Mycoplasma respiratory tract infection complicated by Stevens-Johnson syndrome and surgical...

Acta Pædiatrica ISSN 0803–5253

LETTER TO THE EDITOR

Mycoplasma respiratory tract infection complicated by Stevens-Johnsonsyndrome and surgical emphysemaRakesh Amin ([email protected]), Elisa Smit, Guftar Shaikh, Philippa Rawling, Eliza AlexanderRoyal Manchester Children’s Hospital, Hospital Road, Manchester, UK

CorrespondenceRakesh Amin, M.D., Royal Manchester Children’s Hospital,Hospital Road, Manchester, M27 4HA, UK.Tel: 0161 9222581 | Fax: 0161 9222583 |E-mail: [email protected]

Received20 August 2006; accepted 30 August 2006.

DOI:10.1111/j.1651-2227.2007.00088.x

Sir,An 11-year-old girl presented with a 10-day history of avesicular rash on her extremities, lips and eyelids and pu-rulent conjunctivitis followed by a cough, lethargy, pyrexiaand weight loss. Oxygen saturation in air was 89%, CRPwas 22 mg/L and white cell count was 11.5 × 10∧9/l. ChestX-ray showed bilateral patchy shadowing, thus a diagnosisof atypical pneumonia was made and she was treated withintravenous erythromycin and oxygen.

On day 5 of admission, she developed widespread targetlesions consistent with erythema multiforme. These lesionssubsequently ulcerated including extensive, painful intra-oral lesions consistent with Stevens–Johnson syndrome.

On day 7, she became increasing short of breath, com-plained of chest pain and developed increasing oxygenrequirements. Examination revealed evidence of surgicalemphysema at her neck, shoulders and upper limbs, whichwas confirmed by repeat chest X-ray (Fig. 1). A CT scanshowed extensive air trapping at the mediastinum, neck,chest wall and axillae. In addition, air was evident in theextradural space of the spinal canal.

Serology showed a rise of Mycoplasma titre from 1 out of160 on day 3 of admission to 1 out of 640 on day 10. Bloodcultures, throat and skin swabs and herpes PCR serologywere negative. In view of the surgical emphysema, a gas-trograffin swallow was performed and demonstrated no oe-sophageal perforation, indicating that the air leak was dueto bronchial erosion secondary to the Stevens–Johnson syn-drome lesions.

Daily serial chest X-rays showed no mediastinal expan-sion, therefore she was treated conservatively for 14 dayswith erythromycin, oxygen, pain relief and skin care.

Figure 1 Chest X-ray on day 7 of admission showing patchy, bilateral lung shad-ing consistent with infection and also extensive air trapping at the mediastinumand subcutaneous tissues, consistent with surgical emphysema.

Her oxygen requirement and surgical emphysema resolvedwithin 3 weeks.

We report a complication of Stevens–Johnson syndromeresulting in significant morbidity but which resolved withconservative management.

472 C©2007 The Authors/Journal Compilation C©2007 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 472–479

Letter to the Editor Letter to the Editor

Comments on ‘Lead neurotoxicity in children: is prenatal exposure moreimportant than postnatal exposure?’Joe M. Braun ([email protected])1, Bruce Lanphear2

University of North Carolina-Chapel Hill, Department of Epidemiology, Chapel Hill, USA

Cincinnati Children’s Environmental Health Center, Cincinnati Children’s Hospital Medical Center, Cincinatti, USA

Correspondence

Joe M. Braun, University of North Carolina-ChapelHill,Department ofEpidemiology McGavran-Greenberg Hall,CB 7435 Chapel Hill, North Carolina 27599, USA.Tel.: 919-951-8519 | Fax: 919-966-2089 |Email: [email protected]

Received

11 October 2006; accepted 25 October 2006.

DOI: 10.1111/j.1651-2227.2007.00131.x

Sir,Ronchetti et al. contrasts two different approaches to pre-

venting lead associated neurotoxicity: remediation of leadcontaminated environments and providing women with mi-cronutrient supplementation before and during pregnancyto avoid mobilizing lead stores during pregnancy (1). Theauthors conclude that because it is ‘costly, difficult, and ofuncertain usefulness’ to perform environmental remediationof lead exposures, that efforts should be made to study andreduce prenatal lead exposure through nutritional and socialfactors thus reducing its burden on childhood neurodevel-opment. Reducing prenatal exposure to lead is desirable andmay diminish lead-associated neurodevelopmental deficits,but it is not, by itself, adequate to protect children from theadverse consequences of lead toxicity.

