- Email: [email protected]
L-tryptophan and eosinophilia-myalgia syndrome
drinking 1 L per day would take in 50 ng, or 2-5 yg IGF1/kg body weight. 400 times this amount had no observable effect on the gut or any other organ in hypophysectomised rats.
The concentration of 4 ng/mL for untreated cows which Mepham and colleagues selected’ was the average result for samples of 100 bulk tanks. Each tank would have contained the mixed milk from many cows. Juskevich and Guyer’ cite a study in which the maximum concentration in individual cows was 30-5 ng/mL and another in which the average for a group of four cows was 28-4 ng/mL; none of these cows had
received bST. As these workers state, the concentration of IGF-1 in milk varies widely between animals and it is determined by stage of lactation and parity. Increases in IGF-1 in the milk of cows receiving BST are small in the context of this natural variation. Consumers generally receive milk pooled from a large number of cows, so the concentration of IGF-1 will be much less than 50 ng/mL and the safety margin will be correspondingly wider. Lilly has no data that could be construed to support anything approaching the tenfold increase suggested in the letter of Mepham and colleagues. Mepham and colleagues imply that milk proteins might protect IGF-1 from digestion by proteolytic enzymes. Lilly’s safety evaluation included a test in which the milk of cows receiving more than seven times the recommended dose of BST was given to hypophysectomised rats for 10 days. There were no effects on growth or epiphyseal cartilage development. No regulatory authority has ever concluded that there is a risk to human health from milk from cows receiving bST. They include the UK Veterinary Products Committee and Medicines Commission, the EC Committee for Veterinary Medicinal Products, the US Food and Drug Administration and Joint WHO/FAO Committee on Food Additives.2
26 cases of salivary gland tumours, focal staining for both PSAP and PSA was seen. These findings show that the combined PSAP and PSA staining of adenocarcinomas is not specific for prostate carcinoma. Because of the remarkable regression of tumour after treatment with goserelin (which decreases testicular testosterone), we postulated that this effect is mediated through androgen receptors. Preliminary data on expression of androgen receptor’ in salivary gland tumours show the presence of androgen receptors in adenomas and carcinomas. Further data are required to establish whether androgen receptor staining in parotid tumours may be clinically useful as an indicator of susceptibility to hormonal treatment.
R W M van der Hulst, J H J M van Krieken, Th H J J Gerritsen, R J Baatenburg de Jong, A A B Lycklama à Nijeholt, A E Meinders
van
der Kwast,
Department of General Internal Medicine, University Hospital Leiden, p2300 RC Leiden, Netherlands, Laboratory of Pathology, University Hospital Leiden; Erasmus University Rotterdam, Department of Otolaryngology and Head and Neck Surgery, and Department of Urology, University Hospital, Leiden
1
Brawer MK. Prostate specific 161-68.
2
Allhoff EP, Proppe KH, Chapman CM,
3
4
5
antigen:
a
review. Acta Oncol et
1991; 30:
al. Evaluation of prostate
specific acid phosphatase and prostate specific antigen in identification of prostatic cancer. J Urol 1983; 129: 315-18. Yam LT, Winkler CF, Janckila AJ, et al. Prostatic cancer presenting as metastatic adenocarcmoma of undetermined origin. Cancer 1983; 51: 283-87. Krieken
JHJM. Prostate marker immunoreactivity in salivary gland neoplasms. A rare pitfall in immunohistochemistry. Am J Surg Pathol 1993; 17: 410-14. Ruizeveld de Winter JA, Trapman J, Vermey M, et al. Androgen receptor expression in human tissues: an immunohistochemical study. J Histochem Cytochem 1991; 39: 927-36.
J I D Wilkinson Lilly Industries, Chapel Hill, Basingstoke,
Hants RG21 2SY, UK
1 Juskevich JC, Guyer CG. Bovine growth hormone: human food safety evaluation. Science 1990; 249: 875. 2 Joint FAO/WHO Expert Committee on Food Additives. 40th meeting, Geneva, June 9-18, 1992.
