1231
prognostic similarly.s
value described for
ambulatory
BP
can
be
explained
Our data on the repeatability of ambulatory waking BP averages and of clinic estimates of BP reveal a much higher autocorrelation coefficient for the ambulatory values (083) than for the clinic estimates (059). We calculate that the regression dilution bias would lead to only a 20% underestimation of risk if the initial classification is done by ambulatory monitoring, compared with 69% for clinic BP classification. ANDREW J. S. COATS Cardiac Department, ALBERTO RADAELLI John Radcliffe Hospital, Oxford OX3 9DU, UK SUSAN J. CLARK J. Are there two regressions? J Am Stat Assoc 1950; 45: 164-80. to the mean in epidemiologic and clinical studies. Am J Epidemiol 1976; 104: 493-98. 3. Armitage P, Fox W, Rose GA, Tinker CM. The variability of measurement of casual blood pressure II: survey experience. Clin Sci 1966; 30: 337-44. 4. Devereux RB, Pickering TG. Relationship between ambulatory and exercise blood pressure and cardiac structure. Am Heart J 1988; 116: 1124-33. 5. Perloff D, Sokolow M, Cowan R. The prognostic value of ambulatory blood pressures. JAMA 1983; 249: 2792-98. 1. Berkson
2. Davis CE. The effect of regression
Schematic representation of relation between sodium and blood pressure in
a
population.
— — — —= observed; —————= "true" relation, after correction for
regression
dilution.
dilution bias in the sodium term, the bias in the quadratic term could be as much as sixteen-fold,3rendering regression estimates highly unstable. Furthermore, the "true" minimum point of a (positive) quadratic curve will be shifted to the left by a factor of four after correction for regression dilution. This is illustrated schematically in the figure. The interrupted line shows the observed relation between sodium and blood pressure with a minimum at 200 mmol, apparently illustrating an inverse association across most of the sodium range. After correction for regression dilution (solid line) the curve shifts to the left, with a minimum at 50 mmol, so that the true association emerges as a direct sodium/blood pressure
relationship. This example underlines the conclusions of MacMahon and colleagues, who stress the need for repeated measurements in epidemiological studies so that regression dilution bias can be estimated and its effects corrected. Otherwise studies may be
seriously misleading. Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London WC1 E 7HT, UK
PAUL ELLIOTT
1. Liu K, Cooper R, McKeever S, et al. Assessment of the association between habitual salt intake and high blood pressure: methodological problems. Am J Epidemiol 1979; 110: 219-24. 2 Staessen J, Bulpitt CJ, Thijs L, et al. Sympathetic tone and relation between sodium intake and blood pressure in the general population. Br Med J 1989; 299: 1502-03. 3. Griliches Z, Ringstad V. Error-in-the-variable bias in non-linear contexts. Econometrica 1970; 38: 368-71.
