864
SELECTED
SUMMARIES
patients initially were thought to have sporadic non-A, non-B hepatitis; 5 were thought to have autoimmune chronic hepatitis. Five patients died; 5 survived following liver transplantation. Examination of liver tissue in each instance showed the presence of syncytial multinucleated giant cells replacing hepatocyte cords, most prominently in the centrilobular region, as well as the usual findings of severe acute and chronic hepatitis-bridging or linear necrosis of hepatocytes, ballooning and dropout of hepatocytes, cholestasis, and small round cell inflammation within the lobule and in the portal and periportal spaces. Ultrastructural studies showed the presence of virus-like structures within the giant cells, including those resembling the nucleocapsids of paramyxoviruses in 8 of the 10 liver specimens examined. The inoculation of liver homogenate from one patient into two chimpanzees failed to induce biochemical or histological evidence of hepatitis. However, in one animal an increase in the titer of antibodies to measles virus and parainfluenza 4 was found. No paramyxoviral antigens could be detected in the homogenate, and no agent could be identified following inoculation of cell cultures with the homogenate. The authors suggest that syncytial giant cell hepatitis is a severe manifestation of a paramyxovirus infection. Comment. Identified paramyxoviruses pathogenic for human beings include the parainfluenza viruses, mumps and measles viruses, and the respiratory syncytial virus. They are antigenically stable RNA viruses with defined nucleocapsids and envelopes. Compared with the known agents of human hepatitis (HAV, HBV, HCV, HDV, and HEV), the paramyxoviruses are considerably larger agents and only the measles virus has been causally linked to hepatitis, albeit infrequently. Nothing warms the liver of an older hepatologist more than does the notion that a new form of viral hepatitis has been recognized. Hepatitis associated with measles is an old and familiar but uncommon friend: hepatitis associated with an unknown paramyxovirus is a new and exciting concept. This is especially the case when the clinical disease is far from trivial and presents as chronic hepatitis with features of autoimmune disease, including hemolytic anemia. The syncytial multinucleated giant cell hepatitis described here certainly meets the criterion of seriousness. Half of the patients died and half required liver transplantation. Despite the fascinating and brilliant virologic work undertaken to define the pathogenesis of this syndrome, the current report leaves a number of questions unanswered. Is there direct evidence that this syncytial giant cell hepatic disease is viral in etiology? Are syncytial giant cells, formed by the fusion of hepatocytes, a pathological feature specific for paramyxovirus infection? If so, does this lead to an implication that all syncytial giant hepatocytes might reflect paramyxovirus infections? If so, is there evidence for paramyxovirus infection in biliary atresia or in neonatal hepatitis or the hepatitis syndromes seen in infancy, which may be accompanied by giant hepatocyte formation? Although viral-like particles are described in the hepatocytes of these patients with sporadic syncytial giant cell hepatitis, and certainly these appear to resemble particles associated with paramyxoviruses, the responsible virus has yet to be isolated from the liver of affected patients, and, as indicated by the authors, no evidence of hepatitis was obtained following inoculation of chimpanzees with liver homogenate from an index patient. If viable virus was not present in the liver homogenate, could this reflect inactivation of the agent during preservation, as suggested by the authors, or was the virus absent in a replicating form in vivo? Finally, are these cases truly sporadic, or might there have been
GASTROENTEROLOGY
Vol. 101, No. 3
some clustering in time or geography? Were the families and household contacts of these patients studied? Did any have evidence of hepatocellular dysfunction or serological evidence of recent paramyxovirus infection? Is this giant cell hepatitis peculiar to Canada? How common is this disorder in adolescent or adult populations outside of Canada? In studies of more than 160 patients with chronic hepatitis in greater Boston, I failed to detect a single case with giant cell changes. Hence, this new form of hepatitis may be very uncommon. Whether it will remain uncommon is uncertain. Increased clinical and pathological vigilance, as well as surveys of hepatic transplantation centers, will be needed to define the overall importance of this disorder. R. S. KOFF, M.D.