Partial remission of parotid gland carcinoma after goserelin SIR-We describe partial remission of a parotid gland carcinoma treated with goserelin, a luteinising hormonereleasing hormone analogue commonly used for metastatic prostate carcinoma. The patient presented with a locally invasive, moderately differentiated adenocarcinoma of the parotid gland. Biopsy samples from the tumour showed positive staining for prostatic serum acid phosphatase (PSAP) and prostatespecific antigen (PSA) markers. This staining is regarded as specific for prostate carcinoma.1-3 In our patient no primary prostate carcinoma was detected despite extensive radiological examination and histological examination of biopsy samples from the prostate. Nonetheless, we treated him with goserelin 3-7 mg per month subcutaneously for 3 months, which resulted in partial remission of the parotid tumour mass. Because of the discrepancy between clinical and immunohistochemical findings, we assessed the specificity of PSAP and PSA antibody staining in salivary gland tumours and in normal salivary glands.4 In normal salivary gland tissue, staining for PSA alone was positive in 17 out of 18 cases, whereas staining for both PSAP and PSA was negative in all 18 biopsy samples. By contrast, in 10 of
L-tryptophan and eosinophilia-myalgia syndrome SIR-In their reply accompanying my letter (April 23, p 1035-36) Eidson et al deny that there are only two published case-control studies-theirs’1 and another appearing as a single paragraph2-that show a purported causal link between L-tryptophan and the eosinophiliamyalgia syndrome (EMS). In the additional studies they cite/3 that relation was not examined. Instead, it was claimed that causation was now established, and the further question was whether a contaminant accounted for it. The additional studies could not determine whether there was an overall association since they were confined to cases and controls who used L-tryptophan. Eidson et al do not respond to my point that "a test for an association suspected because of a cluster must be independent" of that cluster. Not only were 2 members of a previously reported cluster’ improperly included in their study but also 6 additional cases were reported to the New Mexico Department of Health from Nov 7 to Nov 9, 1989, before the study began. Their inclusion again violates the principle that a study mounted to confirm a suspicion must be independent of the data that gave rise to that suspicion. Eidson et al stated’ that they excluded cases with any mention "at any period during the patient’s lifetime" of allergic rhinitis or drug hypersensitivity in the "medical record or subsequent interviews" (including questionnaires, my inference). They now state that they relied on contemporaneous "hospital or clinic charts at the facility that had requested the blood counts". After completion of the study they obtained additional records in which they "do find mention of allergies for some of the ... cases". 817
The initial restriction of the reviews to medical records written at the time the eosinophil counts were done cannot explain the investigators’ failure to apply their own exclusion criteria. Of the 7 cases involved, 1 had questionnairerecorded allergic rhinitis, and was improperly included. For all 6 (not "some") remaining cases notations of allergy, and of eosinophilia, were recorded on the same day, in 4 instances on the same page. For 1 of the latter 4 cases that notation was made in January, 1990, a few weeks after the data collection was completed, but there were also earlier notations of sulphonamide allergy recorded in the same hospital in 1985 and 1987. Despite the defects in their study Eidson et al continue to argue that their findings are valid because "asthma or allergies would rarely be expected to produce ... very high eosinophil counts" and because among 6 cases excluded because of asthma or allergy all 5 whose exposure status was known had taken L-tryptophan. The rarity with which these conditions produce eosinophilia is irrelevant. What matters is their prevalence among the cases, as is indicated by the additional data now provided: among 16 L-tryptophanexposed cases, 12 (75%) had allergic histories. That is a remarkably high proportion, and for 7 cases the confounding effect of allergy was not controlled. Eidson et al also argue that even if all allergic cases are excluded, the association for the remaining 4 remains significant (p=002). It is absurd to suggest that such sparse data justify a causal inference. It is a major contravention of accepted scientific standards to publish methods that have not been adhered to. In the absence of litigation the fact that 7 of 11 cases met specified exclusion criteria might never have come to light, and the investigators have not provided a satisfactory explanation. Samuel
Shapiro
Slone Epidemiology Unit, Boston MA 02146, USA
1
2
3
4
5
University School of Medicine, Brookline,
Eidson
M, Philen RM, Sewell CM, Voorhees R, Kilbourne EM. L-tryptophan and eosinophilia-myalgia syndrome in New Mexico. Lancet 1990; 335: 645-48. Eidson M, Voorhees R, Tanuz M, et al. Eosinophilia-myalgia syndrome and L-tryptophan-containing products: New Mexico, Minnesota, Oregon, and New York, 1989. MMWR 1989; 38: 785-88. Slutsker L, Hoesly FC, Miller L, et al. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213-17. Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990; 323: 357-65. Hertzman PA, Blevins WL, Meyer J, et al. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990; 322: 869-73.
