- Email: [email protected]
Pneumococcal meningitis in a patient with IL-1 receptor–associated kinase-4 deficiency: A case of failed prophylaxis
Clinical Communications Pneumococcal meningitis in a patient with IL-1 receptoreassociated kinase-4 deficiency: A case of failed prophylaxis Meredith A. Dilley, MDa, Stacie M. Jones, MDa,b, Tamara T. Perry, MDa,b, Amy M. Scurlock, MDa,b, Marilyn Brodie-Fowler, RNb, Jeremy D. Bufford, MDa,b, and Robbie D. Pesek, MDa,b Clinical Implication
Patients with IL-1 receptoreassociated kinase-4 deficiency are at risk for invasive bacterial infections, and current recommendations include replacement dose immunoglobulin and antimicrobial prophylaxis. If invasive infections continue to occur, then high-dose immunoglobulin and expanded antimicrobial prophylaxis are an effective alternative.
TABLE I. Immune function at 22 months Flow analysis CD2 CD3 Percent Absolute Mitogens Patient Control* CR3 panel
Patient Control* Resting and stimulated index
Patient Control* B-cell populations Cells
IL-1 receptoreassociated kinase-4 (IRAK-4) is a receptorassociated protein kinase involved in toll-like receptor and IL-1 receptor signaling that leads to the production of proinflammatory cytokines (IL-1b, IL-6, IL-8, TNF-a, IFN-a/b, and IFN-l).1 Deficiencies in IRAK-4 signaling can lead to invasive pyogenic bacterial infections, skin infections, and recurrent upper respiratory tract infections.2 Patients with an IRAK-4 deficiency have a weakened ability to mount fever early in infection, and the poor production of IL-6 leads to lower than expected C-reactive protein levels.2 Some patients have impaired antibody production after polysaccharide and protein vaccines and reduced memory (IgMþ, IgDþCD27þ) B cells, and many of those who do respond to vaccines fail to sustain these responses long term.3,4 The risk for invasive infection seems to gradually decline during adolescence, likely due to the compensatory response of the adaptive immune system.3 Prophylaxis with immunoglobulin therapy may be necessary at
CD4
CD8
CD56
CD19
CD20
3 152
28 1420
29 1471
70 3551
66 3348
42 2131
23 1167
PHA 188,437 297,996
PWM 116,694 76,413
ConA 169,941 208,873
Media 1,283 1,657
Resting MPC 66 39
Resting peak
Stim MPC
Stim peak
M S NS ratio
P S NS ratio
67 35
138 116
166 120
2.1 3.0
2.1 3.4
Resting MPC 6 5
Resting PC
Stim MPC
Stim PC
M S NS ratio
P S NS ratio
5 5
986 740
982 784
164.3 148
196.4 156.85
CD19+, CD10+
CD19+, CD27e, CD19+, CD27e, CD19+, CD27e, CD19+, CD27e CD19+, CD27e, CD19+, CD27e, CD10e, CD18++ CD18++, IgM++ CD21e, IgM++ CD21+ IgM+, IgD+
Patient, % 9 Normal range, %* 7-12 Immunoglobulin levels Immunoglobulin Patient Normal range*
TO THE EDITOR:
4.9 4.5-17.8
IgG (mg/dL) IgA (mg/dL) 1167.4 70.1 341-1960 19-220
4.0 0.2-15.9
2.0 0.1-5.1
IgM (mg/dL) 67.0 43-163
IgE (kU/L) 54.7 0.3-133
78 64-84
73 60-74
76 58-78
ConA, Concanavali; MPC, mean peak channel; PC, peak channel; PHA, phytohemagglutinin; PWM, pokeweed mitogen; stim, stimulation; suppr, suppressor. *Control/normal values are age matched. Units for all titers: mg/mL.
