- Email: [email protected]
Arteriovenous malformations and hepatopulmonary syndrome
Correspondence
open-access or closed-access journal, we now wonder whether it is ethical for us to opt for closed access on the grounds of impact factor or preferred specialist audience. In future, we intend to publish our findings only in open-access journals. We welcome the decision of The Lancet to make certain articles open access to the developing world, but we urge the boards of The Lancet and Elsevier to take a bold step and make all their articles open access. It might be that this decision will reduce subscription income, but alternative models exist, such as contribution to the peer review and publication process by submitting institutions, with exemptions for scientists in poorer countries. We would applaud such a move to ensure that The Lancet retains its position as a profitable and leading international health journal.
*Anthony Costello, David Osrin [email protected] International Perinatal Care Unit, Institute of Child Health, University College London, London WC1N 1EH, UK 1 2
3
Horton R. 21st-century biomedical journals: failures and futures. Lancet 2003; 362: 1510. Tamber PS, Godlee F, Newmark P. Open access to peer-reviewed research: making it happen. Lancet 2003; 362: 1575–77. Crawford BD. Open-access publishing: where is the value? Lancet 2003; 362: 1578–80.
HIV treatment in South African children We agree with Abdool Karim (April 24, p 1394)1 that South Africa should create a treatment programme that is readily accessible to all HIV-positive patients, and feel that the problems of funding HIV treatment are especially relevant for children, since they are particularly vulnerable to rapid progression to AIDS. 2·5 million children worldwide are infected with HIV,2 and 3 million have already died from AIDS-related diseases.3 Studies have estimated that 5·6% of children in South Africa are infected with HIV.4 In August, 2003, one of us (LJN) spent an elective period as a medical student on the paediatric HIV ward at Groote Schuur Hospital in Cape Town, South Africa. Despite the high prevalence of paediatric HIV infection in South Africa, 26
this ward had funding for the treatment of only 149 children, from the One-toOne Children’s Fund in the UK (http://www.One2Onekids.org). During the elective, LJN reviewed 50 HIV-related admissions among the 149 children who were at that time receiving highly active antiretroviral therapy (HAART). The current admission was analysed and a retrospective study was done to review each child’s admissions before and after the start of HAART. The study showed a mean annualised admission rate of 4·5 per child before the start of antiretroviral therapy, and 1·6 admissions per child after starting HAART. The mean number of diagnoses made per child declined from 9·4 per year before access to HAART to 1·9 per year afterwards. The mean number of diagnoses made per admission declined from 2·1 before starting HAART to 1·6 on therapy. Diagnoses made before treatment were dermatitis, otitis media, haematological abnormalities, pneumonia, sepsis, candidiasis, diarrhoea, lymphoid interstitial pneumonia, multiple recurrent pneumonia, and wasting. After starting treatment the main diagnoses were dermatitis, recurrent pneumonia, and wasting. The conclusions that can be drawn from this limited study of HIV-infected children are that HAART reduces the number of hospital admissions for HIV-related diagnoses, reduces the number of HIVrelated diagnoses made per admission, and profoundly improves the health of children with HIV. Although this was a small study, it showed that children had substantially less HIV-related morbidity on HAART. A longer study of a larger treatment cohort should be done to confirm and refine these findings. We strongly support widespread access to appropriate primary health care for HIV-infected children throughout South Africa and to antiretroviral therapy for the children who need it.
Laura J Neal, *Kathir Yoganathan, Paul Roux [email protected] University of Wales College of Medicine, Cardiff, UK (LJN); *Singleton Hospital, Sketty, Swansea SA2 8QA, UK (KY); and Groote Schuur Hospital, Cape Town, South Africa (PR)
1
2
3 4
Karim QA. HIV treatment in South Africa: overcoming impediments to get started. Lancet 2004; 363: 1394. Kmietowicz Z. Global efforts to control AIDS are ‘entirely inadequate’. BMJ 2003; 327: 1246. Vazquez E. Children of the epidemic. Posit Aware 1996; 7: 35–36. Sidley P. HIV infection rate among South African children found to be 5·6%. BMJ 2002; 325: 1380.