SiR,—Dr MacMahon and his colleagues remind us of the importance of regression to the mean whenever there is considerable within-subject variability. The "regression dilution bias" is well recognised by statisticiansl-3 and it is very helpful to have large epidemiological databases reanalysed to take into account the effects of regression dilution, yielding a true appreciation of the association between risk and long-term average blood pressure (BP). Correction by the two methods described would not be so important if epidemiological studies took simple steps to lessen regression bias. The use of the average of multiple measurements to classify subjects at inclusion will reduce within-subject variability and thereby the regression effect.3 Ambulatory monitoring is one way of obtaining multiple estimates of BP over a short time. Although probably not as good as the average of the same number of readings over months or years a daytime average of BP is more practicable and is likely to lead to less within-subject variability. The frequent observation that relations between indices thought to be associated with raised BP (such as left-ventricular mass) are stronger for ambulatory mean BP than for clinic estimates ofB!>" is easily explained by the smaller regression dilution bias. The added
Anti-neutrophil cytoplasmic antibodies and subglottic stenosis SIR,-When to diagnose Wegener’s granulomatosis (WG) and the implications of doing so are controversial. This was well illustrated by the patient with isolated subglottic stenosis, reported by Hoare and Rhys Evans,l who was diagnosed and treated as having WG because of the presence of anti-neutrophil cytoplasmic antibodies (ANCA), an approach which was criticised,z This controversy reflects a general difficulty-namely, that early effective treatment of WG based on a presumptive diagnosis may preclude a definite diagnosis on traditional criteria. Isolated subglottic stenosis presents an extreme form of this dilemma; even when it presents in patients with definite WG it often does so without other evidence of disease activity. A 40-year-old
man presented in July, 1988, with necrotising glomerulonephritis, upper and lower respiratory tract disease, and ANCA positivity. He responded to ten 4 litre plasma exchanges, prednisolone, and cyclophosphamide and remained well on maintenance therapy with no clinical or radiological evidence of
active vasculitis. His serum creatinine remained stable and urinary sediment, C-reactive protein, serum alkaline phosphatase, and platelet count were normal. In February, 1989, the patient experienced progressive symptoms of cough and dyspnoea on exertion and, as a late feature, stridor at rest. Respiratory function tests (figure) demonstrated worsening MIFS° (inspiratory flow rate at 50% of vital capacity) compatible with extrathoracic tracheal obstruction. Bronchoscopy confirmed subglottic stenosis and histological study of tissue obtained at operation indicated acute-on-chronic inflammation. There was no other evidence of active disease but ANCA remained The detectable. patient was treated with increased immunosuppression, a temporary tracheostomy, and a tracheal stent. The stent was removed and the tracheostomy closed in November, 1989, and the patient remains well on maintenance
immunotherapy. Tracheal stenosis has been reported in at least six-teen patients with WG and has been invariably subglottic, though the reason for this is unknown.3-8 However, the subglottis is the narrowest part of the trachea and lower lesions may be asymptomatic; it may also be a vascular watershed and so may have less capacity to heal; and it is exposed to a greater quantity of inhaled antigens. There is no evidence to discriminate between these possibilities. The importance of a local factor is indicated by the observation that tracheal stenosis often develops in the absence of active disease elsewhere. In five cases reported in sufficient detail for analysis tracheal stenosis was the first manifestation of WG or was the sole site of relapse.1,5-8 Furthermore, our patient had none of the usual non-specific markers of active disease such as increased C-reactive protein and alkaline phosphatase or thrombocytosis. The role of ANCA in the diagnosis of WG and related vasculitides is becoming clearer. Their presence correlates strongly
1232
EFFECTS OF UREA AND UREASE INHIBITOR ON SURVIVAL OF H PYLORI/ IN ACID
Serial
MIFso during evolution of respiratory symptoms.
with a diagnosis of active vasculitis; false positives are rare and even some of these may indicate early or limited disease, as in our patient with subglottic stenosis.9,lO However, clinicians will continue to be forced into controversial decisions until the pathogenesis of systemic vasculitis is understood and the diagnosis can be established unambiguously even in cases with limited disease.
Hammersmith
Hospital.
London W12 0HS, UK
C. N. Ross F. W. K. TAM R. J. D. WINTER C. D. PUSEY A. J. REES
Hoare TJ, Rhys Evans PH. Anti-neutrophil cytoplasmic antibody assay in diagnosis of recurrent subglottic stenosis. Lancet 1988; ii: 1360. 2. Michaels L. Anti-neutrophil cytoplasmic antibody and subglottic stenosis. Lancet 1989; i: 53. 3. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98: 76-85. 4. Stem MG, Gamsu G, Webb WR, Stulbarg MS. Computed tomography of diffuse tracheal stenosis in Wegener granulomatosis. J Comput Assist Tomogr 1986; 10: 1.
