BCG immunotherapy: be cautious of granulomas. Disseminated BCG infection and mycotic aneurysm as late complications of intravesical BCG instillations

We describe a 65-year-old man with a granulomatous hepatitis and a progressive mycotic aneurysm of the abdominal aorta. One year before he received intravesical bacillus Calmette--Guérin (BCG) for carcinoma of the bladder without any complaints. Only post-mortem investigations could confirm that he suffered from a systemic BCG infection. Literature is reviewed for this rare complication.     

Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation.

BACKGROUND--Bladder instillations with Bacillus Calmette-Guerin (BCG) are commonly used as immunotherapy for bladder carcinoma. Sometimes patients experience serious systemic side effects, such as sepsis or pneumonitis. Granulomatous hepatitis is a rare serious side effect, which has been considered a hypersensitivity reaction to BCG. PATIENT--The first case of granulomatous hepatitis after BCG bladder instillation in which mycobacteria were identified by staining techniques and mycobacterial DNA was detected in liver tissue using the polymerase chain reaction is reported. CONCLUSION--The granulomatous hepatitis was caused by BCG infection of the liver after haematogenous dissemination of BCG, rather than hypersensitivity.     

Hepatitis in disseminated bacillus Calmette-Guérin infection.

Local immunotherapy with an attenuated live strain of Mycobacterium bovis, bacillus Calmette-Guérin (BCG), is an effective and frequently used treatment for in situ transitional cell carcinoma (TCC) of the bladder. Success rates are high, and serious side effects are infrequent but can affect every organ system. A 79-year-old patient with recently diagnosed TCC who was treated with intravesical BCG for a recurrence after initial surgical treatment is reported. After unsuccessful attempts at bladder catheterization with the creation of a false passage for his third treatment, BCG was instilled via a suprapubic catheter the same day and again a week later. Two weeks after the third BCG instillation, the patient presented with profound lethargy and weakness to the point of not being able to get up out of a chair. He was febrile, anorexic, icteric and had hepatosplenomegaly. Disseminated BCG infection was suspected on the basis of history, clinical examination and a liver biopsy that showed noncaseating granulomatous hepatitis. Empirical treatment was started with antituberculous combination therapy. A short course of an oral corticosteroid was given. Clinical improvement was marked and sustained so that the patient could be discharged home for the full six-month course of his treatment. Disseminated BCG infection with granulomatous hepatitis can be severe and life-threatening in cases where a large intravascular inoculum of BCG may have been given inadvertently.     

Bacillus Calmette-Guérin-induced granulomatous hepatitis in a patient with a superficial bladder carcinoma

A 71-year-old male patient with a superficial transitional cell carcinoma of the urinary bladder developed high fever and jaundice, accompanied by progressively increasing serum aminotransferase activities, 2 weeks after the fourth local instillation with an attenuated live strain of Mycobacterium bovis [bacillus Calmette-Guérin (BCG)]. A liver biopsy showed non-caseating granulomatous hepatitis. Cultures for mycobacteria were negative. Mycobacterial DNA was not detected in liver tissue using the polymerase chain reaction. Empirical treatment with rifampicin and isoniazid was started, resulting in partial recovery. After 6 months of therapy, however, serum aminotransferase activities were still twice the upper limit of normal. A second liver biopsy still demonstrated several granulomas. Only after addition of prednisolone, liver tests completely normalized. Also histologically the lesions improved dramatically. This suggests that the BCG hepatitis was at least partially caused by a hypersensitivity reaction. Our patient is the first reported case of BCG hepatitis with histological follow-up under therapy.     

Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin

The differential diagnosis of fever of unknown origin (FUO) includes infectious, neoplastic, rheumatic-inflammatory and miscellaneous diseases. We report the case of a 35-year-old man with FUO caused by Q fever. A liver biopsy showed the characteristic fibrin-ring lipogranulomas compatible with Q fever. The serologic tests confirmed the diagnosis of acute infection by Coxiella burnetii. The therapeutic response was excellent. In conclusion, we described a patient with acute Q fever and granulomatous hepatitis.     

A Superinfection of Salmonella typhi and Hepatitis E Virus Causes Biphasic Acute Hepatitis

A 47-year-old Japanese man was referred to our hospital because of a sustained high fever with diarrhea 12 days after a flight from India. Liver enzymes were elevated with rose spots, hepatosplenomegaly, relative bradycardia, and acute cholecystitis. A liver biopsy depicted the dense infiltration of lymphocytes and Kupffer cells in sinusoids and the granulomatous formation in the parenchyma. The liver damage was initially resolved with the administration of ceftriaxone for 16 days but flared up 1 week later. Laboratory tests yielded positive reactions for Salmonella typhi and hepatitis E virus RNA. The pathophysiological presentations of concurrent typhoid and type E hepatitis are discussed.     