Arteriovenous malformations and hepatopulmonary syndrome Marius Hoeper and colleagues (May 1, p 1461)1 address a very interesting hypothesis about the pathogenesis of underlying pulmonary-vessel dilatation in hepatopulmonary syndrome. We appreciated this Review very much; however, as paediatric cardiologists, we would like to draw hepatologists’ and pulmonologists’ attentions to the following hypothesis. The same pattern of hepatopulmonary syndrome is seen in some patients with “Fontan”-like circulations and exclusion of hepatic venous return through the pulmonary vascular bed. This finding reinforces the likelihood that the cause of the arteriovenous malformations is the absence of an as-yet unidentified hepatic vasoactive substance. However, the development of pulmonary arteriovenous fistulae is not only associated with these low-flow, lowshear-stress pulmonary perfusions caused by vena cavae surgically connected to the pulmonary arteries and resulting in missing right-heart function,2 but also with intact pulsatile pulmonary blood flow only if hepatic venous return is excluded.3 Patients with this disorder have severe hypoxaemia as well as orthodeoxia. The only therapeutic option for these patients is the surgical redirection of hepatic venous flow to the pulmonary arterial system.4 In patients with staging bidirectional cavopulmonary anastomosis and already developed intrapulmonary fistulae, the “hepatic” blood can be included www.thelancet.com Vol 364 July 3, 2004
Correspondence
by “Fontan” completion (total caval pulmonary connection). In this context, the pulmonary vessels are thought to need hepatic blood from a healthy liver to avoid these pulmonary arteriovenous fistulae, which result from an excessive angioproliferative process. This hypothesis raises the question of whether there is some protecting or scavenging factor, produced by or located in a healthy liver, that is missing in patients with cirrhosis or in pulmonary circulations with an excluded firstbypass hepatic circulation. Should we not focus our scientific work on this hypothesis? If true, a genetically engineered factor with a wide range of indications can be imagined.
*Dietmar Schranz, Ina Michel-Behnke [email protected] Department of Paediatric Cardiology, Justus-Liebig University, 35385 Giessen, Germany 1
2
3
4
Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363: 1461–68. Bernstein HS, Brock MM, Silverman NH, Bristow J. Development of pulmonary arteriovenous fistulae in children after cavopulmonary shunt. Circulation 1995; 92: 309–14. Johnson TR, Schamberger MS, Brown JW, Girod DA. Resolution of acquired arteriovenous malformations in a patient with total anomalous systemic venous return. Pediatr Cardiol 2002; 23: 210–12. Knight WB, Mee RB. A cure for pulmonary arteriovenous fistulae? Ann Thorac Surg 1995; 59: 999–1001.
Authors’ reply From a pathophysiological point of view, the formation of arteriovenous malformations after surgical creation of cavopulmonary anastomoses is a fascinating phenomenon. Many lines of evidence suggest that exclusion of hepatic venous blood flow from the lungs causes these vascular malformations.1–3 This problem is nicely illustrated by a case report of a baby born with anomalous hepatic venous drainage into the left atrium in whom pulmonary arteriovenous malformations developed in childhood. These malformations reversed after diversion of the hepatic venous drainage to the www.thelancet.com Vol 364 July 3, 2004
right atrium.4 Thus, the pulmonary circulation seems to require a factor produced or delivered by the liver to suppress the formation of arteriovenous malformations. These vascular malformations carry features similar to hepatopulmonary syndrome. However, to fully understand the pathogenesis of hepatopulmonary syndrome and the formation of arteriovenous malformations in patients with abnormal circulation involving pulmonary blood flow deprived of hepatic venous blood supply, it will be crucial to distinguish between abnormal intrapulmonary vascular dilatations and arteriovenous malformations. As outlined in our Review, there is a solid line of evidence to support the role of nitric oxide and, possibly, endothelin 1 in the development of intrapulmonary vascular dilatations. However, overexpression of nitric oxide and endothelin 1 might not explain the formation of arteriovenous malformations, which result from misguided angiogenesis.5 Here, in fact, there is good reason to postulate deprivation of the pulmonary vasculature from a “scavenging factor” produced in the liver and required to suppress angiogenic processes in the lung. As suggested by Dietmar Schranz and Ina Michel-Behnke, a better understanding of the hepatopulmonary interactions would improve our understanding of many pulmonary vascular diseases and could also offer novel therapeutic options for many of these disorders. Thus, we fully support our colleagues in their call for collaborative studies to address these important issues.
