206
method to ascertain selected causes of death in children in
Philippines. Int, Epidemiol (in press). 15. Greenwood BM, Greenwood AM, Bradely AK, et al. Deaths in infancy and early childhood in a well vaccinated, rural West African population. Ann Trop Pediatr 1987; 7: 91-99. 16. Gray RH, Smith G, Barss P. The use of verbal autopsy methods to determine selected causes of death in children. February 1990, Occasional Paper No. 10. Institute for International Programmes, The Johns Hopkins University, School of Hygiene and Public Health, Baltimore. Munshi MH, Wojtyniak B, et al. Acute lower respiratory infections: a major cause of death in children in Bangladesh. Ann Trop Paediatr 1989; 9: 33-39. 18. World Health Organisation. Lay reporting of health information. 17.
Spika JS,
Geneva: World Health Organisation, 1978. 19. World Health Organisation. International classification of diseases. 9th Revision 1975. Geneva: World Health Organisation, 1977. 20. Battle RM, Pathak D, Humble CG, et al. Factors influencing discrepancies between premortem and postmortem diagnoses.JAMA
1987; 258: 339-44. 21. Kircher T, Anderson RE. Cause of death: proper completion of the death certificate. JAMA 1987; 258: 349-52. 22. Chen LC, Rahman M, Sarder AM. Epidemilogy and causes of death among children in a rural area in Bangladesh. Int J Epidemaol 1980; 9: 25-33. 23. Alonso PL, Bowman A, Marsh K, Greenwood BM. The accuracy of the clinical histories given by mothers of seriously ill African children. Ann Trop Paediatr 1987; 7: 187-89.
Importance of chronic aspiration in recipients of heart-lung transplants
series of eleven recipients of heart-lung transplants (HLT), five have obliterative bronchiolitis. Five of the eleven patients have chronic cough as well as slower than normal In
a
gastric emptying and/or oesophageal dysmotility; all five have evidence of bronchiectasis and three have obliterative bronchiolitis. Three of the patients improved after the introduction of treatment to prevent reflux, and another, who had a large phytobezoar, improved after pyloroplasty. In patients with chronic cough after HLT, with or without dyspeptic symptoms or recurring pulmonary sepsis, investigation of oesophageal motility and gastric emptying should be undertaken.
Introduction Obliterative bronchiolitis was recognised as a complication of heart-lung transplantation (HLT) after the first transplants were carried out for end-stage pulmonary vascular and chronic lung disease. It is the most important long-term complication seen in HLT patients and occurs in up to 50%.1 Chronic cough after HLT is most commonly due either to rejection or to infection, but other factors may contribute. The proximity of the vagus nerves to the posterior aspect of the hila renders them vulnerable to operative injury with possible gastrointestinal sequelae.
Methods All HLT recipients undergo transbronchial biopsy every 2 weeks during the first 3 months after the operation. After that, biopsies are taken every 3 months or when warranted by clinical features. Endoscopy is carried out under topical anaesthesia with oropharyngeal lignocaine (mean 150 mg) and intravenous midazolam (1-2 mg), except in children, for whom general anaesthesia is used. 5-7 samples are taken at each examination.