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least until the adaptive immune system has developed.1 Recommended therapy to prevent invasive bacterial infections in patients with IRAK-4 deficiency includes prophylaxis with penicillin and/or cotrimoxazole, antipneumococcal immunization, and replacement-dose immunoglobulin (400 mg/kg every 3-4 weeks).1,5 We present a 5-year-old white boy with IRAK-4 deficiency. He was first hospitalized for 12 days shortly after birth due to pneumonia. At 4 months, he was hospitalized for a retropharyngeal abscess with cultures positive for enteric gram-negative rods, Pseudomonas species, Neisseria species, and Haemophilus parahemolyticus. At 16 months, he developed pneumonia with loculated effusion, but no organisms were isolated. In addition to these invasive infections, the patient also had multiple episodes of otitis media and sinusitis during his first 2 years of life. At 22 months of age, he presented with right upper quadrant pain and was found to have multiple liver abscesses and right middle lobe pneumonia. Abscesses were drained, and cultures were positive for methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae (serotype unknown). After completing treatment for the liver abscesses, he was started on prophylactic trimethoprim-sulfamethoxazole (2 mg/kg) once daily due to clinical evidence of functional antibody deficiency. He presented
701
TABLE II. Pneumococcal vaccine responses over time Age (mo) Pneumococcal serotypes
1 3 4* 5 6B* 7F 8 9N 9V* 12F 14* 18C* 19F* 23F*
11
24
32
33
84
0.14 0.12 0.18 1.36 0.14 0.23 0.39 0.08 0.42 0.47 0.14 0.31 0.24 0.34
0.18 0.16 2.6 1.46 19.9 0.3 0.55 0.86 5.25 0.65 13.67 15.01 10.11 6.45
0.3 0.05 0.82 3.23 4.51 0.16 0.07 0.33 4.24 0.13 1.9 1.68 2.01 1.55
0.52 2.39 11.97 2.37 37.83 0.64 0.44 3.3 12.55 0.15 38.64 21.5 59.27 6.11
1.1 1.6 0.7 2.5 2.7 3.8 2.4 1.2 4.1 0.5 7.4 1 146.5 6.4
7-valent protein pneumococcal vaccine (Prevnar-7) given at 3 mo, 9 mo, 23 mo, 26 mo. 13-valent protein pneumococcal vaccine (Prevnar-13) given at 60 mo. 23-valent polysaccharide pneumococcal vaccine (Pneumovax-23) given at 32 mo. *Serotypes covered by Prevnar-7.
TABLE I. (Continued) Alpha-beta 97 3248
CD45RO CF45RA T helper T helper 20 80
CD19+, CD27e, CD19+, CD21e, CD38e CD27+ 1.1 0.5-2.9
22 19-37
CD45RO T suppr 11
CD455RA T suppr 89
CD19+, CD27+, CD19+, CD27+, CD19+, CD27+, CD19+, CD19+, CD19+, CD19+, CD19+, CD18++, IgM+, IgD+ IgMe, IgDe IgMe, IgDe B220+ B220+ CD5+ CD5e CD38++, CD138++ ++ (of lymphs) CD138 16 1.2 4.4 92 8 46 54 0.000 0.007 8-22 0.7-5.2 2.8-16 69-91 9-31 29-68 32-71 0.000-0.245 0.000-0.032
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TABLE III. Infectious history Age (mo)
Infection
Pathogen
Newborn 4
None isolated Enteric gram-negative rods, Pseudomonas species, Neisseria species, Haemophilus parahemolyticus None isolated
22
Pneumonia Retropharyngeal abscess Pneumonia with effusion Liver abscesses
22 32
Pneumonia Liver abscesses
None isolated Methicillin-resistant S aureus, S pneumonia
34 57
Meningitis
S pneumonia
59 66
Otitis media
Pseudomonas aeruginosa, Aspergillus fumigatus, Candida parapsilosis, coagulase-negative Staphylococcus, and nonhemolytic Streptococcus
16
Treatment
Methicillin-resistant Staphylococcus aureus, Streptococcal pneumonia
at 32 months of age with recurrence of the liver abscesses as well as a right-sided abdominal wall abscess. Abscesses were drained, and cultures were again positive for methicillin-resistant S aureus. The initial immune evaluation at 22 months of age (Table I) revealed normal immunoglobulin levels, normal T, B, and natural killer cell populations by flow cytometry, and normal T-cell function based on mitogen assay. Oxidative burst, complement receptor 3 (CD11b/CD18) function, CH50, and vaccine responses to tetanus and diphtheria were normal. These studies were repeated at when the patient was 32 months of age and were again were normal. Antibody production after pneumococcal vaccination was inadequate. After receiving 2 doses of Prevnar-7 (Wyeth Pharmaceuticals Inc, Philadelphia, Pa) at 3 months and 9 months, respectively, vaccine responses at 11 months were low (Table II). Prevnar-7 was administered at 23 months and again at 26 months, followed by Pneumovax-23 (Merck Corp, Whitehouse Station, NJ) at 32 months. B-cell phenotyping revealed normal B-cell populations, including IgMþ, IgDþCD27þ B cells (16%). Due to a limited