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WEGENER'S GRANULOMATOSIS
574 "
vitro) reduced the numbers of methicillin-resistant staphylococci by about a hundredfold. Mr Hewitt and Dr Sanderson (March 9, p. 415) report some controlled experiments that showed that guineapigs
in
" infected with " methicillin-resistant strains were successfully treated with methicillin; but they then continue with the assumption that a minority population of highly resistant cells cannot be eliminated by methicillin in man. It is impossible to identify such a resistant cell in vivo, and subculture of this cell on antibiotic-free medium would immediately result in a cell population of variable resistance, similar to that obtained by subculture of a " sensitive " cell from the " methicillin-resistant " organism. Similarly, after subculture of clinical material on methicillin-containing medium, any colonies could also have been derived from a " sensitive " cell. Thus methicillin-resistant staphylococci isolated from patients who have been treated with methicillin (or could well comprise predominantly the analogue) " sensitive " members of the cell population, and treatment failure could have resulted from inadequate host defences. The policy (to be applauded) of reserving certain antimicrobials (e.g., the semisynthetic penicillins) by some clinicians for use in infectious crises could account for Controlled trials are some of the treatment failures. seemingly the only way to resolve whether methicillinresistant staphylococci are susceptible to methicillin or analogues in vivo. Until this information is obtained, staphylococci that show heterogeneous resistance to methicillin in vitro should be reported as methicillindoubtful. Dr Ayliffe and his colleagues hope that animal experiments might clarify the significance of " methicillin resistance " for the patient: they support this by demonstrating that mice infected with " methicillin-resistant " staphylococci are not cured with methicillin. These experiments, however, employed an inoculum equivalent to about 10 litres of pure staphylococcal culture in man and are therefore of doubtful relevance to the clinical situation. The infections in three different rodents (rats by Dr Bulger, guineapigs by Mr Hewitt and Dr Sanderson, and mice by Dr Ayliffe and his colleagues) have shown very variable response to methicillin. Which rodent, if any, represents man ?
Department of
Bacteriology,
University of Bristol,
R. W. LACEY.
Bristol BS8 1TD. 1.
Bulger,
R.
J., Fiegl, P., Nielson, K. J. infect. Dis. 1972, 126, 647.
WEGENER’S GRANULOMATOSIS
SiR,—The interesting and detailed immunological study of Wegener’s granulomatosis by Dr Shillitoe and colleagues (Feb. 23, p. 279) is somewhat marred by the arbitrary inclusion of mid-line granuloma without generalised involvement as an unquestionable form of Wegener’s granulomatosis. It is true that Godman and Churgstated that Wegener’s granulomatosis may begin as a lesion resembling midline granuloma and then involve other organs, but they merely suggested the possibility that the localised midline granuloma may be related to Wegener’s granulomatosis. On the other hand, Wegener2 I myself have always refused to as late as 1968 wrote: "
relate PG and MG because of the fact that these diseases are clinically as well as anatomically different". (PG=
pneumogenic granulomatosis =Wegener’s granulomatosis. MG=midline malignant granuloma.) In the same article he stated emphatically that the triad of respiratory-tract involvement, vasculitis, and glomerulonephritis is necessary for the diagnosis of Wegener’s granulomatosis. It is
entirely possible that the relationship of midline granuloma to Wegener’s granulomatosis is comparable to the relationof the lung to Wegener’s ship of certain localised lesions granulomatosis. In fact, I 3-5 attempted some time ago to establish that very possibility, and coined the term pathergic granulomatosis to cover both localised and generalised lesions, thus limiting the term Wegener’s granulomatosis to the classic generalised phenomenon as defined by Wegener. In contrast, Carrington and Liebowhave chosen to categorise their localised pulmonary forms as limited forms of angiitis and granulomatosis of Wegener’s type. Finally, the surprising and disturbing finding of the article in question that there is a lack of circulating immune complexes in Wegener’s granulomatosis quite unlike that found in polyarteritis nodosa serves as a warning signal against a too ready acceptance of identity of these two entities and underlines the differences noted morphologically. At any rate, in view of the differences of opinion cited, it would perhaps be better to study separately by immunological techniques the localised and generalised lesions under consideration in order to avoid mingling of unrelated or dissimilar entities. Beverly Hospital, Beverly, Massachusetts 01915, U.S.A.
an
inter-
ROBERT FIENBERG.