Results We are actively following eleven HLT recipients (mean time since transplant 19 [range 2-48] months: see table). Five of these patients have evidence of aspiration together
with slower than normal gastric emptying (see below) and three others have evidence of slow gastric emptying on nuclear gastric emptying studies, but no evidence of
aspiration or pulmonary changes (table). Patient 1 underwent HLT for fibrosing alveolitis. After the operation she experienced bloating and morning vomiting and complained of chronic cough. Transbronchial biopsy samples did not show rejection, but on endoscopy there was diffuse tracheobronchitis. Biopsy samples showed evidence of chronic rejection and obliterative bronchiolitis. The results of a nuclear gastric emptying study were normal, but a barium meal X-ray showed slow gastric emptying and aspiration. The patient improved greatly after introduction of domperidone and other measures to prevent reflux. At her latest follow-up examination (4 years after HLT), she had physiological evidence of obliterative bronchiolitis with pronounced impairment of airflow on pulmonary function testing. She also has radiographic evidence of bibasilar bronchiectasis. Patient 2 underwent HLT for primary pulmonary hypertension, but had persistent cough with no evidence of rejection, infection, or obliterative bronchiolitis in transbronchial biopsy samples for 30 months after the operation. Endoscopy showed diffuse tracheobronchitis and the presence of bile in the tracheobronchial tree. Nuclear gastric emptying studies showed significantly slower than normal gastric emptying and a barium meal X-ray showed gastro-oesophageal reflux. The patient improved on domperidone and other measures to prevent reflux. She now has evidence of bronchiectasis on her chest X-ray, and her latest transbronchial biopsy sample shows evidence of obliterative bronchiolitis. Patient 3 underwent HLT for primary pulmonary hypertension. Gastrointestinal symptoms developed soon
ADDRESS. Divisions of Cardiothoracic Surgery, Cardiology, and Respirology, University Hospital, University of Western Ontario, London, Ontario, Canada (K R. Reid, MD, Prof F. N. McKenzie, MD, A. H. Menkis, MD, R J Novick, MD, P W. Pflugfelder, MD, W J. Kostak, MD, D. Ahmad, MD) Correspondence to Dr D Ahmad, 6-OF7, University Hospital, PO Box 5339, Station A, London, Ontario N6A 5A5, Canada
207
DETAILS OF HEART-LUNG RECIPIENTS
apparent. She also has evidence of lipid pneumonitis, which was attributed to cyclosporin aspiration.
Discussion Declining respiratory function after HLT is the major postoperative difficulty for most recipients. In long-term survivors after HLT, the reported frequency of obliterative bronchiolitis varies from 6-5%2 to 50%.1 It is widely agreed that rejection has an important role in the development of obliterative bronchiolitis,2-12 though the aetiology is probably multifactorial. 35-8 The development of obliterative bronchiolitis may also be initiated by the presence of cytomegalovirus infection in a proportion of patients. 4.7,8.11.12 FA= fibrosing alveolitls, PPH = pnmary pulmonary hypertension; KSKartageneis syndrome, 08 = obliterative bronchiolitis, GEgastnc emptying. *On metoclopramide when tested
after the operation. Oesophageal manometry showed normal amplitude and duration of primary waves, but only 50% were propagated beyond the first 5-10 cm of the oesophagus. The lower oesophageal sphincter pressure was 12 mm Hg. The nuclear gastric emptying study was normal. Transbronchial biopsy samples showed acute and chronic tracheobronchitis and chronic vascular rejection, with no evidence of obliterative bronchiolitis. There is evidence of bronchiectasis on radiography. Patient 5 underwent HLT for primary pulmonary hypertension. 1 month later she started to complain of epigastric discomfort with morning bloating, vomiting, and chronic cough. Transbronchial biopsy samples showed neither rejection nor obliterative bronchiolitis, but diffuse tracheobronchitis was present. A barium meal X-ray showed gastro-oesophageal reflux and slow gastric emptying, but no gross aspiration. Endoscopy showed oesophagitis with undigested food particles in the oesophagus and a large amount of retained gastric contents. Oesophageal manometry showed very few primary waves propagated beyond the first 5-10 cm of the oesophagus. The wave amplitude was also diminished, whereas the tone of the lower oesophageal sphincter was normal. The patient’s symptoms improved greatly with metoclopramide and other measures to prevent reflux. There was no clinical or transbronchial biopsy evidence of obliterative bronchiolitis 21 months after the transplant, but there was histological evidence in the biopsy sample of acute and chronic bronchitis. There is radiographic evidence of bilateral bronchiectasis. Patient 9 underwent HLT for primary pulmonary hypertension and complained of persistent cough and nausea within the first month afterwards. Transbronchial biopsy samples initially showed no evidence of rejection, but purulent secretions were seen in the tracheobronchial tree. After treatment with appropriate antibiotics, sputum production diminished and the patient remained afebrile, but the cough persisted and repeat biopsy samples showed no evidence of rejection. A nuclear study of gastric emptying showed a significantly longer than normal emptying time, but oesophageal motility studies were normal. The patient improved transiently on treatment with metoclopramide, but her symptoms worsened and she was found to have a phytobezoar virtually filling her stomach. After pyloroplasty, the symptoms abated and the patient was able to eat normally and began regaining her lost weight. Evidence of bronchiectasis is present on computed tomography and chest X-rays. Histological evidence of rejection and obliterative bronchiolitis has since become