Authors’
reply
SIR-Shapiro essentially restates assertions dealt with in the previous round of correspondence. He contends that our study is not valid because we included cases reported to the New Mexico Department of Health and also some cases with evidence of allergy, and that only one other report supports a causal association between L-tryptophancontaining products (LTCP) and eosinophilia-myalgia syndrome (EMS). We totally agree that "a test for an association suspected of a cluster must be independent of that cluster" and also that merely assembling the list of cases reported to the Health Department during a period of widespread concern about L-tryptophan exposure could have biased a casecontrol study. But that is not what we did. We ignored all case-reports, and instead based our selection on objective data (differential white-blood cell counts) recorded before the epidemic was identified. Every patient having an eosinophil count of 2000/µL or more was a potential case 818
subject; tryptophan consumption
was
not a
factor in the
selection process. We realised that
some LTCP-exposed EMS patients already reported to the Health Department could become potential study subjects if their cases were found again in our review of haematology laboratory results. However, if LTCP exposure were truly independent of the illness producing eosinophilia, our review of laboratory findings should have also led to the discovery of a large number of EMS patients with no exposure to LTCPs ; instead, we found none. Excluding cases on the basis of known exposure is not merely unnecessary; it is an overcorrection. Suppose that EMS were totally independent of LTCP exposure. The expected proportions of LTCP exposure among eosinophilia patients and the general population would then be the same. Under these circumstances, if EMS patients were to be excluded from study because they were members of an LTCP-exposed cluster, LTCPs would falsely appear to have a protective effect. Some patients with a history of allergy were included inadvertently, but if we had known about those histories that would not have happened. We did not intend our phrase at any time during the patient’s lifetime" to "diagnosis that we had reviewed all records for every patient for imply his or her entire life. Our aim was to exclude patients whose current illnesses were unrelated to the EMS epidemic, and ...
for that purpose
we
accepted
any record with recent data
(eg, hospital inpatient and outpatient office records), some more complete
and physician’s than others. Shapiro may have access to additional medical records, but we cannot verify his conclusions about omitted known allergies because we did not document the source of the record we used, and no copies were made. Human error could account for some of the discrepancies: for example, 1 of the 7 patients Shapiro refers to had two consultants’ evaluations, one stating that the patient did have problems with allergy and hay fever and the other recording "Allergies: None known". Even the records currently on file with the Health Department, gathered after our exclusion criteria had been decided upon, appear to lack information contained in Shapiro’s files. For 2 of the 7 patients we still find no mention of allergy. Shapiro states that "allergic rhinitis" is recorded in the questionnaire of one of our cases. The interviewer of that patient ticked "yes" for the symptom (asked as a possible manifestation of EMS) of "nasal stuffiness, congestion, or difficulty breathing through your nose" and wrote the single word "seasonal" close by. Although consistent with seasonal allergic rhinitis, these questionnaire data alone are an insufficient basis on which to judge whether the patient truly suffered from this disease. When EMS first came to the attention of public health officials, we had little idea of its clinical spectrum, although high-grade eosinophilia and severe myalgia seemed conspicuous. Mixing in cases of eosinophilia-associated illness other than EMS would have added "noise" to our study. Thus, any failure to detect exclusion criteria would have tended to bias the study toward an indeterminate outcome and not toward a positive outcome, as Shapiro suggests. Although our case-control study and one other done in Minnesota were the only two to compare EMS patients with controls chosen without regard to L-tryptophan not are the consumption, they only case-control to a causal link. investigations support Others, notably the case-control studies of Belongia,’ SlutskerBack,3and Kamb4 and their co-workers (the last one a cohort study but one with nested comparisons of EMS patients with others), provide important information on aetiology. Furthermore, notes