As noted by Ronchetti et al., there is considerable evi-dence that dietary deficiencies are associated with increasesin blood lead levels (2). The results are less convincing, how-ever, that dietary supplementation with calcium or iron cansignificantly reduce blood lead levels in children or adultfemales (3,4). Thus, it is unwise to suggest that micronutri-ent supplementation is the only tenable solution to eliminatelead-associated neurotoxicity in children.

In an otherwise excellent review, the authors erroneouslyconclude that the majority of lead stores in children are de-rived from maternal and fetal stores of lead and that ‘scien-tific data which allow us to decide whether, at the epidemio-logical level, prenatal or postnatal lead exposure is the mainneurotoxic event, are scarce’. Although maternal stores areclearly an important source of lead exposure during the first6 months of life – and undoubtedly contribute to lifetimeexposure – the predominant source of children’s body leadburden is from exposures to lead-contaminated paints, dust,soil, cosmetics, pottery and water during the first 5 years oflife (5).

In addition, existing research suggests that chronic expo-sure to low-level lead exposure during early childhood is

a stronger predictor of lead-associated intellectual deficitsthan prenatal exposure. Contrary to the authors’ argument,although prenatal exposure is associated with intellectualfunction in several prospective epidemiological studies, theeffect is diminished or absent after adjusting for postnatallead exposure. In a pooled analysis of 696 children fromseven prospective studies that had measures of both pre-natal and postnatal blood lead concentration, we found thatconcurrent blood lead concentration, but not prenatal bloodlead concentration, was a predictor of children’s intellectualability with both variables in the multivariable analysis (6).

It is critical to test and implement cost-effective solutionsto eliminate both prenatal and postnatal lead exposures toprevent the adverse consequences of lead toxicity. Until weeliminate all sources of environmental lead exposure we willfail to protect children from the consequences of lead toxic-ity. Although it will be difficult to convince national agenciesto promulgate regulatory standards to reduce environmen-tal sources of childhood lead exposure, it is not impossi-ble. Indeed, contrary to widespread expectations, children’sblood lead levels plummeted once leaded gasoline and otherenvironmental sources of lead exposure were reduced; itis astounding what can be achieved when we promulgateenvironmental health policy that is based on empirical re-search.

References

1. Ronchetti R, Van Den Hazel P, Schoeters G, Hanke W,Rennezova Z, Barreto M, et al. Lead neurotoxicity in children:Is prenatal exposure more important than postnatal exposure?Acta Paediatr. 2006; 95: 45–9.

2. Mahaffey KR. Nutrition and lead: strategies for public health.Environ Health Perspect 1995; 103(Suppl 6): 191–6.

3. Rosado JL, Lopez P, Kordas K, Garcia-Vargas G, Ronquillo D,Alatorre J, et al. Iron and/or zinc supplementation did notreduce blood lead concentrations in children in a randomized,placebo-controlled trial. J Nutr. 2006; 136: 2378–83.

C©2007 The Authors/Journal Compilation C©2007 Foundation Acta Pædiatrica/Acta Pædiatrica 2007 96, pp. 472–479 473


4. Gulson BL, Mizon KJ, Korsch MJ, Taylor AJ. Low blood leadlevels do not appear to be further reduced by dietarysupplements. Environ Health Perspect 2006 Aug; 114:1186–92.

5. Lanphear BP, Hornung R, Ho M, Howard CR, Eberly S, KnaufK. Environmental lead exposure during early childhood. J

Pediatr 2002; 140: 40–7. Erratum in: J Pediatr 2002 Apr;140(4): 490.

6. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P,Bellinger DC, et al. Low-level environmental lead exposureand children’s intellectual function: an international pooledanalysis. Environ Health Perspect 2005; 113: 894–9.

Lead neurotoxicity in children: is prenatal exposure more important thanpostnatal exposure?Roberto Ronchetti ([email protected])1, Peter van den Hazel2,Greet Schoeters3, Wojtek Hanke4, Zuzana Rennerova5,

Mario Barreto1, Maria Pia Villa1

1.Department of Paediatrics, Second School of Medicine, University “La Sapienza”, Rome, Italy

2.Public Health Services Gelderland Midden, Arnhem, The Netherlands

3.Vlaamse Instelling voor Technologisch Onderzoek, Mol, Belgium

4.Department of Informatics and Statistics Medical University, Nofer Institute of Occupational Medicine, Lodz, Poland

5.Srobar’s Institute for Respiratory Diseases and Tuberculosis for Children, Dolny Smokovec, Vysoke Tatry, Slovak Republic

CorrespondenceProfessor Roberto Ronchetti, Clinica Pediatrica, Ospedale Sant’Andrea,Via Grottarossa 1035/1039, 00189 Rome (RM), Italy.Tel: +39-06-3377 5856 | Fax: +39-06-3377 5941 |Email: [email protected]

Received26 October 2006; revised 31 October 2006; accepted 9 November 2006.

