Epstein-Barr virus infection and hepatic fibrin-ring granulomas

Hepatic fibrin-ring granulomas were the main histological finding in the liver of a 38-year-old man with Epstein-Barr virus primary infection. The patient presented with fever, hepatomegaly, icterus, abnormal liver tests, autoimmune hemolytic anemia, and mononucleosis syndrome. There was neither enanthema nor lymphadenopathy or splenomegaly. Serologic tests disclosed an Epstein-Barr primary infection profile: anti-viral capsid antigen IgM antibodies and anti-early antigen antibodies were present, whereas anti-Epstein-Barr nuclear antigen antibodies were absent. There was no evidence for Q fever, Hodgkin's disease, or allopurinol-induced hepatitis, which are recognized causes of hepatic fibrin-ring granulomas. It is suggested that Epstein-Barr virus infection might be an additional cause of these peculiar hepatic granulomas.     

Hepatic granulomas in Northern Ireland: a thirteen year review

The finding of epithelioid cell granulomas within liver biopsies is a not uncommon occurrence. We undertook this study to investigate the underlying conditions responsible for a diagnosis of granulomatous hepatitis in Northern Ireland during the thirteen year period 1980–1992. One hundred and sixty-three patients with hepatic granulomas were identified, accounting for 4% of all liver biopsies undertaken during the period of the study. In 145 cases (89%) a definite clinical diagnosis was established. The most common clinical diagnoses were primary biliary cirrhosis which accounted for 90 cases (55%) and sarcoidosis which accounted for 30 cases (18%). Other less common conditions associated with hepatic granulomas included tuberculosis (3 cases), Crohn's disease (3 cases), chronic active hepatitis (2 cases), drug hypersensitivity (2 cases) and extra-hepatic biliary obstruction (2 cases). Six patients were identified with a clinical diagnosis of psoriasis. Other miscellaneous conditions accounting for single examples of granulomatous inflammation were schistosomiasis, gout, Hodgkin's disease, secondary adenocarcinoma, collapse and necrosis of tumour following radiotherapy and chemotherapy, granulomatous inflammation within the wall of an abscess cavity and idiopathic cirrhosis. Only eighteen cases (11%) remained idiopathic with no definite diagnosis established after detailed investigation. The findings confirm the wide range of clinical conditions which can result in hepatic epithelioid cell granulomas. This has been emphasised in several previous major studies which are reviewed in this paper.     

Boutonneuse fever transmitted by conjunctival inoculation

Summary We report three cases (two adult males and a 12-year-old child) of boutonneuse fever produced by inoculation of the conjunctival mucosa (probably through accidental entry ofR. conorii fluid into the eyes through rubbing or splashing). All three patients developed similar symptoms of disease, including high fever, headache, maculopapular exanthem, and conjunctivitis, and none had tache noire. Specific immunofluorescent antibodies appeared in these patients' serum mostly after the 2nd week; agglutinins to Proteus OX-19, OX-2 (Weil-Felix reaction) were found. Cure was obtained by oral tetracycline. Conjunctival inoculation ofR. conorii producing boutonneuse fever is very rare; this report will probably be one of the first published in the medical literature.     

Hepatic granulomas: a clinicopathologic analysis of 86 cases

The aim of this study was to determine the prevalence and histopathological characteristics of hepatic granulomas.All records of liver biopsies/resections evaluated in our pathology department between 2002 and 2009 were retrospectively reviewed. Specimens with hepatic granulomas were reexamined by a designated pathologist. Type and localization of granulomas, size of granulomas and epithelioid histiocytes, and the morphological findings of surrounding liver tissue were recorded in an attempt to establish a correlation with relevant clinical, laboratory and radiological findings.Out of 1420 liver biopsy/resected specimens evaluated at our institution during the study period, 86 cases of epithelioid cell granulomas (6.05%) were observed. Of the 86 cases, 23 were men and 63 were women. The most common underlying etiology was PBC in 38 patients, infections in 34, malignancies in five, sarcoidosis in four, and foreign bodies in three patients. One case (1.2%) of a drug-induced hepatic granuloma was encountered, while another case was deemed idiopathic (of unknown etiology). Contrary to common belief, granulomas were observed not only in early stage PBC but also in cases with stage 3 disease. Out of all the PBC cases with granulomas, 55.6% had stage 3 disease, and besides periductal granulomas, intraacinar granulomas were also seen. For sarcoidosis, intra- and peri-granulomatous fibrosis was observed in as many as 75% of cases. A large majority of granulomas (82.4%) associated with infections were of the necrotizing type.Extensive evaluation of the morphological characteristics of hepatic granulomas and surrounding liver tissue along with clinical, radiological, and other laboratory findings may help arrive at an accurate diagnosis in a majority of cases. Rather than being a final diagnosis, the presence of hepatic granulomas entails the need for further investigations towards identifying the underlying etiology, with a pathologist being at the center of the diagnostic process.     

