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What is really the cause of deaths in newborn infants who usually contracted pertussis from their vaccinated family members sufferring whooping cough at the time of these babies' birth
- Dr Viera Scheibner PhD (9 December 2008)
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Pertussis in infants: Some key issues need clarification
- M A Anjay (17 January 2009)
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Re: What is really the cause of deaths in newborn infants who usually contracted pertussis
- Peter J Flegg (19 January 2009)
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Have these cases been reported as possible adverse drug reactions?
- Wouter Havinga (19 January 2009)
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Early ECMO referral must be considered
- Giles J Peek, Abi M Noah, Mahul Gorecha, Gail Faulkner, Andrew W Sosnowski, Richard K Firmin (26 January 2009)
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Dr Viera Scheibner PhD, Scientist/Author Retired Blackheath NSW Australia
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Dear Editor, The cases of newborn infants contracting whooping cough, usually from vaccinated family members, are not unique to Scotland. They occur in countries with many years of intense vaccination programmes. I now describe four newborn infant's pertussis deaths in NSW, Australia. Medical Journal of Australia (MJA; 168, 16 March 1998: 281-283) published a short report on "Intant pertussis deaths in New South Wales 1996-1997" by Williams, Matthews, Choong and Ferson. The authors wrote "Since 1996, south-eastern Australia has been experiencing a pertussis epidemic which has resulted in the deaths of several infants, including four from NSW in the 12 months to July 1997. All were less than than six weeks of age and died from overwhelming cardiovascular compromise despite intensive care support". The authors maintained that "The excessive infant mortality from a preventable disease demonstrates the need for better pertussis immunity in the community and for erythromycin treatment of all suspected cases and family contacts". At the time, the media were intimating that these young infants allegedly contracted whooping cough from some unknown unvaccinated child who suffered whooping cough. Let's now have a look at how, and in my considered opinion why, these four NSW infants contracted whooping cough and what really caused their deaths, based on the data published by Willians et al. (1998). The cases 1,2,3, and 4 represented infants aged 5 weeks, 16 days and four weeks respectively, all obviously too young to have been vaccinated. All contracted pertussis from their fully vaccinated mothers and/or siblings who had whooping cough for a number days/weeks at the time of these babies' birth. The case 3 was a five week old male whose 11-year old sibling had 'immunisation status unknown', meaning that he still could have been vaccinated. The summary of the symptoms suffered by the babies in question is as follows: None of the babies were very ill on admission to respective hospitals. The highest temperature was 37.6 C and none suffered paroxysmal cough. They were doing well initially, until they were administered intravenous antibiotics cefotaxime, erythromycin and/or ceftriaxone. Base on the internal consistency of timing, as outlined below, all quite obviously started deteriorating, and died, after the administration of the above antibiotics. Bordetella pertussis was cultured from all persons involved. Baby 1 was admitted to hospital 48 hours of lethargy, poor feeding, tachypnoea and cough. He remained stable for five days, with satisfactory breast feeding and occasional coughing. On day 3, he was administered intravenous cefotaxime, and, erythromycin on day 5, after which time he immediately developed tachycardia and hypercapnia and required supplemental oxygen. He also developed 'severe pulmonary hypertension and cardiovascular compromise', unresponsive to inhaled nitric oxide and died 72 hours after admission to another hospital. Baby 2 developed progressive tachypnoea with respiratory distress, tachycardia, and hypercapnia unresponsive to different ventilatory regimens. Circulatory compromise developed and was not ameliorated with infusion of adrenaline or inhalation of nitric oxide given to treat presumed pulmonary hypertension. Systemic hypotension and severe metabolic acidosis developed, and the infant died following an asystolic arrest 48 hours after initial presentation. Baby 3 developed intensified respiratory distress ten hours after admission and intravenous cefotaxime administration, with associated hypercapnia and high white blood cell count. Perfusion deteriorated gradually, and the baby died 25 hours after admission. Baby 4. Within hours of admission