1022
there would be a bigger pool of donors, better opportunities for prospective tissue-typing, and much more time to organise the recipient operation. Immunosuppression regimens continue to be refined to reduce the medium-term complications of rejection and infection. Transbronchial biopsy has proved useful in the diagnosis of bacterial infection in the first 2 weeks and in the distinction of rejection from viral infection. Chronic rejection, which is characterised by obliterative bronchiolitis, does not usually occur until at least 6 months postoperatively, and peaks around 2 years. Obliterative bronchiolitis is a non-specific response of the small airways and is essentially a clinical diagnosis, the characteristic feature being an irreversible decline in lung function. Although transbronchial biopsy has not proved useful for surveillance per se, it is very helpful if the clinical features--eg, fall in forced expiratory volume in 1
second, breathlessness, cough, or pyrexia-suggest rejection. 12 Chronic rejection affects 40-50% of recipients, and there is no satisfactory medical In children under the age of 10 who receive heart-lung transplants, obliterative bronchiolitis occurs in up to 80% within 3 years of the operation.13 For most patients with end-stage lung disease lung transplantation will transform their lives. Research and experience will undoubtedly overcome some of the difficulties and shed light on the basic mechanisms of lung receptor physiology and the pulmonary endothelium. Lobar transplantation and, therefore, live-related lung donation remain on the horizon. treatment.
1. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982; 306: 557-64. 2. Cooper JD. Lung transplantation: a new era. Ann Thorac Surg 1987; 44: 447-48. 3. Kreitt JM, Kaye MP. The Registry of the International Society for Heart and Lung Transplantation: eighth official report. J Heart Lung Transpl
1991; 10: 491-98. 4. Yacoub MY, Banner NR, Khaghani A, et al. Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Lung Transpl 1990; 9: 459-67. 5. Editorial. Single lung transplantation for pulmonary emphysema. Lancet 1992; 339: 216-17. 6. Yacoub M, Khaghani A, Theodoropoulos S, Tadjkarimi S, Banner N. Single lung transplantation for obstructive airways disease. Transplant Proc 1991; 23: 1213-14. 7. Kaiser LR, Cooper JD, Trulock EP. The evolution of single lung transplant for emphysema. J Thorac Cardiovasc Surg 1991; 102: 333-41. 8. Lima E, Cooper JD, Peters WJ. Effect of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation. J Thorac Cardiovasc Surg 1981; 82: 211-15. 9. Cooper JD, Patterson GA, Grossman R. Double-lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989; 139: 303-07. 10. Pucci A, Forbes RDC, Berry GJ, Rowan RA, Billingham ME. Accelerated post-transplant coronary arteriosclerosis in combined heart-lung transplantation. Transplant Proc 1991; 23: 1228-29. 11. Gore SM, Cable DJ, Holland AJ. Organ donation from intensive care units in England and Wales: two year confidential audit of deaths in intensive care. Br Med J 1992; 304: 349-55. 12. Higenbottam T, Stewart S, Penketh A. Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant recipients. Transplantation 1988; 46: 532-39. 13. Starnes VA, Marshall SE, Lewiston NJ, Theodore J, Stinson EB, Shumway NE. Heart-lung transplantation in infants, children and adolescents. J Pediatr Surg 1991; 26: 1-4.
