Recent eLetters
Displaying 1-10 letters out of 74 published
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The two fundamental caveats of IGRAs
Submit responseThe reservations exepressed about the interpretation of interferon gamma release assays(IGRAs)(1)are underpinned by the following observations:- IGRAs do not reliably identify subjects with active tuberculosis(even in the context of culture positive disease)(2), as shown by a study where 45 subjects received a diagnosis of active tuberculosis characterised, in 37 of those subjects, by positive cultures for mycobacterium tuberculosis(MTB). Nevertheless, in 17 of the 45 patients with a final diagnosis of active tuberculosis the IGRA test was negative(2). This means that, in that study,the spectrum of 17 negative IGRA tests included, at a bare minimum, at least eight patients with culture positive tuberculosis. The suboptimal sensitivity of IGRAs is compounded by apparently spontaneous reversion from positive to negative test status(3)(4), and also by apparently spontaneous by conversion from negative to positive test status(3)(4). This state of affairs has implications for recognition and management of latent tuberculosis, not only in the context of low disease prevalence(3), but also in the context of high disease prevalence(4). In the former context, an American study utilised IGRAs to screen 3,234 individuals considered to be at low risk of mycobacterium tuberculosis infection, including low risk of infection in the remote past. Of these, 2,819 tested unequivocally negative, 218 tested unequivocally positive, and 177 yielded indeterminate tests per manufaturer's criteria. On retesting 13(9%) of initially negative tests converted to positive, and 15(7%) of initially positive tests reverted to negative test status using the manufacturer's cut-off value(3). In the context of high disease prevalence a review was published which included evaluation of in-subject variability of IGRAs in India and in South Africa. In the Indian context, over a 2 weeks period, 2 of 14 health care workers experienced reversion from positive to negative test status. In the South African study, over a 3 week period, 7 of 26 helth care workers experienced either a conversion or a reversion. In both the Indian and the South African studies subjects who experienced either reversion or conversion had initial values close to the cut-off point(4). These observations(2)(3)(4) should serve as fundamental caveats to the use of IGRAs in clinical practice. References (1) Pollock L., Roy RB., Kampmann B How to use: interferon gamma release assays for tuberculosis Education and Practice 2013;98:99-105 (2)Dewan PK., Grinsdale J., Kawamura M Low sensitivity of a whole blood interferon gamma release assay for detection of active tuberculosis Clinical Infectious Diseases 2007;44:69-73 (3) Metcalfe JZ., Cattamanchi A., McCulloch CE et al Test variability of the QuabtiFERON-TB-Gold in-Tube assay in clinical practice Am J Respir Crit Care Med 2013;187:206-2011 (4) van Zyl Smit RN., Zwerling A., Dheda K., Pai M Within-subject variability of interferon-gamma assay results for tuberculosis and boosting effect of tuberculin skin testing: A systematic review PLoS ONE 2009;4:e8517
Conflict of Interest:
None declared
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Re:autism assessment tools- a (partial) misinterpretation
Submit responseAs part of the team that undertook review of the paper prior to publication I would like to thank Alan for picking up this misinterpretation and to apologise to our readers for the mistake.
It's entirely correct that a negative ADOS will be right - the patient will not have autism - about 88% of the time.
The table 3 is misleadingly titled "prob that the test rules out autism" and should be "post test probability of autism with a negative test" and this mistake is repeated in the text.
I think there's something in the way we describe the 'output' of a diagnostic test.
Sometimes the value of a negative test is given as NPV ie the % with a negative test who are negative for the condition.
Sometimes it's given as the predictive value of a negative test ie the % of those with a negative test that DO HAVE the disorder
Personally, I prefer this latter way of presenting the information as it highlight the negative test 'failures' who you may have 'dismissed'.
So - while it's true that a negative ADOS is right ~88% of the time, that's the same as saying about 12% of the time a patient with negative ADOS actually does have an autistic spectrum disorder.
Conflict of Interest:
None declared
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autism assessment tools- a (partial) misinterpretation
Submit responseCarter and colleagues have done a superb job in summarising the theory and practice of tools used in assessing children for autism. Unfortunately their paper is marred by a mathematical error which, if left unchallenged, could undermine trust in the use of one such tool, the ADOS.
According to the paper, the positive predictive value (ppv, i.e. the proportion of those who test positive who actually have the condition) of the ADOS is 80.4% in a neurodevelopmental clinic population, whilst the negative predictive value (npv, proportion of those who test negative who do not have the condition) in the same population is only 11.9%. If this were true it would mean that the proportion of those in the test negative group who have the condition would actually be higher than in the test positive group- 88.1% against 80.4%. Fortunately it is not true.