*Marius M Hoeper, Michael J Krowka, Christian P Strassburg [email protected] Departments of *Respiratory Medicine (MMH) and Gastroenterology, Hepatology and Endocrinology (CPS), Hannover Medical School, 30623 Hannover, Germany; and Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA (MJK) 1
2
McFaul RC, Tajik AJ, Mair DD, Danielson GK, Seward JB. Development of pulmonary arteriovenous shunt after superior vena cava-right pulmonary artery (Glenn) anastomosis: report of four cases. Circulation 1977; 55: 212–16. Krowka MJ. Hepatopulmonary syndrome: what are we learning from interventional radiology,
3
4
5
liver transplantation, and other disorders? Gastroenterology 1995; 109: 1009–13. Vettukattil JJ, Slavik Z, Lamb RK, et al. Intrapulmonary arteriovenous shunting may be a universal phenomenon in patients with the superior cavopulmonary anastomosis: a radionuclide study. Heart 2000; 83: 425–28. Lee J, Menkis AH, Rosenberg HC. Reversal of pulmonary arteriovenous malformation after diversion of anomalous hepatic drainage. Ann Thorac Surg 1998; 65: 848–49. Duncan BW, Kneebone JM, Chi EY, et al. A detailed histologic analysis of pulmonary arteriovenous malformations in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg 1999; 117: 931–38.
Abuse of health-care workers’ neutral status In a Correspondence letter, John R Cohn and colleagues (May 1, p 1473)1 try to justify Israel’s targeting of Palestinian ambulances (and hospitals), which contradicts international laws and the Protocol Additional to Geneva’s conventions. The authors suggest that ambulances could carry weapons, explosives, and combatants. Israel gives similar explanations to justify the existence of 56 staffed checkpoints and 607 physical roadblocks. Checkpoints often block ambulances for hours, and sometimes sick people have been turned away. Blockades are decided by checkpoint commanders who have no medical education. The authors write: “Such delay is lamentable but usually not as permanently harmful as the murders that provoke it.” There have been at least 38 Palestinian deaths (of which 14 were minors) because of time spent waiting at checkpoints. Ambulance drivers and medics have been harassed and beaten and patients have died because they could not reach a hospital.2 Since the Israeli army is illegally occupying the Palestinian territory, it has total responsibility for any harm to Palestinian civilians and property according to international rules and conventions, signed by Israel itself. In times of preventive “wars on terror”, everything seems allowed. Israel has been able to show only once that Palestinian combatants had used an ambulance to transport explosives.3 27
open-access or closed-access journal, we now wonder whether it is ethical for us to opt for closed access on the grounds of impact factor or preferred specialist audience. In future, we intend to publish our findings only in open-access journals. We welcome the decision of The Lancet to make certain articles open access to the developing world, but we urge the boards of The Lancet and Elsevier to take a bold step and make all their articles open access. It might be that this decision will reduce subscription income, but alternative models exist, such as contribution to the peer review and publication process by submitting institutions, with exemptions for scientists in poorer countries. We would applaud such a move to ensure that The Lancet retains its position as a profitable and leading international health journal.
*Anthony Costello, David Osrin [email protected] International Perinatal Care Unit, Institute of Child Health, University College London, London WC1N 1EH, UK 1 2
3
Horton R. 21st-century biomedical journals: failures and futures. Lancet 2003; 362: 1510. Tamber PS, Godlee F, Newmark P. Open access to peer-reviewed research: making it happen. Lancet 2003; 362: 1575–77. Crawford BD. Open-access publishing: where is the value? Lancet 2003; 362: 1578–80.
