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Mycobacterium tuberculosis infection in travellers: tuberculosis comes home
COMMENTARY
COMMENTARY
Mycobacterium tuberculosis infection in travellers: tuberculosis comes home See page 461 Although about 32% of the world’s population are estimated to be infected with Mycobacterium tuberculosis, the prevalence varies enormously between countries.1 Fuelled in part by the concurrent HIV pandemic, almost 8 million new cases of tuberculosis are estimated to have occurred in 1997.1 What then is the likelihood of travellers acquiring tuberculosis during long visits to an endemic country? In today’s Lancet, Frank Cobelens and colleagues report that, among Dutch people who spent a median of 23 weeks in countries highly endemic for tuberculosis, the incidence rate of acquiring M tuberculosis infection was 7·9/1000 person-months of travel for health-care workers, and 2·8/1000 personmonths for the others. Cobelens and colleagues discuss two possible prevention strategies for long-term visitors to endemic areas: Bacille Calmette-Guérin (BCG) vaccination, or tuberculin skin testing followed by treatment for latent infection. Although studies support the benefit of BCG vaccination in helping to prevent meningeal and miliary tuberculosis in children, data on the vaccine’s efficacy in preventing pulmonary tuberculosis in adults are inconsistent.2 The benefits and drawbacks of BCG vaccination for tuberculosis prevention in health-care workers, including those likely to become infected with multidrug-resistant tuberculosis, have ben debated.2,3 Disadvantages to pre-travel BCG include uncertain efficacy in travellers going to endemic areas, and possible development of a false-positive tuberculin test, which would result in loss of the ability to detect post-travel skin-test conversions. Although the tuberculin skin test may be associated with both false-positive and false-negative responses, it is the method for identifying M tuberculosis infection in people without tuberculosis, and it remains an important component of control of the infection. There is good reason for tuberculin screening before and after travel to become as much a part of the travelmedicine regimen for high-risk travellers as are malaria prophylaxis and recommended immunisations, although the public and providers may need to be educated about the rationale and importance of such a scheme. If tuberculin skin testing is to be done before and after a trip, two-step testing can help distinguish true skin-test conversions from boosted reactions due to old tuberculous infection, previous BCG vaccination, or infection with environmental mycobacteria.4 With two-step testing, people who test negative with tuberculin undergo a second skin test 1–3 weeks later, and the results of the repeat test are taken as the true baseline. 442
A challenge to be faced in the treatment of latent infection (after active disease has been excluded) is the increasing prevalence of drug-resistant tubercle bacilli. Surveillance of M tuberculosis strains from 32 different countries during 1994–97 showed a median rate of 7·3% for primary isoniazid resistance, 1·8% for rifampicin resistance, and 1·4% for multidrug resistance, with considerable variation by country.5 Regimens of rifampicin and pyrazinamide, or rifampicin alone, would be useful for people likely to be infected with isoniazidresistant, rifampicin-susceptible strains.6 For those likely to be infected with multidrug-resistant bacilli, other regimens can be considered, although data for their efficacy in latent infection are generally limited. These considerations support the importance of knowing the local epidemiology of drug resistance. Other important measures for preventing transmission of tuberculosis, to travellers or to anybody else, include maximising infection control in local health-care facilities, prompt diagnosis and treatment, and use of directly observed therapy. However, in view of the global extent of tuberculosis, as well as the very limited resources in many countries, the risk of exposure to M tuberculosis is unlikely to be eliminated. Today’s report of risk of infection with M tuberculosis to travellers highlights the links between the health of those in industrialised countries and the rest of the world. In my home state of Minnesota, in 1999, 78% of cases of tuberculosis were in people born outside the USA.7 Whether one travels or not, the lesson from tuberculosis is that what happens in one part of the planet ultimately affects others elsewhere. Countries with more resources need to help resources-poor nations in their efforts to control this disease.8 Without global control of tuberculosis, no country or population is truly protected. Alan R Lifson Division of Infectious Diseases, Department of Medicine, University of Minnesota, MMC 250, Minneapolis, MN 55455 USA 1
2
3
4
Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–86. CDC. The role of BCG vaccine in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. Morb Mortal Wkly Rep 1996; 45 (RR-4): 1–18. Brewer TF, Colditz GA. Bacille Calmette-Guérin vaccination for the prevention of tuberculosis in health care workers. Clin Infect Dis 1995; 20: 136–42. American Thoracic Society, CDC. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir
THE LANCET • Vol 356 • August 5, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
5
6
7 8
Crit Care Med 2000; 161: 1376–95. Pablos-Méndez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance, 1994–1997. N Engl J Med 1998; 338: 1641–49. CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2000; 49 (RR6): 1–51. Minnesota Department of Health. Epidemiology of tuberculosis in Minnesota. Disease Control Newsletter 2000; 28: 1–3. Fiorentino R, van der Meer J, Kittle D. MSF call for laboratory support. Lancet 2000; 356: 434.