Using the population prevalence of 53% quoted, and the figures of 91% sensitivity and 75% specificity the true figure for ppv is as given, but the npv is actually 87.5%. Carter et al's conclusion, therefore, that tests should be interpreted in the light of history and information from other sources stands, but the ADOS is not as hopeless as their paper might have suggested.
Conflict of Interest:
None declared
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Attention must also be drawn to alternative pathogens for tonsillitis
Submit responseAlthough it may be difficult to make a distinction between retropharyngeal abscess, and retropharyngeal cellulitis attributable to organisms such as Group A bete-haemolytic Streptococcus, Staphylococcus Aureus, and Group B Streptococcus(1), retropharyngeal abscess should remain high in the differential diagnosis because Fusobacterium necrophorum(F necrophorum), the gram negative culprit pathogen,although initially giving rise to pharyngitis(2)or to tonsillitis(3), may ultimately mandate an antibiotic regime different from the one typically used for treatment of gram positive infections(4). Among 14 cases of bacteriologically confirmed F necrophorum infection diagnosed in a children's hospital, the organism was isolated from peritonsillar abscess fluid in eight, from blood cultures in five, and from bronchial-alveolar lavage fluid in one. Lemierre's syndrome(LS) was a complication in four of these bacteriologically confirmed cases. Of note, among two of the four bacteriologically validated cases of LS there was serological evidence suggestive of co-infection with two of the organisms more commonly associated with tonsillitis. In one instance, the serological evidence amounted to elevation in Anti Streptolysin O Titre, and, in the other, it amounted to documentation of a positive Immunoglobulin M titre for Epstein -Barr Virus(2), the latter generally beleived to be "virtually diagnostic of primary EBV infection"(5). Accordingly, to paraphrase one commentator, these cases "draw attention to an alternative pathogen for tonsillitis"(4), thereby justifying a high index of suspicion for F necrophorum. In the event that the oragnism cannot be isolated by culture from appropriate specimens molecular methods, including broad-range 16S rDNA PCR should be used. The latter startegy has the advantage that it also encompasses other bacterial infections, such as Group A Streptococci, Staphylococcus Aureus, and Streptococcus pneumoniae, presenting with similar clinical features. Furthermore, because the test dtects molecular material from bacteria, previous antibiotic treatment does not interfere with the diagnosis(6). References (1)Zacharkiwa A., Williams H A pain in the neck Arch Dis Child Ed Pract 2013;98:71-72 (2)Ramirez S., Hild TG., Rudolph CN et al Increased diagnosis of Lemierre Syndrome and other Fusobacterium necrophorum infections in a children's hospital Pediatrics 2003;112:e380-e385 (3)Klug TE., Henriksen J-J., Fuursted K., Ovensen T Significant pathogens in peritonsillar abscess Eur J Clin Microbiol Infect Dis 2011;30:619-627 (4)Fourage M., Bourguignat C., Fermond B., Delobel P A recurrent tonsillitis Lancet 2013;381:266 (5)Luzuriaga K., Sullivan JL Infectious mononucleosis N Engl J Med 2010;362:1993-2000 (6)Patel M 16S rDNA PCR in diagnosis of Lemierre's syndrome Lancet Infectious Diseases 2013;13:197
Conflict of Interest:
None declared
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How to use lupus anticoagulants in neonates born to mothers with antiphospholipid syndrome
Submit response.Dear Sir, We read with great interest the accurate paper by Sen et al. regarding the indications for testing lupus anticoagulants (LA) in pediatric patients1. We believe that two further considerations might provide a complete overview on this issue. First, it has to be underlined the important contribution given by Boffa MC concerning either the laboratory methods for the detection of LA2 or the association between antiphospholipid syndrome (APS) and obstetrical complications in women3. Second, in the article by Sen et al. the authors do not take into consideration infants born to mothers with APS. To date, it is still unclear how neonates born to mothers with APS should be evaluated and which is the true clinical relevance of neonatal antiphospholipid antibodies (APL). Concerning the indications to LA testing, the authors suggested two main indications: the presence of thrombosis and/or of unexplained prolonged aPTT. We agree with the authors concerning the first indication, i.e. APL testing in all infants with thrombosis even in neonates born to mothers with negative APL4. Concerning the second indication, it should be specified that the activated partial thromboplastin time (aPTT) in neonates is intrinsically longer than in adults and changes according to postnatal age5. Boffa et al. suggested that APL should be sistematically tested at birth in neonates born to mothers with APS6 since unpredictable transplacental passage occurs in about 30% of cases. The low rate and the