DOI: 10.1111/j.1651-2227.2006.00144.x

Dear Sir,We are pleased to see that our review raised the interest of

a recognized expert in the epidemiology of lead neurotoxic-ity, Dr. Lanphear, and of his co-author Dr. Braun. Our review(a paper within the PINCHE EU Project, Workpackage ofToxicology) reported evidence from the literature suggestingthat lead neurotoxicity may depend more on prenatal thanon postnatal exposure (1).

The writers first take issue with our statement that per-forming environmental remediation of lead exposure is‘costly, difficult and of uncertain usefulness’. In Europe, forexample, the general childhood population has measurablemean blood lead levels ranging from 5 to 10 �g/dL (Westernversus Eastern European countries) (1,2). These low levelsrepresent the results of concerted efforts on the part of regu-latory authorities and most important, largely depend fromthe withdrawal of alkyl leads from gasoline. Because most ofthe lead neurotoxicity observed in children at the age of 7 isalready evident at a blood lead level less than 7.5–10 �g/dLand robust epidemiological data (3,4) found no evidence ofa lower threshold (children should have blood lead levelsnear to zero), we find it somewhat hard to envisage the taskof reducing further and near to zero the environmental leadexposure for all our children as being ‘inexpensive, simpleand of undoubted usefulness’.

The second point raised by Drs Lanphear and Braun is theorigin of lead stores in the newborn. In adult women two-thirds (45–75%) of blood lead comes from long-term leadtissue stores (bone), a fact demonstrated by the studies onnatural lead isotopes partition in blood and urine and widelyaccepted in the literature (5–7). Moreover, during pregnancybone resorption undergoes a physiological increase whichfurther increases the contribution of maternal bone lead de-posits in the accumulation into the foetal skeleton of lead (7).In this process lead simply follows the fate of calcium and ifthe mother has high concentration of lead in her bone min-eral deposits, the same concentration will be deposited in thebones of the foetus. These metabolic exchanges take placemainly during the last trimester of pregnancy when maternalblood lead increases 25–100% owing to high mobilization oflead from bone deposits (7). Dietary supplementation withcalcium or other metabolites during this phase of pregnancycan reduce blood lead levels in women: these studies there-fore show that lead mobilization in pregnant women can bereduced by means of calcium or other supplements (8–10).These studies differ in concept from the studies cited inthe letter in which various types of dietary supplementationfailed to reduce blood lead levels in normal children aged 7(11,12).



Finally, in the excellent paper describing the pooled anal-ysis of data from 1333 children and cited in the letter(Lanphear et al., 2005) (4), blood lead levels were measuredat various times from birth (cord blood lead) to the momentof IQ measurement at about 7 years (concurrent blood lead).Both ‘cord blood’ and ‘concurrent’ blood lead levels were sig-nificantly associated with IQ at the age of 7. Even if IQs cor-related more strongly with the ‘concurrent blood lead’ thanwith other blood lead measures the fact that “cord bloodlead” and blood lead measured in early childhood (6 monthsto 2 years) or the ‘average lifetime blood lead’ were eachhighly correlated with IQ suggests that IQ loss could, atleast partially, arise from lead exposure in utero or in thefirst months of life. Newborns normally have a negative leadbalance in the sense that, owing to bone turnover, they elim-inate three times more than their dietary lead intake (6). Wetherefore find it difficult to believe that lead neurotoxicityalready predicted by blood lead level at birth or early post-natally is a consequence of external contamination.

In conclusion, we believe that environmental measuresaimed to reduce lead exposure in children and in thegeneral population are always welcome, but their current‘efficacy’ seems questionable. At the same time (and not asan alternative) we need to focus our attention on the leadbone deposits of the mother and their mobilization duringpregnancy. Scanty and preliminary results suggest that thismobilization could be at least partly avoided through varioustypes of dietary supplementation (8–10) although preciselyhow remains to be fully established.

References

1. Ronchetti R, Van Den Hazel P, Schoeters G, Hanke W,Rennezova Z, Barreto M et al. Lead neurotoxicity: is prenatalexposure more important than postnatal exposure? ActaPaediatr 2006; 95(Suppl 95): 45–49.

2. SCOOP. Report of Task 3-2.11: Assessment of the dietaryexposure to arsenic, cadmium, lead and mercury of thepopulation of the EU Member States, March 2004. URL:www.mhlw.go.jp/shingi/2004/08/dl/s0817-2k2.pdf.