HIV treatment in South African children We agree with Abdool Karim (April 24, p 1394)1 that South Africa should create a treatment programme that is readily accessible to all HIV-positive patients, and feel that the problems of funding HIV treatment are especially relevant for children, since they are particularly vulnerable to rapid progression to AIDS. 2·5 million children worldwide are infected with HIV,2 and 3 million have already died from AIDS-related diseases.3 Studies have estimated that 5·6% of children in South Africa are infected with HIV.4 In August, 2003, one of us (LJN) spent an elective period as a medical student on the paediatric HIV ward at Groote Schuur Hospital in Cape Town, South Africa. Despite the high prevalence of paediatric HIV infection in South Africa, 26
this ward had funding for the treatment of only 149 children, from the One-toOne Children’s Fund in the UK (http://www.One2Onekids.org). During the elective, LJN reviewed 50 HIV-related admissions among the 149 children who were at that time receiving highly active antiretroviral therapy (HAART). The current admission was analysed and a retrospective study was done to review each child’s admissions before and after the start of HAART. The study showed a mean annualised admission rate of 4·5 per child before the start of antiretroviral therapy, and 1·6 admissions per child after starting HAART. The mean number of diagnoses made per child declined from 9·4 per year before access to HAART to 1·9 per year afterwards. The mean number of diagnoses made per admission declined from 2·1 before starting HAART to 1·6 on therapy. Diagnoses made before treatment were dermatitis, otitis media, haematological abnormalities, pneumonia, sepsis, candidiasis, diarrhoea, lymphoid interstitial pneumonia, multiple recurrent pneumonia, and wasting. After starting treatment the main diagnoses were dermatitis, recurrent pneumonia, and wasting. The conclusions that can be drawn from this limited study of HIV-infected children are that HAART reduces the number of hospital admissions for HIV-related diagnoses, reduces the number of HIVrelated diagnoses made per admission, and profoundly improves the health of children with HIV. Although this was a small study, it showed that children had substantially less HIV-related morbidity on HAART. A longer study of a larger treatment cohort should be done to confirm and refine these findings. We strongly support widespread access to appropriate primary health care for HIV-infected children throughout South Africa and to antiretroviral therapy for the children who need it.
Laura J Neal, *Kathir Yoganathan, Paul Roux [email protected] University of Wales College of Medicine, Cardiff, UK (LJN); *Singleton Hospital, Sketty, Swansea SA2 8QA, UK (KY); and Groote Schuur Hospital, Cape Town, South Africa (PR)
1
2
3 4
Karim QA. HIV treatment in South Africa: overcoming impediments to get started. Lancet 2004; 363: 1394. Kmietowicz Z. Global efforts to control AIDS are ‘entirely inadequate’. BMJ 2003; 327: 1246. Vazquez E. Children of the epidemic. Posit Aware 1996; 7: 35–36. Sidley P. HIV infection rate among South African children found to be 5·6%. BMJ 2002; 325: 1380.
Arteriovenous malformations and hepatopulmonary syndrome Marius Hoeper and colleagues (May 1, p 1461)1 address a very interesting hypothesis about the pathogenesis of underlying pulmonary-vessel dilatation in hepatopulmonary syndrome. We appreciated this Review very much; however, as paediatric cardiologists, we would like to draw hepatologists’ and pulmonologists’ attentions to the following hypothesis. The same pattern of hepatopulmonary syndrome is seen in some patients with “Fontan”-like circulations and exclusion of hepatic venous return through the pulmonary vascular bed. This finding reinforces the likelihood that the cause of the arteriovenous malformations is the absence of an as-yet unidentified hepatic vasoactive substance. However, the development of pulmonary arteriovenous fistulae is not only associated with these low-flow, lowshear-stress pulmonary perfusions caused by vena cavae surgically connected to the pulmonary arteries and resulting in missing right-heart function,2 but also with intact pulsatile pulmonary blood flow only if hepatic venous return is excluded.3 Patients with this disorder have severe hypoxaemia as well as orthodeoxia. The only therapeutic option for these patients is the surgical redirection of hepatic venous flow to the pulmonary arterial system.4 In patients with staging bidirectional cavopulmonary anastomosis and already developed intrapulmonary fistulae, the “hepatic” blood can be included www.thelancet.com Vol 364 July 3, 2004
Correspondence
by “Fontan” completion (total caval pulmonary connection). In this context, the pulmonary vessels are thought to need hepatic blood from a healthy liver to avoid these pulmonary arteriovenous fistulae, which result from an excessive angioproliferative process. This hypothesis raises the question of whether there is some protecting or scavenging factor, produced by or located in a healthy liver, that is missing in patients with cirrhosis or in pulmonary circulations with an excluded firstbypass hepatic circulation. Should we not focus our scientific work on this hypothesis? If true, a genetically engineered factor with a wide range of indications can be imagined.
*Dietmar Schranz, Ina Michel-Behnke [email protected] Department of Paediatric Cardiology, Justus-Liebig University, 35385 Giessen, Germany 1
2
3
4
Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004; 363: 1461–68. Bernstein HS, Brock MM, Silverman NH, Bristow J. Development of pulmonary arteriovenous fistulae in children after cavopulmonary shunt. Circulation 1995; 92: 309–14. Johnson TR, Schamberger MS, Brown JW, Girod DA. Resolution of acquired arteriovenous malformations in a patient with total anomalous systemic venous return. Pediatr Cardiol 2002; 23: 210–12. Knight WB, Mee RB. A cure for pulmonary arteriovenous fistulae? Ann Thorac Surg 1995; 59: 999–1001.
