has improved survival in patients with anaemia.18 The association between PNH and aplastic acute myeloid leukaemia remains much less frequent.19 Bone marrow exposed to mutagens or to somatic mutations might be at increased risk of developing PNH or acute myeloid leukaemia or both, but the relation between these two conditions is more specific. In at least one case the leukaemia arose from within the PNH clone2°-ie, PNH qualifies as a pre-leukaemic condition. The only known curative treatment for PNH is bone marrow transplantation. This procedure has been used mostly in PNH patients with aplasia; patients are usually conditioned without radiation, and the results have been indistinguishable from those obtained in aplastic anaemia. In the Seattle series21 only 3 patients had classic haemolytic PNH: they were also conditioned without radiation, and in only 1 was long-term engraftment achieved. Thus, the therapeutic decision in a patient with haemolytic PNH who has an HLA-identical sibling donor remains bone marrow difficult-delaying transplantation means denying the patient the only sound chance of a cure but previous myeloablative treatment may be required for the success of the transplant, and this entails extra risks. To make the decision even more difficult, there are some welldocumented examples of spontaneous remission.2 Thus, although the treatment of PNH is not very satisfactory, information about biochemical abnormalities has narrowed down the range of candidate primary lesions. If, in a PHN patient, somatic mutation has taken place at a single genetic locus, it must be possible to identify and clone the corresponding gene and thereby elucidate the molecular basis of this non-neoplastic clonal disorder. treatment
RE, Hall SE, Rosse WF. Paroxysmal nocturnal hemoglobinuria onset in childhood and adolescence. N EngL J Med 1991; 325:
JV. Paroxysmal nocturnal haemoglobinuria. In: the haemolytic anaemias, vol IV. 2nd ed. London: Churchill, 1967: 1128-60. 3. Oni SB, Osunkoya BO, Luzzatto L. Paroxysmal nocturnal 2. Dacie
hemoglobinuria: evidence for monoclonal origin of abnormal red cells. Blood 1970; 36: 145-52. B, Robledo R, Scarpato N, Luzzatto L. Two populations of erythroid cell progenitors in paroxysmal nocturnal hemoglobinuria. Blood 1984; 64: 847-51. 5. De Sandre G, Ghiotto G, Mastella G. L’acetilcolinesterasi eritrocitaria. II. Rapporti con le malattie emolitiche. Acta Medica Patavina 1956; 16: 310-20. 6. Beck WS, Valentine WN. Biochemical studies on leucocytes. II. Phosphatase activity in chronic lymphatic leukemia, acute leukemia, and miscellaneous hematological conditions. J Lab Clin Med 1951; 38: 245-54. 7. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay-accelerating factor. Proc Natl Acad Sci USA 1983; 80: 5066-70. 8. Pangburn MK, Schreiber RD, Muller-Eberhard HJ. Deficiency of an erythrocyte membrane protein with complement regulatory activity in paroxysmal nocturnal haemoglobinuria. Proc Natl Acad Sci USA 1983; 80: 5430-33. 9. Rosse WF. Phosphatidylinositol-linked proteins and paroxysmal nocturnal hemoglobinuria. Blood 1990; 75: 1595-601. 10. Bessler M, Fehr J. FcgIII-receptors (FcRIII) on granulocytes: a new specific and sensitive test for paroxysmal nocturnal haemoglobinuria (PNH). Eur J Haematol 1991; 47: 179-84. 4. Rotoli
11. Low MG, Saltiel AR. Structural and functional role of glycosylphosphatidylinositol in membranes. Science 1988; 239: 268-75. 12. Merry AH, Rawlinson VI, Uchikawa A, Daha MR, Sim RB. Studies on the sensitivity to complement-mediated lysis of erythrocytes (Inab phenotype) with a deficiency of DAF (decay accelerating factor). Br J Haematol 1989; 73: 248-53. 13. Yamashina N, Ueda E, Kinoshita T, et al. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1990; 323: 1184-89. 14. Yonemura Y, Kawakita M, Koito A, et al. Paroxysmal nocturnal haemoglobinuria with coexisting deficiency of the ninth component of complement: lack of massive haemolytic attack. Brit JHaematol 1990; 74: 108-13. 15. Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PJ. Complement-induced vesiculation and exposure of membrane prothrombinase sites in PNH platelets. Blood 1991; 78: 387a (abstr). 16. Dacie JV. Paroxysmal nocturnal haemoglobinuria. Sangre 1980; 25: 890-95. 17. Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome. Br J Haematol 1967; 13: 236-51. 18. Nissen C, Moser Y, Carbonare VD, Gratwohl A, Speck B. Complete recovery of marrow function after treatment with anti-lymphocyte globulin is associated with high, whereas early failure and development of paroxysmal nocturnal haemoglobinuria are associtated with low endogenous G-CSA release. Br J Haematol 1989; 72: 573-83. 19. Luzzatto L, Familusi JB, Williams CKO, Junaid TA, Rotoli B, Alfinito F. The PNH abnormality in myeloproliferative disorders. Haematologica 1979; 64: 13-30. 20. Devine DV, Gluck WL, Rosse WF, Weinberg JD. Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria. Evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone. J Clin Invest 1987; 79: 314-17. 21. Kawahara K, Witherspoon RP, Storb R. Marrow transplantation for paroxysmal nocturnal hemoglobinuria. Am J Hematol 1992: (in press).