868-70. 5. Cohen MI, Gore RM, August CZ, Ossof RH. Tracheal and bronchial stenosis associated with mediastinal adenopathy in Wegener granulomatosis: CT findings. J Comput Assist Tomogr 1984; 8: 327-29. 6. Gohel VK, Dalinka MK, Israel HL, Libshitz HI. The radiological manifestations of Wegener’s granulomatosis. Br J Radiol 1973; 46: 427-32. 7. Lampman JH, Querubin R, Kondapalli P. Subglottic stenosis in Wegener’s granulomatosis. Chest 1981; 79: 230-34. 8. Scully RE, Mark EJ, McNeely BU. Case records of the Massachusetts General Hospital. N Engl J Med 1986; 315: 378-87. 9. van der Woude FJ, Lobatto S, Petmin H, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985; i: 425-29. 10. Savage COS, Winearls CG, Jones S, Marshall PD, Lockwood CM. Prospective study of a radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet 1987; i: 1389-93.
*Three experiments
tColony-formmg NG = no growth
(1-3)
x units
10-6/ml.
In some patients with urinary tract infections struvite form in urine rendered alkaline by ammonia that is produced by urease-containing organisms. Urease inhibitors such as acetohydroxamic acid are used clinically to prevent stone formation. We grew H pylori for 3 days on sheep blood agar plates in a microaerobic environment at 35°C, suspended in normal saline. 250 ltl samples, some mixed 5 min beforehand with 100 µl of 25 mg acetohydroxamic acid per ml, were added to 4-75 ml 0.1mol/1 HCI + 0-05 mol/I saline (pH 1-0), 0-3 mol/1 citrate (pH 2-0), or phosphate-buffered normal saline (PBS, pH 7-2) at 37’C, +14 mmol/1 urea. After 30 min at 37°C, samples were diluted in PBS, plated in duplicate, grown as above, and colonies counted. Post-30 min incubation pH values were always within 0of the initial value. At pH 1 and 2 acetohydroxamic acid abolished the urea/ureasedependent acid resistance of H pylori (table). Existing treatments for the eradication of H pylori are not always successful. A trial of urease inhibitors might show that they are efficacious alone or in combination with current treatments. Combination with other drugs is likely to be more successful in view of the synergism observed between antibiotics and urease inhibitors in urinary tract infections. Acetohydroxamic acid itself, although possibly mutagenic, may be especially effective because it also prevents the growth of H pylori in vitro, both alone and synergistically with antimicrobial agents.9 In the absence of animal model data, the results of such a trial would elucidate the importance of urease in the pathogenesis of H pylori infection. Even if acid resistance is not a central feature, ammonia affects the gastric mucosal barrier, 10 and it can inhibit bacterial killing by host phagocytes.ll Thus, urease inhibitors may reduce mucosal damage and enhance the ability of the host defences to clear the infection.
suggested.8 stones
Helicobacter pylori acid resistance SIR,-Surprisingly little attention is given to the resistance of Helicobacter pylori to acid, despite the fact that the human stomach and duodenum are the usual site of colonisation. One possible way for this organism to survive in the stomach is that it may occupy regions of higher pH in the mucus layer.1 Several workers have suggested that a period of hypochlorhydria is necessary for successful colonisation.1-3 Barrett and colleagues’ results4 indicate that H pylori can survive for 30 min at pH 1 5, in the presence of 5 mmol/1 urea. We have also shown substantial resistance to acid, even at pH 1 0, and at the more physiological gastric juice urea concentration of 1 4 mmol/1 (table).5 In strong acid H pylori urease and urea seem to provide a physiological