Reply. Dr. Koff raises many important and interesting questions. We appreciate his comments and can respond by saying that we have asked most of the same questions ourselves. However, as with any initial report on a newly recognized entity, not all the ramifications of the condition are immediately or fully understood. Despite this, it was deemed worthwhile to publish these results in the hope that hepatologists and pathologists would be on the alert for this entity. Several of the questions raised can be very briefly answered: others will require further investigations. The giant cells seen in neonatal hepatitis and biliary atresia are smaller and have different morphology, and viral particles of the type described here have not been reported. It can also be stated that not all hepatic disorders with syncytial giant cells are necessarily of paramyxoviral etiology; we have examined a number of cases in which the failure to find paramyxoviruses in the giant cells has left us with an open mind on these cases. It is highly possible that other viruses might form membrane fusion between hepatocytes. The reviewer is correct that as regards paramyxoviral etiology, not all Koch’s postulates were fulfilled. We have no difficulty in asserting that the particles described are viral and are causally related to the cell fusion and to the hepatocellular necrosis; what is in doubt is the taxonomy of the virus. A paramyxovirus is considered a good candidate because of the electron microscopic features and because of the marked tendency to cause cell fusion; members of Sendai group of paramyxoviruses are commonly used by molecular biologists specifically for their propensity to cause cell fusion. The disease is not restricted to Canada; one of the patients in the study was from the Bahamas. We have also examined identical cases from Scotland, and the patient from Switzerland described by Spichtin et al. (Liver 1982;2:355-360) is now considered by Gudet and Bianchi to be an example of this entity (personal communication). The authors have also learned of a recent case in Philadelphia (personal communication). The disease may be uncommon but is probably not rare; in one of our cases with fulminant hepatitis, the needle biopsy showed few syncytial cells because most of the liver was necrotic. At present, the only way to make a definitive diagnosis of this type of hepatitis is to find syncytial giant cells containing the viral particles described. We agree completely that increased clinical and pathological vigilance and surveys of other liver centers are needed. M. J. PHILLIPS, M.D. L. M. BLENDIS, M.D.
PELIOSIS HEPATIS: OLD DISEASE, NEW CAUSE Relman DA, Loutit JS, Schmidt
TM, et al. (Department of Microbiology and Immunology and Division of Infectious Diseases, Stanford University, Stanford, California; Department of Biology, Indiana University, Bloomington, Indiana].
SELECTEDSUMMARIES 865
September 1991
The agent of bacillary angiomatosis. 1573-1580 [December 6).
N Engl J Med 1990;323:
Perkocha LA, Geaghan SM, Yen TSB, et al. [Departments of Pathology, Laboratory Medicine, and Dermatology, University of California, San Francisco, California; Departments of Internal Medicine and Pathology, Mount Zion Hospital, University of California, San Francisco, California; Department of Pathology, Pacific-Presbyterian Medical Center, San Francisco, California; Institute for Forensic Sciences, Oakland, California). Clinical and pathologic features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. N Engl J Med 1990;323:15811586 (December 6). These two reports investigate a novel bacillus that appears to be associated with both peliosis hepatis and bacillary angiomatosis in immunocompromised patients, primarily those infected with the human immunodeficiency virus (HIV). Bacillary angiomatosis is a recently described condition of prominent vascular proliferation in the skin and visceral organs of immunocompromised patients. It is felt to be infectious in nature because the lesions consistently contain clusters of bacilli on Warthin-Starry staining and because the lesions often appear to resolve with antibiotics. Attempts to culture the responsible organism, however, have been unsuccessful. In the methods ism,
first
report,
to obtain
concluding
closely
the
that
related
authors
genotypic it
to the
used
recently
information is
previously
rickettsialike
developed
about
the
organ-
undescribed
organism
and
Rochalimaea