QBC malaria
diagnosis
Malaria parasites, unlike their red cell hosts, contain nucleic acid that can be stained with fluorescent dyes such as acridine orange. As the intraerythrocytic parasites mature, they reduce the buoyant density of the infected erythrocytes. These two properties are exploited in the QBC technique for the diagnosis of haematoparasite infections.1,2 Blood (50-100 Ill) is taken into a capillary tube coated with acridine orange and anticoagulant (originally designed for rapid quantification of leucocytes) which contains a float. The tube is spun in a microhaematocrit centrifuge at about 12 000 g for 5 minutes. The parasitised erythrocytes are thereby concentrated in a 1-2 mm region at the top of the red cell column, just underneath the buffy coat. The float compresses the red cells against the wall of the tube in a thin (40 pm) column. The tube is then mounted on a small holder and examined either with a fluorescent microscope (preferably with a 50 x lens with a high working
distance 3)
or
through
an
ordinary light microscope
with customised fluorescence attachment. The concentrated malaria parasites stain green (DNA) and orange (RNA). The QBC technique is rapid, readily learnt, and in the original studies seemed to be slightly more sensitive than conventional microscopic examination of thick blood films.l-5 However, when the QBC system is taken to the field, away from air conditioning and reliable power supplies to the humid and impoverished reality of the malarious tropics, it does not do so well.5-7 In rural western Palawan in the Philippines, sensitivity and specificity of QBC malaria diagnosis compared with Giemsa-stained thick blood films were 70 % and 99 %, respectively ;5 in eastern Thailand 79% and 97%;6 and in north eastern Irian Jaya 75% and 95%.Low Plasmodium vivax parasitaemias, in which most parasites are mature, pose special difficulties. The P vivax infected erythrocytes are more buoyant and tend to mix with the buffy coat, where they may be obscured. The QBC system is expensive: the microscope attachment, dedicated light source, specialised microhaematocrit centrifuge, and other accessories cost more than the microscope itself. The QBC capillary tubes are over five times more expensive than stained blood slides, and they cannot be reused. Moreover, the tubes should be examined preferably within 20 minutes, and certainly within hours, of drawing up blood, which is often not feasible in the rural tropics; this limitation also precludes later rechecking. Confusing fluorescent material inside the tubes if they are exposed to a precipitates very humid environment for more than a few days.’ Finally, QBC does not distinguish between species of malaria parasites, and does not give a quantitative count. In the diagnosis of severe malaria, conventional microscopy is quicker and more informative.8 So where and when should this technique be used? QBC is too expensive and insufficiently durable to
1023
be deployed in small rural malaria clinics. Insensitivity under field conditions could be a drawback in surveys, but where finances permit, the speed of this method for detection of parasites in the 50-500/ul range is a definite advantage in laboratories that screen large numbers of blood samples. Other diagnostic techniques have been developed recently that allow visualisation of fluorescent dyes through an ordinary microscope with a filter attachment,9,10 but for the diagnosis of malaria their sensitivity, specificity, durability, and cost remain to be determined. Conventional thick and thin blood smears stained with Field’s or Giemsa’s stain are still the cornerstone of malaria diagnosis, especially of severe disease. Spielman A, Perrone JB, Teklahaimanot A, Balcha F, Wardlaw SC, Levine RA. Malaria diagnosis by direct observation of centrifuged samples of blood. Am J Trop Med Hyg 1988; 42: 337-42. 2. Levine RA, Wardlaw SC, Patton CL. Detection of haematoparasites using quantitative buffy coat analysis tubes. Parasitol Today 1989; 5: 1.
132-34. 3. Long GW, Jones TR, Rickman LS, Trimmer R, Hoffman SL. Acridine orange detection of Plasmodium falciparum malaria: relationship between sensitivity and optical configuration. Am J Trop Med Hyg 1991; 44: 402-05. 4. Moody AH, Hunt-Cooke A, Chiodini PL. Experience with the Becton-Dickinson II centrifugal haematology analyser for haemoparasites. Trans R Soc Trop Med Hyg 1990; 84: 782. 5. Rickman LS, Long GW, Oberst R, et al. Rapid diagnosis of malaria by acridine orange staining of centrifuged parasites. Lancet 1989; i: 68-71. 6. Wongsrichanalai C, Pomsilapatip J, Namsiripongpun V, et al. Acridine orange fluorescent microscopy and the detection of malaria in populations with low density parasitemia. Am J Trop Med Hyg 1991; 44: 17-20. 7. Baird JK, Purnomo, Jones TR. Diagnosis of malaria in the field by fluorescence microscopy of QBC(R) capillary tubes. Trans R Soc Trop Med Hyg 1992; 86: 3-5. 8. White NJ, Silamut K. Rapid diagnosis of malaria. Lancet 1989; i: 435. 9. Kawamoto F, Kumada N. Fluorescent probes for detection of protozoan parasites. Parasitol Today 1987; 3: 284-86. 10. Kawamoto F. Rapid diagnosis of malaria by fluorescence microscopy with light microscope and interference filter. Lancet 1991; 337: 200-02.