to hospital and administration of ceftriaxone, the baby's respiratory distress worsened and he developed poor perfusion requiring artificial ventilation, together with substantial colloid and ionotrope support of the circulation. On transfer to another hospital, the x-ray showed bilateral consolidation. Echocardiography confirmed severe refractory pulmonary hypertension, and severe metabolic acidosis which culminated in cardiac arrest six hours later. My conclusions: 1. None of the babies contracted whooping cough from some unknown unvaccinated child. They contracted the disease from their own family members (mothers and/or siblings), all of whom were vaccinated (one probably vaccinated) and suffered whooping cough at the time of the relevant babies' birth. 2. None of the babies in question were protected by the transplacentally-transmitted (maternal) immunity which normally protects small babies against infectious diseases for up to two years of age, provided their mothers acquired natural immunity by experiencing infectious diseases of childhood. Babies born to mothers who were vaccinated as children have poor or no TTI to any infectious disease (and including pertussis) (Lenon and Black 1986. Maternally derived measles immunity in era of vaccine-protected mothers. J Pediatrics; 108 (1): 671- 676. 3. The cause of death - "overwhelming cardiovascular compromise", in my opinion obviously, resulted from, or was greatly facilitated by, the administered antibiotics (supported by the internal consistency of the timing of the start of antibiotic administration and the start of deterioration and death, which closely followed the (different) days on which antibiotics were started). Severe reactions to the administered antibiotics, some fatal, have been known ever since the mass use of penicillin. Coleman and Siegel (1955), in their paper "Studies in penicillin hypersensitivity.II. etc." (Journal of Allergy; 253-261) wrote "Severe immediate reactions to the administered penicillin, some ending in fatalities, are occurring with increasing frequency". Perhaps not with arbitrary coincidence, the Medical Journal of Australia (1998; 169: 16) published an article by Parshuram and Phillips ("Retrospective Review of antibiotic-associated serum sickness in children presenting to a paediatric emergency department"), who found support for their findings, in overseas reports of increased morbidity associated with cefaclor use in children presenting to the emergency departments. They concluded that the estimated rate of serum sickness associated with cefaclor is considerably higher that the rate of 0.026% quoted in the product information. Afterthought: administration of one or more antibiotics of the cephalosporin group in particular, to newborn babies should not be considered safe. Moreover, vaccinating postpartum mothers, fathers and siblings may be doomed to failure. Not only it is not likely to provide the desired immunity to pertussis, but there is a real danger of serious reactions in the adult, as well young, members of the family; certainly not a desired situation in a family already stressed by the arrival of a new baby. Competing interests: None declared |
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M A Anjay, Specialist Registrar in Paediatrics James Paget Hospital, Great Yarmouth NR31 6LA, United Kingdom
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While I must congratulate the authors for highlighting this important topic, (1) I feel some of the statements in the discussion need more clarification. Accurate diagnosis is important for clinical and public health reasons. While the authors have mentioned PCR, culture and serology, it might be worth pointing out that a new oral fluid pertussis antibody test has been available in the United Kingdom from 2007 for laboratory confirmation of notified cases.(2) The discussion mentions that the efficacy of chemoprophylaxis for contacts has not been demonstrated. This view is more or less supported by previous systematic reviews which concluded that the benefit was modest at best.(3) However, the study quoted by the authors excluded infants below 6 months of age who are at highest risk.(4) A few other studies have shown clinically significant benefits for neonates .Evidence for this has been elegantly summarised in the current UK guidelines for use of erythromycin chemoprophylaxis which suggest that although overall efficacy is limited, chemoprophylaxis of neonates should be encouraged.