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Early diagnosis of invasive aspergillosis
Early diagnosis of invasive aspergillosis Despite medical advances, 30% of cases of invasive aspergillosis remain undiagnosed and untreated at death.1,2 When treatment is given, it is not very effective, with mortality exceeding 65%.3 However, early diagnosis and treatment have a beneficial impact. Mortality was 90% when the infection was diagnosed and treated more than 10 days after the first clinical or radiological sign of the disease, but fell to 40% when treatment was instigated early.4 In the 1990s, 4% of unselected patients dying in modern tertiary-care hospitals in Europe had invasive aspergillosis.1,2 How is early diagnosis achieved? As with any complex medical problem, the level of suspicion for vulnerable patients should be high. Unfortunately, the range of patients at risk is large and includes all those with acute and chronic leukaemia, all transplant recipients, those with HIV infection, especially when advanced, certain inherited immune-deficiency states, extensively burned patients, and chronically immunosuppressed patients, such as those with systemic lupus erythematosus, Wegener’s disease, and severe psoriasis requiring methotrexate.5 People outside these risk groups can also be infected. Sputum or respiratory-tract cultures are occasionally positive,6 and the only way to reach an early diagnosis in most groups of patients is to make intensive efforts to collect specimens for culture and histological examination. However, two specific advances, one serological and one radiological, have been made in the past 5 years in haematology patients. The recent paper by J Maertens and colleagues7 from Leuven underscores the importance of the serological advance. Maertens and colleagues studied the value of the aspergillus-antigen test for galactomannan in about 200 haematology patients. 71 of their patients died. At necropsy invasive aspergillosis was found in 27 and excluded in 44. In these patients the aspergillus-antigen test had a sensitivity of 92·6% and specificity of 95·4%. Examination of the temporal sequence of antigenaemia showed that the antigen was detectable in 65% of cases before the first clinical feature (eg, cough, chest pain, haemoptysis), in 71% before any lesion was apparent on the chest radiograph, in 44% before fever occurred, and in 72% before empirical antifungal therapy was given. Like others,810 Maertens and colleagues showed that, with the antigen test, diagnosis could be made a mean of 6–13 days before other diagnostic clues appeared. Since the samples were analysed retrospectively, the use of the antigen test had no impact on effect of therapy in this study. False-positive results do occur with the galactomannan antigen test but are in reality “true positives”. Many soft foods, such as pasta, contain galactomannan and the damage to the gut wall by cytotoxic therapy, total-body irradiation, or graft-versus-host disease sometimes enables translocation of galactomannan from the gut lumen into the blood. For this reason a positive result is defined as positive samples collected on 2 different days and having optical density values of more than 1·0.7 The other major advance in diagnosis is the early use of computed tomographic (CT) scanning of the chest or magnetic-resonance scanning of the sinuses. The characteristic “halo” sign (ground-glass appearance around a nodule or area of consolidation) occurs early in the course of invasive pulmonary aspergillosis in neutropenic and stem-cell-transplant patients and is transient.11 Later, cavitation may appear, and it is commonly referred to as the “air-crescent” sign.11 A halo sign can also be due to
THE LANCET • Vol 355 • February 5, 2000