Hepatic pathology of chronic granulomatous disease of childhood.

We reviewed the hepatic pathology of seven cases of chronic granulomatous disease of childhood. All patients were male, with an age range of 5 to 41 years. Hepatic biopsy with drainage or wedge resection was performed in five cases to remove abscesses. Autopsy was performed in three cases. Presentation was typical of infection (fever, leukocytosis) with an elevated serum alkaline phosphatase level. Histologically, the most consistent feature was the presence of foamy macrophages that contained a finely granular golden brown pigment, seen in all seven cases. These were present as small collections predominantly in the portal tracts but were also found in the lobules. Palisading granulomas with central necrosis and associated giant cells were seen in four cases, one of which also had occasional lobular epithelioid granulomas. One case showed hyalinized portal and lobular granulomas. Four cases that showed palisading granulomas cultured positive for Staphylococcus aureus. One case cultured Pseudomonas cepacia, and one case cultured Streptococcus intermedius. Although palisading granulomas are typical of chronic granulomatous disease, they are not seen in all cases. These granulomas are similar to granulomas that are seen with Candida and other fungal infections and therefore are not specific for chronic granulomatous disease of childhood. The pigmented macrophages appear to be a consequence of the primary defect of the disease and are not secondary to infection and associated inflammation.     

The pathologic spectrum of gastrointestinal and hepatic histoplasmosis

We characterized the pathologic spectrum of lesions in gastrointestinal and hepatic histoplasmosis by studying cases of disseminated disease in immunocompromised and immunocompetent patients from endemic and nonendemic areas. We evaluated 56 specimens from 52 patients with H&E and silver stains. Of these patients, 43% presented with gastrointestinal rather than pulmonary symptoms. Thirty-one percent had gastrointestinal lesions, 10% had liver lesions, and 43% had both. Gross gastrointestinal features included ulcers (49% of patients), nodules (21%), hemorrhage (13%), obstructive masses (6%) and normal mucosa (23%). Microscopic gastrointestinal findings included diffuse lymphohistiocytic infiltration (83%), ulceration (45%), lymphohistiocytic nodules (25%), or minimal inflammatory reaction (15%) but only rare well-formed granulomas (8.5%). The most common hepatic finding was portal lymphohistiocytic inflammation; discrete hepatic granulomas were seen in less than 20% of involved livers. The pathologist must be aware of the broad range of gastrointestinal and hepatic lesions produced by histoplasmosis and, in particular, that well-formed granulomas are rare. Given the appropriate clinical context, histoplasmosis should be considered in both immunocompetent and immunocompromised patients, regardless of pulmonary symptoms, in nonendemic as well as endemic areas.     

Rickettsia conorii isolated fromRhipicephalus sanguineus introduced into Switzerland on a pet dog

A tick/rickettsial survey in a household near Geneva, Switzerland, revealed that 30 (40%) of 75 nymphs and adults of the brown dog tick,Rhipicephalus sanguineus, were infected with a rickettsial agent biologically and antigenically indistinguishable fromR. conorii, the causative agent of boutonneuse fever. Introduced in 1976 from either southern France of Italy by the family's pet dog, the tick infestation had steadily increased until 1981 when control measures were initiated. During 1980 and 1981, four persons associated with the household's pet dog contracted a febrile illness diagnosed as boutonneuse fever.     