3. Canfield RL, Henderson CR Jr., Cory-Slechta DA, Cox C,Jusko TA, Lanphear BP. Intellectual impairment in childrenwith blood lead concentrations below 10 microg/dl. N Engl JMed 2003; 348: 15l7–26.

4. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P,Bellinger DC, et al. Low-level environmental lead exposureand children’s intellectual function: an international pooledanalysis. Environ Health Perspect 2005; 113: 894–9.

5. Gulson BL, Jameson CW, Mahaffey KR, Mizon KJ, Korsch MJ,Vimpani G. Pregnancy increases mobilization of lead frommaternal skeleton. J Lab Ciin Med 1997; 130: 51–62.

6. Gulson BL, Pounds JG, Mushak P, Thomas BJ, Gray B, KorschMJ. Estimation of cumulative lead release (lead flux) from thematernal skeleton during pregnancy and lactation. J Lab Clin,Med 1999; 134: 631–40.

7. Gulson BL, Mizon KJ, Palmer JM, Patison N, Law AJ, KorschMJ, et al. Longitudinal study of daily intake and excretion oflead in newly born infants. Environ Res 2001; 85:232–45.

8. Jarakiraman V, Ettinger A, Mercado-Garcia AQ, Hu H,Hernandez-Avila M. Bone turnover and mineral metabolism inthe last trimester of pregnancy: effects of multiple gestation.Obset Gynecol 1996; 88: 168–73.

9. Hertz-Picciotti I, Schramm M, Watt-Morse M, Chantala K,Anderson J, Osterloh J. Patterns and determinants of bloodlead during pregnancy. Am J Epidemiol 2000; 152: 829–37.

10. Tellez-Rojo MM, Hernandez-Avila M, Lamadrig-Figueroa H,Smith D, Hernandez-Cadena L, Mcrcado A et al. Impact ofbone lead and bone resorption on plasma and whole bloodlead levels during pregnancy. Am J Epidemiol 2004; 160:668–78.

11. Rosado JL, Lopez P, Kordas K, Garcia-Vargas G, Ronquillo D,Alatorre J, et al. Iron and/or zinc supplementation did notreduce blood lead concentrations in children in a randomized,placebo-controlled trial. J Nutr 2006; 136: 2378–83.

12. Gulson BL, Mizon KJ, Korsch MJ, Taylor AJ. Low blood leadlevels do not appear to be further reduced by dietarysupplements. Environ Health Perspect 2006; 114: 1186–92.

Hypoglycaemia in an infant with severe pulmonary hypertension afterprenatal exposure to nimesulide: coincidence or side effect?Monica Manganaro, Paola Papoff, Roberto Cicchetti, Elena Caresta, Corrado Moretti

Department of Pediatrics, Pediatric Intensive Care Unit, “La Sapienza” University of Rome, Rome, Italy

KeywordsHypoglycaemia, Infant, Nimesulide

CorrespondencePaola Papoff, MD, Department of Pediatrics, PICU, Azienda Policlinico Umberto I,Viale Regina Elena, 324, 00161 Rome, Italy.Email: [email protected]

Received13 August 2006; revised 1 September 2006; accepted 19 September 2006.

DOI:10.1111/j.1651-2227.2006.00113.x



Sir,Anecdotal evidence suggests that pulmonary hyperten-

sion may develop in infants who have been exposed to anumber of nonsteroidal anti-inflammatory drugs (NSAIDs)in the third trimester of pregnancy. In a case-controlstudy, Alano and coworkers have demonstrated an inde-pendent association between the use of inhaled nitric oxideand the presence of NSAIDs in the meconium of in-fants with severe pulmonary hypertension (1). By inhibit-ing prostaglandin formation, these agents can cause ductaland pulmonary vessel constriction, increase pulmonary arte-rial smooth muscle thickness, and thus stimulate pulmonaryhypertension.

Nimesulide is a selective cyclo-oxygenase type-2 (COX-2)inhibitor commonly used for pain relief but also prescribedin pregnancies at risk of premature delivery or complicatedwith polydramnios. In this setting, the use of this drug hasbeen associated with a number of complications in the foe-tus, such as renal failure and subsequent oligohydramnios,and pulmonary hypertension if used at the end of pregnancy.

We report here on hypoglycaemia as a possibly rare neona-tal complication of the maternal use of nimesulide, in aninfant who was prenatally exposed to this agent, in whomthe most striking signs were increased pulmonary arterialpressure and prolonged lowered glucose levels.