The
main
cause
of obliterative
bronchiolitis
after
transplantation is without doubt immunologica1.5,7.8 Unrecognised chronic rejection and recurrent episodes of acute rejection are implicated in its development. The routine use of azathioprine, cyclosporin, and prednisone has been suggested to reduce the frequency of obliterative bronchiolitis in HLT patients.7 Early, aggressive treatment of rejection is critical to minimise its development. Another factor may exacerbate respiratory difficulties after HLT. In HLT recipients, the vagus nerves are at risk of injury during the operation owing to their proximity to the posterior aspect of the hila. Visualisation of this area during recipient pneumonectomy may be difficult and inadvertent nerve injury may ensue, either from direct trauma or from thermal injury during cauterisation of blood vessels. Vagal injury may also occur during oversewing of the posterior mediastinum for haemostasis before graft implantation. Incorporation of the technical modifications suggested by Vouhe and Dartevelle ’13 in which the transpericardial portions of the pulmonary veins and tracheobronchial tree are stapled and left in situ, may help to prevent vagal injury. Vagal injury would result in slower than normal gastric emptying with a higher risk of reflux and aspiration. In the HLT recipient with slow gastric emptying, the vigorous postoperative chest physiotherapy used to encourage coughing might increase the frequency and quantity of reflux. Gastro-oesophageal reflux alone may cause chronic cough in non-transplant patients.14 It is well known that mucociliary transport, the cough reflex, and the rheology of the bronchial secretions are abnormal after lung or heartlung transplantations;5--8,15-18 these abnormalities may predispose the patient to infection through poor airway clearance and mucus stasis. If recurrent gastro-oesophageal reflux with aspiration is superimposed, additional airway injury is likely. Slow gastric emptying is certainly a major risk factor in nocturnal or supine reflux.19 In our series of eleven patients, five had slow gastric emptying and aspiration. Most of them responded to treatment with gastric motility agents. Three of the five have evidence of obliterative bronchiolitis and all have bronchiectasis with concomitant recurrent pulmonary sepsis. Unfortunately, we have only lately become aware of the development of gastro-oesophageal reflux in our HLT patients. We have not yet carried out systematic gastrointestinal investigations to detect gastric emptying abnormalities in some of the symptom-free patients. In particular, 24 h pH studies would be useful to document the extent of these abnormalities, since a large percentage of patients with reflux have a component of nocturnal reflux (90%) and 26% have reflux only while supine.19 Thus, the possibility of gastro-oesophageal reflux with aspiration should be considered in any HLT recipient who
208
has
chronic
cough or recurrent pulmonary infection. Chronic pulmonary inflammation secondary to recurrent aspiration in the HLT patient may have a role in the derangement of pulmonary function and recurrent infection leading to bronchiectasis. a
REFERENCES
1. Burke CM, Baldwin JC, Morris AJ, et al. Twenty-eight cases of human heart-lung transplantation. Lancet 1986; i: 517-19. 2. Hutter JA, Despins P, Higenbottam TW, Stewart S, Wallwork J. Heart-lung transplantation: better use of resources. Am J Med 1988; 85: 4-11. 3. Burke CM, Morris AJR, Dawkins KD, et al. Late airflow obstruction in heart-lung transplantation recipients. Heart Transplant 1985; iv: 437-40. 4. Allen MD, Burke CM, McGregor CGA, Baldwin JC, Jamieson SW, Theodore J. Steroid-responsive bronchiolitis after human heart-lung transplantation. J Thorac Cardiovasc Surg 1986; 92: 449-51. 5. Yousem SA, Burke CM, Billingham ME. Pathologic Pulmonary alterations in long-term human heart-lung transplantation. Hum Pathol 1985; 16: 911-23. 6. Burke CM, Theodore J, Dawkins KD, et al. Post-transplant obliterative bronchiolitis and other late sequelae in human heart-lung transplantation. Chest 1984; 86: 824-29. 7. Glanville AR, Baldwin JC, Burke CM, Theodore J, Robin ED. Obliterative bronchiolitis after heart-lung transplantation: apparent arrest by augmented immunosuppression. Ann Intern Med 1987; 107: 300-04. 8. Tazelaar HD, Yousem SA. The pathology of combined heart-lung transplantation: an autopsy study. Hum Pathol 1988; 19: 1403-16.