QBC(R)
Bed rest and
non-proteinuric hypertension in pregnancy
In view of the nature and distribution of blood
within
the
general population, any definition of arterial hypertension is bound to be arbitrary and sometimes devoid of diagnostic significance. This is never more true than during pregnancy, when a rise in pressure may be a transient, insubstantial event or may herald the development of a life-threatening syndrome. Another complication is that blood pressure normally falls in pressure
measurements
the first half of pregnancy and rises towards levels as term prepregnancy approaches. Consequently, even women with longstanding hypertension may appear normotensive when first seen in the antenatal clinic. Obstetricians have often debated whether progression of hypertension to a stage at which it poses a threat to maternal or fetal wellbeing can be prevented. In 1952 Hamlinl noted the virtual disappearance of eclampsia in one pregnant population with a policy of vigorous antenatal education and supervision. Since one of these
had included early admission to hospital, the perception arose that bed rest might improve the outcome of hypertensive pregnancy. In fact the particular programme introduced by Hamlin consisted of numerous interventions besides bed rest, including increased antenatal surveillance, dietary manipulation, and even use of the local constabulary to contact clinic defaulters. Nevertheless, the notion of bed rest became engrained in the minds of health service planners and large numbers of antenatal beds were set aside for the care of hypertensive pregnant
measures
patients. Mathews2,3 was the first to question the value of bed rest in non-proteinuric hypertension. He claimed that routine antenatal admission could be replaced by regular antenatal clinic attendance and self-testing of urine for proteinuria without any apparent detrimental effect on maternal or fetal outcome. More recently, a study of 218 subjects randomised to hospital admission or outpatient management also failed to show that inpatient care had improved the perinatal outcome.4 Although, as in Mathews’ study, more patients managed at home attained a diastolic blood pressure of 110 mm Hg, there was no difference in the proportion who went on to get proteinuria. Perhaps more important from the patient’s perspective, those allocated to outpatient care were spared on average over one week of hospital admission.
Non-proteinuric hypertension seems to carry virtually no risk to fetus,56 but unfortunately a pregnancy can only be classified firmly as nonproteinuric after delivery. About 25-30% of women who present initially with non-proteinuric hypertension will go on to manifest proteinuria7 and other features of pre-eclampsia, and so there is a rational basis for close supervision of all hypertensive pregnant patients. However, there is growing evidence that supervision can be undertaken most efficiently in day-care units,8,9 thereby diminishing the expense and social disruption of hospital admission. It is possible that pregnancy reveals a hypertensive tendency in certain susceptible individuals who are destined to get fixed essential hypertension in later life. This view accords with the observation that the highest rates of chronic hypertension in middle age are found in women whose pregnancies were complicated by mild (especially recurrent) hypertension.10 It is precisely in this group of women with "gestational" or mild essential hypertension that one may anticipate a good perinatal outcome in the absence of superimposed pre-eclampsia. That there is undoubtedly an increased risk of pre-eclampsia may be due to the fact that pre-existing hypertension can compromise the expansion of the maternal plasma volume compartment,11 which is so important to a healthy pregnancy, and thus increase the possibility of uteroplacental ischaemia (the likely root cause of the pre-eclampsia syndrome). Apart from a marginal effect on plasma volume12 it is difficult to perceive a