Insulin glargine The new long-acting insulin analogue, insulin glargine (‘Lantus’, Aventis Pharma) was approved for use in patients with type 1 and type 2 diabetes mellitus by the US Food and Drug Administration in April, 2000, and by the European Agency for the Evaluation of Medicinal Products in June, 2000. The availability of an insulin preparation that would provide basal insulin requirements has long been awaited.1 However, what kind of longacting insulin analogue is insulin glargine, is it safe, and if so, how should it best be used? Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arghuman insulin) is produced by recombinant DNA technology. It results from two modifications of human insulin. The first is the addition of two positive charges (two arginine molecules) to the C-terminus of the Bchain, which shifts the isoelectric point from a pH of 5·4 to 6·7, making the molecule more soluble at a slightly acidic pH and less soluble at the physiological pH of subcutaneous tissue. Because the derivative is formulated at an acidic pH of 4·0 (which means that it cannot be mixed with insulin formulated at a neutral pH, such as regular insulin), a second modification is needed to prevent deamidation and dimerisation via the acidsensitive asparagine residue at position 21 in the A-chain. The replacement of A21 asparagine by glycine is charge neutral and associated with good stability of the resulting human insulin analogue.1 When injected subcutaneously, insulin glargine, which is a clear solution, forms a microprecipitate at the physiological, neutral pH of the subcutaneous space. Because of its stability, absorption of insulin glargine from the subcutaneous site of injection is delayed and lasts a long time, thus providing a fairly constant basal insulin supply, much like that of basal insulin secretion in non-diabetic people in the postabsorptive state. Is insulin glargine a safe analogue? The mitogenic potential of any new insulin preparation is of considerable interest because the preparation is likely to be given long term and because of the development of mammary tumours in a strain of mice given the short-acting B10Asp insulin analogue. Changes in the molecular structure of insulin may alter interactions of the hormone with receptors for insulin and insulin-like growth factor I (IGF1). Insulin glargine has about 50–60% the affinity of human insulin for the insulin receptor, an in-vitro potency (based on lipogenesis) of 60%, but equivalent in-vivo potency because the plasma concentrations reached are twice those of insulin.1 Insulin glargine dissociates from isoform A insulin receptors one and a half times as quickly as human insulin. By contrast, the short-acting AspB10 insulin analogue dissociates at only 10–20% of the rate of human insulin. Like the insulin analogue AspB10, insulin glargine has up to six-fold greater affinity for IGF-1 receptors than human insulin.2 In cell-lines with predominantly a high expression of IGF-1 receptors, such
THE LANCET • Vol 356 • August 5, 2000
as the human osteosarcoma cell line Saos/B102 and human mammary epithelial cells HMEC, a close relation between IGF-1 receptor affinity and mitogenic potency has been described.3 However, since only the AspB10 insulin analogue caused mammary tumours when given in high doses (12·5–200 U/kg) to rats, whereas insulin glargine given to rats and mice at a lower dose (2·0–12·5 U/kg) for up to 2 years did not, the carcinogenic effect is not substance specific. This suggests that a long residence time on the insulin receptor may be an important component of the enhanced mitogenicity of the AspB10 insulin analogue. Insulin glargine and human insulin have a similar time course for insulin-receptor binding and intracellular signalling events, whereas the action of the AspB10 insulin analogue is more persistent. Experiments using cell-lines expressing mainly insulin receptors (rat 1 fibroblasts)4 and human mammary epithelial cell-lines MCF10 (H U Häring, personal communication) have not shown increased mitogenicity, as measured by thymidine incorporation with insulin glargine. The clinical relevance of the recent observations by Kurtzhals et al2 of increased mitogenicity of insulin glargine compared with human insulin in a malignant cellline (human osteosarcoma, Saos/B10) is unknown. Therefore, the availability of the long-term data will be essential to answer this important question. There needs also to be an agreed battery of in-vitro and in-vivo tests to be employed to aid interpretations in the future. The observation of a three-grade progression of retinopathy (according to the scale used in the Early Treatment Diabetic Retinopathy Study) in some patients with type 2 diabetes treated with insulin glargine in studies of 1 year or less raised concern because IGF-1 