antibody response to vaccinations and continued infections despite receiving prophylactic antibiotics, replacement dose intravenous immunoglobulin (IVIG) (500 mg/ kg monthly) was started at 34 months. The patient did well over the next 8 months, without significant infection, and was converted to subcutaneous immunoglobulin (Hizentra; CSL Behring, Danderyd, Sweden), 120 mg/kg weekly. Adherence to Hizentra therapy was adequate over this time period based on reported compliance as well as adequate IgG levels measured over time. Lifetime infections in relation to administration of immunoglobulin are outlined in Table III. At 58 months of age, the patient presented with fever, vomiting, and mental status changes, and was diagnosed with pansinusitis and S pneumoniae (serotype 33 and nontypeable pneumococcus) meningitis diagnosed by lumbar puncture and was cerebrospinal fluid DNA PCR positive for S pneumonia. This hospitalization was complicated by bilateral severe hearing loss, encephalomalacia, and seizures. Prior immune evaluation
Intravenous ampicillin and gentamicin for 10 d Intravenous, oral clindamycin Effusion drained by thoracentesis, treated with intravenous cefotaxime followed by oral cefdinir Percutaneous drainage by interventional radiology; intravenous nafcillin for 7 wk, followed by oral cephalexin for 2 mo Nafcillin Percutaneous drainage by interventional radiology; intravenous cefazolin for 12 wk, followed by oral cephalexin Replacement immunoglobulin started Intravenous Rocephin and vancomycin for 1 mo followed by 4 wk of treatment with amoxicillin with clavulanic acid High-dose weekly immunoglobulin started Trimethoprim sulfamethoxazole, amoxicillin with clavulanic acid, ofloxacin drops
had demonstrated normal adaptive immunity and neutrophil oxidative burst activity (Table I), thus making disorders such as X-linked agammaglobulinemia, common variable immunodeficiency disorder, specific polysaccharide antibody deficiency, severe combined immunodeficiency, and chronic granulomatous disease (all in the initial differential diagnosis) unlikely. Due to the nature of invasive pneumococcal infection, innate immune dysfunction, specifically IRAK-4 deficiency, was considered. Innate immune function was assessed and revealed decreased cytokine production after stimulation of toll-like receptor 1-8 (ARUP Laboratories, Salt Lake City, Utah). Subsequent genetic testing revealed a homozygous nonsense mutation at Q293X in the IRAK-4 gene region of chromosome 12q12 (GeneDx, Gaithersburg, Md). This mutation is caused by a C to T substitution on exon 8 of the IRAK-4 gene, which results in the replacement of glutamine codon (CAG) with a stop codon (TAG) at amino acid position 293. This mutation is denoted c.887C>T at the cDNA level or p.Gln293Stop (Q293X) at the protein level. This mutation leads to the loss of normal protein function through protein truncation and/or mRNA decay, and was previously reported by Picard et al2 as a cause for IRAK-4 deficiency. In this study, patients with IRAK deficiency and with the Q293X and 821delT mutations were examined; there was no detectable IRAK-4 mRNA by Northern blot or cDNA PCR and no detectable protein by Western blotting in the lymphoblastoid B cells from the subjects studied.2 Due to the failure of replacement immunoglobulin to prevent invasive infection, high-dose immunoglobulin (1000 mg/kg) every 2 weeks was started. The rationale for this therapy included the idea that high-dose immunoglobulin would provide enhanced passive immunity in the presence of an impaired inflammatory response. The decision to increase the IVIG dose occurred after failure of response when on replacement dose therapy, with severe central nervous system infection and complications. The patient had a serious, invasive infection while on replacement dose IVIG. The dose was increased to
J ALLERGY CLIN IMMUNOL PRACT VOLUME 1, NUMBER 6