quintana. All cells, including eubacteria, contain copies of a gene encoding a 16s subunit of ribosomal RNA (rRNA). Some segments of the gene (16s rDNA) are highly conserved, while other segments are highly variable. In theory, this variability allows the establishment of phylogenetic relations. The authors were able to amplify the 16s rDNA directly from tissue specimens from four patients with bacillary angiomatosis using the polymerase chain reaction (PCR). They were then able to sequence the DNA that was most likely from eubacteria within the specimen, presumably the causative bacilli. The 241 base pair fragments obtained were identical in three of four patients, differed in the fourth by four base pairs, and were not found in the spleen of a patient with idiopathic thrombocytopenia purpura. Comparison of the sequence with known DNA sequence data files suggested the segment could be aligned with other 16s rRNA eubacteria genes but was not identical to any. The new organism represented by the sequence was designated strain BA-TF and was most similar to the rickettsialike organism I?. quintana, with which it shared 98.3% sequence similarity. In the
second
report,
histological
evidence
is provided
HIV results from opportunistic infection with a bacillus and that this bacillus is probably the same as the one implicated in bacillary angiomatosis. The authors used histological staining and electron microscopy to examine liver tissue from eight patients with peliosis hepatis and HIV infection, two of whom also had bacillary angiomatosis, and from four patients with peliosis hepatis without HIV infection. All of that
peliosis
hepatis
in patients
infected
with
the HIV-infected patients had hepatomegaly, and 6 had splenomegaly. Most had normal or slightly elevated bilirubin levels, normal to moderate elevations of transaminase levels (average, two times normal), and more marked elevations of alkaline phosphatase and y-glutamyl transferase levels [average, five times normal). Liver tissue from the 8 patients showed a spectrum of changes, but all had dilated blood-filled spaces separated from normal liver cells by varying amounts of a fibromyxoid stroma. In all patients, Warthin-Starry staining showed clumps of rod-shaped bacilli within this fibromyxoid stroma. Similar clumps of bacilli were also seen in the peliotic spleens of two of the patients, in angiomatous lymph nodes of two patients, and in the skin lesions of the two patients with bacillary angiomatosis. One of the patients with bacillary angiomatosis had bacilli in his skin lesions, lymph node, liver, and spleen. The fibromyxoid stroma and bacilli were not seen in the four patients with peliosis hepatis without HIV infection. Electron microscopy done on two of the patients confirmed that that the rod-shaped organisms seen with Warthin-Starry staining were indeed bacilli. The bacteria was similar to the bacillus of cat scratch fever in size, staining characteristics, and ultrastructural appearance. The bacteria did not grow on cultures of liver biopsy tissue. Four patients were identified as having bacillary peliosis at the time of biopsy and were treated with erythromycin. Two died of intercurrent medical problems, but the remaining two had resolution of fever and hepatosplenomegaly and improvement in liver enzyme levels. One patient also with bacillary angiomatosis also had resolution of the skin lesions. Comment. Peliosis fested by blood-filled
hepatis is an unusual liver condition manicavities not lined by endothelial cells, often
accompanied by sinusoidal dilatation, that most physicians, even gastroenterologists, rarely encounter. It is most commonly thought of as occurring in patients treated with anabolic steroids (Ann Intern Med 1974;81:610-618) but has been associated with a variety
of other
medications
and conditions.
Most relevant
to this
discussion, infections such as pulmonary tuberculosis (Am J Path01 1950;26:1-151, bacterial liver abscess (Digestion 1988;41:55-60), and cytomegalovirus (Transplant Proc 1987;19:3697-3698) have been seen in association with peliosis hepatis. In these conditions, however, the pathogenetic relationship between the infectious agent and the histological findings has not been clearly understood. Peliosis hepatis has been recognized in patients with HIV infection in reports (Arch Path01 Lab Med 1986;110:611-613; Am J Path01 1988;131:38-47) over the past several years, but the pathogenesis in this subset
of patients
has not been understood
either.
Peliosis hepatis must now be added to the differential diagnosis in patients with HIV infection who develop liver disease. This consideration is particularly important because the peliosis may be responsive to antibiotic therapy but, left untreated, may be rapidly fatal. The diagnosis is not especially difficult once one’s index of suspicion is raised; all patients had hepatomegaly, characteristic histological findings of peliosis, and positive Warthin-Starry staining for rod-shaped bacteria in the fibromyxoid areas of the liver. Liver biopsy cultures were not at all helpful in diagnosing this condition. Although erythromycin seems to have had a clear clinical effect in two of the patients, further experience will need to be garnered with its use in this condition. Erythromycin also seems to be effective in the treatment of cutaneous bacillary angiomatosis
866
SELECTED
[AnnInternMed is not surprising This perceptive
SUMMARIES
GASTROENTEROLOGY
1988;109:449_455;Lancet because the causative piece of clinical
1988;1:960-963), which agent is probably the same.
detective
work by Perkocha
et al.