unpredictable entity of APL crossing through the placenta could depend on the absorption of antibodies by trophoblast cells and by their binding to heparin, administered to mothers with APS during pregnancy. Interesting data have been recently provided by the European registry of babies born to mothers with APS7. First, maternal APL crossing over the placental barrier was confirmed. Second, the kind of neonatal APL correlated with the same mother's isotype before 6 months of life and mostly disappeared thereafter. Third, 10% of children showed persistent APL at 24 months of life. Fourth, de-novo production of antibodies was reported; in particular, de-novo anti-beta2 glycoprotein-I antibodies synthesis occurred in 16% and LA in 4% of cases. It was suggested that prolonged APS exposure could represent an immunological trigger, as well as vaccinations or infections, for de-novo synthesis of APL. Nevertheless, the exact clinical relevance of neonatal APL positivity is still poorly understood. Although only few case reports of thrombosis have been described among children born to mothers with APS6, this increased prothrombotic risk should not be underestimated. In addition, the European registry of babies born to mothers with primary APS reported four cases of neurodevelopmental anomalies during the 5-year follow-up7. According to the current knowledge on this topic, APL screening should be performed at birth only in case of thrombosis, and after 6 months of life in asymptomatic neonates to investigate the eventual persistence of APL. In this case, a long lasting follow-up is required to verify the true clinical significance of persisting APL.
References 1. Sen ES, Beresford MW, Avcin T, Ramanan AV. How to use lupus anticoagulants. Arch Dis Child Educ Pract Ed. 2012 Oct 6. 2. Lambert M, Ferrard-Sasson G, Dubucquoi S, Hachulla Eet al. Diluted Russell viper- venom time improves identification of antiphospholipid syndrome in a lupus anticoagulant-positive patient population. Thromb Haemost 2009;101(3):577- 81. 3. Soulier JP, Boffa MC: Avortements a repetition, thromboses et anticoagulant circulant anti-thromboplastine: trois observations. Nouv Presse Med 1980;9:859. 4 De Carolis MP, Salvi S, Bersani I, De Carolis S. Isolated cerebral sinovenous thrombosis: a rare case of neonatal antiphospholipid syndrome. Indian Pediatr. 2012 May;49(5):411-2. 5. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood 1987;70(1):165-72. 6. Boffa MC, Lachassinne E. Infant perinatal thrombosis and antiphospholipid antibodies: a review. Lupus 2007;16(8):634-41. Review. 7. Mekinian A, Lachassinne E, Nicaise- Roland P, et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2012 May 15.
Conflict of Interest:
None declared
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Suboptimal INH dosage in prophylaxis
Submit responseThe authors state that INH does not prevent the development of active tuberculosis. However, it is well known that with lower dosage than 15mg/kg daily of INH, we cannot assure therapeutical INH levels, precluding its efficacy, as it correlates with lower levels than 3g/l in the pharmacokinetic parameter of response Cmax
Conflict of Interest:
None declared
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Sexual health and contraception
Submit responseStraw and Porter write an important article on Sexual health and Contraception (Arch Dis Chld Educ Pract Ed 2012; 97:177-184), but there are some points which I think need clarification or correction. There may also be missed opportunities for highlighting the most effective methods of contraception in real life situations for young people. The statement that 'Levonelle 1500 is an an oral progestogen which can be obtained over the counter at any pharmacy' is misleading. Levonelle 1500 is a Prescription Only Medicine , whereas Levonelle One Step can only be sold to women over the age of 16. Levonelle 1500 will be issued free in some pharmacies on a Patient Group Direction where pharmacists have been trained and approved for its use. The commissioning arrangements for this are not universal, nor are the upper age limits.
The table of summary of contraceptive methods available for young people in the UK (Table 1) again has some strange and sometimes out of date statements. Combined hormonal contraception (pills, patches and vaginal rings) are no longer consider to become ineffective if non-liver enzyme inducing antibiotics are taken concurrently or during the 7 days after cessation 1. The 'progesterone only pill' for which only one brand name is appended should more correctly be called 'progestogen only pill' as the hormone is the synthetic form of progesterone. The Today sponge has not been available in the UK for several years for prescription (it is not listed in the British National Formulary) but does appear to be available for direct sale from pharmacies or via the internet. It's failure rate is not quoted in Table 1 -perhaps because it this appears to be the same as for spermicide alone, a method which would not be recommended to young highly fertilie people.