a high dose due to the failure of the replacement dose IVIG to prevent serious, invasive infections. Antimicrobial prophylaxis with twice daily dosing of amoxicillin (20 mg/kg per dose) was initiated in addition to twice daily trimethoprim-sulfamethoxazole (4 mg/kg per dose). In the 18 months since starting this therapy, the patient has had chronic otitis media and otorrhea but no further serious or invasive infections. Causative organisms for otitis media include Pseudomonas aeruginosa, Aspergillus fumigatus, Candida parapsilosis, coagulase-negative Staphylococcus, and nonhemolytic Streptococcus. In summary, patients with IRAK-4 deficiency present early in life, with invasive infections caused by pyogenic bacteria. A high index of suspicion is needed because screening immune laboratory tests may be normal. Educating parents and family physicians about patients with IRAK-4 deficiency is critically important. Initiation of empiric antibiotic therapy is essential if infection is suspected because these patients may develop invasion bacterial infection without mounting a typical inflammatory response. Previous case reports show that aggressive prophylaxis with antibiotics, such as penicillin or trimethoprim-sulfamethoxazole, in addition to replacement dose immunoglobulin reduces the risk of invasive infections6; however, some patients may continue to have invasive infections with pyogenic bacteria. In refractory cases, high-dose IVIG (1000 mg/kg every 2 weeks) in combination with broad-spectrum antibiotic prophylaxis should be considered. Since the increase in IVIG in this patient, no additional infections other than chronic otitis media have been noted. To our knowledge, this is the first time that high-dose immunoglobulin has been used to treat IRAK-4 deficiency and thus far has been successful in preventing further invasive infections. a
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Ark b Department of Allergy and Immunology, Arkansas Children’s Hospital, Little Rock, Ark No funding was received for this work. Conflicts of interest: S. M. Jones is on the Food Allergy Research and Education Medical Advisory Board; is on the St Louis Children’s Hospital Food Allergy
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Management and Education National Advisory Board; has received consultancy fees from the Gerson Lehrman Group; has received research support from the National Institutes of Health, Food Allergy Research and Education, and National Peanut Board; has received lecture fees from Abbott Nutrition International; Kentucky Society for Allergy, Asthma and Immunology, New England Allergy Society Meeting, American College of Allergy, Asthma and Immunology Meeting, Indiana University Medical School and Riley Children’s Hospital, Spanish Society of Allergy and Clinical Immunology, Oregon Allergy Asthma and Immunology Society, European Academy of Allergy and Clinical Immunology; has received payment for manuscript preparation from the American Academy of Allergy, Asthma and Immunology; is on the Arkansas Medicaid Drug Review Committee. T. T. Perry and A. M. Scurlock have received research support from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication May 9, 2013; revised September 3, 2013; accepted for publication September 9, 2013. Cite this article as: Dilley MA, Jones SM, Perry TT, Scurlock AM, Brodie-Fowler M, Bufford JD, et al. Pneumococcal meningitis in a patient with IL-1 receptore associated kinase-4 deficiency: A case of failed prophylaxis. J Allergy Clin Immunol Pract 2013;1:700-3. http://dx.doi.org/10.1016/j.jaip.2013.09.003. Corresponding author: Meredith A. Dilley, MD, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Pediatrics, 1 Children’s Way, Little Rock, AR 72201. E-mail: [email protected]. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.09.003 REFERENCES 1. Picard C, Casanova JL, Puel A. Infectious diseases inpatients with IRAK-4, MyD88, NEMO, and IkBa deficiency. Clin Microbiol Rev 2011;24:490-7. 2. Picard C, Puel A, Bonnet M, Ku CK, Bustamenta J, Yang K, et al. Pyogenic bacterial infections in patients with IRAK-4 deficiency. Science 2003;299: 2076-9. 3. Chapel H, Puel A, Bernuth HV, Picard C, Casanova JL. Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first associated with primary immune deficiency. Clin Infect Dis 2005;40:1227-31. 4. Weller S, Bonnet M, Delagreverie H, Israel L, Chrabieh M, Maródi L, et al. IgMþIgDþCD27þ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood 2012;120:4992-5001. 5. Gerban B, Doffinger R, Patel SY, Peskett E, Sinclair JC, Barcenas-Morales G, et al. Impaired neutrophil migration and phagocytosis in IRAK-4 deficiency. Br J Haematol 2009;147:150-6. 6. Enders A, Pannicke U, Berner R, Henneek P, Radlinger K, Schwarz K, et al. Two siblings with lethal pneumococcal meningitis in a family with a mutation in interleukin-1 receptor associated kinase. J Pediatr 2004;145:698-700.
