Letters to the Editor
2. Flinterman AE, Knol EF, Lencer DA, et al. Peanut epitopes for IgE and IgG4 in peanutsensitized children in relation to severity of peanut allergy. J Allergy Clin Immunol 2008: 121 : 737.e10–43.e10. 3. Hong X, Caruso D, Kumar R, et al. IgE, but not IgG4, antibodies to Ara h 2 distinguish peanut allergy from asymptomatic peanut sensitization. Allergy 2012: 67: 1538–46. 4. Stapel SO, Asero R, Ballmer-Weber BK, et al. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report. Allergy 2008: 63: 793–6. 5. Sverremark-Ekstrom E, Hultgren EH, Borres MP, Nilsson C. Peanut sensitization
during the first 5 yr of life is associated with elevated levels of peanut-specific IgG. Pediatr Allergy Immunol 2012: 23: 224–9. 6. Caubet JC, Bencharitiwong R, Moshier E, Godbold JH, Sampson HA, Nowak-Wegrzyn A. Significance of ovomucoid- and ovalbuminspecific IgE/IgG(4) ratios in egg allergy. J Allergy Clin Immunol 2012: 129: 739–47. 7. Astier C, Morisset M, Roitel O, et al. Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy. J Allergy Clin Immunol 2006: 118: 250–6. 8. Tay SS, Clark AT, Deighton J, King Y, Ewan PW. Patterns of immunoglobulin G responses to egg and peanut allergens are
distinct: ovalbumin-specific immunoglobulin responses are ubiquitous, but peanut-specific immunoglobulin responses are up-regulated in peanut allergy. Clin Exp Allergy 2007: 37: 1512–8. 9. Uermosi C, Beerli RR, Bauer M, et al. Mechanisms of allergen-specific desensitization. J Allergy Clin Immunol 2010: 126: 375–83. 10. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009: 39: 469–77.
Septic arthritis or juvenile idiopathic arthritis - the case of a 2 year old boy To the Editor, The International League of Associations for Rheumatology (ILAR) defines juvenile idiopathic arthritis (JIA) as arthritis of unknown origin beginning before the 16th birthday, persisting for at least 6 weeks; other known conditions are excluded (1). Arthritis in JIA may show local warming, redness, swelling, pain or functional deficits, but CrP-levels do usually not rise above 20 mg/l (2), whereas pyogenic arthritis mostly causes CrP-levels above 20 mg/l (3), although CrP-levels are not suitable to differentiate between septic and Lyme arthritis (4). In contrast, despite pyogenic arthritis, patients with defects in TIR-MyD88IRAK4-NFjB-mediated signaling (5, 6) may present with low or delayed signs of inflammation (7) (see Figures S1).
The presented boy developed short swelling of the metacarpophalangeal joints at 2 years. At 2 years and 3 months at a temperature of 39°C, pain and effusion (MRI) developed in his right hip. Streptococcus pneumoniae (serotype 23B) grew in a blood culture; pyogenic arthritis was suspected and treated with cefuroxime intravenously. At 2 years and 7–8 months, a bullous impetigo caused by Staphylococcus aureus developed. At 2 years and 9 months, a coxitis of the left hip developed (treated with naproxen). At 3 years of age, he developed arthritis with effusion in the right hip and elbow and JIA was suspected (treated with naproxen). The patient was born at term; the umbilical cord fell 4 weeks after birth. His parents have a common great-grandmother.
(a) Figure 1 Osteomyelitis with adjacent arthritis of the right elbow but little inflammation. (a) Massive swelling of the right elbow without redness, pain or local warming. (b) Conventional X-ray. Periostal reaction (arrows) suggests an osteomyelitis continuing for at least 2 wks. (c) Conventional X-ray. Small lytic lesion in the distal humerus (arrow). (d, e) Magnet Resonance Imaging (MRI). Massive joint effusion, thickened contrast enhanced synovia, bone and muscle edema as well as corticalis defect. (d: T2-weighted sequence, e: contrast enhanced T1 sequence).
(b)
(d)
(c)
(e)
Abbreviations JIA, juvenile idiopathic arthritis; TIR, Toll-like and interleukin-1 receptors; CrP, C-reactive protein; MyD88, myeloid differentiation antigen 88; IRAK4, interleukin-1 receptor-associated kinase 4; NFjB, nuclear factor jB.