pH in the immediate vicinity of the H pylori cell, without much altering the pH of the medium as a whole. Thus, exposure to acidic gastric juice need not prevent successful H pylori challenge. This resistance to acid may also be important in the maintenance of a continuing infection, by allowing the H pylori organism to escape from host phagocytic cells. Phagocytes can enter the gastric mucus layer,but do not function effectively at low pH.7 If urea/urease-dependent resistance to acid is important for H pylori survival, a different approach to eradication of the organism is
C. MOONEY Department of Surgery. Christchurch School of Medicine, Christchurch, New Zealand
D. J. MUNSTER P. F. BAGSHAW R. A. ALLARDYCE
1. Warren JR. Unidentified curved bacilli on gastnc epithelium in active chronic gastritis Lancet 1983; i: 1273. 2. Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric campylobacter. Med JAust 1985; 142: 436-39. 3. Morris A, Nicholson G. Ingestion of C pyloridis causes gastritis and raised fasting
gastric pH. Am J Gastroenterol 1987; 82: 192-99. 4. Barrett LJ, Marshall BJ, Prakash C, Guerrant RL. Protection of Campylobacter pylori but not Campylobacter jejum against acid susceptibility by urea. In. de Wal J, ed. Campylobacter pylon. Bibliography, Gist-Brocades, 1988. 261 5. Lieber CS, Lefevre A. Ammonia as a source of gastric hypoacidity in patients with uremia. J Clin Invest 1959; 38: 1271-77. 6. Shousha S, Bull TB, Parkins RA. Gastric spiral bacteria. Lancet 1984; ii. 101 7. Gabig TG, Bearman SI, Babior BM. Effects of oxygen tension and pH on the respiratory burst of human neutrophils. Blood 1979; 53: 1133-39. 8. Mobley HLT, Cortesia MJ, Rosenthal LE, Jones BD. Characterization of urease from Campylobacter pylori. J Clin Microbiol 1988; 26: 831-36. 9. McNulty CAM. Bacteriological and pharmacological basis for the treatment of Campylobacter pylori infection. In: Rathbone BJ, Heatley RV, eds. Campylobacter pylori and gastroduodenal disease. Oxford: Blackwell Scientific, 1989 209-16. 10. Sidebotham RL, Baron JH Hypothesis: Helicobacter pylon, urease, mucus, and gastric ulcer. Lancet 1990; 335: 193-95. 11. Gordon AH, D’Arcy Hart P, Young MR Ammonia inhibits phagosome-lysosome fusion in macrophages. Nature 1980; 286: 79-80.
prognostic similarly.s
value described for
ambulatory
BP
can
be
explained
Our data on the repeatability of ambulatory waking BP averages and of clinic estimates of BP reveal a much higher autocorrelation coefficient for the ambulatory values (083) than for the clinic estimates (059). We calculate that the regression dilution bias would lead to only a 20% underestimation of risk if the initial classification is done by ambulatory monitoring, compared with 69% for clinic BP classification. ANDREW J. S. COATS Cardiac Department, ALBERTO RADAELLI John Radcliffe Hospital, Oxford OX3 9DU, UK SUSAN J. CLARK J. Are there two regressions? J Am Stat Assoc 1950; 45: 164-80. to the mean in epidemiologic and clinical studies. Am J Epidemiol 1976; 104: 493-98. 3. Armitage P, Fox W, Rose GA, Tinker CM. The variability of measurement of casual blood pressure II: survey experience. Clin Sci 1966; 30: 337-44. 4. Devereux RB, Pickering TG. Relationship between ambulatory and exercise blood pressure and cardiac structure. Am Heart J 1988; 116: 1124-33. 5. Perloff D, Sokolow M, Cowan R. The prognostic value of ambulatory blood pressures. JAMA 1983; 249: 2792-98. 1. Berkson
2. Davis CE. The effect of regression
Schematic representation of relation between sodium and blood pressure in
a
population.
— — — —= observed; —————= "true" relation, after correction for
regression
dilution.