pollution and acute
respiratory infections in children developed countries pneumonia in childhood is outside the neonatal period, and when it does occur it is seldom fatal. By contrast, in many parts of the developing world acute respiratory infection (ARI), especially pneumonia, remains a major cause of death in childhood.1 Over the past 60 years better medical care in developed countries has reduced the case-fatality rate from pneumonia, but the In
substantial fall in the incidence of pneumonia recorded over the same period must largely be due to improved living conditions. We do not know which environmental factors contributed most to this fall, but improved indoor air quality and reduced crowding are likely candidates. If we can determine the importance of these factors we may enable less developed countries to include environmental improvement in their ARI control strategies, which mainly focus on improved case management and vaccination.2 Parental smoking is a recognised risk factor for childhood pneumonia in developed countries,3 but we should be cautious about extrapolating from findings based on tobacco smoke, which contains specific toxins, to predict the effects of other types of smoke.44 About half the world’s population still relies on biomass fuels (wood, crop residues, and animal dung) for cooking and heating.5 The amount of indoor air pollution produced by these fuels depends on the fuel, the stove design, and the house design. Other factors are the extent to which the stove is used for heating
and the proximity of children when the stove is in use. Several studies of biomass-fuel-burning households have shown levels of respirable particulate matter, carbon monoxide, and toxic oxides of nitrogen and sulphur well above internationally accepted limits.&-1O Moreover, wood burning produces toxic such as benzo[a]pyrene that are known hydrocarbons In less developed countries the to be carcinogenic." relation between domestic air pollution and chronic obstructive airways disease has been documented in adults,12 but the link with childhood respiratory disease has not been shown convincingly. There are several mechanisms by which the smoke from biomass fuels might contribute to ARI in children. Toxic substances in the smoke may impair the mucociliary defences of the respiratory tract, increasing the volume of nasopharyngeal discharge that is usually rich in bacterial pathogens and thereby increasing susceptibility to lower respiratory tract infections. These substances may also cause bronchial hyperreactivity in young children, leading to chronic or recurrent wheezing, as seems to be the case in adults,9 although Anderson’s study of children in two areas of Papua New Guinea showed wheezing to be less common in the highland area where indoor air pollution was more pronounced.13 Chronic carbon monoxide exposure during pregnancy may also result in lower birthweight,14 which is itself a risk factor for pneumonia in infancy. 15 Armstrong and Campbell16 have shown that, in rural Gambia, where heating is not a major reason for fuel use and where cooking is generally done away from the living area, infant girls whose mothers reported carrying them on their backs while cooking, had more lower respiratory tract infections than those who were not carried (this effect was not seen in boys). It is probable that "sickly" children who are prone to recurrent respiratory tract infections or wheezing will be carried around more than healthy children. This study also showed that parental smoking, which is becoming increasingly common in less developed countries, is a significant risk factor. In two studies in Nepal, Pandey et al 17 asked mothers how many hours per day each child under 2 years of age spent near the fireplace. In the better study, in which smoke exposure and ARI were determined by different workers, children were followed for 3 months in winter and all episodes of ARI were documented. There were 2 cases of moderate or severe ARI among 348 children exposed to household smoke for less than 2 hours per day, 7 among 60 exposed for 2-4 hours per day, and 18 among 47 exposed for over 4 hours per day. These fmdings highlight the potential importance of long-term fuelsmoke exposure as a risk factor for moderate and severe ARI in countries where the winters are cold, but would be less relevant in warm countries, where children are exposed to fuel smoke for shorter periods. In both these studies the results may be distorted by confounding variables and both relied on mothers’