Patients with IL-1 receptoreassociated kinase-4 deficiency are at risk for invasive bacterial infections, and current recommendations include replacement dose immunoglobulin and antimicrobial prophylaxis. If invasive infections continue to occur, then high-dose immunoglobulin and expanded antimicrobial prophylaxis are an effective alternative.
TABLE I. Immune function at 22 months Flow analysis CD2 CD3 Percent Absolute Mitogens Patient Control* CR3 panel
Patient Control* Resting and stimulated index
Patient Control* B-cell populations Cells
IL-1 receptoreassociated kinase-4 (IRAK-4) is a receptorassociated protein kinase involved in toll-like receptor and IL-1 receptor signaling that leads to the production of proinflammatory cytokines (IL-1b, IL-6, IL-8, TNF-a, IFN-a/b, and IFN-l).1 Deficiencies in IRAK-4 signaling can lead to invasive pyogenic bacterial infections, skin infections, and recurrent upper respiratory tract infections.2 Patients with an IRAK-4 deficiency have a weakened ability to mount fever early in infection, and the poor production of IL-6 leads to lower than expected C-reactive protein levels.2 Some patients have impaired antibody production after polysaccharide and protein vaccines and reduced memory (IgMþ, IgDþCD27þ) B cells, and many of those who do respond to vaccines fail to sustain these responses long term.3,4 The risk for invasive infection seems to gradually decline during adolescence, likely due to the compensatory response of the adaptive immune system.3 Prophylaxis with immunoglobulin therapy may be necessary at
CD4
CD8
CD56
CD19
CD20
3 152
28 1420
29 1471
70 3551
66 3348
42 2131
23 1167
PHA 188,437 297,996
PWM 116,694 76,413
ConA 169,941 208,873
Media 1,283 1,657
Resting MPC 66 39
Resting peak
Stim MPC
Stim peak
M S NS ratio
P S NS ratio
67 35
138 116
166 120
2.1 3.0
2.1 3.4
Resting MPC 6 5
Resting PC
Stim MPC
Stim PC
M S NS ratio
P S NS ratio
5 5
986 740
982 784
164.3 148
196.4 156.85
CD19+, CD10+
CD19+, CD27e, CD19+, CD27e, CD19+, CD27e, CD19+, CD27e CD19+, CD27e, CD19+, CD27e, CD10e, CD18++ CD18++, IgM++ CD21e, IgM++ CD21+ IgM+, IgD+
Patient, % 9 Normal range, %* 7-12 Immunoglobulin levels Immunoglobulin Patient Normal range*
TO THE EDITOR:
4.9 4.5-17.8
IgG (mg/dL) IgA (mg/dL) 1167.4 70.1 341-1960 19-220
4.0 0.2-15.9
2.0 0.1-5.1
IgM (mg/dL) 67.0 43-163
IgE (kU/L) 54.7 0.3-133
78 64-84
73 60-74
76 58-78
ConA, Concanavali; MPC, mean peak channel; PC, peak channel; PHA, phytohemagglutinin; PWM, pokeweed mitogen; stim, stimulation; suppr, suppressor. *Control/normal values are age matched. Units for all titers: mg/mL.