Granulomatous arthritis in Crohn's disease

A case is described of non-necrotizing, epithelioid cell granulomatous synovitis of the ankle of a 22-year-old man with Crohn's disease. It appears to be the first published example of granulomatous arthritis in association with Crohn's disease.     

Infection with Mycobacterium bovis in a patient with AIDS: a late complication of BCG vaccination.

We present a 28-year-old HIV-infected man with a 2-year delayed complication of BCG immunization. When immunized the man was healthy, with an unknown HIV status, but 2 years later he was diagnosed with AIDS because of a Pneumocystis carinii pneumonia. He was successfully treated and discharged in a state of good health. A few months later he presented with an enlarged lymph node and Mycobacterium bovis, BCG strain, was cultured. No sign of dissemination was found. We discuss the indications for BCG vaccination in adults, especially in areas and in populations with a high prevalence of HIV.     

Granulomatous Hepatitis in a Healthy Adult Following BCG Injection into a Plantar Wart

This is the first reported case of granulomatous hepatitis in a healthy adult following intralesional injection of BCG into a plantar wart. Previous reports of disseminated disease following intralesional injections have all been in patients with malignancies. The clinical course in this patient was characterized by fever, chills and drainage from the injection site. Diagnosis was made by demonstration of noncaseating granulomas on liver biopsy. No acid-fast organisms were identified by stain or culture. The patient responded to antituberculous therapy.     

Severe cholestatic jaundice in hyperthyroidism after treatment with 131-iodine

A 39-year-old white man was referred to our hospital for evaluation of his jaundice and pruritus. The patient was treated with I for diffuse toxic goiter prior to his referral to our hospital. Clinical examination and laboratory investigations excluded viral hepatitis, autoimmune hepatitis, granulomatous disease, primary biliary disease, extrahepatic biliary obstruction, and heart failure. Liver biopsy showed severe intrahepatic and canalicular cholestasis with minimal inflammatory changes. The patient's jaundice promptly resolved with therapy for hyperthyroidism and thyroid storm as bilirubin levels decreased from 35 mg/dL (normal: 0.5-1.2 mg/dL) to 0.4 mg/dL. Thyrotoxicosis can be an uncommon cause of profound cholestasis. Our case differs from all other reports in the literature because of the severity of the cholestasis and its prompt resolution with treatment for thyrotoxicosis.     

Miliary tuberculosis due to intravesical bacillus Calmette-Guerin therapy

While receiving treatment for bladder carcinoma with intravesical BCG, a 78-year-old man developed a clinical illness and roentgenographic manifestation of miliary tuberculosis. The transbronchial lung biopsy demonstrated granulomas with giant cells. Treatment with antituberculosis therapy resulted in complete resolution of the illness. The pathogenesis of this complication was considered to be due to pulmonary infection by BCG from the bladder source and differs from previously reported cases of interstitial pulmonary infiltrates which more likely represent a hypersensitivity reaction to BCG.     

Mycobacterial brain tuberculomas due to Bacille Calmette-Guérin intravesical chemotherapy for bladder cancer: A case report and literature review

Bacille Calmette-Guérin (BCG) immunotherapy is widely used for the treatment of superficial bladder cancer. The authors believe that the present report is one of the first to document cerebral BCG tuberculoma in a 73-year-old immunocompetent man, three years after intra-vesical BCG immunotherapy. His workup revealed no identifiable extracranial source. He responded well to treatment with rifampin, ethambutol and moxifloxacin.Patients undergoing intravesical BCG therapy should be closely monitored for the development of this complication. Prolonged antitubercular therapy, possibly including moxifloxacin, appears to be beneficial in the treatment of central nervous system tuberculous infections.     

Mesalamine-induced granulomatous hepatitis

A 42-yr-old man with ulcerative colitis was admitted for investigation of prolonged fever associated with cholestatic liver tests. Endoscopic retrograde cholangiopancreatography demonstrated a normal biliary tree, and liver biopsy showed granulomata. A clinical diagnosis of drug-induced granulomatous hepatitis was established as the symptoms disappeared after cessation of mesalamine therapy and recurred on rechallenge. Although the differential diagnosis of fever and hepatitis in patients with inflammatory bowel disease is wide, in this case mesalamine is the most likely cause.     