there is evidence from studies other than those of casecontrol design. For example, the nationwide surveillance data for EMS reported by Swygert et all showed a rapid fall in the number of new EMS cases after withdrawal of LTCP from the market. Several case-control comparisons point to the specificity of the association of EMS with tryptophan from one particular company. For example, Belongia et al’ traced the tryptophan in products taken by 29 of 30 EMS patients to that company, and the tryptophan from the 30th patient had a chromatographic signature typical of that company’s product, too (and not that of the other manufacturer, to which it had been traced). Similarly, Slutsker et al traced the LTCPs from at least 45 and possibly all of 46 EMS patients to the implicated company but could make this connection for only 18 of 41 tryptophan-consuming controls.2 Likewise, Back et al found that tryptophan consumed by all of 113 cases, but only 69 of 95 controls, could be traced to the implicated company.3 Kamb et al found not only that all of 47 patients in a tryptophanexposed cohort took tryptophan from the implicated manufacturer but also that the risk of illness increased substantially with higher tryptophan dose. The studies cited here and others fulfil at least five of Bradford Hill’s criteria for causal inference, including strength of association, consistency of association, specificity of the aetiological exposure, temporal relation consistent with a causal exposure, and a dose-response effect. Clearly, the two case-control studies to which Shapiro refers are not the only ones supporting a cause-and-effect relation. Edwin M Kilbourne, Millicent Eidson, Rossanne M Philen, Ron Voorhees, C Mack Sewell Centers for Disease Control and Prevention, Atlanta, GA 30333, USA; and New Mexico Department of Health, Santa Fe
1 Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990; 323: 357-65. 2 Slutsker L, Hoesly FC, Miller L, Williams LP, Watson JC, Fleming DW. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213-17. Back EE, Henning KJ, Kallenbach LR, Brix KA, Gunn RA, Melius JM. Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York. J Rheumatol 1993; 20: 666-72. 4 Kamb ML, Murphy JJ, Jones JL, et al. Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients. JAMA 1992; 267: 77-82. 5 Swygert LA, Maes EF, Sewell LE, Miller L, Falk H, Kilbourne EM. Eosinophilia-myalgia syndrome: results of national surveillance. JAMA
control
policies. As part of our audit of infection control we retrospectively analysed data on MRSA isolates from this hospital for the 15-month period from April, 1993, to July, 1994 inclusive, to assess the value of current screening practices which are broadly in line with the Hospital Infection Society’s guidelines.2 MRSA was isolated from 265 people; 17 were staff members, the rest were patients. In 121 cases, MRSA was isolated from clinically infected sites, including 6 positive blood cultures. The remaining isolates were recovered during routine screening. 13 patients with MRSA carriage discovered during screening subsequently developed infection with MRSA. The mean age of these patients was 81 years (range 67-94); 9 were women. The mean time from positive screening culture to infection was 2 weeks. policies,
isolated from the blood of 3 of the 13 infected 2 of these died while septicaemic, the third is still patients. ill seriously with MRSA septicaemia. These data show that a proportion (10-2% in our series) of patients with positive MRSA screens go on to develop infection. Perhaps because of other factors such as age or underlying medical conditions there is substantial mortality among these patients. In this study, the presence of MRSA was known before blood cultures became positive in 3 seriously ill patients. This was useful information in that it allowed a more appropriate antibiotic to be given sooner. Thus as well as restricting the spread of resistant pathogens in hospital, MRSA screening and infection control may prevent serious hospital acquired infections and alert clinicians to the possibility of these infections. We do not believe that the case is made for relaxing the current widely practised guidelines for MRSA control. MRSA
was
R P Bendall, A Gonzalez-Ruiz, L Batiste, M C Kelsey Department of Microbiology, Whittington Hospital, London N19 5NF, UK
1
2
Mackintosh CA, Marples RR, Kerr GE, Bannister BA. Surveillance of methicillin-resistant Staphylococcus aureus in England and Wales, 1986-1990. J Hosp Infect 1991; 18: 279-92. Working party report. Revised guidelines for the control of epidemic methicillin-resistant Staphylococcus aureus. J Hosp Infect 1990; 16: 351-77.
3
1990; 264: 1698-703.
Outcome of methicillin-resistant
Staphylococcus aureus carriage SIR-Methicillin-resistant
Staphylococcus aureus (MRSA) is important cause of hospital-acquired infection, particularly in London and the south-east of England.’ Its resistance to therapy and the prevalence of carriage have led to the establishment of guidelines for the prevention of cross infection.= These practices, which include screening of symptom-free staff and patients are believed to reduce the incidence of MRSA infection in hospital. However, the practices may also result in closure of beds and limit transfer and discharge of hospital patients, increasing the costs of inpatient care. In the continuing quest for greater efficiency, hospitals are trying to maximise bed occupancy and reduce length of stay. In this light, the value of MRSA screening and control measures is being questioned and infection control teams are being pressured to relax their MRSA an