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least until the adaptive immune system has developed.1 Recommended therapy to prevent invasive bacterial infections in patients with IRAK-4 deficiency includes prophylaxis with penicillin and/or cotrimoxazole, antipneumococcal immunization, and replacement-dose immunoglobulin (400 mg/kg every 3-4 weeks).1,5 We present a 5-year-old white boy with IRAK-4 deficiency. He was first hospitalized for 12 days shortly after birth due to pneumonia. At 4 months, he was hospitalized for a retropharyngeal abscess with cultures positive for enteric gram-negative rods, Pseudomonas species, Neisseria species, and Haemophilus parahemolyticus. At 16 months, he developed pneumonia with loculated effusion, but no organisms were isolated. In addition to these invasive infections, the patient also had multiple episodes of otitis media and sinusitis during his first 2 years of life. At 22 months of age, he presented with right upper quadrant pain and was found to have multiple liver abscesses and right middle lobe pneumonia. Abscesses were drained, and cultures were positive for methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae (serotype unknown). After completing treatment for the liver abscesses, he was started on prophylactic trimethoprim-sulfamethoxazole (2 mg/kg) once daily due to clinical evidence of functional antibody deficiency. He presented
701
TABLE II. Pneumococcal vaccine responses over time Age (mo) Pneumococcal serotypes
1 3 4* 5 6B* 7F 8 9N 9V* 12F 14* 18C* 19F* 23F*
11
24
32
33
84
0.14 0.12 0.18 1.36 0.14 0.23 0.39 0.08 0.42 0.47 0.14 0.31 0.24 0.34
0.18 0.16 2.6 1.46 19.9 0.3 0.55 0.86 5.25 0.65 13.67 15.01 10.11 6.45
0.3 0.05 0.82 3.23 4.51 0.16 0.07 0.33 4.24 0.13 1.9 1.68 2.01 1.55
0.52 2.39 11.97 2.37 37.83 0.64 0.44 3.3 12.55 0.15 38.64 21.5 59.27 6.11
1.1 1.6 0.7 2.5 2.7 3.8 2.4 1.2 4.1 0.5 7.4 1 146.5 6.4
7-valent protein pneumococcal vaccine (Prevnar-7) given at 3 mo, 9 mo, 23 mo, 26 mo. 13-valent protein pneumococcal vaccine (Prevnar-13) given at 60 mo. 23-valent polysaccharide pneumococcal vaccine (Pneumovax-23) given at 32 mo. *Serotypes covered by Prevnar-7.
TABLE I. (Continued) Alpha-beta 97 3248
CD45RO CF45RA T helper T helper 20 80
CD19+, CD27e, CD19+, CD21e, CD38e CD27+ 1.1 0.5-2.9
22 19-37
CD45RO T suppr 11
CD455RA T suppr 89
CD19+, CD27+, CD19+, CD27+, CD19+, CD27+, CD19+, CD19+, CD19+, CD19+, CD19+, CD18++, IgM+, IgD+ IgMe, IgDe IgMe, IgDe B220+ B220+ CD5+ CD5e CD38++, CD138++ ++ (of lymphs) CD138 16 1.2 4.4 92 8 46 54 0.000 0.007 8-22 0.7-5.2 2.8-16 69-91 9-31 29-68 32-71 0.000-0.245 0.000-0.032
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TABLE III. Infectious history Age (mo)
Infection
Pathogen
Newborn 4
None isolated Enteric gram-negative rods, Pseudomonas species, Neisseria species, Haemophilus parahemolyticus None isolated
22
Pneumonia Retropharyngeal abscess Pneumonia with effusion Liver abscesses
22 32
Pneumonia Liver abscesses
None isolated Methicillin-resistant S aureus, S pneumonia
34 57
Meningitis
S pneumonia
59 66
Otitis media
Pseudomonas aeruginosa, Aspergillus fumigatus, Candida parapsilosis, coagulase-negative Staphylococcus, and nonhemolytic Streptococcus
16
Treatment
Methicillin-resistant Staphylococcus aureus, Streptococcal pneumonia
at 32 months of age with recurrence of the liver abscesses as well as a right-sided abdominal wall abscess. Abscesses were drained, and cultures were again positive for methicillin-resistant S aureus. The initial immune evaluation at 22 months of age (Table I) revealed normal immunoglobulin levels, normal T, B, and natural killer cell populations by flow cytometry, and normal T-cell function based on mitogen assay. Oxidative burst, complement receptor 3 (CD11b/CD18) function, CH50, and vaccine responses to tetanus and diphtheria were normal. These studies were repeated at when the patient was 32 months of age and were again were normal. Antibody production after pneumococcal vaccination was inadequate. After receiving 2 doses of Prevnar-7 (Wyeth Pharmaceuticals Inc, Philadelphia, Pa) at 3 months and 9 months, respectively, vaccine responses at 11 months were low (Table II). Prevnar-7 was administered at 23 months and again at 26 months, followed by Pneumovax-23 (Merck Corp, Whitehouse Station, NJ) at 32 months. B-cell phenotyping revealed normal B-cell populations, including IgMþ, IgDþCD27þ B cells (16%). Due to a limited antibody response to