Du Toit, Meyer and Shah have offered an excellent approach to cow's milk protein allergy (CMPA) and related disorders.(1)

There is evidence to suggest that an increasing number of infants are seeking medical attention with symptom-complex suggestive of gastro- oesophageal disease (GORD).(2) Infants with cow's milk protein allergy (CMPA), especially those with non-IgE mediated cow's milk-induced reactions, present with a variety of symptoms which may be clinically indistinguishable from those with primary GORD.(2,3)

CMPA and GORD occur frequently in young infants and various studies have demonstrated that CMPA may be present in up to 50% case of GORD and in a high proportion of the patients GORD symptoms may be induced by the underlying CMPA.(4)

Recognising the fact that there is a strong association between GORD and CMPA, all infants presenting with symptoms of GORD require careful evaluation to detect whether the GORD is primary or secondary to CMPA. A detailed history, observation of feeding and physical examination of the infant are always mandatory to detect signs of secondary GORD.(5) Oesophageal pH monitoring shows some typical characteristics and immunological tests may be helpful if an association is suspected (6); however the only clue to the diagnosis especially in non-IgE mediated CMPA, is often by elimination diet and milk challenge. The time interval between the milk intake and the suspected reaction to milk is of crucial importance; most infants with immediate symptoms may have IgE-mediated CMPA and should be referred for allergy evaluation with further delay and milk challenges should only be undertaken in a supervised environment.

Infants presenting with symptom-complex suggestive of GORD with the clinical history of atopy or cutaneous allergic reactions (as urticaria, angio-oedema, facial or buccal mucosal oedema), respiratory symptoms (cyanosis, croup, respiratory distress or wheeze) or symptoms suggestive of cardiopulmonary collapse (pallor, shock) or apparent life threatening event should alert the clinician that GORD is secondary to CMPA to initiate cow's milk-free diet and hypoallergic feeds.

Although soya-based infant formulas have been recommended as a first- choice alternative for infants with cow's milk allergy, it must be remembered that nearly half the children with CMPA also have an allergy to soya (7) and hence the symptoms may remain unchanged or show only partial improvement if the feeds are switched over from cow's milk to soya-based formula.

References:

1) du Toit G, Meyer R, Shah N, Identifying and managing cow's milk protein allergy. Arch Dis Child Educ Pract Ed 2010;95:134-144 doi:10.1136/adc.2007.118018

2) Mir Nisar. Epidemic of gastro-oesophageal reflux in young infants. Rapid response to: From Drugs and Therapeutics Bulletin. Managing gastro- oesophageal reflux in infants. Brit Med J 2010; 341:495-498 Doi:10,1136/bmj.c4420

3) Vandenplas Y, Brueton M, Dupont C et al. Guidelines for the diagnosis and management of cow's milk protein allergy in infants Arch Dis Child 2007;92:902-908 doi:10.1136/adc.2006.110999

4) Salvatore S, Vendenplas Y. Gastroesophageal Reflex and Cow Milk Allergy; Is There a Link? Pediatr 2002; 110; 972-984 Doi: 10.1542/peds.110.5.972

5) Mir, Nisar. Presentation and Diagnosis of Gastro-oesophageal Reflux in babies MIMS Advances. Infant Nutrition 2005;4:1-4

6) Cavataio F, Lacona G, Montalto G et al. Clinical and pH-metric characteristics of gastro-oesophageal reflex secondary to cows' milk protein allergy. Arch Dis Child 196; 75: 51-56 Doi; 10.1136/adc.75.1.51

7) Klemola T, Vanto T, Juntunen-Backman K et al. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. J Pediatr. 2002 ;140(2):219-24.

Nisar A Mir Consultant Paediatrician Warrington & Halton Hospitals NHS Foundation Trust

Clinical Lecturer (Hon) University of Liverpool

E-mail: nisar.mir@whh.nhs.uk

Conflict of Interest:

None declared

We were grateful to a number of people who contacted us about our article on How to use C - reactive protein [1].

Dr Abelian of Wrexham Maelor Hospital drew out attention to data on plasma half-life suggesting this was 19 hours in an adult [2] rather than the previously quoted 4-7 hours [3,4].