Relation between sudden infant death syndrome and adult sleep apnoea/hypopnoea
syndrome SiR-The cause of the sudden death syndrome (SIDS) is unclear. Recent studies show bradycardia precedes sudden infant deaths.’ SIDS victims have small upper airways2 and SIDS is familial. We have previously found that the sleep apnoea/hypopnoea syndrome (SAHS) in adults is familial,4 and SAHS is associated with small upper airways and bradycardia. We postulated that SIDS and SAHS are manifestations of one condition. Thus we studied the reported frequency of SIDS in families of patients with SAHS and control families. Index SAHS patients had more than 15 apnoeas or hour of on standard per hypopnoeas sleep polysomnography;’ body mass indices were less than 30 kg/m2. 1 first-degree relative of each SAHS patient was randomly selected and matched for age, sex, height, and weight with a subject on a local general practice register. 38 SAHS relatives and 38 controls were asked to complete a questionnaire enquiring "were there any unexpected infant deaths under one year of age" and about the cause of death, if known. Each was asked to consider up to four generations and to indicate the number of family members considered. The SAHS relatives and matched controls were invited for
819
The concentration of 4 ng/mL for untreated cows which Mepham and colleagues selected’ was the average result for samples of 100 bulk tanks. Each tank would have contained the mixed milk from many cows. Juskevich and Guyer’ cite a study in which the maximum concentration in individual cows was 30-5 ng/mL and another in which the average for a group of four cows was 28-4 ng/mL; none of these cows had
received bST. As these workers state, the concentration of IGF-1 in milk varies widely between animals and it is determined by stage of lactation and parity. Increases in IGF-1 in the milk of cows receiving BST are small in the context of this natural variation. Consumers generally receive milk pooled from a large number of cows, so the concentration of IGF-1 will be much less than 50 ng/mL and the safety margin will be correspondingly wider. Lilly has no data that could be construed to support anything approaching the tenfold increase suggested in the letter of Mepham and colleagues. Mepham and colleagues imply that milk proteins might protect IGF-1 from digestion by proteolytic enzymes. Lilly’s safety evaluation included a test in which the milk of cows receiving more than seven times the recommended dose of BST was given to hypophysectomised rats for 10 days. There were no effects on growth or epiphyseal cartilage development. No regulatory authority has ever concluded that there is a risk to human health from milk from cows receiving bST. They include the UK Veterinary Products Committee and Medicines Commission, the EC Committee for Veterinary Medicinal Products, the US Food and Drug Administration and Joint WHO/FAO Committee on Food Additives.2
26 cases of salivary gland tumours, focal staining for both PSAP and PSA was seen. These findings show that the combined PSAP and PSA staining of adenocarcinomas is not specific for prostate carcinoma. Because of the remarkable regression of tumour after treatment with goserelin (which decreases testicular testosterone), we postulated that this effect is mediated through androgen receptors. Preliminary data on expression of androgen receptor’ in salivary gland tumours show the presence of androgen receptors in adenomas and carcinomas. Further data are required to establish whether androgen receptor staining in parotid tumours may be clinically useful as an indicator of susceptibility to hormonal treatment.
R W M van der Hulst, J H J M van Krieken, Th H J J Gerritsen, R J Baatenburg de Jong, A A B Lycklama à Nijeholt, A E Meinders
van
der Kwast,
Department of General Internal Medicine, University Hospital Leiden, p2300 RC Leiden, Netherlands, Laboratory of Pathology, University Hospital Leiden; Erasmus University Rotterdam, Department of Otolaryngology and Head and Neck Surgery, and Department of Urology, University Hospital, Leiden
1
Brawer MK. Prostate specific 161-68.
2
Allhoff EP, Proppe KH, Chapman CM,
3
4
5
antigen:
a
review. Acta Oncol et
1991; 30:
al. Evaluation of prostate
specific acid phosphatase and prostate specific antigen in identification of prostatic cancer. J Urol 1983; 129: 315-18. Yam LT, Winkler CF, Janckila AJ, et al. Prostatic cancer presenting as metastatic adenocarcmoma of undetermined origin. Cancer 1983; 51: 283-87. Krieken
JHJM. Prostate marker immunoreactivity in salivary gland neoplasms. A rare pitfall in immunohistochemistry. Am J Surg Pathol 1993; 17: 410-14. Ruizeveld de Winter JA, Trapman J, Vermey M, et al. Androgen receptor expression in human tissues: an immunohistochemical study. J Histochem Cytochem 1991; 39: 927-36.
J I D Wilkinson Lilly Industries, Chapel Hill, Basingstoke,
Hants RG21 2SY, UK
1 Juskevich JC, Guyer CG. Bovine growth hormone: human food safety evaluation. Science 1990; 249: 875. 2 Joint FAO/WHO Expert Committee on Food Additives. 40th meeting, Geneva, June 9-18, 1992.