Pediatric Allergy and Immunology 26 (2015) 383–392 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
389
Letters to the Editor
(a)
LPS
Pam2
R848
TNF-α Isotype Unstimuldated Activated
Patient
Control
CD62L
(b) 30,000 IL-6 (pg/ml)
20,000 10,000 4000 2000
PM A/ Io no
S
IL1β
LP
M ed iu m Pa m 2C SK 2
0
Figure 2 Impaired acute phase response ex vivo.(a) CD62L shedding on granulocytes. Upon activation with TLR agonists, patient’s granulocytes show no CD62L shedding in contrast to normal CD62L shedding on granulocytes of a healthy control (dark line); unstimulated control (dotted line); and isotype control (gray filled histogram). (b) IL-6 production in whole blood upon activation with TLR agonists and IL-1. Patient’s whole blood cells do not produce IL-6 upon activation with TLR agonists and IL-1, yet produce IL-6 normally in response to phorbol myristate acetate (PMA) (filled bars) in contrast to normal IL-6 production of healthy controls upon activation with PMA, TLR agonists and IL-1 (white bars). Methods have been previously described (5, 6, 9, 10).
Six weeks after manifestation of elbow arthritis, he presented for the first time to our institution. His right elbow was strongly swollen, warm, and bendable by only 60° but neither red nor painful (Fig. 1a). On admission, CrP was 11.6 mg/l (Normal < 5 mg/l), erythrocyte sedimentation rate 52 mm/h, hemoglobin 11.1 g/dl (11.7–14.7 g/dl), MCV 72 fl (77–96 fl), and fibrinogen 4.66 g/l (1.6–4 g/l). Conventional X-ray and MRI revealed osteomyelitis (Fig. 1b–e). Puncture of the joint revealed 37.3 polymorphnuclear cells/nl and gram-positive
diplococci, which also grew in a blood culture (Streptococcus pneumoniae, Serotype 23B). Due to the discrepancy between a septic arthritis on one side but only slight warming, no redness, no pain, only mildly elevated CrP and polymorphnuclear cells below 50/nl cells in the effusion on the other side, we suspected a primary immunodeficiency with impaired TIR signaling. TIR signaling controls the production of pro-inflammatory cytokines such as IL-6 and post-translational ectodomain shedding of L-selectin, CD62 ligand, and CD62L (‘CD62L shedding’) (see Fig. S1). A complete lack of IL-6 production and CD62L shedding of patient’s cells upon stimulation with Toll-like receptor agonists (Fig. 2) and a homozygous mutation Q293X in IRAK4 confirmed the hypothesis of a deficient TIR signaling (see Data S1). Before being diagnosed with autosomal-recessive IRAK4 deficiency, the patient probably suffered three episodes of pyogenic arthritis and an extended skin infection. In retrospect, JIA was unlikely as Streptococcus pneumoniae had been isolated in a previous blood culture at 2 years and 3 months. In TIRdeficient signaling, septic arthritis may be mistaken for JIA as both are not accompanied by strong acute phase responses. However, patients with deficiencies in TIR signaling may also develop strong acute phase responses if infections take a chronic course (8, 9). So in pyogenic arthritis, low inflammatory signs are highly suggestive for a defect in TIR-MyD88-IRAK4-NFjBmediated signaling, but high inflammatory signs do not exclude such defects. In conclusion, we propose to consider the search for primary immunodeficiencies in any infant or young child with septic arthritis (see Figures S1). Tilmann Kallinich1; Uwe K€ olsch2; Mareike Lieber1; Nadine Unterwalder2; Birgit Spors3; Myriam Lorenz4; Klaus Schwarz4; Christian Meisel2 & Horst von Bernuth1,2 1 Pediatric Pneumology and Immunology, Charit e University Medicine; 2 Department of Immunology, Labor Berlin Charit e Vivantes GmbH; 3 Department of Pediatric Radiology, Charit e University Medicine, Berlin; 4 Institute for Transfusion Medicine and Institute for Clinical Transfusion Medicine and Immunogenetics, University Hospital Ulm, Ulm, Germany E-mail: [email protected], [email protected] DOI:10.1111/pai.12373
References 1. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004: 31: 390–2. 2. 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: 141: 34–40. 3. Paakkonen M, Kallio MJ, Peltola H, Kallio PE. Pediatric septic hip with or without arthrotomy: retrospective analysis of 62 consecutive nonneonatal culturepositive cases. J Pediatr Orthop B 2010: 19: 264–9.