dilution bias in the sodium term, the bias in the quadratic term could be as much as sixteen-fold,3rendering regression estimates highly unstable. Furthermore, the "true" minimum point of a (positive) quadratic curve will be shifted to the left by a factor of four after correction for regression dilution. This is illustrated schematically in the figure. The interrupted line shows the observed relation between sodium and blood pressure with a minimum at 200 mmol, apparently illustrating an inverse association across most of the sodium range. After correction for regression dilution (solid line) the curve shifts to the left, with a minimum at 50 mmol, so that the true association emerges as a direct sodium/blood pressure
relationship. This example underlines the conclusions of MacMahon and colleagues, who stress the need for repeated measurements in epidemiological studies so that regression dilution bias can be estimated and its effects corrected. Otherwise studies may be
seriously misleading. Department of Epidemiology and Population Sciences, London School of Hygiene and Tropical Medicine, London WC1 E 7HT, UK
PAUL ELLIOTT
1. Liu K, Cooper R, McKeever S, et al. Assessment of the association between habitual salt intake and high blood pressure: methodological problems. Am J Epidemiol 1979; 110: 219-24. 2 Staessen J, Bulpitt CJ, Thijs L, et al. Sympathetic tone and relation between sodium intake and blood pressure in the general population. Br Med J 1989; 299: 1502-03. 3. Griliches Z, Ringstad V. Error-in-the-variable bias in non-linear contexts. Econometrica 1970; 38: 368-71.
SiR,—Dr MacMahon and his colleagues remind us of the importance of regression to the mean whenever there is considerable within-subject variability. The "regression dilution bias" is well recognised by statisticiansl-3 and it is very helpful to have large epidemiological databases reanalysed to take into account the effects of regression dilution, yielding a true appreciation of the association between risk and long-term average blood pressure (BP). Correction by the two methods described would not be so important if epidemiological studies took simple steps to lessen regression bias. The use of the average of multiple measurements to classify subjects at inclusion will reduce within-subject variability and thereby the regression effect.3 Ambulatory monitoring is one way of obtaining multiple estimates of BP over a short time. Although probably not as good as the average of the same number of readings over months or years a daytime average of BP is more practicable and is likely to lead to less within-subject variability. The frequent observation that relations between indices thought to be associated with raised BP (such as left-ventricular mass) are stronger for ambulatory mean BP than for clinic estimates ofB!>" is easily explained by the smaller regression dilution bias. The added
Anti-neutrophil cytoplasmic antibodies and subglottic stenosis SIR,-When to diagnose Wegener’s granulomatosis (WG) and the implications of doing so are controversial. This was well illustrated by the patient with isolated subglottic stenosis, reported by Hoare and Rhys Evans,l who was diagnosed and treated as having WG because of the presence of anti-neutrophil cytoplasmic antibodies (ANCA), an approach which was criticised,z This controversy reflects a general difficulty-namely, that early effective treatment of WG based on a presumptive diagnosis may preclude a definite diagnosis on traditional criteria. Isolated subglottic stenosis presents an extreme form of this dilemma; even when it presents in patients with definite WG it often does so without other evidence of disease activity. A 40-year-old
man presented in July, 1988, with necrotising glomerulonephritis, upper and lower respiratory tract disease, and ANCA positivity. He responded to ten 4 litre plasma exchanges, prednisolone, and cyclophosphamide and remained well on maintenance therapy with no clinical or radiological evidence of
active vasculitis. His serum creatinine remained stable and urinary sediment, C-reactive protein, serum alkaline phosphatase, and platelet count were normal. In February, 1989, the patient experienced progressive symptoms of cough and dyspnoea on exertion and, as a late feature, stridor at rest. Respiratory function tests (figure) demonstrated worsening MIFS° (inspiratory flow rate at 50% of vital capacity) compatible with extrathoracic tracheal obstruction. Bronchoscopy confirmed subglottic stenosis and histological study of tissue obtained at operation indicated acute-on-chronic inflammation. There was no other evidence of active disease but ANCA remained The detectable. patient was treated with increased immunosuppression, a temporary tracheostomy, and a tracheal stent. The stent was removed and the tracheostomy closed in November, 1989, and the patient remains well on maintenance
immunotherapy. Tracheal stenosis has been reported in at least six-teen patients with WG and has been invariably subglottic, though the reason for this is unknown.3-8 However, the subglottis is the narrowest part of the trachea and lower lesions may be asymptomatic; it may also be a vascular watershed and so may have less capacity to heal; and it is exposed to a greater quantity of inhaled antigens. There is no evidence to discriminate between these possibilities. The importance of a local factor is indicated by the observation that tracheal stenosis often develops in the absence of active disease elsewhere. In five cases reported in sufficient detail for analysis tracheal stenosis was the first manifestation of WG or was the sole site of relapse.1,5-8 Furthermore, our patient had none of the usual non-specific markers of active disease such as increased C-reactive protein and alkaline phosphatase or thrombocytosis. The role of ANCA in the diagnosis of WG and related vasculitides is becoming clearer. Their presence correlates strongly
1232
EFFECTS OF UREA AND UREASE INHIBITOR ON SURVIVAL OF H PYLORI/ IN ACID
Serial
MIFso during evolution of respiratory symptoms.
