and non-Hodgkin lymphoma is well known. However, multiple myeloma also can occur rarely in association with sarcoidosis. We describe a patient with sarcoidosis who subsequently developed multiple myeloma. The patient was a 49-year-old woman with a 4-year history of severe, chronic, active sarcoidosis involving her lungs, lymph nodes, eyes, and bone marrow. During the initial clinical workup, a serum monoclonal paraprotein was detected and bone marrow examination revealed a slight increase in plasma cells (4%), in addition to noncaseating granulomas. Thus, the diagnoses of monoclonal gammopathy of undetermined significance and sarcoidosis were established simultaneously. She sought medical attention for her current illness when she developed low back pain and weakness of her lower extremities. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin (Ig) G kappa type, and quantification revealed an IgG level of 46.67 g/L (normal, 5.88--15.73 g/L). Bone marrow aspiration and biopsy revealed multiple myeloma and sarcoidosis. Including this patient, 11 cases of sarcoidosis and multiple myeloma have been reported to date, including 3 patients with monoclonal gammopathy of undetermined significance preceding the onset of multiple myeloma. In this case, as in most of the cases reported previously, sarcoidosis preceded the development of multiple myeloma.     

Sarcoidosis-associated hepatocellular carcinoma

Sarcoidosis is a systemic granulomatous inflammation of unknown etiology, and seems to involve the liver parenchyma in most cases. However, sarcoidosis-associated hepatocellular carcinoma is rare. We report here a case in which a hepatocellular carcinoma occurred within the liver, which was probably involved as a result of systemic sarcoidosis. A 57-year-old Japanese man had been followed up for 2 years because of diabetic nephropathy and sarcoidosis. On admission for pneumonia, imaging studies revealed an unexpected hepatic tumor. Histology revealed a hepatocellular carcinoma accompanied by T-lymphocytic infiltration and marked granulomatous inflammation, which was surrounding some tumor nodules. The background liver parenchyma exhibited a moderate degree of fibrosis with granulomatous inflammation. The patient had no other apparent liver disease such as viral hepatitis, steatohepatitis, or primary biliary cirrhosis. Therefore, in the present case, sarcoidosis may be considered the probable background etiology for hepatocarcinogenesis.     

Granuloma faciale

Granuloma faciale is a rare, benign skin condition that usually occurs on the face. Using an exemplary case of granuloma faciale, we will present the clinical and histological characteristics of this dermatosis. A 49-year-old man presented with a 6-month history of a 10 mm-diameter asymptomatic papulo-nodular red-brown lesion of the nose. A biopsy specimen led to the diagnosis of granuloma faciale. The patient received a session of pulsed-dye laser therapy, which led to significant improvement. This benign and usually isolated dermatosis can more rarely be extrafacial. It may often be mistaken for other benign dermatoses (sarcoidosis, discoid lupus erythematosus) as well as for malignant dermatoses (lymphoma, basal cell carcinoma). Histology is     

Oligoclonal CD8+ T-Cell Expansion in Patients with Chronic Hepatitis C Is Associated with Liver Pathology and Poor Response to Interferon-α Therapy

The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.     

Myasthenia gravis during low-dose IFN-alpha therapy for chronic hepatitis C.

We describe the case of a 56-year-old man who had high aminotransferase levels and anti-hepatitis C virus (HCV) antibodies. He underwent liver biopsy and biochemical screening to evaluate whether he would benefit from interferon (IFN) treatment. The patient was discharged with a diagnosis of HCV-related active chronic hepatitis, skin porphyria, and type 2 diabetes. On December 5, 1995, he began therapy with recombinant IFN-alpha at a dose of 3 MIU three times a week. He stopped this therapy in February 1996 because of asthenia, diplopia, headache, and anxiety. During IFN therapy, he had normal aminotransferase levels and no detectable HCV RNA, a condition that persists to the present. Between March and May 1996, the patient was admitted several times to a neurology clinic, where myasthenia gravis was diagnosed and treatment with pyridostigmine and cyclosporine was initiated. This case and others indicate that caution should be exercised in administering IFN because low doses can be correlated with myasthenia gravis in patients without malignancies.     

Association of idiopathic thrombocytopenic purpura and type 1 diabetes mellitus in a patient with sarcoidosis]

Occurrence of autoimmune diseases with sarcoidosis is well known. However, a case in which more than one of these diseases coexist with sarcoidosis is rare. We present a young man with suspected sarcoidosis, complicated by idiopathic thrombocytopenic purpura (ITP) and type 1 A diabetes mellitus (DM). A 21-year-old man was admitted to our hospital because of thrombocytopenia, hyperglycemia, and bilateral hilar lymphadenopathy (BHL). Although a histological proof could not be obtained, the patient was considered to have sarcoidosis because 67-gallium scintigraphy disclosed "Lambda" and "Panda" signs which are highly specific for sarcoidosis. Type 1 A DM was also diagnosed as the patient had antiglutamic acid decarboxylase antibodies. The patient disclosed no hepatosplenomegaly or no lymphadenopathy and diagnosis of ITP was confirmed by bone marrow examination. High dose steroid was started as the thrombocytopenia progressed. The platelet number increased satisfactorily and shrinkage of BHL was also observed with the therapy.     

Cryptococcal meningitis in an HIV negative patient with systemic sarcoidosis

A case of Cryptococcus neoformans meningitis is described in an HIV negative patient with undiagnosed systemic sarcoidosis. The patient presented with signs of meningitis together with generalised lymphadenopathy and hepatosplenomegaly. Cryptococcal meningitis was diagnosed on lumbar puncture. She was treated with intravenous amphotericin B but died within two weeks of admission. Necropsy revealed lesions in the lungs, liver, spleen, lymph nodes, small intestine, and bone marrow consistent with sarcoidosis. Microscopically the lesions contained non-caseating epithelioid cell granulomas typical of sarcoidosis. No Schaumann or Hamazaki-Wesenberg bodies were identified. Cryptococcus neoformans meningitis is generally associated with immunosuppressive disorders. As T cell abnormalities have been described in sarcoidosis, this could have been a case of opportunistic infection. Although rare, sarcoidosis merits consideration in patients with cryptococcal disease in the absence of HIV infection.     

A case of cholestatic autoimmune hepatitis and acute liver failure: an unusual hepatic manifestation of mixed connective tissue disease and Sjögren's syndrome

Although hepatomegaly is reported to occur occasionally in patients with mixed connective tissue disease (MCTD) or Sjögren''s syndrome (SS), autoimmune liver diseases such as primary biliary cirrhosis, sclerosing cholangitis, and autoimmune hepatitis in association with MCTD or SS have rarely been described. We report a case of severe cholestatic autoimmune hepatitis presenting with acute liver failure in a 40-yr-old female patient suffering from MCTD and SS. The diagnosis of MCTD and SS was made at the age of 38. The patient presented severe jaundice and elevation of conjugated bilirubin. The patient denied alcohol and drug use and had no evidence of viral hepatitis. On the 8th day of her hospitalization, the patient developed grade III hepatic encephalopathy. She was diagnosed as autoimmune hepatitis presenting with acute liver failure based on clinical features, positive FANA and anti-smooth muscle antibodies, negative anti-mitochondrial antibodies, high titers of serum globulin, liver biopsy findings, and a good response to corticosteroid therapy, The patient was managed with prednisolone and the clinical symptoms, liver function test results, and liver biopsy findings showed much improvement after steroid therapy.