Pathogenesis of rickettsial eschars: The tache noire of boutonneuse fever

Prospective investigation of cutaneous lesions of 24 Sicilian patients revealed that 17 were taches noires from patients with a documented diagnosis of boutonneuse fever. Immunofluorescent Rickettsia conorii were demonstrated in 14 of 17 taches noires. The major pathologic lesions observed were a moderate-to-severe lymphohistiocytic vasculitis (17 of 17 cases), generally moderate dermal edema (17 of 17 cases), and cutaneous necrosis (12 of 16 cases). In contrast with previous observations of eschars in Rocky Mountain spotted fever, thrombosis was usually absent (nine of 17 cases) or inconsequential (five of 17 cases). Thus, it appears that the pathogenic mechanism of the ischemic necrosis is not thrombosis, suggesting either compression of the microcirculation by the dermal edema or another mechanism. Review of the biomedical literature related to eschars and cutaneous arthropod bites strongly argues against a pathogenetic contribution of the tick bite itself other than the intradermal inoculation of rickettsiae. The tache noire offers an excellent, accessible model for the study of the human-rickettsia interaction, including the pathogenic mechanisms leading to necrosis and the immune mechanisms resulting in killing the rickettsiae.     

Hepatic granulomas: a 10 year single centre experience

BACKGROUND: Epithelioid granulomas have been reported in 2-15% of unselected liver biopsies, with numerous underlying aetiologies described. However, all UK series were reported before identification of hepatitis C virus (HCV). AIM: To evaluate the current aetiologies of hepatic granulomas and to assess the prognosis for the "idiopathic" group, in which all investigations for a recognised cause were negative or normal. METHODS: A retrospective review of patient case notes between 1991 and 2001; all patients who had a liver biopsy at Glasgow Royal Infirmary revealing epithelioid granulomas had their case notes and liver biopsies reviewed and a standard proforma completed. RESULTS: Over the study period, 1662 liver biopsies were performed. Hepatic granulomas were found in 63. Of those identified, 47 were female, with a mean age of 42 years (range, 17-81). Underlying aetiologies were as follows: primary biliary cirrhosis (PBC; 23.8%), sarcoidosis (11.1%), idiopathic (11.1%), drug induced (9.5%), HCV (9.5%), PBC/autoimmune hepatitis (AIH) overlap (6.3%), Hodgkin lymphoma (6.3%), AIH (4.8%), tuberculosis (4.8%), resolving biliary obstruction (3.2%), and other single miscellaneous causes (9.5%). Of the seven patients with idiopathic hepatic granulomas, one was lost to follow up, one died of stroke, and the remaining five were well with no liver related morbidity at a mean follow up of 6.2 years. CONCLUSIONS: The aetiology of hepatic granulomas is broad ranging, with HCV an important cause in this population. Despite extensive investigations, a 10-15% of patients still had "idiopathic" hepatic granulomas. However, the prognosis for this last group appears to be excellent.     

Granulomatous gastritis: a morphological and diagnostic approach

The final diagnosis of granulomatous gastritis is based on morphological findings and clinical and laboratory data. Detailed analysis of the morphological features of the granulomas together with associated mucosal changes could generate more information on aetiology and pathogenesis. Biopsies from 71 patients diagnosed as having granulomatous gastritis were reviewed. Thirty-seven of these patients (52%) had Crohn's disease. In 18 patients (25%) an isolated granulomatous gastritis was diagnosed. In seven patients (10%) the final diagnosis was a foreign body reaction. Of the remaining cases, four (7%) corresponded to tumour-associated granulomas and one case each of sarcoidosis (1%), Whipple's disease (1%) and vasculitis-associated disease (1%). Two cases (3%) were unclassifiable. The granulomas were mainly found in the antrum (64% antrum only, 11% antrum and corpus, 6% transitional mucosa corpus-antrum). Granulomas were usually small. This was particularly true for those found in patients with Crohn's disease. Multiple granulomas were observed in the sarcoidosis, the Whipple's disease and vasculitis-associated cases. A pattern of chronic gastritis with atrophy was present in 95% of the biopsies (68/71 patients). Helicobacter pylori was detected in 92% of the biopsies (64/71 patients).     