CASE REPORTThis baby girl was born at 37 weeks gestation by elective cae-sarean section. Her birth weight was 3300 g. The pregnancywas uneventful except for sciatica a week before delivery,because of which nimesulide (100 mg twice a day) was pre-scribed. At 1 min her Apgar score was 7. Three min later, thebaby became pale, hypotonic and presented signs of respira-tory distress. She was immediately ventilated and because ofpersistent bradycardia was intubated and given epinephrineand hydrocortisone. A blood gas analysis showed markedmetabolic acidosis (base excess −25), which was correctedwith sodium bicarbonate. On admission to our paediatricintensive care unit, the baby appeared extremely hypotonic,cyanotic and bradycardic. Epinephrine was administeredand mechanical ventilation was started in association withnitric oxide (35 ppm) with the potential of pulmonary hyper-tension. Bedside echocardiography confirmed the clinicalsuspicion of pulmonary hypertension, but also showed clo-sure of ductus arteriosus, reduced contractility and markeddilation of the right heart. A chest X-ray showed only mildlung hypoexpansion but marked enlargement of the heart.Surfactant was given and high frequency oscillatory venti-lation was started. In addition, administration of 10% dex-trose in water with calcium and sodium as well as empiricantibiotics (amplital and nettacin) and phenobarbital treat-ment because of increased alertness were begun. The baby’scondition rapidly improved, and five days later she was extu-bated. Serum creatinine remained 1.2 mg/dL for 3 days afteradmission and then it returned to normal values. Urine out-put in the first day of life decreased to less than 1 mL/kg/hbut improved after furosemide. Blood tests (including cul-

tures) obtained on admission were negative or within normallimits, except for arterial gas analysis and blood glucose lev-els. For 6 days after admission, we observed mild metabolicacidosis (base excess −7 to −9) with slightly high lactate lev-els (3 to 4 mmoL/L) that required bicarbonate supplemen-tation and hypotension, which was treated with dopamineinfusion. Similarly, the blood glucose level, which was abovethe normal range on arrival, dropped to 37 mg/dL at 7 h oflife, and a bolus of 2 mL/kg 10% dextrose in water was given.After 24 h, blood glucose levels were low again (39 mg/dL).The rate of the dextrose infusion was gradually increasedup to 15 mg/kg/min, but glucose levels continued to stay be-tween 40 and 50 mg/dL. Hydrocortisone (2.5 mg/kg × 2 i.v.)was then started and this treatment resulted in rapid stabil-isation of glucose levels. No symptoms relating to hypogly-caemia were detected in this period. The rate of dextroseinfusion and hydrocortisone treatment was tapered after6 days. Several causes of hypoglycaemia were investigated.Immunoreactive insulin, cortisol, urinary organic acids,plasma aminoacids and acylcarnitines were negative orwithin normal range. An abdominal ultrasound performedto exclude a pancreatic adenoma resulted negative. Renalfunction tests were normal. The infant gained weight overthe coming weeks and was discharged home on the 18thpostnatal day. At the time of discharge, blood glucose levelwas 86 mg/dL. An elective echocardiogram examination onday 13 of life showed resolution of pulmonary hypertensionand marked regression of right ventricular dysfunction. Amagnetic resonance imaging of the brain showed no abnor-malities on day 17 of life.

DISCUSSIONAlthough the adverse effects of NSAIDs most commonlyinclude gastrointestinal disturbances, renal dysfunction anddecreased platelet aggregation, there are some reports sug-gesting that these drugs may cause hypoglycaemia. In 1877,Ebstein first advocated a better tolerance to carbohydrates inpatients receiving salicylates (2). Subsequently, several otherinvestigators reported that NSAIDs could ameliorate glu-cose clearance in diabetic subjects especially if assumed atlarge doses. The mechanisms underlying the blood glucosereducing effects of NSAIDs remain unclear. In vitro and invivo studies have suggested that prostaglandins might par-ticipate in the regulation of glucose homeostasis and it hasbeen speculated that decreased basal rates of hepatic glu-cose production, enhanced peripheral insulin sensitivity, anddecreased insulin clearance may explain hypoglycaemia intreated subjects (3).

In neonates, indomethacin has been invariably reportedto cause a decrease in blood glucose levels when used forclosure of patent ductus arteriosus in preterm babies, andincreased glucose intake and hydrocortisone treatment havebeen necessary to resolve hypoglycaemia in these infants (4).Moreover, in a retrospective study, Hosono et al. showedthat an increase in glucose infusion rate might prevent theoccurrence of hypoglycaemia in preterm infants followingindomethacin therapy (5). In contrast, the evidence on a



possible association of hypoglycaemia and the use of nime-sulide is scanty. In the English literature we were able tofind only one report, by Yapakci et al., on a 3-year-old boywho developed hypoglycaemia after ingestion of a high doseof nimesulide. He also showed hypotension and metabolicacidosis (6).