(5) As the article mentions, an adolescent/adult booster vaccine has been introduced in some countries, but at present its cost-effectiveness remains questionable. A recent systematic review highlighted the lack of strong evidence for this strategy. (6) References 1.Theilen U, Johnston ED, Robinson PA. Rapidly fatal invasive pertussis in young infants—how can we change the outcome? BMJ 2008; 337: a343 2.Health Protection Agency. New enhanced surveillance test for pertussis. Health Protection Report 2007 June; 1:25. Available online at http://www.hpa.org.uk/hpr/archives/2007/hpr2507.pdf 3.Dodhia H, Miller E. Review of the evidence for the use of erythromycin in the management of persons exposed to pertussis. Epidemiol Infect 1998;120:143–149. 4.Halperin SA, Bortolussi R, Langley JM, Eastwood BJ, De Serres G. A randomized, placebo-controlled trial of erythromycin estolate chemoprophylaxis for household contacts of children with culture-positive bordetella pertussis infection. Pediatrics 1999;104:e42 5.Dodhia H, Crowcroft NS, Bramley JC, Miller E. UK guidelines for use of erythromycin chemoprophylaxis in persons exposed to pertussis. J Pub Health Med 2002;24:200–206. 6.Rodríguez-Cobo I, Chen YF, Olowokure B, Litchfield I. Clinical and economic assessment of different general population strategies of pertussis vaccine booster regarding number of doses and age of application for reducing whooping cough disease burden: A systematic review. Vaccine 2008;26(52):6768-76. Epub 2008 Oct 7. Competing interests: None declared |
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Peter J Flegg, Consultant Physician Blackpool, UK, FY3 8NR
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Vera Scheibner makes a number of assumptions in her opinion piece about the cause of death in infants with pertussis. She is wrong in assuming natural pertussis infection conveys significant transplacental immunity. In fact, this is minimal following both naturally acquired pertussis infections and with vaccine-induced immunity to pertussis (1), as the articles authors expressly stated. So maternal status would have had no influence on the susceptibility of the infant to acquiring pertussis.
Although Scheibner is correct in stating these infants probably acquired infection from older, previously vaccinated family members (and the article’s authors actually say so), her implication seems to be that the vaccination status of the family members is somehow responsible for their own and therefore the infant’s infection. As the author’s point out, vaccine-induced immunity wanes after several years, so adolescents and adults themselves again become more susceptible to pertussis. This usually is not a great clinical problem for the adults, since pertussis in their age group is usually a mild illness of fairly short duration that is often ascribed to a bad cold or mild chest infection. The problem is that waning of natural and artificially acquired immunity in this age group results in a reservoir of susceptible adults, who if infected can pass this on to infants. The answer would be, as the authors again recommend, that vaccination boosters be given in adolescence and adulthood to improve their immunity and reduce infections in these age groups.
Scheibner attributes the deaths of these infants to antibiotic adminisration [and reactions], but in so doing she should not fall into the fallacy of post hoc ergo propter hoc reasoning. Just because B follows A, it does not mean that A causes B, particularly when C, D, E, F and G might also have followed A, and they all might be coincidental. The same logic would have us ascribing deaths in children with meningitis to their antibiotics and not the disease.
Although the precise pathophysiological mechanisms involved in the lethal forms of infant pertussis remain unclear, the mode of death is one of a severe pertussis toxin-mediated cytokine cascade with severe hypoxia, resultant refractory pulmonary hypertension and haemodynamic cardiovascular collapse (2). Although antibiotics can cause fatal reactions, this does not appear to be the mechanism in any of these cases or the cases Scheibner describes, so their death does not appear to have been from a serum sickness type illness or immediate anaphylaxis.
However, antibiotics may indeed play a part in the disease pathogenesis, since bacterial lysis can result in release of preformed toxin and worsen the clinical outcome. In general, Bordetella pertussis strains are resistant to cephalosporins and penicillins, so these drugs would be ineffective at killing bacteria and therefore would not contribute to toxin release. Scheibner’s suggestion that ceftriaxone or cefotaxime they received contributed to their deaths or that these infants had penicillin or other antibiotic hypersensitivity reaction seems speculative at best. However, it is possible that the use of macrolide antibiotics could have an adverse impact, perhaps as described in the case of “baby one” that Scheibner describes. How best to balance the effects of these antibiotics between the desirable outcome of killing bacteria but still avoiding harmful toxin release is something that needs further study.