poor radiological technique (eg, one causing breathing artefacts), other fungal infections (Mucorales, Fusarium, and Pseudallescheria), and Pseudomonas infection. However, according to the new consensus on the definitions of invasive fungal infections,12 the combination of aspergillus antigenaemia (on two occasions) and a halo sign in a patient with a high-risk haematological disorder is evidence that is almost equivalent to a biopsy sample showing hyphae, with or without a positive culture of Aspergillus. Many European centres now run a galactomannan test on all their high-risk haematology patients twice a week. If a test is positive, another test is done the next day. If the repeat test is also positive and the optical density is more than 1 for each test, a CT scan of the chest or bronchoscopy or both are done. Treatment is instigated on the basis of a combination of positive tests, not simply on antigenaemia. Monitoring of galactomannan concentrations may assist in the assessment of therapeutic response and when to re-scan the patient. A limitation of the aspergillus-antigen test is that it is not licenced by the US Food and Drug Administration and therefore is not available for use in most patients in the USA. Another is that its value in non-haematology patients has barely been investigated. However, further study may show other possible uses for the test. Early indications suggest that detection of galactomannan in cerebrospinal fluid may establish Aspergillus as the cause of a cerebral abscess or meningitis, without need for biopsy. Bronchoalveolar lavage fluid is commonly positive for galactomannan in cases of invasive aspergillosis, but the appropriate cut-off and performance of the test with this fluid are unknown. This definition of cut-off could be valuable in distinguishing infection from colonisation in, for example, transplant patients in whom interpretation of a positive culture can be difficult. The real challenge, though, is to show that early detection of galactomannan reduces mortality. One group treating patients for acute leukaemia has reported that early CT scanning combined with antigen detection (and surgery and azole therapy) reduced mortality from 60% to 12% over 6 years.13 The integration of serological testing, bronchoscopy, and CT scanning enabled early diagnosis and decision-making—for example, about surgery or switching of antifungal drugs. Perhaps other units can emulate this group’s experience. David W Denning Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, University of Manchester, Manchester M8 6RB, UK 1
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Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996; 33: 23–32. Vogeser M,Wanders A, Haas A, Ruckdeschel G. A four-year review of fatal aspergillosis. Eur J Clin Microbiol Infect Dis 1999; 18: 42–45. Denning DW. Therapeutic outcome of invasive aspergillosis. Clin Infect Dis 1996; 23: 608–15. von Eiff M, Zuhlsdorf M, Roos N, Hesse M, Schulten R, van de Loo J. Pulmonary fungal infections in patients with hematological malignancies—diagnostic approaches. Ann Hematol 1995; 70: 135–41. Verweij PE, Denning DW. The challenge of invasive aspergillosis: increasing numbers in diverse patient groups. Int J Infect Dis 1997; 2: 61–63. Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996; 100: 171–78. Maertens J,Verhaegen J, Demuynck H, et al. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive aspergillosis. J Clin Microbiol 1999; 37: 3223–28.
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Sulahin A, Talbot M, Ribaud P, et al. Comparison of an enzyme linked immunoassay and latex agglutination test for detection of galactomannan in the diagnosis of invasive aspergillosis. Eur J Clin Microbiol Infect Dis 1996; 15: 139–45. Verweij PE, Rijs AJMM, De Pauw BE, Horrevorts AM, HoogkampKorstanje JAA, Meis JFGM. Clinical evaluation and reproducibility of the Pastorex Aspergillus antigen latex agglutination test for diagnosing invasive aspergillosis. J Clin Pathol 1995; 48: 474–76. Rohrlich P, Sarfati J, Mariani P, et al. Prospective sandwich enzyme linked immunosorbent assay for serum galactomannan: early predictive value and clinical use in invasive aspergillosis. Pediatr Infect Dis J 1996; 15: 232–37. Blum U,Windfuhr M, Buitrago-Tellez C, Sigmund G, Herbst EW, Langer M. Invasive pulmonary aspergillosis: MRI, CT, and plain radiographic findings and their contribution for early diagnosis. Chest 1994; 106: 1156–67. Ascioglu S, De Pauw B, Bennett JE, et al. Analysis of definitions used in clinical research on invasive fungal infections (IFI): consensus proposal for new, standardized definitions. Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Sept 1999, Abstr J92. Caillot D, Casasnovas O, Bernard A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997; 15: 139–47.