signalling has been implicated in the regulation of vascular endothelial growth-factor-dependent retinal neovascularisation.5 However, review of the retinopathy data and the absence of optic-disc swelling during the studies (the most common ocular adverse effect of IGF-1 treatment) led an independent panel convened by Aventis Pharma to conclude that this finding was not related to therapy with insulin glargine. Do insulin-requiring diabetic patients really need a new long-acting insulin? Clearly they do. Existing intermediate-acting (netral protamine Hagedorn [NPH], Lente) and long-acting insulin formulations (Ultralente) cannot mimic the effect of basal insulin. All existing longacting insulin preparations have a peak-action profile (except for bovine Ultralente, which is not available because of its high immunogenic potential), a short duration of action, and a large within and between subject variability in subcutaneous absorption. Glucose homoeostasis in the interprandial and nocturnal periods is finely regulated by slow, continuous insulin secretion. Because the plasma concentration of insulin remains steady throughout the night, non-diabetic people do not experience hypoglycaemia in the night or hyperglycaemia at dawn. Thus, just by mimicking nature, use of an insulin with a peakless action profile should improve blood glucose control in type 1 diabetic patients, especially in those with absolute failure of the pancreatic -cells. This idea was tested by Pickup and co-workers nearly 25 years ago in their pioneering work with continuous subcutaneous insulin infusion (CSII).6 CSII still remains the reference standard against which any new candidate “basal” insulin, such as glargine, has to be compared. In type 1 diabetes, the action of a bolus dose of glargine, as assessed with the isoglycaemic clamp technique, starts about 90 min after subcutaneous 443
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
Mycobacterium tuberculosis infection in travellers: tuberculosis comes home See page 461 Although about 32% of the world’s population are estimated to be infected with Mycobacterium tuberculosis, the prevalence varies enormously between countries.1 Fuelled in part by the concurrent HIV pandemic, almost 8 million new cases of tuberculosis are estimated to have occurred in 1997.1 What then is the likelihood of travellers acquiring tuberculosis during long visits to an endemic country? In today’s Lancet, Frank Cobelens and colleagues report that, among Dutch people who spent a median of 23 weeks in countries highly endemic for tuberculosis, the incidence rate of acquiring M tuberculosis infection was 7·9/1000 person-months of travel for health-care workers, and 2·8/1000 personmonths for the others. Cobelens and colleagues discuss two possible prevention strategies for long-term visitors to endemic areas: Bacille Calmette-Guérin (BCG) vaccination, or tuberculin skin testing followed by treatment for latent infection. Although studies support the benefit of BCG vaccination in helping to prevent meningeal and miliary tuberculosis in children, data on the vaccine’s efficacy in preventing pulmonary tuberculosis in adults are inconsistent.2 The benefits and drawbacks of BCG vaccination for tuberculosis prevention in health-care workers, including those likely to become infected with multidrug-resistant tuberculosis, have ben debated.2,3 Disadvantages to pre-travel BCG include uncertain efficacy in travellers going to endemic areas, and possible development of a false-positive tuberculin test, which would result in loss of the ability to detect post-travel skin-test conversions. Although the tuberculin skin test may be associated with both false-positive and false-negative responses, it is the method for identifying M tuberculosis infection in people without tuberculosis, and it remains an important component of control of the infection. There is good reason for tuberculin screening before and after travel to become as much a part of the travelmedicine regimen for high-risk travellers as are malaria prophylaxis and recommended immunisations, although the public and providers may need to be educated about the rationale and importance of such a scheme. If tuberculin skin testing is to be done before and after a trip, two-step testing can help distinguish true skin-test conversions from boosted reactions due to old tuberculous infection, previous BCG vaccination, or infection with environmental mycobacteria.4 With two-step testing, people who test negative with tuberculin undergo a second skin test 1–3 weeks later, and the results of the repeat test are taken as the true baseline. 442