is complemented by the discovery by Relman et al. that the causative agent for cutaneous bacillary angiomatosis and probably peliosis hepatis in association with HIV infection is a previously uncharacterized quintana. Using
Rickettsia-like the polymerase
organism, closely related chain reaction, sequences
to R. of the
16s rRNA gene can be amplified and compared with a reference sequence data base to construct phylogenetic trees. R. quintana is the cause of trench fever characterized by fever, rash, splenomegaly, and bone and muscle pain: this organism is sensitive to erythromycin and the tetracyclines (Antimicrob Agents Chemother 1984;25:690-693). Bartonella bocilliformis is another member of the order Rickeftsiales and can result in skin lesions very similar to bacillary angiomatosis (Annu Rev Microbial 1981;35:325-338). Because there are no 16s rRNA sequences available for B. bacilliformis yet, cannot be disease has those of the
its relationship to the agent of bacillary angiomatosis ascertained. The bacillus responsible for cat scratch some characteristics (Lancet 1988;1:960-963) similar to organism of bacillary angiomatosis, but the former has
not yet been clearly characterized. The organism responsible for cat scratch disease is currently being investigated by Relman et al. using this same 16s rRNA technique, and when this is accomplished its relationship to the agent of bacillary angiomatosis will be better understood. The powerful techniques used for identification of the organism of bacillary angiomatosis could serve as a paradigm for the characterization of other uncultured organisms in the future. These methods allow genotypic comparisons between organisms instead of the traditional phenotypic comparisons that have been used for many years (N Engl J Med 1991;323:1625-1627). The usefulness of these new techniques to clinical medicine will hopefully become evident over the next decades as more hitherto baffling diseases reveal themselves to more sophisticated molecular-level probes. P. F. MALET, MD. II. MOONKA, MD. Reply. Studies on the composition of environmental microbial communities have demonstrated that reliance on microbial growth in the laboratory may lead to a biased picture (Nature 1990;345:6063; Nature 1990;345:63-65). This finding may have relevance to our understanding of human pathogen diversity. This bias may be avoided by directly amplifying 16s rRNA sequences from relevant human tissue samples with broad-range polymerase chain reaction primers, and the spectrum of known pathogens may be expanded. The agent of bacillary angiomatosis (BA-TF) may be the first of many new human pathogens identified in this manner (N Engl J Med 1990;323:1573-1580). Work is currently underway to identify the causative agents of cat scratch disease and Whipple’s disease. Further characterization of BA-TF now suggests that it is highly related to Bartonella bacilliformis, as well as to Rochalimaea quintana (Relman DA, Falkow S, Schmidt TM, manuscript in preparation). The entire 16s rRNA genes from these three organisms have been amplified and cloned. The exact relationships among these different a-purple eubacteria must await completed analysis of their 16s rRNA gene sequences. At the time we reported the identification of the agent of bacillary angiomatosis (BA-TF) (NEngl J Med 1990;323:1573-1580) we were unaware of work by Slater et al. (N Engl J Med 1990;323:15871593) who had isolated a fastidious bacillus from the blood of some patients with persistent fever. A liver biopsy specimen from one of these patients (patient 1) subsequently revealed bacillary peliosis hepatis (NEngl JMed 1999;323:1581-1586). Since the time of these reports, we have determined partial 16SrRNA sequence from this patient’s blood isolate. The results suggest that this organism is the
Vol. 101, No. 3
as or highly related to BA-TF [N Engl J Med 1991;324 (in press)]. These findings further suggest that the same organism may cause bacillary angiomatosis, bacillary peliosis hepatis, and persistent fever in some patients. The application of our molecular technique to other tissue samples from patients with bacillary peliosis hepatis will be necessary to confirm these results. However, it seems that the full spectrum of human disease attributable to this organism remains to be defined. same
D. A. RELMAN, M.D.
A BIOPSYCHOSOCIAL MODEL FOR FUNCTIONAL DYSPEPSIA Hui W, Shiu LP, Lam SK (University Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong]. The perception of life events and daily stress in nonulcer dyspepsia. Am J Gastroenterol 1991;86:292-296 (March). The association of dyspepsia of unknown cause (functional dyspepsia) and stress in life is often suggested, but so far, inconsistent results have been reported. Methodological problems may be at fault because most studies have emphasized the number of major life events but have neglected the fact that the severity of an event depends on the way the person perceives it. Therefore, an accurate assessment of life stresses should include an individual’s rating of the impact and desirability of the events. The present study examined the perception of major life events and, in addition, the role of daily “hassles” (annoying daily events) in patients with functional dyspepsia. Thirty-three consecutive patients were identified who complained of epigastric pain, nausea, vomiting, and belching without evidence of peptic ulcer disease or gallstones as defined by normal endoscopy and ultrasonography. Severity of dyspeptic symptoms was recorded and graded as mild (bothersome but not interfering with work), moderate (interfering with work and/or resulting in sick leave), or severe (requiring immediate medical care). Thirty-three healthy unpaid volunteers of comparable sex, age, and social class were recruited as the control group for this