Transplantation for alcoholic liver disease in an era of organ shortage Alcoholic liver disease (ALD) is a leading cause of liver cirrhosis and accounts for 7·9 deaths per 100 000 population.1 It is the main indication for liver transplantation in males and, after viral hepatitis, is the second commonest indication overall. With organ shortage meaning that 5–15% of patients die before a liver becomes available, the degree of priority to be given to patients with alcoholic disease has long been a controversial issue. One of the debatable points is whether an individual whose own actions led to the alcoholic cirrhosis should receive the same priority as others for a liver transplant. Other points are whether the effect of transplantation is as good in patients with ALD as in non-alcoholics, and the likelihood of recidivism and its influence on outcome. How much do ALD patients benefit from transplantation? The overwhelming evidence is that most patients with ALD do well after transplantation, with 1-year survival rates of more than 85% and 5-year survival rates of 70% (European Liver Registry data) being similar to those for non-alcoholics.2 In a study by Poynard and colleagues3 in which patients with alcoholic cirrhosis were compared with two groups treated conservatively, 5-year survival rates were 66% for the transplanted group, and 52% for the group matched for prognostic factors The benefit of transplantation over conservative treatment was greatest for the subgroup with the most severe disease (5-year survival was 58%), and Poynard and colleagues3 suggest that, in the selection of patients for liver transplantation, severity of disease might deserve greater weight than the underlying cause of the liver failure. Liver transplantation produces the same health-related quality-of-life benefits in patients with ALD as in those with non-alcoholic disease.4 Although return to full employment was less common among the ALD group, this difference may relate more to pre-transplantation employment status than to the patient’s ability to recover. In the early years after transplantation, therefore, there is little evidence that patients with ALD fare less well than patients with non-ALD disease. Longer-term outcome (eg, beyond 10 years) needs to be compared because of the prevalence of concurrent disorders among patients with ALD—for instance, they are likely to have been heavy smokers, and a high prevalence of throat cancer has been 424
reported.5 The second point in the debate is recidivism. At the US National Institutes of Health Consensus Conference in 1997, more than 85% of transplant units stated that they required ALD patients to abstain from alcohol for 6 months before acceptance for transplantation,6 and acute alcoholic hepatitis is generally not deemed an appropriate indication for transplantation. Because continuing to drink alcohol is perceived to be a factor associated with poor outlook, the potential for remaining abstinent after transplantation is an important factor in the selection of patients for transplantation.7 This potential is increasingly being evaluated on the basis of whether the patient recognises that he has a major alcoholic problem and agrees to enter support programmes to minimise likelihood of recidivism in the post-transplant period. Such approaches are being assessed. Meanswhile, what evidence is there of the influence of recidivism? Rates of recidivism at 3–5 years range between 11 and 49%,8 with recent data suggesting that 27% patients have resumed drinking alcohol a year after transplantation, 32% by 2 years, and 32% by 3 years.4 The rate depends to some extent on mode of assessment. Higher rates are likely to be obtained with objective criteria such as concentrations of alcohol in the urine or the ratio of serum carbohydrate-deficient transferrin to serum transferrin, or with a detailed structured interview, rather than with unstructured questioning of the patient.8 Fewer than 10% of patients drink heavily (up to 40 g/day) after transplantation,9 but 5% drink amounts associated with histological evidence of early alcoholic damage, steatosis, and lobular hepatitis,10 or with early cirrhosis.11 An 82% 5year survival rate for 31 patients who reverted to drinking modest amounts of alcohol, compared with 75% for 101 patients who remained abstinent, indicates that, in the early years, resumption of moderate drinking has little influence on survival. Nevertheless any reduction in survival attributable to resumption of drinking is regrettable since the loss is preventable, unlike that due to recurrence of hepatitis B or C, which is difficult to prevent. A concern about the acceptance of patients with ALD for liver transplantation is the patient’s ability to comply with clinical protocols and immunosuppressive drug regimens. However, despite poor follow-up attendance and compliance with therapy among a minority of patients, graft-rejection rates are similar for ALD and non-ALD patients (for acute rejection 41% in ALD and 43·7% in non-ALD patients, and for chronic rejection 5·6 and 6·2%, respectively).11 The likelihood of high rejection rates are thus probably not a major clinical issue in the selection of ALD patients for liver transplantation, even among patients who do return to drinking. The third point in the debate in decisions about priority for liver transplantation is whether the general public is likely to support organ donation for patients with ALD. In Oregon, when the public were asked to allocate priorities for 714 disorders or treatments,12 they gave transplantation for non-ALD liver failure mid priority (364/714) but a much lower ranking (695/714) for ALD patients. A survey in the UK13 showed that health-care professionals tend to base their decision on medical urgency and severity of disease, coupled with prospects for long-term survival, whereas the public gave preference to the younger patients irrespective of outlook, and low priority to people with antisocial behaviour, such as alcoholics.