Infection of genetically immunodeficient mice with Rickettsia conorii

In order to determine the definitive importance of T- and B-lymphocytes in immunity to Rickettsia conorii, mice genetically deficient in T-cells, B-cells, or both T- and B-cells were infected experimentally. T-lymphocytes rather than humoral antibodies were crucial to rickettsial clearance and a reduced mortality rate. Mice incapable of an antibody response to polysaccharide capsular antigens effectively controlled rickettsial infection with no mortality. In contrast, nude mice produced antibody to thymus-independent antigens early in the course of infection, yet experienced severe rickettsial infection resulting in deaths. The observed hepatic lesions are similar to those of boutonneuse fever. This model offers the opportunity to investigate rickettsial immune mechanisms and hepatic injury.     

GRANULOMAS AND HEPATITIS C

Hepatitis C (HCV) is associated with a number of characteristic histological features.. A recent paper has identified an increased frequency of granulomas in resection specimens from cases of HCV. We have carried out a retrospective study of 155 cases of HCV to assess the frequency of granulomas in biopsy specimens. We had two control groups: 151 cases of hepatitis B (HBV) and 129 cases of alcohol induced liver disease. Granulomas were found in 14 cases of HCV (10%), three cases of HBV (2%) and three cases of alcohol induced liver disease (2%). Granulomas were significantly commoner in cases of HCV than in the other two groups. Of the 14 cases of HCV, the granulomas could be ascribed to another cause in seven cases. When the analysis was carried out, excluding those granulomas which could be ascribed to another cause, they were still significantly commoner in cases of HCV. We conclude that granulomas are more frequent in HCV but that in half of cases in which they are found another cause can be identified. This means that if granulomas are seen in association with hepatitis C another aetiology should be sought before ascribing them to HCV.     

Toxoplasmosis in cord blood transplantation recipients

Toxoplasmosis is a devastating opportunistic infection that can affect immunocompromised patients such as cord blood transplantation (CBT) recipients. The clinical characteristics of 4 toxoplasmosis CBT patients treated at our institution are reviewed, together with 5 cases collected from the literature. The rate of toxoplasmosis in our hospital was 6% in CBT recipients and 0.2% in other types of allogeneic hematopoietic stem cell transplantation (P?相似文献   

Cytologic diagnosis of cat scratch disease (CSD) by fine-needle aspiration

Cat scratch disease (CSD) is usually a benign, self-limited lymphadenitis, characterized by suppurative granulomas. It can, however, produce a wide spectrum of clinical symptoms and cytologic changes and be the source of diagnostic dilemmas. Identification of pleomorphic bacilli (PB) with silver impregnation stains aids in the diagnosis, but this has not been well documented in cytologic preparations or in cases without the classic morphologic changes. We reviewed 13 aspirations from eight patients (aged 13–36 yr) occurring over a 15 mo time period, all clinically or cytologically suspicious for CSD. Sites included: axilla (6), parotid (3), epitrochlear (1), neck (1), submental (1), and intraclavicular (1) nodes. Neoplasia was initially suspected clinically in 38% of the cases. All but two patients had cat exposure on subsequent interview. The cytologic differential included bacterial abscess and lymphoproliferative disorders in 31%. Neither granulomas nor suppurative inflammation were seen in all cases. Changes included: granulomas (77%), PMNs (62%), dispersed epithelioid histiocytes (46%), and suppurative granulomas (38%). A modified silver stain (Modified Steiner, Sigma Diagnostics, St. Louis, MO) was performed on all specimens. Silver positive organisms were seen in 69% of cases and were not limited to those preparations with suppurative granulomas. Fine-needle aspiration biopsy (FNAB) is an effective method for diagnosing CSD despite its heterogeneous appearance; and, when combined with clinical information and silver staining, may obviate the need for excision. © 1995 Wiley-Liss, Inc.     

A recombinant Rickettsia conorii vaccine protects guinea pigs from experimental boutonneuse fever and Rocky Mountain spotted fever.