study. Both groups completed two self-report questionnaires translated into Chinese that could be finished within 15-20 minutes. The first part was the Life Experience Survey (LES), which listed 56 major life events such as marriage, death of a spouse, pregnancy, and retirement. Subjects were asked to circle those events experienced in the preceding 6 months and rate the desirability and severity of each circled event. The rating scale involved seven points ranging from -3 to +3. A negative sign indicated a negative impact of the event on the person’s life, whereas a positive sign indicated the converse. The number indicated the perceived magnitude of the impact, with 3 being the strongest. Five scores were derived from the LES: number of negative and number of positive events, magnitude of negative and magnitude of positive events, and life-change score obtained by adding the magnitude scores of negative and positive events together. The second part was a “hassles scale” designed to measure daily activities or events that were irritating, frustrating or distressing. For example, these included misplacing and losing things, not having enough time for
SELECTED
SUMMARIES
patients initially were thought to have sporadic non-A, non-B hepatitis; 5 were thought to have autoimmune chronic hepatitis. Five patients died; 5 survived following liver transplantation. Examination of liver tissue in each instance showed the presence of syncytial multinucleated giant cells replacing hepatocyte cords, most prominently in the centrilobular region, as well as the usual findings of severe acute and chronic hepatitis-bridging or linear necrosis of hepatocytes, ballooning and dropout of hepatocytes, cholestasis, and small round cell inflammation within the lobule and in the portal and periportal spaces. Ultrastructural studies showed the presence of virus-like structures within the giant cells, including those resembling the nucleocapsids of paramyxoviruses in 8 of the 10 liver specimens examined. The inoculation of liver homogenate from one patient into two chimpanzees failed to induce biochemical or histological evidence of hepatitis. However, in one animal an increase in the titer of antibodies to measles virus and parainfluenza 4 was found. No paramyxoviral antigens could be detected in the homogenate, and no agent could be identified following inoculation of cell cultures with the homogenate. The authors suggest that syncytial giant cell hepatitis is a severe manifestation of a paramyxovirus infection. Comment. Identified paramyxoviruses pathogenic for human beings include the parainfluenza viruses, mumps and measles viruses, and the respiratory syncytial virus. They are antigenically stable RNA viruses with defined nucleocapsids and envelopes. Compared with the known agents of human hepatitis (HAV, HBV, HCV, HDV, and HEV), the paramyxoviruses are considerably larger agents and only the measles virus has been causally linked to hepatitis, albeit infrequently. Nothing warms the liver of an older hepatologist more than does the notion that a new form of viral hepatitis has been recognized. Hepatitis associated with measles is an old and familiar but uncommon friend: hepatitis associated with an unknown paramyxovirus is a new and exciting concept. This is especially the case when the clinical disease is far from trivial and presents as chronic hepatitis with features of autoimmune disease, including hemolytic anemia. The syncytial multinucleated giant cell hepatitis described here certainly meets the criterion of seriousness. Half of the patients died and half required liver transplantation. Despite the fascinating and brilliant virologic work undertaken to define the pathogenesis of this syndrome, the current report leaves a number of questions unanswered. Is there direct evidence that this syncytial giant cell hepatic disease is viral in etiology? Are syncytial giant cells, formed by the fusion of hepatocytes, a pathological feature specific for paramyxovirus infection? If so, does this lead to an implication that all syncytial giant hepatocytes might reflect paramyxovirus infections? If so, is there evidence for paramyxovirus infection in biliary atresia or in neonatal hepatitis or the hepatitis syndromes seen in infancy, which may be accompanied by giant hepatocyte formation? Although viral-like particles are described in the hepatocytes of these patients with sporadic syncytial giant cell hepatitis, and certainly these appear to resemble particles associated with paramyxoviruses, the responsible virus has yet to be isolated from the liver of affected patients, and, as indicated by the authors, no evidence of hepatitis was obtained following inoculation of chimpanzees with liver homogenate from an index patient. If viable virus was not present in the liver homogenate, could this reflect inactivation of the agent during preservation, as suggested by the authors, or was the virus absent in a replicating form in vivo? Finally, are these cases truly sporadic, or might there have been
GASTROENTEROLOGY
Vol. 101, No. 3
some clustering in time or geography? Were the families and household contacts of these patients studied? Did any have evidence of hepatocellular dysfunction or serological evidence of recent paramyxovirus infection? Is this giant cell hepatitis peculiar to Canada? How common is this disorder in adolescent or adult populations outside of Canada? In studies of more than 160 patients with chronic hepatitis in greater Boston, I failed to detect a single case with giant cell changes. Hence, this new form of hepatitis may be very uncommon. Whether it will remain uncommon is uncertain. Increased clinical and pathological vigilance, as well as surveys of hepatic transplantation centers, will be needed to define the overall importance of this disorder. R. S. KOFF, M.D.