It is a shame that space was not given to emphasising the differing rates of failure between perfect use of a method when compared to typical (every day real life) use. Trussell 2 has published updated tables showing (at the end of 1 year of use in the USA) that user-dependent methods (such as combined hormonal contraception, POP, and to a lesser degree the injectable methods) have a much higher failure rates than those quoted in Table 1 of the article. For this reason, long acting reversible contraception (such as implants, IUDs and IUS), with additional use of condoms to decrease transmission of STIs, are encouraged particularly amongst young women where life styles may make 100% adherence difficult.
References 1. Drug interactions with Hormonal Contraception. Clinical Effectiveness Unit of Faculty of Sexual and Reproductive Healthcare Jan 2011, http://www.fsrh.org/pdfs/CEUGuidanceDrugInteractionsHormonal.pdf accessed 30.9.12 2.Trussell,J Contraceptive Failure in the United States. Contraception 83 (2011) 397-404 accessed 30.9.12
Yours sincerely
Dr Alyson Elliman B Sc(Hons) MBBS DCH FFSRH MIPM Consultant in Sexual and Reproductive Healthcare 2 Edridge Rd, Croydon, CR9 1PJ Alyson.elliman@nhs.net
Conflict of Interest:
I receive educational grants from Durbin Sales and Bayer Schering
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Unde venis? loosely paraphrased to "where did you spend your last holiday?"
Submit responseSurprisingly, especially in view of a recent article highlighting the importance of including a history of recent travel when evaluating neurological symptoms and signs(1), such an inquiry was not mentioned as a fundamental requirement in the 15 minute consultation on facial paralysis(2). In the anecdotal report of a patient with multiple cranial nerve involvement(inclusing facial nerve paralysis) in whom the diagnosis of neuroborreliosis was initially missed, it was only after an inquiry abour recent travel was made that the "penny" dropped, and progress was made towards the correct diagnosis(1). Facial nerve paralysis arguably has greater relevance in paediatric neuroborreliosis than in adult cases, having been documented in as many as 71% of chidren with neuroborreliosis(3). In a review of 66 paediatric cases of central nervous system infection covering the period January 1, 2004 to December 31, 2006, in a university hospital in Helsinki, facial nerve paralysis was a presenting feature in 19 patients with a variety of central nervous system infections. Thirty two percent of those CNS infections characterised by facial nerve paralysis were attributable to Lyme disease(4). In the United Kingdom itself, the true incidence of Lyme disease is unknown but, according to one view, "it is more common than is thought", as shown by an audit of a "highly aware" GP parctice in Scotland which found "an incidence of 370/100,000 population, based on clinical diagnosis of the erythema migrans rash..."(5). The rash may be on the back of the body and not seen, or may be present behind the hair line in children, or may have been forgotten by the time later symptoms develop(5). The latter may have been the case in the instance of a 12 year old Canadian girl admitted to hospital with a 10 day history of unilateral facial weakness and midscapular pain after returning from a holiday in rural France. She did not recall any insect bites, and the family did not recall a preceding rash. On examination she had a right sided lower motor neurone facial nerve palsy, but the unusual additional feature was the coexistence of spinal cord involvement in a patient of her age(3). Progressive motor weakness with universal arreflexia is another unusual presenting feature of neuroborreliosis(6), and this can simulate Guillain- Barre syndrome. The presence of cerebrospinal fluid(CSF)pleocytosis is one of the important features which distinguishes this presentation from Guillain- Barre syndrome(7)(8), given the fact that it is highly exceptional for Guillain-Barre sysndrome to be characterised by CSF white cell counts(WCC) of the order of 25-197/microlitre as was the case in 3 patients aged 77, 82, and 82, respectively, who were the subject of one report(9).Lower CSF white cell counts were documented in the other 2 patients, aged 78 and 82, who were the subjects of the same report(9). References (1) Hobson J., Weatherall MW A patient's journey. Lyme borreliosis BMJ 2012;344:46-47 (2) Malik V., Joshi V., Green KMJ., Bruce IA 15 minute consultation: A structured approach to the management of facial paralysis in a child Arch Dis Child : Education and Practice 2012;97:82-85 (3)Makhani N., Morris SK., Page AV et al A twist on Lyme: the challenge of diagnosisng European Lyme neuroborreliosis J Clin Microl 2011;49:455-457 (4) Huttunen P., Lappalainen M., Salo E et al Differential diagnosis of acute central nervous system infections in children using modern