The coexistence of neonatal hypoglycemia and maternaluse of nimesulide is here reported for the first time. In theneonate we have described, hypoglycaemia was associatedwith prolonged and unexplained hypotension and metabolicacidosis. These findings are similar to those previously re-ported by Yapakci after accidental ingestion of high dosenimesulide. We speculate that in our patient a long exposureto a full dose (100 mg twice a day) of nimesulide before birthmight have contributed to the occurrence of this uncommonadverse effect. This hypothesis is supported by previous find-ings in adults showing that the effects on blood glucose levelsof NSAIDs depend on the amount of drug assumed and thelength of treatment.

In conclusion, based on the current knowledge we believethat the possibility that our case represents an actual patho-physiological association rather than a mere coincidenceis plausible. Alertness to this possibility in infants born tomothers who had been taking NSAIDs and early initiation

of appropriate treatment should be considered to preventunwarranted evaluations and potential complications.

References

1. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysisof nonsteroidal antiinflammatory drugs in meconium and itsrelation to persistent pulmonary hypertension of the newborn.Pediatrics 2001; 107: 519–23.

2. Ebstein W: Zur therapie des diabetes mellitus, insbesondereuber die anwendung der salicylsauren natron bei demselben.Berl Klin Wochenschr 1877; 24: 337–40.

3. Hundal RS, Petersen KF, Mayerson AB, Randhawa PS,Inzucchi S, Shoelson SE, et al. Mechanism by which high-doseaspirin improves glucose metabolism in type 2 diabetes. J ClinInvest 2002; 109: 1321–6.

4. Hosono S, Ohono T, Kimoto H, Nagoshi R, Shimizu M,Nozawa M. Preventive management of hypoglycemia in verylow-birthweight infants following indomethacin therapy forpatent ductus arteriosus. Pediatr Int 2001; 43: 465–8.

5. Hosono S, Ohno T, Ojima K, Kimoto H, Nagoshi R, Shimizu M,et al. Intractable hypoglycemia following indomethacin therapyfor patent ductus arteriosus. Pediatr Int 2000; 42: 372–4.

6. Yapaci E, Uysal O, Demirbilek H, Olgar S, Nacar N, Ozen H.Hypoglycaemia and hypothermia due to nimesulide overdose.Arch Dis Child 2001; 85: 510.

Is early identification of asymptomatic infants with ‘mild’ CFTR genotypesclinically useful?C Colombo ([email protected])1, D Costantini1, MC Russo1, L Claut1, L Porcaro2, R Nobili1

1.IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF Center

2.IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Molecular Genetic Laboratory, Milan, Italy

CorrespondenceCarla Colombo, IRCCS “Ospedale MaggiorePoliclinico,Mangiagalli e Regina Elena,Department of Pediatrics, CF Center, ViaCommenda 9, I-20122 Milano, Italy.Tel: +39 02 5503 2456 | Fax: +39 02 5503 2814 |Email: [email protected]

Received24 July 2006; revised 27 September 2006;accepted 13 November 2006.

DOI: 10.1111/j.1651-2227.2006.00142.x

Dear Sir,We read with interest the paper by Padoan et al. (1) con-

cerning identification of the 5T-12TG allele of the cysticfibrosis transmembrane regulator (CFTR) gene in hyper-trypsinaemic newborns. Their finding that this mutation wasthe second most frequent allele in infants with biochemicalalterations suggestive of cystic fibrosis (CF) raises the impor-tant issue of the pathogenetic role and clinical significanceof this and other mild CFTR alleles (2).

We would like to report here the long term follow up ofthe same subjects selected by the neonatal screening pro-gramme between October 1998 and October 2000 (Table 1)and described in the paper as mild and atypical forms ofCF (3). All these 18 infants had been referred to the re-gional CF Centre in Milano where they underwent clini-cal examination, blood biochemistry, chest X-ray, sputum



Table 1 Follow-up data of 18 children with atypical CF identified by newborn screening

Age at Age at Weight Height Sweatfirst visit last visit Respiratory for age for age FEV1 FVC FEF 25–75 chloride

Genotype Sex (years) (years) symptoms z-score z-score % % % (mmol/L)