there would be a bigger pool of donors, better opportunities for prospective tissue-typing, and much more time to organise the recipient operation. Immunosuppression regimens continue to be refined to reduce the medium-term complications of rejection and infection. Transbronchial biopsy has proved useful in the diagnosis of bacterial infection in the first 2 weeks and in the distinction of rejection from viral infection. Chronic rejection, which is characterised by obliterative bronchiolitis, does not usually occur until at least 6 months postoperatively, and peaks around 2 years. Obliterative bronchiolitis is a non-specific response of the small airways and is essentially a clinical diagnosis, the characteristic feature being an irreversible decline in lung function. Although transbronchial biopsy has not proved useful for surveillance per se, it is very helpful if the clinical features--eg, fall in forced expiratory volume in 1
second, breathlessness, cough, or pyrexia-suggest rejection. 12 Chronic rejection affects 40-50% of recipients, and there is no satisfactory medical In children under the age of 10 who receive heart-lung transplants, obliterative bronchiolitis occurs in up to 80% within 3 years of the operation.13 For most patients with end-stage lung disease lung transplantation will transform their lives. Research and experience will undoubtedly overcome some of the difficulties and shed light on the basic mechanisms of lung receptor physiology and the pulmonary endothelium. Lobar transplantation and, therefore, live-related lung donation remain on the horizon. treatment.
1. Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982; 306: 557-64. 2. Cooper JD. Lung transplantation: a new era. Ann Thorac Surg 1987; 44: 447-48. 3. Kreitt JM, Kaye MP. The Registry of the International Society for Heart and Lung Transplantation: eighth official report. J Heart Lung Transpl
1991; 10: 491-98. 4. Yacoub MY, Banner NR, Khaghani A, et al. Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Lung Transpl 1990; 9: 459-67. 5. Editorial. Single lung transplantation for pulmonary emphysema. Lancet 1992; 339: 216-17. 6. Yacoub M, Khaghani A, Theodoropoulos S, Tadjkarimi S, Banner N. Single lung transplantation for obstructive airways disease. Transplant Proc 1991; 23: 1213-14. 7. Kaiser LR, Cooper JD, Trulock EP. The evolution of single lung transplant for emphysema. J Thorac Cardiovasc Surg 1991; 102: 333-41. 8. Lima E, Cooper JD, Peters WJ. Effect of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation. J Thorac Cardiovasc Surg 1981; 82: 211-15. 9. Cooper JD, Patterson GA, Grossman R. Double-lung transplant for advanced chronic obstructive lung disease. Am Rev Respir Dis 1989; 139: 303-07. 10. Pucci A, Forbes RDC, Berry GJ, Rowan RA, Billingham ME. Accelerated post-transplant coronary arteriosclerosis in combined heart-lung transplantation. Transplant Proc 1991; 23: 1228-29. 11. Gore SM, Cable DJ, Holland AJ. Organ donation from intensive care units in England and Wales: two year confidential audit of deaths in intensive care. Br Med J 1992; 304: 349-55. 12. Higenbottam T, Stewart S, Penketh A. Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant recipients. Transplantation 1988; 46: 532-39. 13. Starnes VA, Marshall SE, Lewiston NJ, Theodore J, Stinson EB, Shumway NE. Heart-lung transplantation in infants, children and adolescents. J Pediatr Surg 1991; 26: 1-4.