with a diagnosis of active vasculitis; false positives are rare and even some of these may indicate early or limited disease, as in our patient with subglottic stenosis.9,lO However, clinicians will continue to be forced into controversial decisions until the pathogenesis of systemic vasculitis is understood and the diagnosis can be established unambiguously even in cases with limited disease.
Hammersmith
Hospital.
London W12 0HS, UK
C. N. Ross F. W. K. TAM R. J. D. WINTER C. D. PUSEY A. J. REES
Hoare TJ, Rhys Evans PH. Anti-neutrophil cytoplasmic antibody assay in diagnosis of recurrent subglottic stenosis. Lancet 1988; ii: 1360. 2. Michaels L. Anti-neutrophil cytoplasmic antibody and subglottic stenosis. Lancet 1989; i: 53. 3. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98: 76-85. 4. Stem MG, Gamsu G, Webb WR, Stulbarg MS. Computed tomography of diffuse tracheal stenosis in Wegener granulomatosis. J Comput Assist Tomogr 1986; 10: 1.
868-70. 5. Cohen MI, Gore RM, August CZ, Ossof RH. Tracheal and bronchial stenosis associated with mediastinal adenopathy in Wegener granulomatosis: CT findings. J Comput Assist Tomogr 1984; 8: 327-29. 6. Gohel VK, Dalinka MK, Israel HL, Libshitz HI. The radiological manifestations of Wegener’s granulomatosis. Br J Radiol 1973; 46: 427-32. 7. Lampman JH, Querubin R, Kondapalli P. Subglottic stenosis in Wegener’s granulomatosis. Chest 1981; 79: 230-34. 8. Scully RE, Mark EJ, McNeely BU. Case records of the Massachusetts General Hospital. N Engl J Med 1986; 315: 378-87. 9. van der Woude FJ, Lobatto S, Petmin H, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener’s granulomatosis. Lancet 1985; i: 425-29. 10. Savage COS, Winearls CG, Jones S, Marshall PD, Lockwood CM. Prospective study of a radioimmunoassay for antibodies against neutrophil cytoplasm in diagnosis of systemic vasculitis. Lancet 1987; i: 1389-93.
*Three experiments
tColony-formmg NG = no growth
(1-3)
x units
10-6/ml.
In some patients with urinary tract infections struvite form in urine rendered alkaline by ammonia that is produced by urease-containing organisms. Urease inhibitors such as acetohydroxamic acid are used clinically to prevent stone formation. We grew H pylori for 3 days on sheep blood agar plates in a microaerobic environment at 35°C, suspended in normal saline. 250 ltl samples, some mixed 5 min beforehand with 100 µl of 25 mg acetohydroxamic acid per ml, were added to 4-75 ml 0.1mol/1 HCI + 0-05 mol/I saline (pH 1-0), 0-3 mol/1 citrate (pH 2-0), or phosphate-buffered normal saline (PBS, pH 7-2) at 37’C, +14 mmol/1 urea. After 30 min at 37°C, samples were diluted in PBS, plated in duplicate, grown as above, and colonies counted. Post-30 min incubation pH values were always within 0of the initial value. At pH 1 and 2 acetohydroxamic acid abolished the urea/ureasedependent acid resistance of H pylori (table). Existing treatments for the eradication of H pylori are not always successful. A trial of urease inhibitors might show that they are efficacious alone or in combination with current treatments. Combination with other drugs is likely to be more successful in view of the synergism observed between antibiotics and urease inhibitors in urinary tract infections. Acetohydroxamic acid itself, although possibly mutagenic, may be especially effective because it also prevents the growth of H pylori in vitro, both alone and synergistically with antimicrobial agents.9 In the absence of animal model data, the results of such a trial would elucidate the importance of urease in the pathogenesis of H pylori infection. Even if acid resistance is not a central feature, ammonia affects the gastric mucosal barrier, 10 and it can inhibit bacterial killing by host phagocytes.ll Thus, urease inhibitors may reduce mucosal damage and enhance the ability of the host defences to clear the infection.