Godman, G. C., Churg, J. J. Archs Path. 1954, 58, 533. Wegener, F. Morgagni, 1968, 1, 5. 3. Fienberg, R. Am. J. clin. Path. 1953, 23, 413. 4. Fienberg, R. Am. J. Path. 1953, 29, 913. 5. Fienberg, R. Am. J. Med. 1955, 19, 829. 6. Carrington, C. B., Liebow, A. A. ibid. 1966, 41, 497.
1. 2.
HL-A ANTIGENS IN INFLAMMATORY BOWE DISEASE
SIR,-In their report of the frequency of histocompatibility phenotypes in patients with inflammatory bowel disease, Dr Asquith and his colleagues (Jan. 26, p. 113) discuss various possible explanations for the variability between their results and those previously reported. They omit, however, to mention the most obvious and likely explanation-i.e., that there is no association between the HL-A system and inflammatory bowel disease. When the HL-A
or
any other
polymorphic
system is
being studied to see if there is an association of a phenotype with a disease, two types of comparison are often made. It may be that as a result of a previous series or some other consideration there is a hypothesis that one phenotype is most likely to be associated with the disorder. In the paper of Asquith et al. the apparently most " significant " of their findings was the difference between the incidence of HL-A 11 in patients with ulcerative colitis and controls. The probability that the difference would have occurred by chance is 0-008291. If before the study was started the question asked had been whether the incidence of HL-A 11 antigen differed between colitis patients and controls, then this value of p would have provided a valid answer. " Very often, however, in association " studies there is no hypothesis available (other than the null hypothesis) and this was the situation with regard to ulcerative colitis at the time the study of Asquith et al. was undertaken. The question actually asked was whether one or more of the twelve comparisons revealed evidence for a significant difference between the two series of patients and the controls. Therefore, a correction for the p value given above is necessary if it is to be used as an indication of the presence of such differences. One can multiply p by the number of comparisons made, to give a corrected p of 0-0995. Using a more refined method2 the corrected p is 0-0952. This level of significance is unacceptable as
vitro) reduced the numbers of methicillin-resistant staphylococci by about a hundredfold. Mr Hewitt and Dr Sanderson (March 9, p. 415) report some controlled experiments that showed that guineapigs
in
" infected with " methicillin-resistant strains were successfully treated with methicillin; but they then continue with the assumption that a minority population of highly resistant cells cannot be eliminated by methicillin in man. It is impossible to identify such a resistant cell in vivo, and subculture of this cell on antibiotic-free medium would immediately result in a cell population of variable resistance, similar to that obtained by subculture of a " sensitive " cell from the " methicillin-resistant " organism. Similarly, after subculture of clinical material on methicillin-containing medium, any colonies could also have been derived from a " sensitive " cell. Thus methicillin-resistant staphylococci isolated from patients who have been treated with methicillin (or could well comprise predominantly the analogue) " sensitive " members of the cell population, and treatment failure could have resulted from inadequate host defences. The policy (to be applauded) of reserving certain antimicrobials (e.g., the semisynthetic penicillins) by some clinicians for use in infectious crises could account for Controlled trials are some of the treatment failures. seemingly the only way to resolve whether methicillinresistant staphylococci are susceptible to methicillin or analogues in vivo. Until this information is obtained, staphylococci that show heterogeneous resistance to methicillin in vitro should be reported as methicillindoubtful. Dr Ayliffe and his colleagues hope that animal experiments might clarify the significance of " methicillin resistance " for the patient: they support this by demonstrating that mice infected with " methicillin-resistant " staphylococci are not cured with methicillin. These experiments, however, employed an inoculum equivalent to about 10 litres of pure staphylococcal culture in man and are therefore of doubtful relevance to the clinical situation. The infections in three different rodents (rats by Dr Bulger, guineapigs by Mr Hewitt and Dr Sanderson, and mice by Dr Ayliffe and his colleagues) have shown very variable response to methicillin. Which rodent, if any, represents man ?
Department of
Bacteriology,
University of Bristol,
R. W. LACEY.
Bristol BS8 1TD. 1.
Bulger,
R.