QBC malaria
diagnosis
Malaria parasites, unlike their red cell hosts, contain nucleic acid that can be stained with fluorescent dyes such as acridine orange. As the intraerythrocytic parasites mature, they reduce the buoyant density of the infected erythrocytes. These two properties are exploited in the QBC technique for the diagnosis of haematoparasite infections.1,2 Blood (50-100 Ill) is taken into a capillary tube coated with acridine orange and anticoagulant (originally designed for rapid quantification of leucocytes) which contains a float. The tube is spun in a microhaematocrit centrifuge at about 12 000 g for 5 minutes. The parasitised erythrocytes are thereby concentrated in a 1-2 mm region at the top of the red cell column, just underneath the buffy coat. The float compresses the red cells against the wall of the tube in a thin (40 pm) column. The tube is then mounted on a small holder and examined either with a fluorescent microscope (preferably with a 50 x lens with a high working
distance 3)
or
through
an
ordinary light microscope
with customised fluorescence attachment. The concentrated malaria parasites stain green (DNA) and orange (RNA). The QBC technique is rapid, readily learnt, and in the original studies seemed to be slightly more sensitive than conventional microscopic examination of thick blood films.l-5 However, when the QBC system is taken to the field, away from air conditioning and reliable power supplies to the humid and impoverished reality of the malarious tropics, it does not do so well.5-7 In rural western Palawan in the Philippines, sensitivity and specificity of QBC malaria diagnosis compared with Giemsa-stained thick blood films were 70 % and 99 %, respectively ;5 in eastern Thailand 79% and 97%;6 and in north eastern Irian Jaya 75% and 95%.Low Plasmodium vivax parasitaemias, in which most parasites are mature, pose special difficulties. The P vivax infected erythrocytes are more buoyant and tend to mix with the buffy coat, where they may be obscured. The QBC system is expensive: the microscope attachment, dedicated light source, specialised microhaematocrit centrifuge, and other accessories cost more than the microscope itself. The QBC capillary tubes are over five times more expensive than stained blood slides, and they cannot be reused. Moreover, the tubes should be examined preferably within 20 minutes, and certainly within hours, of drawing up blood, which is often not feasible in the rural tropics; this limitation also precludes later rechecking. Confusing fluorescent material inside the tubes if they are exposed to a precipitates very humid environment for more than a few days.’ Finally, QBC does not distinguish between species of malaria parasites, and does not give a quantitative count. In the diagnosis of severe malaria, conventional microscopy is quicker and more informative.8 So where and when should this technique be used? QBC is too expensive and insufficiently durable to
1023
be deployed in small rural malaria clinics. Insensitivity under field conditions could be a drawback in surveys, but where finances permit, the speed of this method for detection of parasites in the 50-500/ul range is a definite advantage in laboratories that screen large numbers of blood samples. Other diagnostic techniques have been developed recently that allow visualisation of fluorescent dyes through an ordinary microscope with a filter attachment,9,10 but for the diagnosis of malaria their sensitivity, specificity, durability, and cost remain to be determined. Conventional thick and thin blood smears stained with Field’s or Giemsa’s stain are still the cornerstone of malaria diagnosis, especially of severe disease. Spielman A, Perrone JB, Teklahaimanot A, Balcha F, Wardlaw SC, Levine RA. Malaria diagnosis by direct observation of centrifuged samples of blood. Am J Trop Med Hyg 1988; 42: 337-42. 2. Levine RA, Wardlaw SC, Patton CL. Detection of haematoparasites using quantitative buffy coat analysis tubes. Parasitol Today 1989; 5: 1.
132-34. 3. Long GW, Jones TR, Rickman LS, Trimmer R, Hoffman SL. Acridine orange detection of Plasmodium falciparum malaria: relationship between sensitivity and optical configuration. Am J Trop Med Hyg 1991; 44: 402-05. 4. Moody AH, Hunt-Cooke A, Chiodini PL. Experience with the Becton-Dickinson II centrifugal haematology analyser for haemoparasites. Trans R Soc Trop Med Hyg 1990; 84: 782. 5. Rickman LS, Long GW, Oberst R, et al. Rapid diagnosis of malaria by acridine orange staining of centrifuged parasites. Lancet 1989; i: 68-71. 6. Wongsrichanalai C, Pomsilapatip J, Namsiripongpun V, et al. Acridine orange fluorescent microscopy and the detection of malaria in populations with low density parasitemia. Am J Trop Med Hyg 1991; 44: 17-20. 7. Baird JK, Purnomo, Jones TR. Diagnosis of malaria in the field by fluorescence microscopy of QBC(R) capillary tubes. Trans R Soc Trop Med Hyg 1992; 86: 3-5. 8. White NJ, Silamut K. Rapid diagnosis of malaria. Lancet 1989; i: 435. 9. Kawamoto F, Kumada N. Fluorescent probes for detection of protozoan parasites. Parasitol Today 1987; 3: 284-86. 10. Kawamoto F. Rapid diagnosis of malaria by fluorescence microscopy with light microscope and interference filter. Lancet 1991; 337: 200-02.