microbiological methods Acta Paediatrica 2009;98:1300-1306 (5) Pearson S., Huyshe-Shire S Re: Tick bite and early Lyne borreliosis BMJ rapid response 25th June 2012 (6) Sterman AB., Nelson S., Barclay P Demyelinating neuropathy accaompanying Lyme disease Neurology 1982;32:1302-1305 (7) Hartung H-P., van der Meche FGA., Pollard J Guillain-Barre syndrome Current Opinion in Neurology 1998;11:497-513 (8) Burns TEM Guillain-Barre syndrome Semin Neurol 2008;28:152-167 (9) Rauschka H., Jellinger K., Lassmann H., Braier F., Schmidbauer M Guillain-Barre syndrome with marked pleocytosis or a significant proportion of polymorphonuclear granulocytes in the cerebrospinal fluid: neuropathological investigation in five cases and review of differential diagnoses European Journal of Neurology 2003;10:479-486
Conflict of Interest:
None declared
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The abbreviated patient-held health record should be part of the process of transition
Submit responseAt the heart of good management of the health transition process(figure 1)(1) should be a recognition of the "power of information- putting all of us in control of the healthcare information we need"(2). This can be achieved, in part, through the medium of the so-called "abbreviated patient-held record"(3), so as to bridge the communication gap between a variety of healthcare services when the young person makes the transition to adult services. In order to optimise the quality and content of the abbreviated patient-held record its format should, not only be structured, as recommended for clinic correspondence(4), but also standardised, so as to include an updated problem list and an updated drug list(3). The former shuld be mutually agreed between the young person and the relevant healthcare professional, and the latter should include prescribed medicines, over the counter medicines, as well as homeopathic medication. At each encounter with healthcare professionals, the contents of the abbreviated health record should be updated, and one copy placed in the hands of the young person, and one copy transmitted to his general practitioner. References (1) Gleeson H., Turner G Transition to adult services Arch Dis Child Educ Pract Ed 2012;97:86-92 (2) The Choice Team, Department of Health, 79 Whitehall, London A model for shared decision-making In "Liberating the NHS; No decision about me, without me:Further consulatation proposals to secure shared decision-making", page 12-13, 23 May 2012 (3) Jolobe OMP The abbreviated patient-held record: bridging the communication gap British Journal of Hospital Medicine 1012;73:234 (4) Melville C., Hands S., Jones P Randomised trial of the effects of structuring clinic correspondence Arch Dis Child 2001;86:374-5
Conflict of Interest:
None declared
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Options for procedural pain, current practice in England
Submit responseIn her review of options for procedural pain in newborn infants Judith Meek is herself premature in her assertion that "the statement that we are no longer in equipoise over the use of sucrose may be premature..."[1].
We surveyed current practice and attitudes to procedural pain in English Neonatal Units in 2011 using paper questionnaires sent to the lead clinician in each unit. Replies were received from 102 of 179 units contacted, of which 29 units had more than 400 admissions/yr, 54 units had 200-400 admissions/yr and 14 units had less than 200 admissions/yr. 5 units did not report their admission rates.
70 units used sucrose on more than 50% of times for painful procedures, 10 used sucrose on less than 50% of occasions and 15 did not use sucrose at all. 72 units agreed that sucrose was safe and effective at reducing procedural pain. Of the 70 units using sucrose, 60 had a written guideline for pain relief; such a policy was present in 16 of the 25 units seldom or never using sucrose. Lack of time or demand and forgetfulness were stated to be the commonest reasons for non-use of sucrose.
The fact that sucrose is used routinely in at least 73% of units, and that those units not reporting routine use quoted lack of time or other operator-dependent factors as being the main reasons for non-use, suggests that most practitioners are convinced by the considerable scientific evidence and their own personal experience of the utility of this simple and safe measure.
We endorse Meek's view of the importance of promoting good nursing and developmental care; in our study 42 respondents stated that other non- pharmacological method of pain relief including breast feeding, non- nutritive sucking, swaddling, cuddling, holding and containment were useful for reducing procedural pain.
Reference
1 Meek J, Options for procedural pain in newborn infants Arch Dis Child Educ Pract Ed 2012;97:23-8
Conflict of Interest:
None declared
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