Dr Emmerson asked if there was robust data in support of the range of non infectious conditions quoted to cause a rise in CRP in the newborn period. Our article had quoted a review by Hengst [5]. We therefore reviewed the papers referenced in this review. Chiesa et al [6] showed that mean CRP concentration at birth was increased by a factor of 1.50 (95% CI, 1.32 to 2.03) if the 5-min Apgar score was <8 and by a factor of 1.32 (95% CI, 1.07 to 1.61) if the time from rupture of membranes was >18 hours. This effect on CRP was no longer present by 48 hours of life. Other studies quoted were observational studies which describe findings in neonates with raised serum CRP who did not have evidence of bacterial infection on blood culture [7-9]. Meconium aspiration syndrome, pneumothorax, intraventricular haemorrhage and severe asphyxia were reported in these studies but they were unable to rule out co-existing infection as a cause for the rise in CRP. A literature search provided some further information. Wasunna et al found no evidence that intraventricular haemorrhage was associated with elevation of CRP in neonates with no evidence of infection [10]. Schouten- Van Meeteren et al demonstrated no significant difference between the CRP levels of neonates with perinatal asphyxia, prolonged rupture of membranes, hyperbilirubinaemia or respiratory distress syndrome, and those of a control group [11]. Xanthou et al also found no difference between the CRP levels in neonates with asphyxia compared to controls [12].

There is thus some evidence that low Apgar scores and rupture of membranes can increase CRP at birth [6], but this rise is small and the effect is not present by 48 hours of age. We agree with Dr Emmerson that there is a lack of robust evidence to support a claim that CRP can be raised in neonates as a result of non-infectious causes, and would certainly not advocate withholding antibiotics in neonates with a raised CRP. We disagree, however, with the statement that reference to old papers is of "suspect value". In assessing evidence we must look at its quality, not at its age.

Howman et al question if preterm infants mount a lower CRP response compared to term infants and older children. There is good evidence to show that neonates with infection have lower CRP responses than older children (median CRP in preterm neonates with sepsis 40mg/l vs median in children 1-36 months old with bacterial infection 97 mg/l [13; 14]). 75% of preterm infants with sepsis have maximum CRP levels below 80mg/l [13], it is thus not true that preterm infants with proven infection often have CRP values of >100mg/L.

Dr Marks commented that CRP is a non-specific indicator of systemic inflammation, as stated in our article. We did not elaborate on this as the scenarios we chose all featured bacterial infection as the diagnosis to be confirmed or excluded. Dr Marks referenced a textbook for his assertions, so we reviewed the literature to confirm his statements. Juvenile idiopathic arthritis is associated with a raised CRP early in the course of the disease, especially in those with systemic or polyarticular onset [15]. However in children presenting with arthritis an elevated CRP is an independent predictor of septic arthritis in patients with acute monoarthritis, whereas a low CRP value is an independent predictor for the diagnosis of Juvenile idiopathic arthritis in patients whose disease duration exceeds two weeks [16].

The correct use of CRP requires careful review of the literature. We are grateful to those who have highlighted areas in our article which required better evidence and hope this response will improve our review.

References

1. McWilliam S, Riordan A. How to use: C-reactive protein. Arch Dis Child Educ Pract Ed, 2010. 95(2):55-8

2. Vigushin DM, Pepys MB, Hawkins PN. Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease. J Clin Invest. 1993 Apr;91(4):1351-7.

3. Young B, Gleeson M, Cripps AW. C-reactive protein: a critical review. Pathology 1991;23:118-24.

4. Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentraxins) and serum amyloid A protein. Adv Immunol 1983;34:141-211

5. Hengst, J.M., The role of C-reactive protein in the evaluation and management of infants with suspected sepsis. Adv Neonatal Care, 2003. 3(1):3-13

6. Chiesa C, Fabrizio S, Assumma M, Buffone E, Tramontozzi P, et al. Serial measurements of C-reactive protein and interleukin-6 in the immediate postnatal period: reference intervals and analysis of maternal and perinatal confounders. Clin Chem 2001;47:1016-1022.

7. Berger, C., et al., Comparison of C-reactive protein and white blood cell count with differential in neonates at risk for septicaemia. Eur J Pediatr, 1995. 154(2): p. 138-44. 8. Ainbender, E., et al., Serum C-reactive protein and problems of newborn infants. J Pediatr, 1982. 101(3):438-40.

9. Pourcyrous, M., et al., Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics, 1993. 92(3):431-5

10. Wasunna, A., et al., C-reactive protein and bacterial infection in preterm infants. Eur J Pediatr, 1990. 149(6):424-7

11. Schouten-Van Meeteren, N.Y., et al., Influence of perinatal conditions on C-reactive protein production. J Pediatr, 1992. 120(4 Pt 1):621-4.