reporting to document children’s exposure to smoke. Their conclusions would be stronger if supported by more objective measures of smoke exposure. Investigators in Zimbabwel8 and the USA19 found that children who get pneumonia are more likely to from homes where wood is used for fuel. These studies, like the Nepalese study, were confounded by the effect of socioeconomic status. The dramatic findings of Pandey and colleagues need to be repeated in a larger study, covering all seasons, controlling for potential confounding variables, and incorporating other measures of smoke exposure. The need to reduce exposure of young children to tobacco smoke in all countries is self-evident. In less developed countries control of indoor air pollution by methods such as the introduction of more efficient stoves, use of alternative fuels, and improved ventilation can be expected to have many desirable effects.9 Apart from the ecological and economic advantages, adult health, especially that of women, will be improved, and it is likely that in young children morbidity and mortality due to ARI will likewise be reduced. It is also possible that there will be a reduction in the incidence of low birthweight with an associated improvement in infant survival. The extent of these health effects can be adequately assessed only by intervention studies. The results of Pandey et al suggest that the need for these studies is now urgent, so that the national ARI control programmes underway in many countries can consider whether they should add improvement of the domestic environment to their control strategies. come
1. Leowski J. Mortality from acute respiratory infections in children under 5 years of age: global estimates. World Health Stat Q 1986; 39: 138-44. 2. World Health Organisation. Programme for control of acute respiratory infections. Fourth programme report 1988-1989. Document (WHO/ ARI/90.7). Geneva: WHO, 1990. 3. Colley JRT. Influence of passive smoking and parental phlegm on pneumonia and bronchitis in early childhood. Lancet 1974; ii: 1031-34. 4. Pandey MR, Boleij JSM, Smith KR, Wafula EM. Indoor air pollution in developing countries and acute respiratory infection in children. Lancet 1989; i: 427-27. 5. De Koning HW, Smith KR, Last JM. Biomass fuel combustion and health. Bull WHO 1985; 63: 11-26. 6. Boleij JSM, Wafula E, Onyango F, De Koning HW. Domestic air pollution from biomass burning in Kenya. Atmos Environ 1989; 23: 1677-81. 7. Smith KR, Aggarwal AL, Dave RM. Air pollution and rural biomass fuels in developing countries: a pilot village study in India and implications for research and policy. Atmos Environ 1983; 17: 2343-62. 8. Davidson CI, Lin S-F, Osbom JF, Pandey MR, Rasmussen RA, Khalil MAK. Indoor and outdoor air pollution in the Himalayas. Environ Sci Technol 1986; 20: 561-67. 9. Reid HR, Smith KR, Sherchand B. Indoor smoke exposures from traditional and improved cookstoves—comparisons among rural Nepali women. Mountain Res Dev 1986; 6: 293-304. 10. World Health Organisation. Biomass fuel combustion and health (WHO/EFP/84.64). Geneva: WHO, 1990. 11. Cooper JA. Environmental impact of residential wood combustion emissions and its implications. J Air Pollution Control Assoc 1980; 30: 855-61. 12. Norboo T, Yahya M, Bruce NG, Heady JA, Ball KP. Domestic pollution and respiratory illness in a Himalayan village. Int J Epidemiol 1991; 20: 749-57. 13. Anderson HR. Respiratory abnormalities in Papua New Guinea children: the effects of locality and domestic wood smoke pollution. Int J Epidemiol 1978; 7: 63-72.
14. Astrup P. Some physiological and pathological effects of moderate carbon monoxide exposure. Br Med J 1972; 4: 447-52. 15. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82-90. 16. Armstrong JRM, Campbell H. Indoor air pollution exposure and lower respiratory infections in young Gambian children. Int J Epidemiol 1991; 20: 424-29. 17. Pandey MR, Neupane RP, Gautam A, Shrestha IB. Domestic smoke pollution and acute respiratory infections in a rural community of the hill region of Nepal. Environ Int 1989; 15: 337-40. 18. Collings DA, Sithole SD, Martin KS. Indoor woodsmoke pollution causing lower respiratory disease in children. Trop Doctor 1990; 20: 151-55. 19. Morris K, Morganlander M, Coulehan JL, Gahagen S, Arena VC. Wood-burning stoves and lower respiratory tract infection in American Indian children. Am J Dis Child 1990; 144: 105-08.