390
4. Milewski MD, Cruz A, Miller CP, Peterson AT, Smith BG. Lyme arthritis in children presenting with joint effusions. J Bone Joint Surg Am 2011: 93: 252–60. 5. Picard C, Puel A, Bonnet M, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 2003: 299: 2076–9. 6. von Bernuth H, Picard C, Jin Z, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 2008: 321: 691–6. 7. Picard C, von Bernuth H, Ghandil P, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 2010: 89: 403–25.
8. Ku CL, Picard C, Erdos M, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 2007: 44: 16–23. 9. Sch€ ondorf D, von Bernuth H, Simon A, et al. Liver abscess complicated by diaphragm perforation and pleural empyema leads to the discovery of Interleukin-1 receptorassociated kinase 4 deficiency. Pediatr Infect Dis J 2014: 33: 767–9. 10. von Bernuth H, Ku CL, Rodriguez-Gallego C, et al. A fast procedure for the detection of defects in Toll-like receptor signaling. Pediatrics 2006: 118: 2498–503.
Pediatric Allergy and Immunology 26 (2015) 383–392 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Letters to the Editor
Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Upon activation with TLR-agonists or cytokines TLR-receptors and IL-1 receptors (1) form a multimeric complex comprising MyD88 and IRAK4 (2). This complex (‘MyDDosome’) controls the phopshorylation of IRAK-1 which is degraded upon phosphorylation. (3) IRAK-1 degradation
leads to the activation of ADAM17, which in turn controls the posttranslational clevage of CD62L from the cell surface on neutrophilic granulocytes. (4) IRAK-1 degradation also leads to the activation of a complex that phosphorylartes inhibitors of NFkB (the IKK) and to the activation of MAP – Kinases (MAPK). Both pathways control the transcription of cytokines or pro.cytokines which spur acute-phase reactions (5). Data S1. Methods.
Acute generalized exanthematous pustulosis following paracetamol ingestion in a child To the Editor, Acute generalized exanthematous pustolosis (AGEP) is a rare, sometimes life-threatening, cutaneous reaction more frequent in adults than in children (1) caused by drugs in more than 90% of cases (2). A 5-yr-old Philippino boy was admitted to Primary Children’s Medical Center with malaise, temperature of 39°C and a 2-day history of pustular eruption. His mother reported that 4 days prior he had been suffering from a sore throat and fever and was given two doses of an over-the-counter (OTC) product (originating from the Philippines) containing paracetamol (acetaminophen). Clinical examination revealed oropharingeal erythema, red strawberry tongue, cheilitis, and a severe itchy erythema of the trunk that extended to the arms and legs, covered with hundreds of white micropustules. Inguinal folds were spared, as the abdominal one. Somewhere small islands of intact skin were seen intermingled with affected skin (Fig. 1a). (a)
(b)
The patient was hospitalized in the pediatric clinic, and paracetamol was discontinued. After 24 h, his condition worsened and the micropustules coalesced with the pustulation spreading to involve previously unaffected skin (Fig. 1b). Fever reached 40°C. The boy was given ampicillin–sulbactam 150 mg/kg, and a bland emollient lotion was used on the body surface. On the third day, fever subsided and general conditions started to improve (Fig. 1c). The skin completely healed by desquamation in 10 days. Laboratory investigations showed leukocytosis (14 9 109/l) with striking neutrophilia (up to 9.9 9 109/l) and elevated CRP (94.3 mg/l). Tests for influenza A and B virus, metapneumovirus, coronavirus, adenovirus, bocavirus, RSV, mycoplasma pneumonia, CMV, EBV, Group A streptococcus pyogenes, and toxoplasma gondii were all negative. Only Group A streptococci on throat swab was found positive. Due to the rapid healing, no skin biopsy was carried out. (c)
Figure 1 Evolution of clinical presentation of AGEP. (a) Hundreds of micropustules of the trunk on day one. (b) coalescing of pustules on day two. (c) initial resolution with desquamation of previously involved skin on day three.