ARL, Higenbottam TW, Hutter J, Coutts C, Stewart S, Wallwork J. Clinical experience in the management of pulmonary opportunistic infection and rejection in recipients of heart-lung transplants. Thorax 1988; 43: 762-69. 10. Millet B, Higenbottam TW, Flower CDR, Stewart S, Wallwork J. The radiographic appearances of infection and acute rejection of the lung after heart-lung transplantation. Am Rev Respir Dis 1989; 140: 62-67. 11. Reitz BA. Heart-lung transplantation. Chest 1988; 93: 450-51. 12. Higenbottam LTW. Lung rejection after transplantation. Eur Respir J 9. Penketh
1989; 2: 1-2. 13. Vouhe PR, Dartevelle PG. Heart-lung transplantation: technical modifications that may improve the early outcome. J Thorac Cardiovasc Surg 1989; 97: 906-10. 14. Irwin RS, Zawaki JK, Curley FJ, French CL, Hoffman PJ. Chronic cough as the sole presenting manifestation of gastroesophageal reflux. Am Rev Respir Dis 1989; 140: 1294-300. 15. Seggev JS, Mason UG, Worthen S, Stanford RE, Fernandez E. Bronchiolitis obliterans: report of three cases with detailed physiologic studies. Chest 1983; 83: 169-74. 16. Paul A, Marelli D, Shennib H, et al. Mucociliary function in autotransplanted, allotransplanted, and sleeve-resected lungs. Surg Forum 1988; 39: 298-300. 17. Higenbottam T, Jackson M, Rashdi T, Stewart S, Coutts C, Wallwork J. Lung rejection and bronchial hyperresponsiveness to methacholine and ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989; 140: 52-57. 18. Higenbottam T, Jackson M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients Am Rev Respir Dis 1989; 140: 58-61. 19. Little AG, DeMeester TR, Kirchner PT, O’Sullivan GC, Skinner DB. Pathogenesis of esophagitis in patients with gastroesophageal reflux. Surgery 1980; 88: 101-07.
Evidence for intrafamilial transmission of hepatitis B virus from sequence analysis of mutant HBV DNAs in two Chinese families
study the heterogeneity of hepatitis B virus (HBV) DNAs in Hong Kong, where HBV infection is endemic, serum specimens from 90 HBsAg carrier children were systematically tested with nine oligonucleotide probes representing conserved sequences in the viral genome. In a pair of twins and their cousin (belonging to family H) and an unrelated child (family Y) serum HBV DNA annealed to all but one probe, a sequence located between the core and pre-S regions of the viral genome (positions 2723-2738; EcoRI site 1). Serum from the H twins’ aunt and the father and paternal grandparents in the Y family were also HBV DNA-positive. The nucleotide sequences in positions 2701-2800 were analysed. The same point mutation, C to T in position 2735, was
Introduction
To
present in the HBV DNAs from 7 individuals in the two families. All 4 H
In South-East Asia, HBV infection is acquired at an early agel and the clustering of such infection within families has been demonstrated by epidemiological studies.2 Evidence
for intrafamilial HBV infection has in a few instances been supported by serological studies.1.3 However, the usefulness of serological typing is very limited in this respect because of the small number of subdeterminants.4,5 We have taken a different approach to the study of HBV transmission by using oligonucleotide probes with sequences taken from conserved regions of the HBV genome. The sequences of the 13 cloned HBV DNAs representing all four subtypes and a mixed subtype showed more than 30 conserved regions with 15 or more nucleotides.6-14 We used as probes nine S-strand sequences with 5’-ends at positions 56, 455, 970, 1257, 1584, 1952, 2385, 2723, and 2820 (fig 1).
family members had the same
HBV DNA sequence. The HBV DNA sequences found in the Y daughter, father, and grandfather were identical and they were different from the H
family mutant. These results provided evidence at the DNA level of intrafamilial transmission within these Chinese families.