Reply. Dr. Koff raises many important and interesting questions. We appreciate his comments and can respond by saying that we have asked most of the same questions ourselves. However, as with any initial report on a newly recognized entity, not all the ramifications of the condition are immediately or fully understood. Despite this, it was deemed worthwhile to publish these results in the hope that hepatologists and pathologists would be on the alert for this entity. Several of the questions raised can be very briefly answered: others will require further investigations. The giant cells seen in neonatal hepatitis and biliary atresia are smaller and have different morphology, and viral particles of the type described here have not been reported. It can also be stated that not all hepatic disorders with syncytial giant cells are necessarily of paramyxoviral etiology; we have examined a number of cases in which the failure to find paramyxoviruses in the giant cells has left us with an open mind on these cases. It is highly possible that other viruses might form membrane fusion between hepatocytes. The reviewer is correct that as regards paramyxoviral etiology, not all Koch’s postulates were fulfilled. We have no difficulty in asserting that the particles described are viral and are causally related to the cell fusion and to the hepatocellular necrosis; what is in doubt is the taxonomy of the virus. A paramyxovirus is considered a good candidate because of the electron microscopic features and because of the marked tendency to cause cell fusion; members of Sendai group of paramyxoviruses are commonly used by molecular biologists specifically for their propensity to cause cell fusion. The disease is not restricted to Canada; one of the patients in the study was from the Bahamas. We have also examined identical cases from Scotland, and the patient from Switzerland described by Spichtin et al. (Liver 1982;2:355-360) is now considered by Gudet and Bianchi to be an example of this entity (personal communication). The authors have also learned of a recent case in Philadelphia (personal communication). The disease may be uncommon but is probably not rare; in one of our cases with fulminant hepatitis, the needle biopsy showed few syncytial cells because most of the liver was necrotic. At present, the only way to make a definitive diagnosis of this type of hepatitis is to find syncytial giant cells containing the viral particles described. We agree completely that increased clinical and pathological vigilance and surveys of other liver centers are needed. M. J. PHILLIPS, M.D. L. M. BLENDIS, M.D.
PELIOSIS HEPATIS: OLD DISEASE, NEW CAUSE Relman DA, Loutit JS, Schmidt
TM, et al. (Department of Microbiology and Immunology and Division of Infectious Diseases, Stanford University, Stanford, California; Department of Biology, Indiana University, Bloomington, Indiana].
SELECTEDSUMMARIES 865
September 1991
The agent of bacillary angiomatosis. 1573-1580 [December 6).
N Engl J Med 1990;323:
Perkocha LA, Geaghan SM, Yen TSB, et al. [Departments of Pathology, Laboratory Medicine, and Dermatology, University of California, San Francisco, California; Departments of Internal Medicine and Pathology, Mount Zion Hospital, University of California, San Francisco, California; Department of Pathology, Pacific-Presbyterian Medical Center, San Francisco, California; Institute for Forensic Sciences, Oakland, California). Clinical and pathologic features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. N Engl J Med 1990;323:15811586 (December 6). These two reports investigate a novel bacillus that appears to be associated with both peliosis hepatis and bacillary angiomatosis in immunocompromised patients, primarily those infected with the human immunodeficiency virus (HIV). Bacillary angiomatosis is a recently described condition of prominent vascular proliferation in the skin and visceral organs of immunocompromised patients. It is felt to be infectious in nature because the lesions consistently contain clusters of bacilli on Warthin-Starry staining and because the lesions often appear to resolve with antibiotics. Attempts to culture the responsible organism, however, have been unsuccessful. In the methods ism,
first
report,
to obtain
concluding
closely
the
that
related
authors
genotypic it
to the
used
recently
information is
previously
rickettsialike
developed
about
the
organ-
undescribed
organism
and
Rochalimaea