J., Fiegl, P., Nielson, K. J. infect. Dis. 1972, 126, 647.
WEGENER’S GRANULOMATOSIS
SiR,—The interesting and detailed immunological study of Wegener’s granulomatosis by Dr Shillitoe and colleagues (Feb. 23, p. 279) is somewhat marred by the arbitrary inclusion of mid-line granuloma without generalised involvement as an unquestionable form of Wegener’s granulomatosis. It is true that Godman and Churgstated that Wegener’s granulomatosis may begin as a lesion resembling midline granuloma and then involve other organs, but they merely suggested the possibility that the localised midline granuloma may be related to Wegener’s granulomatosis. On the other hand, Wegener2 I myself have always refused to as late as 1968 wrote: "
relate PG and MG because of the fact that these diseases are clinically as well as anatomically different". (PG=
pneumogenic granulomatosis =Wegener’s granulomatosis. MG=midline malignant granuloma.) In the same article he stated emphatically that the triad of respiratory-tract involvement, vasculitis, and glomerulonephritis is necessary for the diagnosis of Wegener’s granulomatosis. It is
entirely possible that the relationship of midline granuloma to Wegener’s granulomatosis is comparable to the relationof the lung to Wegener’s ship of certain localised lesions granulomatosis. In fact, I 3-5 attempted some time ago to establish that very possibility, and coined the term pathergic granulomatosis to cover both localised and generalised lesions, thus limiting the term Wegener’s granulomatosis to the classic generalised phenomenon as defined by Wegener. In contrast, Carrington and Liebowhave chosen to categorise their localised pulmonary forms as limited forms of angiitis and granulomatosis of Wegener’s type. Finally, the surprising and disturbing finding of the article in question that there is a lack of circulating immune complexes in Wegener’s granulomatosis quite unlike that found in polyarteritis nodosa serves as a warning signal against a too ready acceptance of identity of these two entities and underlines the differences noted morphologically. At any rate, in view of the differences of opinion cited, it would perhaps be better to study separately by immunological techniques the localised and generalised lesions under consideration in order to avoid mingling of unrelated or dissimilar entities. Beverly Hospital, Beverly, Massachusetts 01915, U.S.A.
an
inter-
ROBERT FIENBERG.
Godman, G. C., Churg, J. J. Archs Path. 1954, 58, 533. Wegener, F. Morgagni, 1968, 1, 5. 3. Fienberg, R. Am. J. clin. Path. 1953, 23, 413. 4. Fienberg, R. Am. J. Path. 1953, 29, 913. 5. Fienberg, R. Am. J. Med. 1955, 19, 829. 6. Carrington, C. B., Liebow, A. A. ibid. 1966, 41, 497.
1. 2.
HL-A ANTIGENS IN INFLAMMATORY BOWE DISEASE
SIR,-In their report of the frequency of histocompatibility phenotypes in patients with inflammatory bowel disease, Dr Asquith and his colleagues (Jan. 26, p. 113) discuss various possible explanations for the variability between their results and those previously reported. They omit, however, to mention the most obvious and likely explanation-i.e., that there is no association between the HL-A system and inflammatory bowel disease. When the HL-A
or
any other
polymorphic
system is
being studied to see if there is an association of a phenotype with a disease, two types of comparison are often made. It may be that as a result of a previous series or some other consideration there is a hypothesis that one phenotype is most likely to be associated with the disorder. In the paper of Asquith et al. the apparently most " significant " of their findings was the difference between the incidence of HL-A 11 in patients with ulcerative colitis and controls. The probability that the difference would have occurred by chance is 0-008291. If before the study was started the question asked had been whether the incidence of HL-A 11 antigen differed between colitis patients and controls, then this value of p would have provided a valid answer. " Very often, however, in association " studies there is no hypothesis available (other than the null hypothesis) and this was the situation with regard to ulcerative colitis at the time the study of Asquith et al. was undertaken. The question actually asked was whether one or more of the twelve comparisons revealed evidence for a significant difference between the two series of patients and the controls. Therefore, a correction for the p value given above is necessary if it is to be used as an indication of the presence of such differences. One can multiply p by the number of comparisons made, to give a corrected p of 0-0995. Using a more refined method2 the corrected p is 0-0952. This level of significance is unacceptable as