There are no vaccines against boutonneuse fever and Rocky Mountain spotted fever. Previous studies have identified a Rickettsia rickettsii surface protein as a vaccine candidate and shown that an antigenically related protein is present in R. conorii, which causes boutonneuse fever. The gene encoding the R. rickettsii protein has been cloned and expressed in Escherichia coli. We confirmed by 7.5% sodium dodecyl sulfate-polyacrylamide gel electrophoresis of rickettsial lysates followed by immunoblotting with a monoclonal antibody raised against the R. rickettsii protein that an analogous protein exists in R. conorii. Although these proteins were previously called 155-kilodalton (kDa) proteins, we found that their apparent molecular masses were 198 kDa for R. conorii Kenya tick typhus and 190 kDa for R. rickettsii R. Using the R. rickettsii gene probe, we cloned and expressed a 5.5-kilobase HindIII fragment from R. conorii Kenya tick typhus genomic DNA in E. coli JM107. The expressed recombinant product was recognized by a monospecific polyclonal rabbit antiserum prepared against the 198-kDa protein. Guinea pigs immunized with sonic lysates of the E. coli strain expressing the recombinant gene product developed antibodies recognizing R. conorii when tested by a microimmunofluorescence antibody assay. Upon immunoblotting of rickettsial lysates, those antisera specifically recognized the 198-kDa R. conorii protein and its 190-kDa analog in R. rickettsii. Guinea pigs immunized with sonic lysates of the recombinant E. coli expressing the 198-kDa protein were protected from experimental infections with the homologous R. conorii strain and partially protected from experimental infections with a strain of the heterologous species R. rickettsii. These findings show that the 198-kDa R. conorii protein is a candidate for a vaccine against boutonneuse fever.     

Value of PCR for evaluating occurrence of parasitemia in immunocompromised patients with cerebral and extracerebral toxoplasmosis.

PCR was used to evaluate the occurrence of Toxoplasma gondii parasitemia by detection of the B1 gene in blood samples in two groups of immunosuppressed patients (148 subjects) suspected of having cerebral or extracerebral infection, respectively. Group I consisted of 52 patients with AIDS with suspected cerebral toxoplasmosis. The diagnosis was clinically proven in 15 cases. Parasitemia was detected by PCR in only two of these patients (13.3%), both showing evidence of disseminated infection. Group II consisted of 96 immunocompromised patients, either with AIDS or receiving iatrogenic immunosuppressive therapy. Of these patients, 65 (34 with AIDS and 31 others) showed abnormalities only in chest radiography and were first screened for the presence of Toxoplasma DNA in bronchoalveolar lavage fluid. Blood was then analyzed when the parasite was detected in the bronchoalveolar lavage fluid. The remaining 31 subjects (22 with AIDS and 9 others) were suspected of having extracerebral, pulmonary, or disseminated toxoplasmosis, and blood was studied directly in these cases. Among the nine patients with clinically diagnosed extracerebral infection in group II, the parasite was detected by PCR in the blood of five patients (55.5%), all having pulmonary toxoplasmosis. If all patients with clinical manifestations of extracerebral toxoplasmosis (from both groups) who had not received antitoxoplasma therapy when the samples were collected are considered, PCR detected parasitemia in seven of the nine cases (77.8%). The present study indicates that examination of blood by PCR may be valuable in cases of extracerebral toxoplasmosis because of the disseminated nature of the disease. Since most cases of cerebral toxoplasmosis result from the local reactivation of latent brain cysts, detection of parasitemia by PCR is useful only in cases associated with severe cerebral infection or dissemination of this disease.     

Bone marrow examination for the diagnosis of mycobacterial and fungal infections in the acquired immunodeficiency syndrome.

