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More on SIDS andH pylori—Authors' response
  1. JONATHAN R KERR
  1. Infectious Diseases Research Group
  2. University of Manchester, Manchester, UK
  3. jonathankerr{at}hotmail.com
  4. Department of Medicine
  5. University of Missouri at Kansas City School of Medicine
  6. Kansas City, Missouri, USA
    1. C PHILLIP PATTISON
    1. Infectious Diseases Research Group
    2. University of Manchester, Manchester, UK
    3. jonathankerr{at}hotmail.com
    4. Department of Medicine
    5. University of Missouri at Kansas City School of Medicine
    6. Kansas City, Missouri, USA

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      Editor,—At present, we do not understand the pathogenesis of sudden infant death syndrome (SIDS), however, it is accepted to be a multifactorial disease for which certain risk factors have been identified. Various theories have been developed to explain the existence of these risk factors.

      Blackwell reminds us of the accepted fact that PCR detects DNA from both live and dead organisms, but her phrase “transient contamination of the infant with DNA from non-viable bacteria” seems inappropriate. The detection of H pylori DNA in the trachea and lung of such babies is a finding of particular importance both for our understanding of the pathogenesis of SIDS and for our understanding of the pathogenesis and epidemiology of H pylori infection in infants.

      The study by Kerr et al 1 showedH pylori DNA in the stomach, trachea, and lung tissues of SIDS cases, but did not visualise bacteria at these sites. As stated in the paper and by several other authors, the study used haematoxylin and eosin staining, a suboptimal methodology for visualisation of gastric bacteria. Other studies have shown inflammatory changes in both antrum and trachea ofH pylori-PCR positive SIDS cases.2

      Genetic subtyping would be valuable as suggested, but not essential, as the PCR-ELISA utilised was specific, tests were performed in duplicate and positive and negative controls consistently gave expected results.1

      Our hypothesis is that H pylori infection accounts for a proportion of cases of SIDS. Blackwell cites several epidemiological papers, stating that they argue against this hypothesis, but she does not state how exactly she considers that they do argue against it. Epidemiological data for H pylori and socioeconomic factors in various ethnic groups are not clear cut and are incomplete. Such factors as prevalence of bottle feeding, parental smoking, family size, adherence to supine sleep position, etc, may explain differences of SIDS incidence in various ethnic groups. Blackwell's use of data regarding breath testing in children aged 12–15 months is in contrast to the finding of 44%H pylori positivity by 13C-urea breath testing of 2 year olds in childcare centres serving low socioeconomic groups in Houston, Texas.3

      Blackwell reminds us of the accepted fact that animal work is not directly applicable to events in the human infant. But, it is relevant. The proposed hypothesis cannot be verified in the human infant, but this should not be taken as evidence that it does not account for infant mortality.

      The common bacterial hypothesis4 has been useful for studies of other bacteria,5 but is not a basis for rejection of conflicting data.

      While other bacteria may be readily transmitted from mother to infant,5 none has been consistently linked with SIDS, and transmission efficiency does not equate with pathogenicity in a particular setting.

      There are three proposed routes of transmission ofH pylori; oral-oral, gastro-oral and faecal-oral.6 Blackwell has misunderstood these, as she refers to transmission by vomit as “oral-oral”, when this is actually gastro-oral.6 The transmission ofH pylori is more complex than that of other oral bacteria.

      The proposed pathogenesis of the involvement of H pylori in SIDS is that death may occur as a result of one or both of two events7 both of which have been demonstrated in a rat model.8 9 First, H pylori produces large amounts of urease, which will be fully active in the neutral pH of the H pylori-infected stomach.10 Therefore, aspiration of this gastric juice may lead to large amounts of urease in the alveolae in close proximity to plasma urea. In this setting, urea hydrolysis may lead to ammonia production and supply directly to the systemic circulation where it cannot be detoxified by the liver8; unlike the case of ammonia production within the gastric mucosa. Intravenous administration of ammonia is known to be fatal.11 Second, IL-1β produced in theH pylori-infected gastric mucosa may lead to fever, immune activation and increased deep sleep, which in combination with supply of ammonia to the systemic circulation may be lethal.9 Increased production of IL-1β alone as a result of gastric H pylori infection may predispose to the development of SIDS due to other factors.12

      Blackwell states that the proposed pathogenesis cannot be substantiated due to the following:

      (a) “There is no inflammation in the lungs of SIDS cases”. This is not true; mild inflammation of the upper respiratory tract is a recurrent, although not invariable, finding in SIDS.13

      (b) “Ammonia in the lower respiratory tract would cause bronchospasm and wheezing which has not been reported by SIDS parents”. In animal studies (not yet published as a full paper), bronchospasm was suggested by progressively less bronchoalveolar lavage (BAL) fluid return after sequential doses of intratracheal urease.8 Since parents are invariably absent at the time of death, it would be unlikely that wheezing would be detected. “If bronchospasm occurs, this should be demonstrable histologically”. Findings of relevance in SIDS include intrathoracic petechiae, patchy pulmonary oedema, emphysema, and increased muscle mass in pulmonary arteries,13 although these are not invariable findings.

      (c) “If ammonia accounts for death, this should be demonstrable in blood and vitreous”. Our hypothesis is supported by intratracheal urease adminisatration to rats which caused increased ammonia in BAL fluid although this was not accompanied by significantly increased serum ammonia.8 The physiological effects of pre-treatment with IL-1β could not be clearly defined.9

      (d) “The liver should be affected by hyperammonaemia and it is not in SIDS”. Blackwell has misunderstood our hypothesis. First, interleukin-1β production in the H pylori-infected stomach, and second, aspiration of urease into the lung and supply of ammonia to the systemic circulation (and not the hepatic circulation as Blackwell implies).

      (e) “The brain should be affected by hyperammonaemia and it is not in SIDS”. If our hypothesis is correct, then the terminal event, involving hyperammonaemia in the systemic circulation is an acute and rapidly fatal occurrence, which may not result in brain pathology.

      (f) We do not understand this point.

      Marshall's views on controls used in the original paper1do not take account of further information provided at the request of other authors14 which show that of eight controls used, five had an exposure to the home environment of more than one month.

      Marshall states that H pylori is a gastric organism and that it is surprising to find evidence of infection in lung and trachea. However, H pylori has been detected at other sites, for example, the respiratory tract of intubated adults,15 and in the liver of patients with primarysclerosing cholangitis and primary biliary cirrhosis.17

      The pathogenesis of SIDS is accepted to be multifactorial, and therefore, small studies with a negative association betweenH pylori and SIDS, such as that of Leung and colleagues, are to be expected.

      Emotion aside, the fact remains that three groups have foundH pylori in some cases of SIDS, and all three groups have detected the organism in the lung.1 2 17

      References

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