The most appropriate way to avoid infants being infected with pertussis before they are old enough to be protected by vaccination is to reduce the possibility of their exposure. This would require a reduction in the reservoir of infected adults. The best way to eliminate this reservoir and generate a degree of “herd immunity” would be by giving booster vaccinations in adolescence and in adulthood. This would both reduce the burden of mild disease in adults (which is numerically considerable) and reduce infections in infants.
(1) Van Rie A, Wendelboe AM, Englund JA. Role of maternal antibodies in infants. Ped Inf Dis J 2005;24:S62-65.
(2). Paddock CD, et al. Pathology and Pathogenesis of Fatal Bordetella pertussis Infection in Infants. Clinical Infectious Diseases 2008;47:328–338.
Competing interests: None declared |
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Wouter Havinga, GL locum GL6 6JL
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Competing interests: None declared |
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Giles J Peek, Cardiac Surgeon and ECMO Consultant ECMO Unit, Glenfield Hospital, Groby road, Glenfield Leicester, LE3 9QP, UK, Abi M Noah, Mahul Gorecha, Gail Faulkner, Andrew W Sosnowski, Richard K Firmin
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Editor, We read with interest the insightful publication of U Theilen, E D Johnston and P A Robinson. Pertussis is still associated with a high mortality despite immunisation and advances in current Intensive Care practice including Extracorporeal membrane oxygenation (ECMO). We agree that primary prevention should be the main aim of future research. The current UK vaccination schedule advises the first dose of pertussis vaccine be given at two months age(1), leaving neonates vulnerable to this disorder. In our experience as a large ECMO unit we have treated 18 babies with confirmed Bordetella Pertussis with ECMO after failure of conventional management, 6 survived ECMO and 5 survived to discharge. We have noticed that patients are more likely to survive when they are referred early for ECMO before they have developed the haemodynamic collapse with severe pulmonary hypertension characteristic of this disease. We have been able to treat patients who are referred early with veno-venous ECMO, maintaining normal pulmonary blood flow, and this may be a factor in improving outcome. Patients who are moribund and referred late require veno-arterial ECMO for circulatory support, resulting in much reduced pulmonary blood flow, and seem to invariably develop consolidation and infiltration of the lungs with leucocytes. Most of these patients die. Micro-vessel embolisation which may be due to a significantly elevated white cell count is a major problem with pertussis. By the time a referral to ECMO is made, this embolic phenomenon in combination with high pressure ventilation makes the probability of lung necrosis or irreversible lung injury more likely. Also bronchoscopy of these patients reveals pale bronchial mucosa suggesting devascularisation. While ECMO is an ideal support for patients with reversible respiratory failure, the presence of irreversible damage or necrosis makes recovery unlikely. We believe that early referral for ECMO permitting low pressure ventilation may produce more favourable results(2,3). We have on occasion used a leucocyte filter in a bid to reduce the white cell count but have not noted any improvement in prognosis. A definite diagnosis of pertussis is made late in the course of illness, therefore a baby in respiratory failure with significantly elevated white cell count (lymphocytes) should raise the suspicion of pertussis and should prompt early discussion of the patient with an ECMO centre. No competing interests to declare References 1. NHS immunisation website accessed 21/01/2009 http://www.immunisation.nhs.uk/Immunisation_Schedule 2. Halasa NB, Barr FE, Johnson JE, Edwards KM. Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal membrane oxygenation have a role Pediatrics. 2003 Dec;112(6 Pt 1):1274-8 3. Pooboni S, Roberts N, Westrope C, Jenkins DR, Killer H, Pandya HC, Firmin RK. Extracorporeal life support in pertussis Pediatr Pulmonol. 2003 Oct;36(4):310-5 Competing interests: None declared |
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