Pediatric Allergy and Immunology 26 (2015) 383–392 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
391
2. Flinterman AE, Knol EF, Lencer DA, et al. Peanut epitopes for IgE and IgG4 in peanutsensitized children in relation to severity of peanut allergy. J Allergy Clin Immunol 2008: 121 : 737.e10–43.e10. 3. Hong X, Caruso D, Kumar R, et al. IgE, but not IgG4, antibodies to Ara h 2 distinguish peanut allergy from asymptomatic peanut sensitization. Allergy 2012: 67: 1538–46. 4. Stapel SO, Asero R, Ballmer-Weber BK, et al. Testing for IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report. Allergy 2008: 63: 793–6. 5. Sverremark-Ekstrom E, Hultgren EH, Borres MP, Nilsson C. Peanut sensitization
during the first 5 yr of life is associated with elevated levels of peanut-specific IgG. Pediatr Allergy Immunol 2012: 23: 224–9. 6. Caubet JC, Bencharitiwong R, Moshier E, Godbold JH, Sampson HA, Nowak-Wegrzyn A. Significance of ovomucoid- and ovalbuminspecific IgE/IgG(4) ratios in egg allergy. J Allergy Clin Immunol 2012: 129: 739–47. 7. Astier C, Morisset M, Roitel O, et al. Predictive value of skin prick tests using recombinant allergens for diagnosis of peanut allergy. J Allergy Clin Immunol 2006: 118: 250–6. 8. Tay SS, Clark AT, Deighton J, King Y, Ewan PW. Patterns of immunoglobulin G responses to egg and peanut allergens are
distinct: ovalbumin-specific immunoglobulin responses are ubiquitous, but peanut-specific immunoglobulin responses are up-regulated in peanut allergy. Clin Exp Allergy 2007: 37: 1512–8. 9. Uermosi C, Beerli RR, Bauer M, et al. Mechanisms of allergen-specific desensitization. J Allergy Clin Immunol 2010: 126: 375–83. 10. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy 2009: 39: 469–77.
Septic arthritis or juvenile idiopathic arthritis - the case of a 2 year old boy To the Editor, The International League of Associations for Rheumatology (ILAR) defines juvenile idiopathic arthritis (JIA) as arthritis of unknown origin beginning before the 16th birthday, persisting for at least 6 weeks; other known conditions are excluded (1). Arthritis in JIA may show local warming, redness, swelling, pain or functional deficits, but CrP-levels do usually not rise above 20 mg/l (2), whereas pyogenic arthritis mostly causes CrP-levels above 20 mg/l (3), although CrP-levels are not suitable to differentiate between septic and Lyme arthritis (4). In contrast, despite pyogenic arthritis, patients with defects in TIR-MyD88IRAK4-NFjB-mediated signaling (5, 6) may present with low or delayed signs of inflammation (7) (see Figures S1).
The presented boy developed short swelling of the metacarpophalangeal joints at 2 years. At 2 years and 3 months at a temperature of 39°C, pain and effusion (MRI) developed in his right hip. Streptococcus pneumoniae (serotype 23B) grew in a blood culture; pyogenic arthritis was suspected and treated with cefuroxime intravenously. At 2 years and 7–8 months, a bullous impetigo caused by Staphylococcus aureus developed. At 2 years and 9 months, a coxitis of the left hip developed (treated with naproxen). At 3 years of age, he developed arthritis with effusion in the right hip and elbow and JIA was suspected (treated with naproxen). The patient was born at term; the umbilical cord fell 4 weeks after birth. His parents have a common great-grandmother.
(a) Figure 1 Osteomyelitis with adjacent arthritis of the right elbow but little inflammation. (a) Massive swelling of the right elbow without redness, pain or local warming. (b) Conventional X-ray. Periostal reaction (arrows) suggests an osteomyelitis continuing for at least 2 wks. (c) Conventional X-ray. Small lytic lesion in the distal humerus (arrow). (d, e) Magnet Resonance Imaging (MRI). Massive joint effusion, thickened contrast enhanced synovia, bone and muscle edema as well as corticalis defect. (d: T2-weighted sequence, e: contrast enhanced T1 sequence).
(b)
(d)
(c)
(e)
Abbreviations JIA, juvenile idiopathic arthritis; TIR, Toll-like and interleukin-1 receptors; CrP, C-reactive protein; MyD88, myeloid differentiation antigen 88; IRAK4, interleukin-1 receptor-associated kinase 4; NFjB, nuclear factor jB.