suggested.8 stones
Helicobacter pylori acid resistance SIR,-Surprisingly little attention is given to the resistance of Helicobacter pylori to acid, despite the fact that the human stomach and duodenum are the usual site of colonisation. One possible way for this organism to survive in the stomach is that it may occupy regions of higher pH in the mucus layer.1 Several workers have suggested that a period of hypochlorhydria is necessary for successful colonisation.1-3 Barrett and colleagues’ results4 indicate that H pylori can survive for 30 min at pH 1 5, in the presence of 5 mmol/1 urea. We have also shown substantial resistance to acid, even at pH 1 0, and at the more physiological gastric juice urea concentration of 1 4 mmol/1 (table).5 In strong acid H pylori urease and urea seem to provide a physiological pH in the immediate vicinity of the H pylori cell, without much altering the pH of the medium as a whole. Thus, exposure to acidic gastric juice need not prevent successful H pylori challenge. This resistance to acid may also be important in the maintenance of a continuing infection, by allowing the H pylori organism to escape from host phagocytic cells. Phagocytes can enter the gastric mucus layer,but do not function effectively at low pH.7 If urea/urease-dependent resistance to acid is important for H pylori survival, a different approach to eradication of the organism is
C. MOONEY Department of Surgery. Christchurch School of Medicine, Christchurch, New Zealand
D. J. MUNSTER P. F. BAGSHAW R. A. ALLARDYCE
1. Warren JR. Unidentified curved bacilli on gastnc epithelium in active chronic gastritis Lancet 1983; i: 1273. 2. Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric campylobacter. Med JAust 1985; 142: 436-39. 3. Morris A, Nicholson G. Ingestion of C pyloridis causes gastritis and raised fasting
gastric pH. Am J Gastroenterol 1987; 82: 192-99. 4. Barrett LJ, Marshall BJ, Prakash C, Guerrant RL. Protection of Campylobacter pylori but not Campylobacter jejum against acid susceptibility by urea. In. de Wal J, ed. Campylobacter pylon. Bibliography, Gist-Brocades, 1988. 261 5. Lieber CS, Lefevre A. Ammonia as a source of gastric hypoacidity in patients with uremia. J Clin Invest 1959; 38: 1271-77. 6. Shousha S, Bull TB, Parkins RA. Gastric spiral bacteria. Lancet 1984; ii. 101 7. Gabig TG, Bearman SI, Babior BM. Effects of oxygen tension and pH on the respiratory burst of human neutrophils. Blood 1979; 53: 1133-39. 8. Mobley HLT, Cortesia MJ, Rosenthal LE, Jones BD. Characterization of urease from Campylobacter pylori. J Clin Microbiol 1988; 26: 831-36. 9. McNulty CAM. Bacteriological and pharmacological basis for the treatment of Campylobacter pylori infection. In: Rathbone BJ, Heatley RV, eds. Campylobacter pylori and gastroduodenal disease. Oxford: Blackwell Scientific, 1989 209-16. 10. Sidebotham RL, Baron JH Hypothesis: Helicobacter pylon, urease, mucus, and gastric ulcer. Lancet 1990; 335: 193-95. 11. Gordon AH, D’Arcy Hart P, Young MR Ammonia inhibits phagosome-lysosome fusion in macrophages. Nature 1980; 286: 79-80.