DF508/Y1032C M 1.20 7.27 None −0.08 0.75 108 94 106 44/41DF508/D1152H M 0.62 6.91 None 3.19 1.70 109 96 128 33DF508/D1152H M 0.28 3.10 Occasional bronchitis −0.05 0.39 Not done 44/57DF508/S1455X M 5.91 8.45 Occasional bronchitis 0.53 0.57 121 113 116 102/97DF508/R117L F 0.91 5.71 Occasional bronchitis −0.38 0.33 130 117 117 36/33/35DF508/F1074L F 0.68 5.25 None 0,09 −0,55 106.6 93.4 112.6 40/32DF508/5T-12TG F 0.41 6.26 None 1,61 0,95 Not done 39/38/36D110E/D110E F 0.16 0.70 Lost at follow-up 53/40R117H/5T-12TG F 0.44 0.60 Lost at follow-up 21/27/34R347P/5T-12TG M 0.26 5.09 None −0.62 0.64 Not done 31R347P/D1152H M 0.18 6.32 None 1.41 1.04 140.3 130.9 123.3 42G542X/D614G F 0.66 2.93 Occasional bronchitis 0.58 1.29 Not done 47/46/52G542X/5T-12TG F 0.13 6.42 Occasional bronchitis −0.46 1.23 112.3 105.8 98.4 32/48R553X/L997F M 0.24 0.43 Lost at follow-up (adopted) 33/29D1152H/4382DelA F 1.13 5.40 Pneumonia, atelectasis 2.19 2.08 135 121 130 35

first year of lifeN1303K/5T-12TG F 0.23 5.96 Occasional bronchitis 0.78 1.79 102.8 94.1 101.3 38/33/482183-AA>G/5T-12TG F 0.35 6.35 Occasional bronchitis 0.25 0.66 114.7 102.6 102.6 33/33/342789 + 5G>A/S42F/ F 0.36 7.08 Recurrent sinusitis 3.15 1.47 104.5 99.6 83.2 32/33/44

5T-12TGMean ± SD 0.79 ± 1.32 5.01 ± 2.43 0.78 ± 1.21 0.81 ± 0.88 116.75 ± 13.00 106.13 ± 12.70 107.40 ± 13.44

culture, abdominal ultrasound and fecal pancreatic elastasedetermination.

At first visit all patients were in good clinical conditionsand were completely asymptomatic, with normal growth andnutritional status; there was no biochemical and ultrasono-graphic evidence of pancreatic and liver involvement. Pa-tients then entered an annual follow-up programme whichincludes clinical evaluation, anthropometric measurements,sputum culture, chest X-ray (when needed); pulmonaryfunction tests (FEV1, FVCX, FEF 25–75) were determinedby means of spirometry in patients older than 5 years. Ateach control visit z scores for weight-for-age and height-for-age were calculated using the CDC-WHO reference values(ANTHRO software program, version 1.01, 1990, Centresfor Disease Control and Prevention, Atlanta, Georgia, U.S.).All patients were instructed to perform nasal washings; onlythose found to have symptoms were put on preventive treat-ment with PEP mask and antibiotics were promptly givenwhen necessary.

Median duration of follow-up was 4.81 years (range 0.43–8.45 years); three children (one bearing L997F, that has re-cently been suggested to be a polimorphysm rather than aCF disease-causing mutation) (4), were lost at follow-up af-ter the first visit. As shown in the Table 1, anthropometricparameters were satisfactory in all cases and mild respiratorysymptoms were reported by eight children. None developedpancreatic and liver involvement and chronic Pseudomonasaeruginosa infection. In the 11 children older than 5 years,pulmonary function tests were normal or even above the pre-dicted range for age. This may be the result of prompt andadequate treatment of respiratory symptoms. In another se-ries of children in whom intermediate sweat chloride results

and mild CFTR genotype were detected because of respira-tory symptoms at a mean age of 4.8 years, the respiratoryphenotype at follow up was relatively more severe than inour patients (5).

Finally the sweat test was repeated in 14 patients (twicein seven and three times in other seven); chloride concen-trations persisted to be in the borderline range with theonly exception of the patient bearing the S1455X mutation,who showed a pathologic chloride values on two occasions.Indeed, this mutation has been associated with isolatedincreased sweat chloride concentrations (6), hyponatremiaand metabolic alkalosis (7).

Two patients carrying the D1152H mutation showed ra-diological evidence of moderate lung involvement, withoccasional bronchitis and no pathological flora in the lungs;this mutation is associated with a broad clinical spectrum,with lung disease that may be evident from infancy and maybe quite severe in some adults (8). The only patient with earlydevelopment of CF pulmonary disease (D1152H/4382delAgenotype) complicated with right lobe atelectasis andtreated with antibiotic therapy, repeated bronchoscopy andbronchoalveaolar lavage during the first year of life be-fore being referred to our Center, has been thereafter ingood clinical condition, with normal pulmonary functionand without Pseudomonas infection at the age of5.4 years.