A challenge to be faced in the treatment of latent infection (after active disease has been excluded) is the increasing prevalence of drug-resistant tubercle bacilli. Surveillance of M tuberculosis strains from 32 different countries during 1994–97 showed a median rate of 7·3% for primary isoniazid resistance, 1·8% for rifampicin resistance, and 1·4% for multidrug resistance, with considerable variation by country.5 Regimens of rifampicin and pyrazinamide, or rifampicin alone, would be useful for people likely to be infected with isoniazidresistant, rifampicin-susceptible strains.6 For those likely to be infected with multidrug-resistant bacilli, other regimens can be considered, although data for their efficacy in latent infection are generally limited. These considerations support the importance of knowing the local epidemiology of drug resistance. Other important measures for preventing transmission of tuberculosis, to travellers or to anybody else, include maximising infection control in local health-care facilities, prompt diagnosis and treatment, and use of directly observed therapy. However, in view of the global extent of tuberculosis, as well as the very limited resources in many countries, the risk of exposure to M tuberculosis is unlikely to be eliminated. Today’s report of risk of infection with M tuberculosis to travellers highlights the links between the health of those in industrialised countries and the rest of the world. In my home state of Minnesota, in 1999, 78% of cases of tuberculosis were in people born outside the USA.7 Whether one travels or not, the lesson from tuberculosis is that what happens in one part of the planet ultimately affects others elsewhere. Countries with more resources need to help resources-poor nations in their efforts to control this disease.8 Without global control of tuberculosis, no country or population is truly protected. Alan R Lifson Division of Infectious Diseases, Department of Medicine, University of Minnesota, MMC 250, Minneapolis, MN 55455 USA 1
2
3
4
Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. JAMA 1999; 282: 677–86. CDC. The role of BCG vaccine in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. Morb Mortal Wkly Rep 1996; 45 (RR-4): 1–18. Brewer TF, Colditz GA. Bacille Calmette-Guérin vaccination for the prevention of tuberculosis in health care workers. Clin Infect Dis 1995; 20: 136–42. American Thoracic Society, CDC. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir
THE LANCET • Vol 356 • August 5, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
5
6
7 8
Crit Care Med 2000; 161: 1376–95. Pablos-Méndez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistance, 1994–1997. N Engl J Med 1998; 338: 1641–49. CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 2000; 49 (RR6): 1–51. Minnesota Department of Health. Epidemiology of tuberculosis in Minnesota. Disease Control Newsletter 2000; 28: 1–3. Fiorentino R, van der Meer J, Kittle D. MSF call for laboratory support. Lancet 2000; 356: 434.
Insulin glargine The new long-acting insulin analogue, insulin glargine (‘Lantus’, Aventis Pharma) was approved for use in patients with type 1 and type 2 diabetes mellitus by the US Food and Drug Administration in April, 2000, and by the European Agency for the Evaluation of Medicinal Products in June, 2000. The availability of an insulin preparation that would provide basal insulin requirements has long been awaited.1 However, what kind of longacting insulin analogue is insulin glargine, is it safe, and if so, how should it best be used? Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arghuman insulin) is produced by recombinant DNA technology. It results from two modifications of human insulin. The first is the addition of two positive charges (two arginine molecules) to the C-terminus of the Bchain, which shifts the isoelectric point from a pH of 5·4 to 6·7, making the molecule more soluble at a slightly acidic pH and less soluble at the physiological pH of subcutaneous tissue. Because the derivative is formulated at an acidic pH of 4·0 (which means that it cannot be mixed with insulin formulated at a neutral pH, such as regular insulin), a second modification is needed to prevent deamidation and dimerisation via the acidsensitive asparagine residue at position 21 in the A-chain. The replacement of A21 asparagine by glycine is charge neutral and associated with good stability of the resulting human insulin analogue.1 When injected subcutaneously, insulin glargine, which is a clear solution, forms a microprecipitate at the physiological, neutral pH of the subcutaneous space. Because of its stability, absorption of insulin glargine from the subcutaneous site of injection is delayed and lasts a long time, thus providing a fairly constant basal insulin supply, much like that of basal insulin secretion in non-diabetic people in the postabsorptive state. Is insulin glargine a safe analogue? The mitogenic potential of any new insulin