ADDRESSES. Clinical Biochemistry Unit (H. J Lin, DSc, M. W. Fong), Department of Medicine (C-L. Lai, FRCP, J Y.-N Lau, MRCP, H -T Chung, MRCP), and Department of Statistics (I. J. Lauder, of Hong Kong, Hong Kong. Correspondence to Dr H J Lin, Clinical Biochemistry Unit, University of Hong Kong, Queen
PhD), University
Mary Hospital Compound, Hong Kong
method to ascertain selected causes of death in children in
Philippines. Int, Epidemiol (in press). 15. Greenwood BM, Greenwood AM, Bradely AK, et al. Deaths in infancy and early childhood in a well vaccinated, rural West African population. Ann Trop Pediatr 1987; 7: 91-99. 16. Gray RH, Smith G, Barss P. The use of verbal autopsy methods to determine selected causes of death in children. February 1990, Occasional Paper No. 10. Institute for International Programmes, The Johns Hopkins University, School of Hygiene and Public Health, Baltimore. Munshi MH, Wojtyniak B, et al. Acute lower respiratory infections: a major cause of death in children in Bangladesh. Ann Trop Paediatr 1989; 9: 33-39. 18. World Health Organisation. Lay reporting of health information. 17.
Spika JS,
Geneva: World Health Organisation, 1978. 19. World Health Organisation. International classification of diseases. 9th Revision 1975. Geneva: World Health Organisation, 1977. 20. Battle RM, Pathak D, Humble CG, et al. Factors influencing discrepancies between premortem and postmortem diagnoses.JAMA
1987; 258: 339-44. 21. Kircher T, Anderson RE. Cause of death: proper completion of the death certificate. JAMA 1987; 258: 349-52. 22. Chen LC, Rahman M, Sarder AM. Epidemilogy and causes of death among children in a rural area in Bangladesh. Int J Epidemaol 1980; 9: 25-33. 23. Alonso PL, Bowman A, Marsh K, Greenwood BM. The accuracy of the clinical histories given by mothers of seriously ill African children. Ann Trop Paediatr 1987; 7: 187-89.
Importance of chronic aspiration in recipients of heart-lung transplants
series of eleven recipients of heart-lung transplants (HLT), five have obliterative bronchiolitis. Five of the eleven patients have chronic cough as well as slower than normal In
a
gastric emptying and/or oesophageal dysmotility; all five have evidence of bronchiectasis and three have obliterative bronchiolitis. Three of the patients improved after the introduction of treatment to prevent reflux, and another, who had a large phytobezoar, improved after pyloroplasty. In patients with chronic cough after HLT, with or without dyspeptic symptoms or recurring pulmonary sepsis, investigation of oesophageal motility and gastric emptying should be undertaken.
Introduction Obliterative bronchiolitis was recognised as a complication of heart-lung transplantation (HLT) after the first transplants were carried out for end-stage pulmonary vascular and chronic lung disease. It is the most important long-term complication seen in HLT patients and occurs in up to 50%.1 Chronic cough after HLT is most commonly due either to rejection or to infection, but other factors may contribute. The proximity of the vagus nerves to the posterior aspect of the hila renders them vulnerable to operative injury with possible gastrointestinal sequelae.
Methods All HLT recipients undergo transbronchial biopsy every 2 weeks during the first 3 months after the operation. After that, biopsies are taken every 3 months or when warranted by clinical features. Endoscopy is carried out under topical anaesthesia with oropharyngeal lignocaine (mean 150 mg) and intravenous midazolam (1-2 mg), except in children, for whom general anaesthesia is used. 5-7 samples are taken at each examination.
Results We are actively following eleven HLT recipients (mean time since transplant 19 [range 2-48] months: see table). Five of these patients have evidence of aspiration together
with slower than normal gastric emptying (see below) and three others have evidence of slow gastric emptying on nuclear gastric emptying studies, but no evidence of
aspiration or pulmonary changes (table). Patient 1 underwent HLT for fibrosing alveolitis. After the operation she experienced bloating and morning vomiting and complained of chronic cough. Transbronchial biopsy samples did not show rejection, but on endoscopy there was diffuse tracheobronchitis. Biopsy samples showed evidence of chronic rejection and obliterative bronchiolitis. The results of a nuclear gastric emptying study were normal, but a barium meal X-ray showed slow gastric emptying and aspiration. The patient improved greatly after introduction of domperidone and other measures to prevent reflux. At her latest follow-up examination (4 years after HLT), she had physiological evidence of obliterative bronchiolitis with pronounced impairment of airflow on pulmonary function testing. She also has radiographic evidence of bibasilar bronchiectasis. Patient 2 underwent HLT for primary pulmonary hypertension, but had persistent cough with no evidence of rejection, infection, or obliterative bronchiolitis in transbronchial biopsy samples for 30 months after the operation. Endoscopy showed diffuse tracheobronchitis and the presence of bile in the tracheobronchial tree. Nuclear gastric emptying studies showed significantly slower than normal gastric emptying and a barium meal X-ray showed gastro-oesophageal reflux. The patient improved on domperidone and other measures to prevent reflux. She now has evidence of bronchiectasis on her chest X-ray, and her latest transbronchial biopsy sample shows evidence of obliterative bronchiolitis. Patient 3 underwent HLT for primary pulmonary hypertension. Gastrointestinal symptoms developed soon
ADDRESS. Divisions of Cardiothoracic Surgery, Cardiology, and Respirology, University Hospital, University of Western Ontario, London, Ontario, Canada (K R. Reid, MD, Prof F. N. McKenzie, MD, A. H. Menkis, MD, R J Novick, MD, P W. Pflugfelder, MD, W J. Kostak, MD, D. Ahmad, MD) Correspondence to Dr D Ahmad, 6-OF7, University Hospital, PO Box 5339, Station A, London, Ontario N6A 5A5, Canada
207
DETAILS OF HEART-LUNG RECIPIENTS
apparent. She also has evidence of lipid pneumonitis, which was attributed to cyclosporin aspiration.