quintana. All cells, including eubacteria, contain copies of a gene encoding a 16s subunit of ribosomal RNA (rRNA). Some segments of the gene (16s rDNA) are highly conserved, while other segments are highly variable. In theory, this variability allows the establishment of phylogenetic relations. The authors were able to amplify the 16s rDNA directly from tissue specimens from four patients with bacillary angiomatosis using the polymerase chain reaction (PCR). They were then able to sequence the DNA that was most likely from eubacteria within the specimen, presumably the causative bacilli. The 241 base pair fragments obtained were identical in three of four patients, differed in the fourth by four base pairs, and were not found in the spleen of a patient with idiopathic thrombocytopenia purpura. Comparison of the sequence with known DNA sequence data files suggested the segment could be aligned with other 16s rRNA eubacteria genes but was not identical to any. The new organism represented by the sequence was designated strain BA-TF and was most similar to the rickettsialike organism I?. quintana, with which it shared 98.3% sequence similarity. In the
second
report,
histological
evidence
is provided
HIV results from opportunistic infection with a bacillus and that this bacillus is probably the same as the one implicated in bacillary angiomatosis. The authors used histological staining and electron microscopy to examine liver tissue from eight patients with peliosis hepatis and HIV infection, two of whom also had bacillary angiomatosis, and from four patients with peliosis hepatis without HIV infection. All of that
peliosis
hepatis
in patients
infected
with
the HIV-infected patients had hepatomegaly, and 6 had splenomegaly. Most had normal or slightly elevated bilirubin levels, normal to moderate elevations of transaminase levels (average, two times normal), and more marked elevations of alkaline phosphatase and y-glutamyl transferase levels [average, five times normal). Liver tissue from the 8 patients showed a spectrum of changes, but all had dilated blood-filled spaces separated from normal liver cells by varying amounts of a fibromyxoid stroma. In all patients, Warthin-Starry staining showed clumps of rod-shaped bacilli within this fibromyxoid stroma. Similar clumps of bacilli were also seen in the peliotic spleens of two of the patients, in angiomatous lymph nodes of two patients, and in the skin lesions of the two patients with bacillary angiomatosis. One of the patients with bacillary angiomatosis had bacilli in his skin lesions, lymph node, liver, and spleen. The fibromyxoid stroma and bacilli were not seen in the four patients with peliosis hepatis without HIV infection. Electron microscopy done on two of the patients confirmed that that the rod-shaped organisms seen with Warthin-Starry staining were indeed bacilli. The bacteria was similar to the bacillus of cat scratch fever in size, staining characteristics, and ultrastructural appearance. The bacteria did not grow on cultures of liver biopsy tissue. Four patients were identified as having bacillary peliosis at the time of biopsy and were treated with erythromycin. Two died of intercurrent medical problems, but the remaining two had resolution of fever and hepatosplenomegaly and improvement in liver enzyme levels. One patient also with bacillary angiomatosis also had resolution of the skin lesions. Comment. Peliosis fested by blood-filled
hepatis is an unusual liver condition manicavities not lined by endothelial cells, often
accompanied by sinusoidal dilatation, that most physicians, even gastroenterologists, rarely encounter. It is most commonly thought of as occurring in patients treated with anabolic steroids (Ann Intern Med 1974;81:610-618) but has been associated with a variety
of other
medications
and conditions.
Most relevant
to this
discussion, infections such as pulmonary tuberculosis (Am J Path01 1950;26:1-151, bacterial liver abscess (Digestion 1988;41:55-60), and cytomegalovirus (Transplant Proc 1987;19:3697-3698) have been seen in association with peliosis hepatis. In these conditions, however, the pathogenetic relationship between the infectious agent and the histological findings has not been clearly understood. Peliosis hepatis has been recognized in patients with HIV infection in reports (Arch Path01 Lab Med 1986;110:611-613; Am J Path01 1988;131:38-47) over the past several years, but the pathogenesis in this subset
of patients
has not been understood
either.
Peliosis hepatis must now be added to the differential diagnosis in patients with HIV infection who develop liver disease. This consideration is particularly important because the peliosis may be responsive to antibiotic therapy but, left untreated, may be rapidly fatal. The diagnosis is not especially difficult once one’s index of suspicion is raised; all patients had hepatomegaly, characteristic histological findings of peliosis, and positive Warthin-Starry staining for rod-shaped bacteria in the fibromyxoid areas of the liver. Liver biopsy cultures were not at all helpful in diagnosing this condition. Although erythromycin seems to have had a clear clinical effect in two of the patients, further experience will need to be garnered with its use in this condition. Erythromycin also seems to be effective in the treatment of cutaneous bacillary angiomatosis
866
SELECTED
[AnnInternMed is not surprising This perceptive
SUMMARIES
GASTROENTEROLOGY
1988;109:449_455;Lancet because the causative piece of clinical
1988;1:960-963), which agent is probably the same.
detective
work by Perkocha
et al.