Acalculous cholecystitis: an uncommon form of presentation of Q fever

Acute acalculous cholecystitis is a very rare clinical presentation of Q fever. We report the case of a 38-year-old man who presented with fever associated with elevation of liver enzyme levels and thickening of the gallbladder wall on abdominal ultrasonography and who was initially diagnosed with acute acalculous cholecystitis. Due to the persistence of fever and transaminase elevation despite antibiotic treatment, a liver biopsy was performed. Characteristic "doughnut" epithelioid granulomas were observed, suggesting a diagnosis of granulomatous hepatitis caused by Q fever, which was confirmed by serological methods. Treatment with doxycycline was commenced and the patient subsequently showed rapid clinical improvement, with disappearance of fever and normalization of liver enzyme levels. We review 8 cases of acute cholecystitis associated with Q fever published in the literature and stress the importance of liver biopsy in the etiological diagnosis of patients with prolonged fever and abnormal liver function tests.     

Granulomatous infiltration with replacement of liver parenchyma: first case report

A 76-year-old man presented with fever, weight loss and abnormal liver function tests. Imaging demonstrated a diffusely abnormal liver, and a liver biopsy revealed a fibrosing granulomatous process infiltrating and replacing liver parenchyma. There was no clinical, radiological or laboratory evidence of autoimmune liver disease, sarcoidosis, lymphoma or tuberculosis. Treatment with steroids resulted in a remarkable resolution of the clinical symptoms and radiology. This is the first case of granulomatous infiltration of the liver replacing normal hepatic parenchyma.     

Nearly fatal complications of cervical lymphadenitis following BCG immunotherapy for superficial bladder cancer.

This report describes the case of a 68-year-old man with bilateral cervical lymphadenitis and chorioretinitis due to bacille Calmette-Guérin (BCG), originating from BCG immunotherapy for treatment of superficial bladder cancer 2 years ago. During antimycobacterial therapy a fistula between the right-sided lymph node and an aneurysm of the carotid artery developed. This led to life-threatening spontaneous bleeding which required vascular graft surgery. Like other known systemic side effects, cervical lymphadenitis may also occur following intravesical BCG immunotherapy, and life-threatening complications cannot be excluded despite adequate medical treatment.     

Systemic sarcoidosis presenting as a granulomatous tattoo reaction secondary to interferon-alpha treatment for chronic hepatitis C and review of the literature

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Immune alterations involving heightened T-helper-1 responses have been proposed to play a major role in the pathogenesis of sarcoidosis. Interferon-alpha therapy and hepatitis C infection have been implicated in the development of a variety of autoimmune diseases. However, despite the wide use of IFN-alpha therapy for hepatitis C, only a few cases of sarcoidosis have been reported in this context. We report the case of a 42-year-old white female with hepatitis C, who developed systemic sarcoidosis shortly after therapy with IFN-alpha2b. The disease was heralded by the appearance of a cutaneous sarcoid/ foreign body granulomatous reaction at the site of an old tattoo. The sarcoidosis responded to a short course of oral prednisone therapy. We also reviewed the other reported cases and discussed the possible immunological mechanisms involved.     

Ramucirumab-related Oral Pyogenic Granuloma: A Report of Two Cases

Pyogenic granuloma (PG) is a granulomatous elevated lesion that occurs on the skin and mucous membranes. We herein report two cases of intra-oral PG that developed during the administration of ramucirumab for gastric cancer. Case 1 involved a 55-year-old man with a 6-mm tumor on the right tongue, and case 2 involved a 67-year-old man with a 5-mm tumor on the upper lip. The imbalance in angiogenesis caused by ramucirumab and the deterioration in the local oral environment were suggested to have caused the PG. Medical and dental collaboration is essential during the administration of ramucirumab.     

Carbimazole induced eosinophilic granulomatous vasculitis localized to the stomach

Vasculitis associated with anti-neutrophil cytoplasmic antibodies has been reported in patients treated with anti-thyroid drugs and especially propylthiouracil. We report here a case of granulomatous eosinophilic vasculitis mimicking gastric neoplasm and peripheral eosinophilia in a 27-year-old man who was treated with carbimazole for 5 months for Graves' disease. Clinical and morphologic features resolved within 2 months after stopping the drug, suggesting a causative role for the drug. To our knowledge, this is the first biopsy-proven granulomatous eosinophilic vasculitis associated with this drug.     

Necrotizing granulomatous gastritis and gastric perforation of unknown etiology: a first case report

A unique case of granulomatous gastritis of unknown etiology is reported. The patient, a 43-year-old Haitian woman, suffered a gastric perforation from a disease process limited to the stomach. The stomach was markedly enlarged and edematous with transmural, serpiginous granulomatous tracks throughout the gastric wall, but most numerous in the fundic region. Accompanying acute and chronic inflammatory infiltrates were scant. No microorganisms, parasites, foreign body particles, or other known granulogenic materials could be identified. Clinical and pathologic features also differed markedly from granulomatous gastritis seen in sarcoidosis, Crohn's disease, or isolated granulomatous gastritis as defined by Fahmi et al. Infection by a parasite for which man is not the definitive host seems the most likely etiology.