Of the seven patients bearing 5T-12TG allele (one male,six females), one was lost at follow-up after her second visit,whereas of the six who remained compliant at the follow-upprogramme, three complained of minimal respiratory symp-toms and one of recurrent sinusitis. It has been recently re-ported that the 5T variant has a milder clinical consequence



than previously estimated in females (2). Obviously we can-not exclude that congenital bilateral absence of the vas def-erens (CBAVD) associated infertility may possibly occur inthe only one male patient of our cohort bearing this allele(9).

Overall our data may give a contribution to the debateabout selection and identification of atypical forms of CFby newborn screening. It has been recently pointed out thata good screening programme should identify the maximumnumber of cases that are likely to be severely affected, en-sure that as many as possible of the missed cases are mildlyaffected and detect as few unaffected carriers as possible(10). On the other hand, an expert panel has recently rec-ommended that newborn screening should ‘report of anyabnormal result that may be associated with clinically sig-nificant conditions, including the definitive identification ofcarrier status’ (11).

Despite the favourable follow-up data documented in thissmall cohort of children bearing mild CFTR genotype, thediagnostic dilemma in front of a screening positive infantwithout CF symptoms and a borderline sweat test remains.While awaiting for further long term follow-up informationthat should permit to define the clinical phenotype associ-ated with the 5T-12TG allele and other mild mutations, someaspects need to be taken into account: first, the impact of thediagnosis of mild or atypical CF on a growing up child hasnot yet been assessed, and, second, the risk that parents ofasymptomatic children, regardless of their genotype, couldnot cope with their children’s developing symptoms, maybeas a defence against the sorrow of having an ‘imperfect’ child(12). Thirdly, financial issues also deserve consideration.

References

1. Padoan R, Corbetta C, Bassotti A, Seia M. Identification of the5T-12TG allele of the cystic fibrosis transmembrane

conductance regulator gene in hypertrypsinaemic newborns.Acta Paediatr 2006; 95: 871–3.

2. Sun W, Anderson B, Redman J, Milunsky A, Buller A,McGinniss MJ, et al. CFTR 5T variant has a low penetrance infemales that is partially attributable to its haplotype. GenetMed 2006; 8: 339–45.

3. De Boeck K, Wilschanski M, Castellani C, Taylor C, CuppensH, Dodge J, et al. Cystic Fibrosis:terminology and diagnosticalgorithms. Thorax 2006; 61: 627–35.

4. Derichs N, Schuster A, Grund I, Ernsting A, Stolpe C,Kortge-Jung S, et al. Homozygosity for L997F in a child withnormal clinical and chloride secretory phenotype providesevidence that this cystic fibrosis transmembrane conductanceregulator mutation does not cause cystic fibrosis. Clin Genet2005; 67: 529–31.

5. Desmarquest P, Feldmann D, Tamalat A, Boule M, Fauroux B,Tournier G, et al. Genotype analysis and phenotypicmanifestations of children with intermediate sweat chlorideresults. Chest 2000; 188: 1591–97.

6. Salvatore D, Tomaiuolo R, Vanacore B, Elce A, Castaldo G,Salvatore F. Isolated elevated sweat chloride concentrations inthe presence of the rare mutation S1455X: an extremely mildform of CFTR dysfunction. Am J Med Genet A 2005; 133:207–8.

7. Epaud R, Girodon E, Corvol H, Niel F, Guigonis V, ClementA, et al. Mild cystic fibrosis revealed by persistenthyponatremia during the French 2003 heat wave, associatedwith the S1455X C-terminus CFTR mutation. Clin Genet 2005Dec; 68: 552–3.

8. Mussaffi H, Prais D, Mei-Zahav M, Blau H. Cystic fibrosismutations with widely variable phenotype: the D1152Hexample. Pediatr Pulmonol 2006 Mar; 41: 250–4.

9. Cuppens H, Cassiman JJ. CFTR mutations and polymorphismsin male infertility. Int J Androl 2004; 27: 251–6.

10. Price JF. Newborn screening for cystic fibrosis: do we need asecond IRT? Arch Dis Child 2006; 91: 209–10.

11. Newborn screening: toward a uniform screening panel andsystem. http://mihb.hrsa.gov/screening/summary.htm

12. Farrel MH, Farrel PM. Newborn screening for cystic fibrosis:ensuring more good than harm. J Pediatr 2003; 143: 707–12.


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