vaccinations and continued infections despite receiving prophylactic antibiotics, replacement dose intravenous immunoglobulin (IVIG) (500 mg/ kg monthly) was started at 34 months. The patient did well over the next 8 months, without significant infection, and was converted to subcutaneous immunoglobulin (Hizentra; CSL Behring, Danderyd, Sweden), 120 mg/kg weekly. Adherence to Hizentra therapy was adequate over this time period based on reported compliance as well as adequate IgG levels measured over time. Lifetime infections in relation to administration of immunoglobulin are outlined in Table III. At 58 months of age, the patient presented with fever, vomiting, and mental status changes, and was diagnosed with pansinusitis and S pneumoniae (serotype 33 and nontypeable pneumococcus) meningitis diagnosed by lumbar puncture and was cerebrospinal fluid DNA PCR positive for S pneumonia. This hospitalization was complicated by bilateral severe hearing loss, encephalomalacia, and seizures. Prior immune evaluation
Intravenous ampicillin and gentamicin for 10 d Intravenous, oral clindamycin Effusion drained by thoracentesis, treated with intravenous cefotaxime followed by oral cefdinir Percutaneous drainage by interventional radiology; intravenous nafcillin for 7 wk, followed by oral cephalexin for 2 mo Nafcillin Percutaneous drainage by interventional radiology; intravenous cefazolin for 12 wk, followed by oral cephalexin Replacement immunoglobulin started Intravenous Rocephin and vancomycin for 1 mo followed by 4 wk of treatment with amoxicillin with clavulanic acid High-dose weekly immunoglobulin started Trimethoprim sulfamethoxazole, amoxicillin with clavulanic acid, ofloxacin drops
had demonstrated normal adaptive immunity and neutrophil oxidative burst activity (Table I), thus making disorders such as X-linked agammaglobulinemia, common variable immunodeficiency disorder, specific polysaccharide antibody deficiency, severe combined immunodeficiency, and chronic granulomatous disease (all in the initial differential diagnosis) unlikely. Due to the nature of invasive pneumococcal infection, innate immune dysfunction, specifically IRAK-4 deficiency, was considered. Innate immune function was assessed and revealed decreased cytokine production after stimulation of toll-like receptor 1-8 (ARUP Laboratories, Salt Lake City, Utah). Subsequent genetic testing revealed a homozygous nonsense mutation at Q293X in the IRAK-4 gene region of chromosome 12q12 (GeneDx, Gaithersburg, Md). This mutation is caused by a C to T substitution on exon 8 of the IRAK-4 gene, which results in the replacement of glutamine codon (CAG) with a stop codon (TAG) at amino acid position 293. This mutation is denoted c.887C>T at the cDNA level or p.Gln293Stop (Q293X) at the protein level. This mutation leads to the loss of normal protein function through protein truncation and/or mRNA decay, and was previously reported by Picard et al2 as a cause for IRAK-4 deficiency. In this study, patients with IRAK deficiency and with the Q293X and 821delT mutations were examined; there was no detectable IRAK-4 mRNA by Northern blot or cDNA PCR and no detectable protein by Western blotting in the lymphoblastoid B cells from the subjects studied.2 Due to the failure of replacement immunoglobulin to prevent invasive infection, high-dose immunoglobulin (1000 mg/kg) every 2 weeks was started. The rationale for this therapy included the idea that high-dose immunoglobulin would provide enhanced passive immunity in the presence of an impaired inflammatory response. The decision to increase the IVIG dose occurred after failure of response when on replacement dose therapy, with severe central nervous system infection and complications. The patient had a serious, invasive infection while on replacement dose IVIG. The dose was increased to
J ALLERGY CLIN IMMUNOL PRACT VOLUME 1, NUMBER 6