Pediatric Allergy and Immunology 26 (2015) 383–392 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
389
Letters to the Editor
(a)
LPS
Pam2
R848
TNF-α Isotype Unstimuldated Activated
Patient
Control
CD62L
(b) 30,000 IL-6 (pg/ml)
20,000 10,000 4000 2000
PM A/ Io no
S
IL1β
LP
M ed iu m Pa m 2C SK 2
0
Figure 2 Impaired acute phase response ex vivo.(a) CD62L shedding on granulocytes. Upon activation with TLR agonists, patient’s granulocytes show no CD62L shedding in contrast to normal CD62L shedding on granulocytes of a healthy control (dark line); unstimulated control (dotted line); and isotype control (gray filled histogram). (b) IL-6 production in whole blood upon activation with TLR agonists and IL-1. Patient’s whole blood cells do not produce IL-6 upon activation with TLR agonists and IL-1, yet produce IL-6 normally in response to phorbol myristate acetate (PMA) (filled bars) in contrast to normal IL-6 production of healthy controls upon activation with PMA, TLR agonists and IL-1 (white bars). Methods have been previously described (5, 6, 9, 10).
Six weeks after manifestation of elbow arthritis, he presented for the first time to our institution. His right elbow was strongly swollen, warm, and bendable by only 60° but neither red nor painful (Fig. 1a). On admission, CrP was 11.6 mg/l (Normal < 5 mg/l), erythrocyte sedimentation rate 52 mm/h, hemoglobin 11.1 g/dl (11.7–14.7 g/dl), MCV 72 fl (77–96 fl), and fibrinogen 4.66 g/l (1.6–4 g/l). Conventional X-ray and MRI revealed osteomyelitis (Fig. 1b–e). Puncture of the joint revealed 37.3 polymorphnuclear cells/nl and gram-positive
diplococci, which also grew in a blood culture (Streptococcus pneumoniae, Serotype 23B). Due to the discrepancy between a septic arthritis on one side but only slight warming, no redness, no pain, only mildly elevated CrP and polymorphnuclear cells below 50/nl cells in the effusion on the other side, we suspected a primary immunodeficiency with impaired TIR signaling. TIR signaling controls the production of pro-inflammatory cytokines such as IL-6 and post-translational ectodomain shedding of L-selectin, CD62 ligand, and CD62L (‘CD62L shedding’) (see Fig. S1). A complete lack of IL-6 production and CD62L shedding of patient’s cells upon stimulation with Toll-like receptor agonists (Fig. 2) and a homozygous mutation Q293X in IRAK4 confirmed the hypothesis of a deficient TIR signaling (see Data S1). Before being diagnosed with autosomal-recessive IRAK4 deficiency, the patient probably suffered three episodes of pyogenic arthritis and an extended skin infection. In retrospect, JIA was unlikely as Streptococcus pneumoniae had been isolated in a previous blood culture at 2 years and 3 months. In TIRdeficient signaling, septic arthritis may be mistaken for JIA as both are not accompanied by strong acute phase responses. However, patients with deficiencies in TIR signaling may also develop strong acute phase responses if infections take a chronic course (8, 9). So in pyogenic arthritis, low inflammatory signs are highly suggestive for a defect in TIR-MyD88-IRAK4-NFjBmediated signaling, but high inflammatory signs do not exclude such defects. In conclusion, we propose to consider the search for primary immunodeficiencies in any infant or young child with septic arthritis (see Figures S1). Tilmann Kallinich1; Uwe K€ olsch2; Mareike Lieber1; Nadine Unterwalder2; Birgit Spors3; Myriam Lorenz4; Klaus Schwarz4; Christian Meisel2 & Horst von Bernuth1,2 1 Pediatric Pneumology and Immunology, Charit e University Medicine; 2 Department of Immunology, Labor Berlin Charit e Vivantes GmbH; 3 Department of Pediatric Radiology, Charit e University Medicine, Berlin; 4 Institute for Transfusion Medicine and Institute for Clinical Transfusion Medicine and Immunogenetics, University Hospital Ulm, Ulm, Germany E-mail: [email protected], [email protected] DOI:10.1111/pai.12373
References 1. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004: 31: 390–2. 2. 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: 141: 34–40. 3. Paakkonen M, Kallio MJ, Peltola H, Kallio PE. Pediatric septic hip with or without arthrotomy: retrospective analysis of 62 consecutive nonneonatal culturepositive cases. J Pediatr Orthop B 2010: 19: 264–9.