preparation is of considerable interest because the preparation is likely to be given long term and because of the development of mammary tumours in a strain of mice given the short-acting B10Asp insulin analogue. Changes in the molecular structure of insulin may alter interactions of the hormone with receptors for insulin and insulin-like growth factor I (IGF1). Insulin glargine has about 50–60% the affinity of human insulin for the insulin receptor, an in-vitro potency (based on lipogenesis) of 60%, but equivalent in-vivo potency because the plasma concentrations reached are twice those of insulin.1 Insulin glargine dissociates from isoform A insulin receptors one and a half times as quickly as human insulin. By contrast, the short-acting AspB10 insulin analogue dissociates at only 10–20% of the rate of human insulin. Like the insulin analogue AspB10, insulin glargine has up to six-fold greater affinity for IGF-1 receptors than human insulin.2 In cell-lines with predominantly a high expression of IGF-1 receptors, such
THE LANCET • Vol 356 • August 5, 2000
as the human osteosarcoma cell line Saos/B102 and human mammary epithelial cells HMEC, a close relation between IGF-1 receptor affinity and mitogenic potency has been described.3 However, since only the AspB10 insulin analogue caused mammary tumours when given in high doses (12·5–200 U/kg) to rats, whereas insulin glargine given to rats and mice at a lower dose (2·0–12·5 U/kg) for up to 2 years did not, the carcinogenic effect is not substance specific. This suggests that a long residence time on the insulin receptor may be an important component of the enhanced mitogenicity of the AspB10 insulin analogue. Insulin glargine and human insulin have a similar time course for insulin-receptor binding and intracellular signalling events, whereas the action of the AspB10 insulin analogue is more persistent. Experiments using cell-lines expressing mainly insulin receptors (rat 1 fibroblasts)4 and human mammary epithelial cell-lines MCF10 (H U Häring, personal communication) have not shown increased mitogenicity, as measured by thymidine incorporation with insulin glargine. The clinical relevance of the recent observations by Kurtzhals et al2 of increased mitogenicity of insulin glargine compared with human insulin in a malignant cellline (human osteosarcoma, Saos/B10) is unknown. Therefore, the availability of the long-term data will be essential to answer this important question. There needs also to be an agreed battery of in-vitro and in-vivo tests to be employed to aid interpretations in the future. The observation of a three-grade progression of retinopathy (according to the scale used in the Early Treatment Diabetic Retinopathy Study) in some patients with type 2 diabetes treated with insulin glargine in studies of 1 year or less raised concern because IGF-1 signalling has been implicated in the regulation of vascular endothelial growth-factor-dependent retinal neovascularisation.5 However, review of the retinopathy data and the absence of optic-disc swelling during the studies (the most common ocular adverse effect of IGF-1 treatment) led an independent panel convened by Aventis Pharma to conclude that this finding was not related to therapy with insulin glargine. Do insulin-requiring diabetic patients really need a new long-acting insulin? Clearly they do. Existing intermediate-acting (netral protamine Hagedorn [NPH], Lente) and long-acting insulin formulations (Ultralente) cannot mimic the effect of basal insulin. All existing longacting insulin preparations have a peak-action profile (except for bovine Ultralente, which is not available because of its high immunogenic potential), a short duration of action, and a large within and between subject variability in subcutaneous absorption. Glucose homoeostasis in the interprandial and nocturnal periods is finely regulated by slow, continuous insulin secretion. Because the plasma concentration of insulin remains steady throughout the night, non-diabetic people do not experience hypoglycaemia in the night or hyperglycaemia at dawn. Thus, just by mimicking nature, use of an insulin with a peakless action profile should improve blood glucose control in type 1 diabetic patients, especially in those with absolute failure of the pancreatic -cells. This idea was tested by Pickup and co-workers nearly 25 years ago in their pioneering work with continuous subcutaneous insulin infusion (CSII).6 CSII still remains the reference standard against which any new candidate “basal” insulin, such as glargine, has to be compared. In type 1 diabetes, the action of a bolus dose of glargine, as assessed with the isoglycaemic clamp technique, starts about 90 min after subcutaneous 443
For personal use only. Not to be reproduced without permission of The Lancet.