Partial remission of parotid gland carcinoma after goserelin SIR-We describe partial remission of a parotid gland carcinoma treated with goserelin, a luteinising hormonereleasing hormone analogue commonly used for metastatic prostate carcinoma. The patient presented with a locally invasive, moderately differentiated adenocarcinoma of the parotid gland. Biopsy samples from the tumour showed positive staining for prostatic serum acid phosphatase (PSAP) and prostatespecific antigen (PSA) markers. This staining is regarded as specific for prostate carcinoma.1-3 In our patient no primary prostate carcinoma was detected despite extensive radiological examination and histological examination of biopsy samples from the prostate. Nonetheless, we treated him with goserelin 3-7 mg per month subcutaneously for 3 months, which resulted in partial remission of the parotid tumour mass. Because of the discrepancy between clinical and immunohistochemical findings, we assessed the specificity of PSAP and PSA antibody staining in salivary gland tumours and in normal salivary glands.4 In normal salivary gland tissue, staining for PSA alone was positive in 17 out of 18 cases, whereas staining for both PSAP and PSA was negative in all 18 biopsy samples. By contrast, in 10 of
L-tryptophan and eosinophilia-myalgia syndrome SIR-In their reply accompanying my letter (April 23, p 1035-36) Eidson et al deny that there are only two published case-control studies-theirs’1 and another appearing as a single paragraph2-that show a purported causal link between L-tryptophan and the eosinophiliamyalgia syndrome (EMS). In the additional studies they cite/3 that relation was not examined. Instead, it was claimed that causation was now established, and the further question was whether a contaminant accounted for it. The additional studies could not determine whether there was an overall association since they were confined to cases and controls who used L-tryptophan. Eidson et al do not respond to my point that "a test for an association suspected because of a cluster must be independent" of that cluster. Not only were 2 members of a previously reported cluster’ improperly included in their study but also 6 additional cases were reported to the New Mexico Department of Health from Nov 7 to Nov 9, 1989, before the study began. Their inclusion again violates the principle that a study mounted to confirm a suspicion must be independent of the data that gave rise to that suspicion. Eidson et al stated’ that they excluded cases with any mention "at any period during the patient’s lifetime" of allergic rhinitis or drug hypersensitivity in the "medical record or subsequent interviews" (including questionnaires, my inference). They now state that they relied on contemporaneous "hospital or clinic charts at the facility that had requested the blood counts". After completion of the study they obtained additional records in which they "do find mention of allergies for some of the ... cases". 817
The initial restriction of the reviews to medical records written at the time the eosinophil counts were done cannot explain the investigators’ failure to apply their own exclusion criteria. Of the 7 cases involved, 1 had questionnairerecorded allergic rhinitis, and was improperly included. For all 6 (not "some") remaining cases notations of allergy, and of eosinophilia, were recorded on the same day, in 4 instances on the same page. For 1 of the latter 4 cases that notation was made in January, 1990, a few weeks after the data collection was completed, but there were also earlier notations of sulphonamide allergy recorded in the same hospital in 1985 and 1987. Despite the defects in their study Eidson et al continue to argue that their findings are valid because "asthma or allergies would rarely be expected to produce ... very high eosinophil counts" and because among 6 cases excluded because of asthma or allergy all 5 whose exposure status was known had taken L-tryptophan. The rarity with which these conditions produce eosinophilia is irrelevant. What matters is their prevalence among the cases, as is indicated by the additional data now provided: among 16 L-tryptophanexposed cases, 12 (75%) had allergic histories. That is a remarkably high proportion, and for 7 cases the confounding effect of allergy was not controlled. Eidson et al also argue that even if all allergic cases are excluded, the association for the remaining 4 remains significant (p=002). It is absurd to suggest that such sparse data justify a causal inference. It is a major contravention of accepted scientific standards to publish methods that have not been adhered to. In the absence of litigation the fact that 7 of 11 cases met specified exclusion criteria might never have come to light, and the investigators have not provided a satisfactory explanation. Samuel
Shapiro
Slone Epidemiology Unit, Boston MA 02146, USA
1
2
3
4
5
University School of Medicine, Brookline,
Eidson
M, Philen RM, Sewell CM, Voorhees R, Kilbourne EM. L-tryptophan and eosinophilia-myalgia syndrome in New Mexico. Lancet 1990; 335: 645-48. Eidson M, Voorhees R, Tanuz M, et al. Eosinophilia-myalgia syndrome and L-tryptophan-containing products: New Mexico, Minnesota, Oregon, and New York, 1989. MMWR 1989; 38: 785-88. Slutsker L, Hoesly FC, Miller L, et al. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213-17. Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990; 323: 357-65. Hertzman PA, Blevins WL, Meyer J, et al. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990; 322: 869-73.