Discussion Declining respiratory function after HLT is the major postoperative difficulty for most recipients. In long-term survivors after HLT, the reported frequency of obliterative bronchiolitis varies from 6-5%2 to 50%.1 It is widely agreed that rejection has an important role in the development of obliterative bronchiolitis,2-12 though the aetiology is probably multifactorial. 35-8 The development of obliterative bronchiolitis may also be initiated by the presence of cytomegalovirus infection in a proportion of patients. 4.7,8.11.12 FA= fibrosing alveolitls, PPH = pnmary pulmonary hypertension; KSKartageneis syndrome, 08 = obliterative bronchiolitis, GEgastnc emptying. *On metoclopramide when tested
after the operation. Oesophageal manometry showed normal amplitude and duration of primary waves, but only 50% were propagated beyond the first 5-10 cm of the oesophagus. The lower oesophageal sphincter pressure was 12 mm Hg. The nuclear gastric emptying study was normal. Transbronchial biopsy samples showed acute and chronic tracheobronchitis and chronic vascular rejection, with no evidence of obliterative bronchiolitis. There is evidence of bronchiectasis on radiography. Patient 5 underwent HLT for primary pulmonary hypertension. 1 month later she started to complain of epigastric discomfort with morning bloating, vomiting, and chronic cough. Transbronchial biopsy samples showed neither rejection nor obliterative bronchiolitis, but diffuse tracheobronchitis was present. A barium meal X-ray showed gastro-oesophageal reflux and slow gastric emptying, but no gross aspiration. Endoscopy showed oesophagitis with undigested food particles in the oesophagus and a large amount of retained gastric contents. Oesophageal manometry showed very few primary waves propagated beyond the first 5-10 cm of the oesophagus. The wave amplitude was also diminished, whereas the tone of the lower oesophageal sphincter was normal. The patient’s symptoms improved greatly with metoclopramide and other measures to prevent reflux. There was no clinical or transbronchial biopsy evidence of obliterative bronchiolitis 21 months after the transplant, but there was histological evidence in the biopsy sample of acute and chronic bronchitis. There is radiographic evidence of bilateral bronchiectasis. Patient 9 underwent HLT for primary pulmonary hypertension and complained of persistent cough and nausea within the first month afterwards. Transbronchial biopsy samples initially showed no evidence of rejection, but purulent secretions were seen in the tracheobronchial tree. After treatment with appropriate antibiotics, sputum production diminished and the patient remained afebrile, but the cough persisted and repeat biopsy samples showed no evidence of rejection. A nuclear study of gastric emptying showed a significantly longer than normal emptying time, but oesophageal motility studies were normal. The patient improved transiently on treatment with metoclopramide, but her symptoms worsened and she was found to have a phytobezoar virtually filling her stomach. After pyloroplasty, the symptoms abated and the patient was able to eat normally and began regaining her lost weight. Evidence of bronchiectasis is present on computed tomography and chest X-rays. Histological evidence of rejection and obliterative bronchiolitis has since become
The
main
cause
of obliterative
bronchiolitis
after