QBC(R)
Bed rest and
non-proteinuric hypertension in pregnancy
In view of the nature and distribution of blood
within
the
general population, any definition of arterial hypertension is bound to be arbitrary and sometimes devoid of diagnostic significance. This is never more true than during pregnancy, when a rise in pressure may be a transient, insubstantial event or may herald the development of a life-threatening syndrome. Another complication is that blood pressure normally falls in pressure
measurements
the first half of pregnancy and rises towards levels as term prepregnancy approaches. Consequently, even women with longstanding hypertension may appear normotensive when first seen in the antenatal clinic. Obstetricians have often debated whether progression of hypertension to a stage at which it poses a threat to maternal or fetal wellbeing can be prevented. In 1952 Hamlinl noted the virtual disappearance of eclampsia in one pregnant population with a policy of vigorous antenatal education and supervision. Since one of these
had included early admission to hospital, the perception arose that bed rest might improve the outcome of hypertensive pregnancy. In fact the particular programme introduced by Hamlin consisted of numerous interventions besides bed rest, including increased antenatal surveillance, dietary manipulation, and even use of the local constabulary to contact clinic defaulters. Nevertheless, the notion of bed rest became engrained in the minds of health service planners and large numbers of antenatal beds were set aside for the care of hypertensive pregnant
measures
patients. Mathews2,3 was the first to question the value of bed rest in non-proteinuric hypertension. He claimed that routine antenatal admission could be replaced by regular antenatal clinic attendance and self-testing of urine for proteinuria without any apparent detrimental effect on maternal or fetal outcome. More recently, a study of 218 subjects randomised to hospital admission or outpatient management also failed to show that inpatient care had improved the perinatal outcome.4 Although, as in Mathews’ study, more patients managed at home attained a diastolic blood pressure of 110 mm Hg, there was no difference in the proportion who went on to get proteinuria. Perhaps more important from the patient’s perspective, those allocated to outpatient care were spared on average over one week of hospital admission.
Non-proteinuric hypertension seems to carry virtually no risk to fetus,56 but unfortunately a pregnancy can only be classified firmly as nonproteinuric after delivery. About 25-30% of women who present initially with non-proteinuric hypertension will go on to manifest proteinuria7 and other features of pre-eclampsia, and so there is a rational basis for close supervision of all hypertensive pregnant patients. However, there is growing evidence that supervision can be undertaken most efficiently in day-care units,8,9 thereby diminishing the expense and social disruption of hospital admission. It is possible that pregnancy reveals a hypertensive tendency in certain susceptible individuals who are destined to get fixed essential hypertension in later life. This view accords with the observation that the highest rates of chronic hypertension in middle age are found in women whose pregnancies were complicated by mild (especially recurrent) hypertension.10 It is precisely in this group of women with "gestational" or mild essential hypertension that one may anticipate a good perinatal outcome in the absence of superimposed pre-eclampsia. That there is undoubtedly an increased risk of pre-eclampsia may be due to the fact that pre-existing hypertension can compromise the expansion of the maternal plasma volume compartment,11 which is so important to a healthy pregnancy, and thus increase the possibility of uteroplacental ischaemia (the likely root cause of the pre-eclampsia syndrome). Apart from a marginal effect on plasma volume12 it is difficult to perceive a