THE LANCET • Vol 355 • February 5, 2000
THE LANCET • Vol 355 • February 5, 2000
poor radiological technique (eg, one causing breathing artefacts), other fungal infections (Mucorales, Fusarium, and Pseudallescheria), and Pseudomonas infection. However, according to the new consensus on the definitions of invasive fungal infections,12 the combination of aspergillus antigenaemia (on two occasions) and a halo sign in a patient with a high-risk haematological disorder is evidence that is almost equivalent to a biopsy sample showing hyphae, with or without a positive culture of Aspergillus. Many European centres now run a galactomannan test on all their high-risk haematology patients twice a week. If a test is positive, another test is done the next day. If the repeat test is also positive and the optical density is more than 1 for each test, a CT scan of the chest or bronchoscopy or both are done. Treatment is instigated on the basis of a combination of positive tests, not simply on antigenaemia. Monitoring of galactomannan concentrations may assist in the assessment of therapeutic response and when to re-scan the patient. A limitation of the aspergillus-antigen test is that it is not licenced by the US Food and Drug Administration and therefore is not available for use in most patients in the USA. Another is that its value in non-haematology patients has barely been investigated. However, further study may show other possible uses for the test. Early indications suggest that detection of galactomannan in cerebrospinal fluid may establish Aspergillus as the cause of a cerebral abscess or meningitis, without need for biopsy. Bronchoalveolar lavage fluid is commonly positive for galactomannan in cases of invasive aspergillosis, but the appropriate cut-off and performance of the test with this fluid are unknown. This definition of cut-off could be valuable in distinguishing infection from colonisation in, for example, transplant patients in whom interpretation of a positive culture can be difficult. The real challenge, though, is to show that early detection of galactomannan reduces mortality. One group treating patients for acute leukaemia has reported that early CT scanning combined with antigen detection (and surgery and azole therapy) reduced mortality from 60% to 12% over 6 years.13 The integration of serological testing, bronchoscopy, and CT scanning enabled early diagnosis and decision-making—for example, about surgery or switching of antifungal drugs. Perhaps other units can emulate this group’s experience. David W Denning Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, University of Manchester, Manchester M8 6RB, UK 1
2 3 4
5
6
7
Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996; 33: 23–32. Vogeser M,Wanders A, Haas A, Ruckdeschel G. A four-year review of fatal aspergillosis. Eur J Clin Microbiol Infect Dis 1999; 18: 42–45. Denning DW. Therapeutic outcome of invasive aspergillosis. Clin Infect Dis 1996; 23: 608–15. von Eiff M, Zuhlsdorf M, Roos N, Hesse M, Schulten R, van de Loo J. Pulmonary fungal infections in patients with hematological malignancies—diagnostic approaches. Ann Hematol 1995; 70: 135–41. Verweij PE, Denning DW. The challenge of invasive aspergillosis: increasing numbers in diverse patient groups. Int J Infect Dis 1997; 2: 61–63. Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996; 100: 171–78. Maertens J,Verhaegen J, Demuynck H, et al. Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich enzyme-linked immunosorbent assay for hematological patients at risk for invasive aspergillosis. J Clin Microbiol 1999; 37: 3223–28.
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Sulahin A, Talbot M, Ribaud P, et al. Comparison of an enzyme linked immunoassay and latex agglutination test for detection of galactomannan in the diagnosis of invasive aspergillosis. Eur J Clin Microbiol Infect Dis 1996; 15: 139–45. Verweij PE, Rijs AJMM, De Pauw BE, Horrevorts AM, HoogkampKorstanje JAA, Meis JFGM. Clinical evaluation and reproducibility of the Pastorex Aspergillus antigen latex agglutination test for diagnosing invasive aspergillosis. J Clin Pathol 1995; 48: 474–76. Rohrlich P, Sarfati J, Mariani P, et al. Prospective sandwich enzyme linked immunosorbent assay for serum galactomannan: early predictive value and clinical use in invasive aspergillosis. Pediatr Infect Dis J 1996; 15: 232–37. Blum U,Windfuhr M, Buitrago-Tellez C, Sigmund G, Herbst EW, Langer M. Invasive pulmonary aspergillosis: MRI, CT, and plain radiographic findings and their contribution for early diagnosis. Chest 1994; 106: 1156–67. Ascioglu S, De Pauw B, Bennett JE, et al. Analysis of definitions used in clinical research on invasive fungal infections (IFI): consensus proposal for new, standardized definitions. Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Sept 1999, Abstr J92. Caillot D, Casasnovas O, Bernard A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997; 15: 139–47.