is complemented by the discovery by Relman et al. that the causative agent for cutaneous bacillary angiomatosis and probably peliosis hepatis in association with HIV infection is a previously uncharacterized quintana. Using
Rickettsia-like the polymerase
organism, closely related chain reaction, sequences
to R. of the
16s rRNA gene can be amplified and compared with a reference sequence data base to construct phylogenetic trees. R. quintana is the cause of trench fever characterized by fever, rash, splenomegaly, and bone and muscle pain: this organism is sensitive to erythromycin and the tetracyclines (Antimicrob Agents Chemother 1984;25:690-693). Bartonella bocilliformis is another member of the order Rickeftsiales and can result in skin lesions very similar to bacillary angiomatosis (Annu Rev Microbial 1981;35:325-338). Because there are no 16s rRNA sequences available for B. bacilliformis yet, cannot be disease has those of the
its relationship to the agent of bacillary angiomatosis ascertained. The bacillus responsible for cat scratch some characteristics (Lancet 1988;1:960-963) similar to organism of bacillary angiomatosis, but the former has
not yet been clearly characterized. The organism responsible for cat scratch disease is currently being investigated by Relman et al. using this same 16s rRNA technique, and when this is accomplished its relationship to the agent of bacillary angiomatosis will be better understood. The powerful techniques used for identification of the organism of bacillary angiomatosis could serve as a paradigm for the characterization of other uncultured organisms in the future. These methods allow genotypic comparisons between organisms instead of the traditional phenotypic comparisons that have been used for many years (N Engl J Med 1991;323:1625-1627). The usefulness of these new techniques to clinical medicine will hopefully become evident over the next decades as more hitherto baffling diseases reveal themselves to more sophisticated molecular-level probes. P. F. MALET, MD. II. MOONKA, MD. Reply. Studies on the composition of environmental microbial communities have demonstrated that reliance on microbial growth in the laboratory may lead to a biased picture (Nature 1990;345:6063; Nature 1990;345:63-65). This finding may have relevance to our understanding of human pathogen diversity. This bias may be avoided by directly amplifying 16s rRNA sequences from relevant human tissue samples with broad-range polymerase chain reaction primers, and the spectrum of known pathogens may be expanded. The agent of bacillary angiomatosis (BA-TF) may be the first of many new human pathogens identified in this manner (N Engl J Med 1990;323:1573-1580). Work is currently underway to identify the causative agents of cat scratch disease and Whipple’s disease. Further characterization of BA-TF now suggests that it is highly related to Bartonella bacilliformis, as well as to Rochalimaea quintana (Relman DA, Falkow S, Schmidt TM, manuscript in preparation). The entire 16s rRNA genes from these three organisms have been amplified and cloned. The exact relationships among these different a-purple eubacteria must await completed analysis of their 16s rRNA gene sequences. At the time we reported the identification of the agent of bacillary angiomatosis (BA-TF) (NEngl J Med 1990;323:1573-1580) we were unaware of work by Slater et al. (N Engl J Med 1990;323:15871593) who had isolated a fastidious bacillus from the blood of some patients with persistent fever. A liver biopsy specimen from one of these patients (patient 1) subsequently revealed bacillary peliosis hepatis (NEngl JMed 1999;323:1581-1586). Since the time of these reports, we have determined partial 16SrRNA sequence from this patient’s blood isolate. The results suggest that this organism is the
Vol. 101, No. 3
as or highly related to BA-TF [N Engl J Med 1991;324 (in press)]. These findings further suggest that the same organism may cause bacillary angiomatosis, bacillary peliosis hepatis, and persistent fever in some patients. The application of our molecular technique to other tissue samples from patients with bacillary peliosis hepatis will be necessary to confirm these results. However, it seems that the full spectrum of human disease attributable to this organism remains to be defined. same
D. A. RELMAN, M.D.
A BIOPSYCHOSOCIAL MODEL FOR FUNCTIONAL DYSPEPSIA Hui W, Shiu LP, Lam SK (University Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong]. The perception of life events and daily stress in nonulcer dyspepsia. Am J Gastroenterol 1991;86:292-296 (March). The association of dyspepsia of unknown cause (functional dyspepsia) and stress in life is often suggested, but so far, inconsistent results have been reported. Methodological problems may be at fault because most studies have emphasized the number of major life events but have neglected the fact that the severity of an event depends on the way the person perceives it. Therefore, an accurate assessment of life stresses should include an individual’s rating of the impact and desirability of the events. The present study examined the perception of major life events and, in addition, the role of daily “hassles” (annoying daily events) in patients with functional dyspepsia. Thirty-three consecutive patients were identified who complained of epigastric pain, nausea, vomiting, and belching without evidence of peptic ulcer disease or gallstones as defined by normal endoscopy and ultrasonography. Severity of dyspeptic symptoms was recorded and graded as mild (bothersome but not interfering with work), moderate (interfering with work and/or resulting in sick leave), or severe (requiring immediate medical care). Thirty-three healthy unpaid volunteers of comparable sex, age, and social class were recruited as the control group for this study. Both groups completed two self-report questionnaires translated into Chinese that could be finished within 15-20 minutes. The first part was the Life Experience Survey (LES), which listed 56 major life events such as marriage, death of a spouse, pregnancy, and retirement. Subjects were asked to circle those events experienced in the preceding 6 months and rate the desirability and severity of each circled event. The rating scale involved seven points ranging from -3 to +3. A negative sign indicated a negative impact of the event on the person’s life, whereas a positive sign indicated the converse. The number indicated the perceived magnitude of the impact, with 3 being the strongest. Five scores were derived from the LES: number of negative and number of positive events, magnitude of negative and magnitude of positive events, and life-change score obtained by adding the magnitude scores of negative and positive events together. The second part was a “hassles scale” designed to measure daily activities or events that were irritating, frustrating or distressing. For example, these included misplacing and losing things, not having enough time for