transplantation is without doubt immunologica1.5,7.8 Unrecognised chronic rejection and recurrent episodes of acute rejection are implicated in its development. The routine use of azathioprine, cyclosporin, and prednisone has been suggested to reduce the frequency of obliterative bronchiolitis in HLT patients.7 Early, aggressive treatment of rejection is critical to minimise its development. Another factor may exacerbate respiratory difficulties after HLT. In HLT recipients, the vagus nerves are at risk of injury during the operation owing to their proximity to the posterior aspect of the hila. Visualisation of this area during recipient pneumonectomy may be difficult and inadvertent nerve injury may ensue, either from direct trauma or from thermal injury during cauterisation of blood vessels. Vagal injury may also occur during oversewing of the posterior mediastinum for haemostasis before graft implantation. Incorporation of the technical modifications suggested by Vouhe and Dartevelle ’13 in which the transpericardial portions of the pulmonary veins and tracheobronchial tree are stapled and left in situ, may help to prevent vagal injury. Vagal injury would result in slower than normal gastric emptying with a higher risk of reflux and aspiration. In the HLT recipient with slow gastric emptying, the vigorous postoperative chest physiotherapy used to encourage coughing might increase the frequency and quantity of reflux. Gastro-oesophageal reflux alone may cause chronic cough in non-transplant patients.14 It is well known that mucociliary transport, the cough reflex, and the rheology of the bronchial secretions are abnormal after lung or heartlung transplantations;5--8,15-18 these abnormalities may predispose the patient to infection through poor airway clearance and mucus stasis. If recurrent gastro-oesophageal reflux with aspiration is superimposed, additional airway injury is likely. Slow gastric emptying is certainly a major risk factor in nocturnal or supine reflux.19 In our series of eleven patients, five had slow gastric emptying and aspiration. Most of them responded to treatment with gastric motility agents. Three of the five have evidence of obliterative bronchiolitis and all have bronchiectasis with concomitant recurrent pulmonary sepsis. Unfortunately, we have only lately become aware of the development of gastro-oesophageal reflux in our HLT patients. We have not yet carried out systematic gastrointestinal investigations to detect gastric emptying abnormalities in some of the symptom-free patients. In particular, 24 h pH studies would be useful to document the extent of these abnormalities, since a large percentage of patients with reflux have a component of nocturnal reflux (90%) and 26% have reflux only while supine.19 Thus, the possibility of gastro-oesophageal reflux with aspiration should be considered in any HLT recipient who
208
has
chronic
cough or recurrent pulmonary infection. Chronic pulmonary inflammation secondary to recurrent aspiration in the HLT patient may have a role in the derangement of pulmonary function and recurrent infection leading to bronchiectasis. a
REFERENCES
1. Burke CM, Baldwin JC, Morris AJ, et al. Twenty-eight cases of human heart-lung transplantation. Lancet 1986; i: 517-19. 2. Hutter JA, Despins P, Higenbottam TW, Stewart S, Wallwork J. Heart-lung transplantation: better use of resources. Am J Med 1988; 85: 4-11. 3. Burke CM, Morris AJR, Dawkins KD, et al. Late airflow obstruction in heart-lung transplantation recipients. Heart Transplant 1985; iv: 437-40. 4. Allen MD, Burke CM, McGregor CGA, Baldwin JC, Jamieson SW, Theodore J. Steroid-responsive bronchiolitis after human heart-lung transplantation. J Thorac Cardiovasc Surg 1986; 92: 449-51. 5. Yousem SA, Burke CM, Billingham ME. Pathologic Pulmonary alterations in long-term human heart-lung transplantation. Hum Pathol 1985; 16: 911-23. 6. Burke CM, Theodore J, Dawkins KD, et al. Post-transplant obliterative bronchiolitis and other late sequelae in human heart-lung transplantation. Chest 1984; 86: 824-29. 7. Glanville AR, Baldwin JC, Burke CM, Theodore J, Robin ED. Obliterative bronchiolitis after heart-lung transplantation: apparent arrest by augmented immunosuppression. Ann Intern Med 1987; 107: 300-04. 8. Tazelaar HD, Yousem SA. The pathology of combined heart-lung transplantation: an autopsy study. Hum Pathol 1988; 19: 1403-16.