In a series of 342 bone marrow examinations from 314 patients with human immunodeficiency virus infection, 70 examinations (20%) detected opportunistic mycobacterial or fungal infections. One hundred eleven of the 314 patients had such infections, and, hence, 63% (70/111) were detected by bone marrow examination. Special stains for microorganisms detected 16 (32%) of 50 Mycobacterium avium complex infections, 10 (22%) of 45 Mycobacterium tuberculosis infections, eight (73%) of 11 Histoplasma capsulatum infections, and five (83%) of six Cryptococcus neoformans infections. Bone marrow cultures detected 36 (72%) of the 50 M avium complex infections, 13 (29%) of the 45 M tuberculosis infections, and 63% of the fungal infections. Marrow examination revealed infection in only one of the 70 specimens (1%) collected to evaluate thrombocytopenia alone or hematologic malignancy, but in 69 (25%) of 274 with fever, neutropenia, anemia, or miscellaneous other indications for marrow examination. Granulomas were detected in 102 (30%) of the biopsy specimens, including 71 (64%) of those in cases with mycobacterial or fungal infection. The granulomas showed caseous necrosis in nine cases, all in patients with tuberculosis, and the 27 cases with tuberculosis-associated granulomas tended to show large, tightly cohesive granulomas. The presence of granulomas correlated with opportunistic infection in 82 (80%) of 102 cases. Without granulomas, special stains were positive in only eight (3%) of 240 specimens. These results suggest that (1) bone marrow granulomas are a common and valuable histologic clue to opportunistic infection; (2) without them, special stains may not be a cost-efficient way to diagnose such infection; and (3) bone marrow examination can be a useful method of diagnosing opportunistic mycobacterial and fungal infections in patients with fever, anemia or neutropenia, and underlying human immunodeficiency virus infection.     

Isolated hepatic involvement of cat scratch disease in immunocompetent adults: Enhanced magnetic resonance imaging, pathological findings, and molecular analysis--two cases

Visceral involvement in absence of lymphadenopathy is a rare manifestation in cat scratch disease; hepatic granulomas are rare, representing 0.3% of systemic manifestations of cat scratch disease, and gallbladder extension is a singular case. The present article refers to 2 rare cases of visceral cat scratch disease in immunocompetent adults with hepatic granulomatous inflammation, caused by Bartonella henselae infection, with gallbladder involvement in 1 case and no lymphadenopathy. Histological features demonstrated the presence of inflammatory necrotizing granulomatous nonneoplastic process. Molecular studies (polymerase chain reaction) were performed to confirm the infectious etiology.     

Bone marrow pathology of culture proven typhoid fever.

The authors analysed bone marrow findings of sixteen cases of culture proven typhoid fever to reveal the pathologic changes according to the disease stage. The most frequent finding was chronic granulomatous inflammation (eight cases). Infection (bacteria) associated hemophagocytic syndrome (four cases), reactive marrow (two cases), and non specific findings (two cases) were also encountered. Granulocytic hyperplasia with hemophagocytosis appeared at the early stage and was followed by infection (bacteria) associated hemophagocytosis and granuloma in proliferative stage. In lysis (late) stage, granulomatous inflammation was noted. However, resolution of granulomatous inflammation was not distinct. Some nuclear debris and phagocytosis were remarkable in well-formed granulomas. Thrombocytopenia was the most remarkable peripheral blood finding at the time of biopsy. Anemia, leukopenia, and pancytopenia were also observed in descending order.     

Autopsy cases of miliary tuberculosis: clinicopathologic features including background factors

To assist physicians, especially young physicians, in identifying tuberculosis (TB) infection before the terminal stage, we analyzed 7 cases of numerous tuberculous granulomas in multiple organs and compared clinical and autopsy findings between cases. Patients ranged in age from 41 to 86 years at the time of death. The main chief complaint was fever of unknown origin (3 of 7 cases [43%]). The main underlying conditions were liver cirrhosis (2 of 7 cases [29%]) and chronic renal failure (2 of 7 cases [29%]). Two patients (29%) had been given methylprednisolone pulse therapy for various lung disorders. Active TB was not diagnosed before autopsy in 4 of 7 (57%) patients. Calcified lesions indicative of old TB were present in 4 of 7 (57%) patients. Thus, miliary tuberculosis may represent a re-emergence of latent TB infection in these cases. Various histologic features of nonreactive exudative inflammation were seen, along with granulomas containing Langhans giant cells with or without caseous necrosis in hypervascular organs, such as the lung, liver, and bone marrow. Physicians should be mindful of the possibility of miliary TB when older patients with hepatorenal disease and a history of TB infection have undergone immunosuppressive treatment. Active tuberculous infection can depend on the presence of an underlying disease and immunocompromise.