Vesicoureteric reflux and
nephropathy Reflux nephropathy is responsible for renal failure in 25% of children entering the European dialysis and transplantation programme1 and is one of the main causes of hypertension in children and young adults.It is widely believed that this disorder results from vesicoureteric and intrarenal reflux of infected urine; it is also possible that reflux nephropathy is not a homogeneous condition but the final common pathway of many types of renal tract
dysfunction. Anderson and Rickwood3investigated the finding of renal tract dilatation detected by antenatal ultrasonography, and identified a group of infants (90% of whom were boys) with serious renal tract abnormalities. On cystography, usually with 1 month of birth, of 34 infants with primary vesicoureteric reflux (VUR), about 65% had severe reflux (grade IV or V).4 29% had associated genitourinary abnormalities such as complete duplex system, pelviureteric junction obstruction, and solitary kidney. These infants differ from most children with VUR, among whom girls outnumber boys five to one,’’ those affected are older, and the clinical course is more
Antenatal sonography detects pelviureteric dilatation and so can only identify infants with grade III VUR or worse. Whilst this fact may account for the predominance of cases with severe reflux it does not explain other features such as the male preponderance and the high frequency of associated abnormalities. Likewise, antenatal detection of VUR does not explain why a significant proportion of such infants have renal perfusion defects as detected by 99Tc dimercaptosuccinic acid (DMSA) renography. Thus Anderson and Rickwood found that DMSA scans done at 1-3 months of age were abnormal in more than 75% of boys with antenatally detected reflux, 80% of whom had never experienced a urinary tract infection (with or without clinical features). It is reasonable to conclude that this high frequency of abnormal DMSA scans is an accurate representation of the state of the kidneys at birth and that most of the renal perfusion defects detected in infancy are the
result of dysplasia rather than infection. These findings accord with those of Najmaldin et al,who reported that antenatally detected reflux was associated with a 65% incidence of reduction in renal function despite the absence of urinary tract infection in all but 2 of 14 patients. Another feature in Anderson and Rickwood’s patients was the histological appearance of severe dysplasia and growth arrest rather than the scarring of reflux and infection in the few who underwent nephrectomy. Several research groups have used DMSA imaging to study children with urinary tract infection and have found a low frequency of progressive scarring despite proven repeated infections.7,8 One interpretation is that most renal scarring occurs at the time of initial infection. Perhaps these scars are renal perfusion defects of prenatal origin,9 noted incidentally when children with renal tract abnormalities present with infection. It had been hoped that routine ultrasound scanning might detect dilatation antenatally, 10 but this does not seem to be the case. In a prospective study, Gunn et al11 did routine ultrasound scanning of 3228 fetuses at 16-20 weeks’ gestation and repeated the scans if there were obstetric indications (761 fetuses). No renal tract abnormalities were detected before 28 weeks’ gestation, even in fetuses with urinary tract abnormalities on later scans. Subsequent ultrasound scans of these 761 fetuses revealed dilatation of the renal pelvis in 8%. Postnatally, 10 (16%) of these infants were found to have serious renal tract abnormalities-5 had pelviureteric junction 2 had and 3 died of associated VUR, obstruction, serious congenital abnormalities. To provide a screening service it would therefore be necessary to repeat ultrasound examinations on all fetuses at more than 28 weeks’ gestation. This strategy would identify otherwise unsuspected renal tract abnormalities in 9-2/1000 (7 of 761) infants, or possibly fewer if the whole population was screened and not merely those with adverse obstetric factors. The small group of male infants identified antenatally is important in terms of individual morbidity, but is not representative of the majority of children (usually girls) with reflux. Closer consideration of this larger group shows that they may have evidence of renal tract dysfunction. In a prospective study12 videourodynamic examinations were done in children with reflux and the results were compared before and during anticholinergic therapy (oxybutynin), with controls receiving oxyphenonium bromide or antibiotic prophylaxis alone. Before treatment, bladder instability was present in 40%. Oxybutynin significantly decreased the strength of detrusor contraction during voiding and detrusor pressure at maximum flow rate. These changes were accompanied by a significant decrease in VUR in 8 of 9 kidneys with reflux, which was not seen in controls. The importance of functional obstruction is further emphasised by the finding that nearly two-thirds of