Authors’
reply
SIR-Shapiro essentially restates assertions dealt with in the previous round of correspondence. He contends that our study is not valid because we included cases reported to the New Mexico Department of Health and also some cases with evidence of allergy, and that only one other report supports a causal association between L-tryptophancontaining products (LTCP) and eosinophilia-myalgia syndrome (EMS). We totally agree that "a test for an association suspected of a cluster must be independent of that cluster" and also that merely assembling the list of cases reported to the Health Department during a period of widespread concern about L-tryptophan exposure could have biased a casecontrol study. But that is not what we did. We ignored all case-reports, and instead based our selection on objective data (differential white-blood cell counts) recorded before the epidemic was identified. Every patient having an eosinophil count of 2000/µL or more was a potential case 818
subject; tryptophan consumption
was
not a
factor in the
selection process. We realised that
some LTCP-exposed EMS patients already reported to the Health Department could become potential study subjects if their cases were found again in our review of haematology laboratory results. However, if LTCP exposure were truly independent of the illness producing eosinophilia, our review of laboratory findings should have also led to the discovery of a large number of EMS patients with no exposure to LTCPs ; instead, we found none. Excluding cases on the basis of known exposure is not merely unnecessary; it is an overcorrection. Suppose that EMS were totally independent of LTCP exposure. The expected proportions of LTCP exposure among eosinophilia patients and the general population would then be the same. Under these circumstances, if EMS patients were to be excluded from study because they were members of an LTCP-exposed cluster, LTCPs would falsely appear to have a protective effect. Some patients with a history of allergy were included inadvertently, but if we had known about those histories that would not have happened. We did not intend our phrase at any time during the patient’s lifetime" to "diagnosis that we had reviewed all records for every patient for imply his or her entire life. Our aim was to exclude patients whose current illnesses were unrelated to the EMS epidemic, and ...
for that purpose
we
accepted
any record with recent data
(eg, hospital inpatient and outpatient office records), some more complete
and physician’s than others. Shapiro may have access to additional medical records, but we cannot verify his conclusions about omitted known allergies because we did not document the source of the record we used, and no copies were made. Human error could account for some of the discrepancies: for example, 1 of the 7 patients Shapiro refers to had two consultants’ evaluations, one stating that the patient did have problems with allergy and hay fever and the other recording "Allergies: None known". Even the records currently on file with the Health Department, gathered after our exclusion criteria had been decided upon, appear to lack information contained in Shapiro’s files. For 2 of the 7 patients we still find no mention of allergy. Shapiro states that "allergic rhinitis" is recorded in the questionnaire of one of our cases. The interviewer of that patient ticked "yes" for the symptom (asked as a possible manifestation of EMS) of "nasal stuffiness, congestion, or difficulty breathing through your nose" and wrote the single word "seasonal" close by. Although consistent with seasonal allergic rhinitis, these questionnaire data alone are an insufficient basis on which to judge whether the patient truly suffered from this disease. When EMS first came to the attention of public health officials, we had little idea of its clinical spectrum, although high-grade eosinophilia and severe myalgia seemed conspicuous. Mixing in cases of eosinophilia-associated illness other than EMS would have added "noise" to our study. Thus, any failure to detect exclusion criteria would have tended to bias the study toward an indeterminate outcome and not toward a positive outcome, as Shapiro suggests. Although our case-control study and one other done in Minnesota were the only two to compare EMS patients with controls chosen without regard to L-tryptophan not are the consumption, they only case-control to a causal link. investigations support Others, notably the case-control studies of Belongia,’ SlutskerBack,3and Kamb4 and their co-workers (the last one a cohort study but one with nested comparisons of EMS patients with others), provide important information on aetiology. Furthermore, notes
there is evidence from studies other than those of casecontrol design. For example, the nationwide surveillance data for EMS reported by Swygert et all showed a rapid fall in the number of new EMS cases after withdrawal of LTCP from the market. Several case-control comparisons point to the specificity of the association of EMS with tryptophan from one particular company. For example, Belongia et al’ traced the tryptophan in products taken by 29 of 30 EMS patients to that company, and the tryptophan from the 30th patient had a chromatographic signature typical of that company’s product, too (and not that of the other manufacturer, to which it had been traced). Similarly, Slutsker et al traced the LTCPs from at least 45 and possibly all of 46 EMS patients to the implicated company but could make this connection for only 18 of 41 tryptophan-consuming controls.2 Likewise, Back et al found that tryptophan consumed by all of 113 cases, but only 69 of 95 controls, could be traced to the implicated company.3 Kamb et al found not only that all of 47 patients in a tryptophanexposed cohort took tryptophan from the implicated manufacturer but also that the risk of illness increased substantially with higher tryptophan dose. The studies cited here and others fulfil at least five of Bradford Hill’s criteria for causal inference, including strength of association, consistency of association, specificity of the aetiological exposure, temporal relation consistent with a causal exposure, and a dose-response effect. Clearly, the two case-control studies to which Shapiro refers are not the only ones supporting a cause-and-effect relation. Edwin M Kilbourne, Millicent Eidson, Rossanne M Philen, Ron Voorhees, C Mack Sewell Centers for Disease Control and Prevention, Atlanta, GA 30333, USA; and New Mexico Department of Health, Santa Fe