390
4. Milewski MD, Cruz A, Miller CP, Peterson AT, Smith BG. Lyme arthritis in children presenting with joint effusions. J Bone Joint Surg Am 2011: 93: 252–60. 5. Picard C, Puel A, Bonnet M, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 2003: 299: 2076–9. 6. von Bernuth H, Picard C, Jin Z, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 2008: 321: 691–6. 7. Picard C, von Bernuth H, Ghandil P, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 2010: 89: 403–25.
8. Ku CL, Picard C, Erdos M, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet 2007: 44: 16–23. 9. Sch€ ondorf D, von Bernuth H, Simon A, et al. Liver abscess complicated by diaphragm perforation and pleural empyema leads to the discovery of Interleukin-1 receptorassociated kinase 4 deficiency. Pediatr Infect Dis J 2014: 33: 767–9. 10. von Bernuth H, Ku CL, Rodriguez-Gallego C, et al. A fast procedure for the detection of defects in Toll-like receptor signaling. Pediatrics 2006: 118: 2498–503.
Pediatric Allergy and Immunology 26 (2015) 383–392 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Letters to the Editor
Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Upon activation with TLR-agonists or cytokines TLR-receptors and IL-1 receptors (1) form a multimeric complex comprising MyD88 and IRAK4 (2). This complex (‘MyDDosome’) controls the phopshorylation of IRAK-1 which is degraded upon phosphorylation. (3) IRAK-1 degradation
leads to the activation of ADAM17, which in turn controls the posttranslational clevage of CD62L from the cell surface on neutrophilic granulocytes. (4) IRAK-1 degradation also leads to the activation of a complex that phosphorylartes inhibitors of NFkB (the IKK) and to the activation of MAP – Kinases (MAPK). Both pathways control the transcription of cytokines or pro.cytokines which spur acute-phase reactions (5). Data S1. Methods.
Acute generalized exanthematous pustulosis following paracetamol ingestion in a child To the Editor, Acute generalized exanthematous pustolosis (AGEP) is a rare, sometimes life-threatening, cutaneous reaction more frequent in adults than in children (1) caused by drugs in more than 90% of cases (2). A 5-yr-old Philippino boy was admitted to Primary Children’s Medical Center with malaise, temperature of 39°C and a 2-day history of pustular eruption. His mother reported that 4 days prior he had been suffering from a sore throat and fever and was given two doses of an over-the-counter (OTC) product (originating from the Philippines) containing paracetamol (acetaminophen). Clinical examination revealed oropharingeal erythema, red strawberry tongue, cheilitis, and a severe itchy erythema of the trunk that extended to the arms and legs, covered with hundreds of white micropustules. Inguinal folds were spared, as the abdominal one. Somewhere small islands of intact skin were seen intermingled with affected skin (Fig. 1a). (a)
(b)
The patient was hospitalized in the pediatric clinic, and paracetamol was discontinued. After 24 h, his condition worsened and the micropustules coalesced with the pustulation spreading to involve previously unaffected skin (Fig. 1b). Fever reached 40°C. The boy was given ampicillin–sulbactam 150 mg/kg, and a bland emollient lotion was used on the body surface. On the third day, fever subsided and general conditions started to improve (Fig. 1c). The skin completely healed by desquamation in 10 days. Laboratory investigations showed leukocytosis (14 9 109/l) with striking neutrophilia (up to 9.9 9 109/l) and elevated CRP (94.3 mg/l). Tests for influenza A and B virus, metapneumovirus, coronavirus, adenovirus, bocavirus, RSV, mycoplasma pneumonia, CMV, EBV, Group A streptococcus pyogenes, and toxoplasma gondii were all negative. Only Group A streptococci on throat swab was found positive. Due to the rapid healing, no skin biopsy was carried out. (c)
Figure 1 Evolution of clinical presentation of AGEP. (a) Hundreds of micropustules of the trunk on day one. (b) coalescing of pustules on day two. (c) initial resolution with desquamation of previously involved skin on day three.
Pediatric Allergy and Immunology 26 (2015) 383–392 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
391