a high dose due to the failure of the replacement dose IVIG to prevent serious, invasive infections. Antimicrobial prophylaxis with twice daily dosing of amoxicillin (20 mg/kg per dose) was initiated in addition to twice daily trimethoprim-sulfamethoxazole (4 mg/kg per dose). In the 18 months since starting this therapy, the patient has had chronic otitis media and otorrhea but no further serious or invasive infections. Causative organisms for otitis media include Pseudomonas aeruginosa, Aspergillus fumigatus, Candida parapsilosis, coagulase-negative Staphylococcus, and nonhemolytic Streptococcus. In summary, patients with IRAK-4 deficiency present early in life, with invasive infections caused by pyogenic bacteria. A high index of suspicion is needed because screening immune laboratory tests may be normal. Educating parents and family physicians about patients with IRAK-4 deficiency is critically important. Initiation of empiric antibiotic therapy is essential if infection is suspected because these patients may develop invasion bacterial infection without mounting a typical inflammatory response. Previous case reports show that aggressive prophylaxis with antibiotics, such as penicillin or trimethoprim-sulfamethoxazole, in addition to replacement dose immunoglobulin reduces the risk of invasive infections6; however, some patients may continue to have invasive infections with pyogenic bacteria. In refractory cases, high-dose IVIG (1000 mg/kg every 2 weeks) in combination with broad-spectrum antibiotic prophylaxis should be considered. Since the increase in IVIG in this patient, no additional infections other than chronic otitis media have been noted. To our knowledge, this is the first time that high-dose immunoglobulin has been used to treat IRAK-4 deficiency and thus far has been successful in preventing further invasive infections. a
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Ark b Department of Allergy and Immunology, Arkansas Children’s Hospital, Little Rock, Ark No funding was received for this work. Conflicts of interest: S. M. Jones is on the Food Allergy Research and Education Medical Advisory Board; is on the St Louis Children’s Hospital Food Allergy
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Management and Education National Advisory Board; has received consultancy fees from the Gerson Lehrman Group; has received research support from the National Institutes of Health, Food Allergy Research and Education, and National Peanut Board; has received lecture fees from Abbott Nutrition International; Kentucky Society for Allergy, Asthma and Immunology, New England Allergy Society Meeting, American College of Allergy, Asthma and Immunology Meeting, Indiana University Medical School and Riley Children’s Hospital, Spanish Society of Allergy and Clinical Immunology, Oregon Allergy Asthma and Immunology Society, European Academy of Allergy and Clinical Immunology; has received payment for manuscript preparation from the American Academy of Allergy, Asthma and Immunology; is on the Arkansas Medicaid Drug Review Committee. T. T. Perry and A. M. Scurlock have received research support from the National Institutes of Health. The rest of the authors declare that they have no relevant conflicts of interest. Received for publication May 9, 2013; revised September 3, 2013; accepted for publication September 9, 2013. Cite this article as: Dilley MA, Jones SM, Perry TT, Scurlock AM, Brodie-Fowler M, Bufford JD, et al. Pneumococcal meningitis in a patient with IL-1 receptore associated kinase-4 deficiency: A case of failed prophylaxis. J Allergy Clin Immunol Pract 2013;1:700-3. http://dx.doi.org/10.1016/j.jaip.2013.09.003. Corresponding author: Meredith A. Dilley, MD, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Pediatrics, 1 Children’s Way, Little Rock, AR 72201. E-mail: [email protected]. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.09.003 REFERENCES 1. Picard C, Casanova JL, Puel A. Infectious diseases inpatients with IRAK-4, MyD88, NEMO, and IkBa deficiency. Clin Microbiol Rev 2011;24:490-7. 2. Picard C, Puel A, Bonnet M, Ku CK, Bustamenta J, Yang K, et al. Pyogenic bacterial infections in patients with IRAK-4 deficiency. Science 2003;299: 2076-9. 3. Chapel H, Puel A, Bernuth HV, Picard C, Casanova JL. Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first associated with primary immune deficiency. Clin Infect Dis 2005;40:1227-31. 4. Weller S, Bonnet M, Delagreverie H, Israel L, Chrabieh M, Maródi L, et al. IgMþIgDþCD27þ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood 2012;120:4992-5001. 5. Gerban B, Doffinger R, Patel SY, Peskett E, Sinclair JC, Barcenas-Morales G, et al. Impaired neutrophil migration and phagocytosis in IRAK-4 deficiency. Br J Haematol 2009;147:150-6. 6. Enders A, Pannicke U, Berner R, Henneek P, Radlinger K, Schwarz K, et al. Two siblings with lethal pneumococcal meningitis in a family with a mutation in interleukin-1 receptor associated kinase. J Pediatr 2004;145:698-700.