ARL, Higenbottam TW, Hutter J, Coutts C, Stewart S, Wallwork J. Clinical experience in the management of pulmonary opportunistic infection and rejection in recipients of heart-lung transplants. Thorax 1988; 43: 762-69. 10. Millet B, Higenbottam TW, Flower CDR, Stewart S, Wallwork J. The radiographic appearances of infection and acute rejection of the lung after heart-lung transplantation. Am Rev Respir Dis 1989; 140: 62-67. 11. Reitz BA. Heart-lung transplantation. Chest 1988; 93: 450-51. 12. Higenbottam LTW. Lung rejection after transplantation. Eur Respir J 9. Penketh
1989; 2: 1-2. 13. Vouhe PR, Dartevelle PG. Heart-lung transplantation: technical modifications that may improve the early outcome. J Thorac Cardiovasc Surg 1989; 97: 906-10. 14. Irwin RS, Zawaki JK, Curley FJ, French CL, Hoffman PJ. Chronic cough as the sole presenting manifestation of gastroesophageal reflux. Am Rev Respir Dis 1989; 140: 1294-300. 15. Seggev JS, Mason UG, Worthen S, Stanford RE, Fernandez E. Bronchiolitis obliterans: report of three cases with detailed physiologic studies. Chest 1983; 83: 169-74. 16. Paul A, Marelli D, Shennib H, et al. Mucociliary function in autotransplanted, allotransplanted, and sleeve-resected lungs. Surg Forum 1988; 39: 298-300. 17. Higenbottam T, Jackson M, Rashdi T, Stewart S, Coutts C, Wallwork J. Lung rejection and bronchial hyperresponsiveness to methacholine and ultrasonically nebulized distilled water in heart-lung transplantation patients. Am Rev Respir Dis 1989; 140: 52-57. 18. Higenbottam T, Jackson M, Woolman P, Lowry R, Wallwork J. The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients Am Rev Respir Dis 1989; 140: 58-61. 19. Little AG, DeMeester TR, Kirchner PT, O’Sullivan GC, Skinner DB. Pathogenesis of esophagitis in patients with gastroesophageal reflux. Surgery 1980; 88: 101-07.
Evidence for intrafamilial transmission of hepatitis B virus from sequence analysis of mutant HBV DNAs in two Chinese families
study the heterogeneity of hepatitis B virus (HBV) DNAs in Hong Kong, where HBV infection is endemic, serum specimens from 90 HBsAg carrier children were systematically tested with nine oligonucleotide probes representing conserved sequences in the viral genome. In a pair of twins and their cousin (belonging to family H) and an unrelated child (family Y) serum HBV DNA annealed to all but one probe, a sequence located between the core and pre-S regions of the viral genome (positions 2723-2738; EcoRI site 1). Serum from the H twins’ aunt and the father and paternal grandparents in the Y family were also HBV DNA-positive. The nucleotide sequences in positions 2701-2800 were analysed. The same point mutation, C to T in position 2735, was
Introduction
To
present in the HBV DNAs from 7 individuals in the two families. All 4 H
In South-East Asia, HBV infection is acquired at an early agel and the clustering of such infection within families has been demonstrated by epidemiological studies.2 Evidence
for intrafamilial HBV infection has in a few instances been supported by serological studies.1.3 However, the usefulness of serological typing is very limited in this respect because of the small number of subdeterminants.4,5 We have taken a different approach to the study of HBV transmission by using oligonucleotide probes with sequences taken from conserved regions of the HBV genome. The sequences of the 13 cloned HBV DNAs representing all four subtypes and a mixed subtype showed more than 30 conserved regions with 15 or more nucleotides.6-14 We used as probes nine S-strand sequences with 5’-ends at positions 56, 455, 970, 1257, 1584, 1952, 2385, 2723, and 2820 (fig 1).
family members had the same
HBV DNA sequence. The HBV DNA sequences found in the Y daughter, father, and grandfather were identical and they were different from the H
family mutant. These results provided evidence at the DNA level of intrafamilial transmission within these Chinese families.
ADDRESSES. Clinical Biochemistry Unit (H. J Lin, DSc, M. W. Fong), Department of Medicine (C-L. Lai, FRCP, J Y.-N Lau, MRCP, H -T Chung, MRCP), and Department of Statistics (I. J. Lauder, of Hong Kong, Hong Kong. Correspondence to Dr H J Lin, Clinical Biochemistry Unit, University of Hong Kong, Queen
PhD), University
Mary Hospital Compound, Hong Kong