Authors’ reply From a pathophysiological point of view, the formation of arteriovenous malformations after surgical creation of cavopulmonary anastomoses is a fascinating phenomenon. Many lines of evidence suggest that exclusion of hepatic venous blood flow from the lungs causes these vascular malformations.1–3 This problem is nicely illustrated by a case report of a baby born with anomalous hepatic venous drainage into the left atrium in whom pulmonary arteriovenous malformations developed in childhood. These malformations reversed after diversion of the hepatic venous drainage to the www.thelancet.com Vol 364 July 3, 2004
right atrium.4 Thus, the pulmonary circulation seems to require a factor produced or delivered by the liver to suppress the formation of arteriovenous malformations. These vascular malformations carry features similar to hepatopulmonary syndrome. However, to fully understand the pathogenesis of hepatopulmonary syndrome and the formation of arteriovenous malformations in patients with abnormal circulation involving pulmonary blood flow deprived of hepatic venous blood supply, it will be crucial to distinguish between abnormal intrapulmonary vascular dilatations and arteriovenous malformations. As outlined in our Review, there is a solid line of evidence to support the role of nitric oxide and, possibly, endothelin 1 in the development of intrapulmonary vascular dilatations. However, overexpression of nitric oxide and endothelin 1 might not explain the formation of arteriovenous malformations, which result from misguided angiogenesis.5 Here, in fact, there is good reason to postulate deprivation of the pulmonary vasculature from a “scavenging factor” produced in the liver and required to suppress angiogenic processes in the lung. As suggested by Dietmar Schranz and Ina Michel-Behnke, a better understanding of the hepatopulmonary interactions would improve our understanding of many pulmonary vascular diseases and could also offer novel therapeutic options for many of these disorders. Thus, we fully support our colleagues in their call for collaborative studies to address these important issues.
*Marius M Hoeper, Michael J Krowka, Christian P Strassburg [email protected] Departments of *Respiratory Medicine (MMH) and Gastroenterology, Hepatology and Endocrinology (CPS), Hannover Medical School, 30623 Hannover, Germany; and Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA (MJK) 1
2
McFaul RC, Tajik AJ, Mair DD, Danielson GK, Seward JB. Development of pulmonary arteriovenous shunt after superior vena cava-right pulmonary artery (Glenn) anastomosis: report of four cases. Circulation 1977; 55: 212–16. Krowka MJ. Hepatopulmonary syndrome: what are we learning from interventional radiology,
3
4
5
liver transplantation, and other disorders? Gastroenterology 1995; 109: 1009–13. Vettukattil JJ, Slavik Z, Lamb RK, et al. Intrapulmonary arteriovenous shunting may be a universal phenomenon in patients with the superior cavopulmonary anastomosis: a radionuclide study. Heart 2000; 83: 425–28. Lee J, Menkis AH, Rosenberg HC. Reversal of pulmonary arteriovenous malformation after diversion of anomalous hepatic drainage. Ann Thorac Surg 1998; 65: 848–49. Duncan BW, Kneebone JM, Chi EY, et al. A detailed histologic analysis of pulmonary arteriovenous malformations in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg 1999; 117: 931–38.
Abuse of health-care workers’ neutral status In a Correspondence letter, John R Cohn and colleagues (May 1, p 1473)1 try to justify Israel’s targeting of Palestinian ambulances (and hospitals), which contradicts international laws and the Protocol Additional to Geneva’s conventions. The authors suggest that ambulances could carry weapons, explosives, and combatants. Israel gives similar explanations to justify the existence of 56 staffed checkpoints and 607 physical roadblocks. Checkpoints often block ambulances for hours, and sometimes sick people have been turned away. Blockades are decided by checkpoint commanders who have no medical education. The authors write: “Such delay is lamentable but usually not as permanently harmful as the murders that provoke it.” There have been at least 38 Palestinian deaths (of which 14 were minors) because of time spent waiting at checkpoints. Ambulance drivers and medics have been harassed and beaten and patients have died because they could not reach a hospital.2 Since the Israeli army is illegally occupying the Palestinian territory, it has total responsibility for any harm to Palestinian civilians and property according to international rules and conventions, signed by Israel itself. In times of preventive “wars on terror”, everything seems allowed. Israel has been able to show only once that Palestinian combatants had used an ambulance to transport explosives.3 27