1 Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990; 323: 357-65. 2 Slutsker L, Hoesly FC, Miller L, Williams LP, Watson JC, Fleming DW. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213-17. Back EE, Henning KJ, Kallenbach LR, Brix KA, Gunn RA, Melius JM. Risk factors for developing eosinophilia myalgia syndrome among L-tryptophan users in New York. J Rheumatol 1993; 20: 666-72. 4 Kamb ML, Murphy JJ, Jones JL, et al. Eosinophilia-myalgia syndrome in L-tryptophan-exposed patients. JAMA 1992; 267: 77-82. 5 Swygert LA, Maes EF, Sewell LE, Miller L, Falk H, Kilbourne EM. Eosinophilia-myalgia syndrome: results of national surveillance. JAMA
control
policies. As part of our audit of infection control we retrospectively analysed data on MRSA isolates from this hospital for the 15-month period from April, 1993, to July, 1994 inclusive, to assess the value of current screening practices which are broadly in line with the Hospital Infection Society’s guidelines.2 MRSA was isolated from 265 people; 17 were staff members, the rest were patients. In 121 cases, MRSA was isolated from clinically infected sites, including 6 positive blood cultures. The remaining isolates were recovered during routine screening. 13 patients with MRSA carriage discovered during screening subsequently developed infection with MRSA. The mean age of these patients was 81 years (range 67-94); 9 were women. The mean time from positive screening culture to infection was 2 weeks. policies,
isolated from the blood of 3 of the 13 infected 2 of these died while septicaemic, the third is still patients. ill seriously with MRSA septicaemia. These data show that a proportion (10-2% in our series) of patients with positive MRSA screens go on to develop infection. Perhaps because of other factors such as age or underlying medical conditions there is substantial mortality among these patients. In this study, the presence of MRSA was known before blood cultures became positive in 3 seriously ill patients. This was useful information in that it allowed a more appropriate antibiotic to be given sooner. Thus as well as restricting the spread of resistant pathogens in hospital, MRSA screening and infection control may prevent serious hospital acquired infections and alert clinicians to the possibility of these infections. We do not believe that the case is made for relaxing the current widely practised guidelines for MRSA control. MRSA
was
R P Bendall, A Gonzalez-Ruiz, L Batiste, M C Kelsey Department of Microbiology, Whittington Hospital, London N19 5NF, UK
1
2
Mackintosh CA, Marples RR, Kerr GE, Bannister BA. Surveillance of methicillin-resistant Staphylococcus aureus in England and Wales, 1986-1990. J Hosp Infect 1991; 18: 279-92. Working party report. Revised guidelines for the control of epidemic methicillin-resistant Staphylococcus aureus. J Hosp Infect 1990; 16: 351-77.
3
1990; 264: 1698-703.
Outcome of methicillin-resistant
Staphylococcus aureus carriage SIR-Methicillin-resistant
Staphylococcus aureus (MRSA) is important cause of hospital-acquired infection, particularly in London and the south-east of England.’ Its resistance to therapy and the prevalence of carriage have led to the establishment of guidelines for the prevention of cross infection.= These practices, which include screening of symptom-free staff and patients are believed to reduce the incidence of MRSA infection in hospital. However, the practices may also result in closure of beds and limit transfer and discharge of hospital patients, increasing the costs of inpatient care. In the continuing quest for greater efficiency, hospitals are trying to maximise bed occupancy and reduce length of stay. In this light, the value of MRSA screening and control measures is being questioned and infection control teams are being pressured to relax their MRSA an
Relation between sudden infant death syndrome and adult sleep apnoea/hypopnoea
syndrome SiR-The cause of the sudden death syndrome (SIDS) is unclear. Recent studies show bradycardia precedes sudden infant deaths.’ SIDS victims have small upper airways2 and SIDS is familial. We have previously found that the sleep apnoea/hypopnoea syndrome (SAHS) in adults is familial,4 and SAHS is associated with small upper airways and bradycardia. We postulated that SIDS and SAHS are manifestations of one condition. Thus we studied the reported frequency of SIDS in families of patients with SAHS and control families. Index SAHS patients had more than 15 apnoeas or hour of on standard per hypopnoeas sleep polysomnography;’ body mass indices were less than 30 kg/m2. 1 first-degree relative of each SAHS patient was randomly selected and matched for age, sex, height, and weight with a subject on a local general practice register. 38 SAHS relatives and 38 controls were asked to complete a questionnaire enquiring "were there any unexpected infant deaths under one year of age" and about the cause of death, if known. Each was asked to consider up to four generations and to indicate the number of family members considered. The SAHS relatives and matched controls were invited for
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