12. Xanthou, M., et al., Inflammatory mediators in perinatal asphyxia and infection. Acta Paediatr Suppl, 2002. 91(438):92-7.

13. Ng PC, Cheng SH, Chui KM, Fok TF, Wong MY, Wong W, Wong RP, Cheung KL. Diagnosis of late onset neonatal sepsis with cytokines, adhesion molecule, and C-reactive protein in preterm very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1997 Nov;77(3):F221-7.

14. Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics. 2001;108(6):1275-9.

15. Gwyther M, Schwarz H, Howard A, Ansell BM. C-reactive protein in juvenile chronic arthritis: an indicator of disease activity and possibly amyloidosis. Ann Rheum Dis. 1982 Jun;41(3):259-6

16. Kunnamo I, Kallio P, Pelkonen P, Hovi T. Clinical signs and laboratory tests in the differential diagnosis of arthritis in children. Am J Dis Child. 1987 Jan;141(1):34-40.

Conflict of Interest:

None declared

The recommendation that a 12-lead electrocardiogram(ECG) should be performed on every patient presenting with transient loss of consciousness(TLOC)(1)) is a sound one, regardless of whether the provisional diagnosis is syncope or epilepsy, given the fact that convulsive syncope can simulate epilepsy(1). An important caveat regarding investigation of underlying causes of TLOC using the 12 lead ECG in settings such as the Accident and Emergency department is that "standard automated reporting of QT interval on modern ECG equipment can be erroneous", as shown by missed diagnosis(with fatal outcome) where the "automated" QT interval was reported as normal in spite of being prolonged when evaluated manually using the following formula:- QTc(corrected QT interval)=QT interval/square root of the heart rate in beats per minute(2). Another caveat is the requirement to recognise that the association of paroxysmal atrial fibrillation(with normal QRS morphology) and syncope might be indicative of potentially lethal channelopathies such as short QT syndrome(SQTS)(3) and Brugada syndrome(BS)(4). Both SQTS(3) and BS(5) can occur during childhood, the occurence of BS during childhood being the subject of a wide-ranging review in a recent report(5). When paroxysmal atrial fibrillation is a feature of BS other manifestations include syncope, aborted sudden death, ventricular fibrillation, and polymorphic ventricular tachycardia(4). References (1) Martin K., Bates G., Whitehouse WP Transient loss of consciousness and syncope in children and young people:what you need to know Arch Dis child Education and Practice 2010;95:66-72 (2) Chadwick D., Jelen P., Almond S Life and death diagnosis Practical Neurology 2010;10:155-159 (3)Schimpf R., Wolpert C., Gaita F., Giustetto C., Borggrefe M Short QT syndrome Cardiovascular Research 2005;67:357-366 (4) Bigi MA., Aslani A., Shahrzad S Clinical predictors of atrial fibrillation in Brugada syndrome EUROPACE 2007;9:947-950 (5) Lee YS., Baek JS., Kim SY et al Childhood Brugada syndrome in 2 Korean families Korean Circulation Journal 2010;40:143-147

Conflict of Interest:

None declared

Dear Editor we read with interest the recent article regarding how to use C- reactive protein (CRP). While the authors discuss the role of CRP as a non-specific indicator of serious bacterial infection (SBI) they do not acknowledge that CRP is a non-specific indicator of systemic inflammation, the causes of which are many and varied with acute infective processes being only one.

It is important to consider alternative conditions that may cause a rise in CRP levels, especially when these diseases can mimic systemic infection. Juvenile idiopathic arthritis (JIA) and vasculitis are very commonly associated with significant rises in CRP, often in association with other systemic features such as fever, rash and constitutional upset. Children presenting with this constellation of clinical features may be misdiagnosed as suffering from SBI. In these conditions, CRP is often used as a marker of ongoing disease activity and may be persistently and markedly elevated in uncontrolled disease. Acute reactive arthritis is also associated with a significantly raised CRP level reflecting the degree of ongoing synovitis.

A normal CRP can also be falsely reassuring even in the presence of acute inflammation. This is especially true in patients with acute flares of systemic lupus erythematosus (SLE) where typically CRP levels may remain normal in the presence of marked inflammation despite significant changes in other markers of inflammation such as ESR and compliment levels [1].

Reference: Szer I S; Kimura Y; Malleson P N; Southwood TR. Arthritis in children and adolescents. Chapter 1.6. Oxford University Press, 2006.

Conflict of Interest:

None declared