Transplantation for alcoholic liver disease in an era of organ shortage Alcoholic liver disease (ALD) is a leading cause of liver cirrhosis and accounts for 7·9 deaths per 100 000 population.1 It is the main indication for liver transplantation in males and, after viral hepatitis, is the second commonest indication overall. With organ shortage meaning that 5–15% of patients die before a liver becomes available, the degree of priority to be given to patients with alcoholic disease has long been a controversial issue. One of the debatable points is whether an individual whose own actions led to the alcoholic cirrhosis should receive the same priority as others for a liver transplant. Other points are whether the effect of transplantation is as good in patients with ALD as in non-alcoholics, and the likelihood of recidivism and its influence on outcome. How much do ALD patients benefit from transplantation? The overwhelming evidence is that most patients with ALD do well after transplantation, with 1-year survival rates of more than 85% and 5-year survival rates of 70% (European Liver Registry data) being similar to those for non-alcoholics.2 In a study by Poynard and colleagues3 in which patients with alcoholic cirrhosis were compared with two groups treated conservatively, 5-year survival rates were 66% for the transplanted group, and 52% for the group matched for prognostic factors The benefit of transplantation over conservative treatment was greatest for the subgroup with the most severe disease (5-year survival was 58%), and Poynard and colleagues3 suggest that, in the selection of patients for liver transplantation, severity of disease might deserve greater weight than the underlying cause of the liver failure. Liver transplantation produces the same health-related quality-of-life benefits in patients with ALD as in those with non-alcoholic disease.4 Although return to full employment was less common among the ALD group, this difference may relate more to pre-transplantation employment status than to the patient’s ability to recover. In the early years after transplantation, therefore, there is little evidence that patients with ALD fare less well than patients with non-ALD disease. Longer-term outcome (eg, beyond 10 years) needs to be compared because of the prevalence of concurrent disorders among patients with ALD—for instance, they are likely to have been heavy smokers, and a high prevalence of throat cancer has been 424
reported.5 The second point in the debate is recidivism. At the US National Institutes of Health Consensus Conference in 1997, more than 85% of transplant units stated that they required ALD patients to abstain from alcohol for 6 months before acceptance for transplantation,6 and acute alcoholic hepatitis is generally not deemed an appropriate indication for transplantation. Because continuing to drink alcohol is perceived to be a factor associated with poor outlook, the potential for remaining abstinent after transplantation is an important factor in the selection of patients for transplantation.7 This potential is increasingly being evaluated on the basis of whether the patient recognises that he has a major alcoholic problem and agrees to enter support programmes to minimise likelihood of recidivism in the post-transplant period. Such approaches are being assessed. Meanswhile, what evidence is there of the influence of recidivism? Rates of recidivism at 3–5 years range between 11 and 49%,8 with recent data suggesting that 27% patients have resumed drinking alcohol a year after transplantation, 32% by 2 years, and 32% by 3 years.4 The rate depends to some extent on mode of assessment. Higher rates are likely to be obtained with objective criteria such as concentrations of alcohol in the urine or the ratio of serum carbohydrate-deficient transferrin to serum transferrin, or with a detailed structured interview, rather than with unstructured questioning of the patient.8 Fewer than 10% of patients drink heavily (up to 40 g/day) after transplantation,9 but 5% drink amounts associated with histological evidence of early alcoholic damage, steatosis, and lobular hepatitis,10 or with early cirrhosis.11 An 82% 5year survival rate for 31 patients who reverted to drinking modest amounts of alcohol, compared with 75% for 101 patients who remained abstinent, indicates that, in the early years, resumption of moderate drinking has little influence on survival. Nevertheless any reduction in survival attributable to resumption of drinking is regrettable since the loss is preventable, unlike that due to recurrence of hepatitis B or C, which is difficult to prevent. A concern about the acceptance of patients with ALD for liver transplantation is the patient’s ability to comply with clinical protocols and immunosuppressive drug regimens. However, despite poor follow-up attendance and compliance with therapy among a minority of patients, graft-rejection rates are similar for ALD and non-ALD patients (for acute rejection 41% in ALD and 43·7% in non-ALD patients, and for chronic rejection 5·6 and 6·2%, respectively).11 The likelihood of high rejection rates are thus probably not a major clinical issue in the selection of ALD patients for liver transplantation, even among patients who do return to drinking. The third point in the debate in decisions about priority for liver transplantation is whether the general public is likely to support organ donation for patients with ALD. In Oregon, when the public were asked to allocate priorities for 714 disorders or treatments,12 they gave transplantation for non-ALD liver failure mid priority (364/714) but a much lower ranking (695/714) for ALD patients. A survey in the UK13 showed that health-care professionals tend to base their decision on medical urgency and severity of disease, coupled with prospects for long-term survival, whereas the public gave preference to the younger patients irrespective of outlook, and low priority to people with antisocial behaviour, such as alcoholics.
THE LANCET • Vol 355 • February 5, 2000