Secondary Logo

Journal Logo

Immunology Reports

Deficiency of Interleukin-1 Receptor-associated Kinase 4 Presenting as Fatal Pseudomonas aeruginosa Bacteremia in Two Siblings

Stergiopoulou, Theodouli MD, PhD*; Walsh, Thomas J. MD, PhD; Seghaye, Marie-Christine MD, PhD*; Netea, Mihai G. MD, PhD; Casanova, Jean-Laurent MD, PhD§¶**; Moutschen, Michel MD, PhD††; Picard, Capucine MD, PhD¶‡‡

Author Information
The Pediatric Infectious Disease Journal: March 2015 - Volume 34 - Issue 3 - p 299-300
doi: 10.1097/INF.0000000000000550
  • Free


Pseudomonas aeruginosa, a Gram-negative bacillus and an opportunistic environmental microorganism, causes serious infections in children with impaired defense mechanisms and chronic diseases.1Pseudomonas sepsis is rare in healthy children and the empirical antibiotic treatment for sepsis does not include agents against this microorganism.2 Among the primary immunodeficiencies (PIDs) which predispose to P. aeruginosa sepsis are the impairments of toll-like receptor (TLR)–interleukin-1R (TIR) intracellular signal transduction pathway proteins, such as the interleukin (IL)-1 receptor-associated kinase 4 (IRAK-4) and myeloid differentiation factor (MyD)88.3,4 Leukocytes from these patients do not respond to stimulation with cytokines of the IL-1 superfamily such as IL-1β or IL-18, as well as stimulation with agonists of the TLRs, except with TLR3 agonist.3 Due to this impaired activation of innate immune responses, IRAK-4-deficient patients develop recurrent pyogenic bacterial infections, while retaining a normal resistance to common fungi, parasites and viruses.5,6 Herein, we report a case of two siblings with fatal fulminant P. aeruginosa sepsis as initial presenting manifestation of IRAK-4 deficiency.


A previously healthy 14-month-old male was admitted to the emergency department of the University Hospital of Liege with a history of 2 days fever to 39.9°C, upper respiratory symptoms and fatigue. The previous day, the child had been admitted with the same symptoms for 24 hours to another hospital, but the parents preferred to seek medical consultation in an academic pediatric department. The boy had no sick contacts, no history of repeated infections or recent travel and no known drug allergies. He had received immunizations appropriate for age. His sister died at the age of 18 months due to fulminant P. aeruginosa septic shock. There was no contributory medical history from his parents. The father and the mother had Belgian and Russian origin, respectively, and they lived in Belgium. The parents reported that the child’s sister died similarly because of fulminant P. aeruginosa sepsis. They also reported that the separation of umbilical cord in both children took place 3–4 weeks after the birth.

The physical examination revealed a well-developed and nourished child with weakness, nasal secretions and tachypnea. Temperature was 39.9°C, pulse 163/min and O2 saturation 100%. Fine inspiratory rales were present on auscultation. An indurated erythematous nodule measuring approximately 5 cm in diameter was located on the left knee and a diffuse erythematous papular rash was present on the trunk and limbs. Because of suspected bacteremia, intravenous treatment with 200 mg/kg cefotaxime was initiated. Parenteral fluid therapy and monitoring of the vital signs were also commenced. Laboratory studies from the previous hospital revealed white blood cells: 5260/mm3 (47.3% neutrophils and 35.5% lymphocytes), hemoglobin: 12.2 g/dL, platelet count: 250,000/mm3 and CRP: 8.8 mg/L. Urine analysis was normal. The chest radiograph demonstrated left-sided pulmonary infiltrates. Five hours after admission, the child developed respiratory distress with intercostal and subcostal retractions and diffuse petechiae. Oxygen saturation deceased from 100% to 80%. Distributive shock was diagnosed and the appropriate resuscitation protocol was started. Despite the resuscitation efforts with intubation and inotropic support, the child died. After death, blood was obtained and an autopsy was performed. The lesion on the left knee was consistent with ecthyma gangrenosum. Cultures of blood and cerebrospinal fluid grew P. aeruginosa, which was pan-susceptible. The nasopharynx also was colonized by P. aeruginosa.

To identify the source of this P. aeruginosa isolate, which colonized and infected the child, cultures of the toys that the child used for playing during the bath were obtained. P. aeruginosa was isolated from 2 of his toys. A molecular typing by pulsed-field gel electrophoresis of DNA macrorestriction fragments was performed. The isolates of P. aeruginosa from the patient and the toys were identical by pulsed-field gel electrophoresis. Cultures from the tap water in kitchen and in bathroom, as well as from other sites of the house were negative.

To elucidate the underlying immunogenetic factors that predisposed the child to Pseudomonas sepsis, fibroblasts of the patient and DNA of the parents were sent to the Study Center of Immunodeficiencies, Paris, France. A functional assay was performed on fibroblast cells from the patient, 1 control patient and IRAK-4-deficient patient upon stimulation with IL-1β or tumor necrosis factor alpha. The functional study on the patient’s fibroblasts cells and on those from the IRAK-4-deficient patient found an absence IL-6 production upon IL-1β stimulation that confirmed the impairment of TLR–TIR signaling pathway (Fig. 1). The fibroblasts were cultured for DNA extraction and polymerase chain reaction was performed. The child was found to bear compound heterozygous splice mutations in the IRAK4 gene. The mother was found to be heterozygous for the splice mutation 1189-1G>A and the father heterozygous for the splice mutation 831+5G>T. Finally, the deceased sibling, who died from P. aeruginosa sepsis, was considered by inference from her personal history to have had IRAK-4 deficiency.

Interleukin-6 (IL-6) production after stimulation during 24 hours with interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) by fibroblasts of healthy control, IRAK-4 −/− deficient patient, and the index patient reported herein. NS, nonstimulated.


We describe 2 previously healthy siblings who died from fulminant P. aeruginosa sepsis in the context of an inherited IRAK-4 deficiency. P. aeruginosa sepsis in children is uncommon, mostly occurs after prolonged hospitalization, and most commonly affects patients with profound persistent chemotherapy-induced neutropenia, or with PIDs.1,7Pseudomonas invasive infection has been reported in patients with deficiencies in TIR pathway such as IRAK-4 and MyD88 deficiency patients, but is less common than sepsis due to Gram-positive bacteria.3,4P. aeruginosa causes a higher incidence of non-invasive bacterial infection of the upper respiratory tract.3 Although the patient reported herein was colonized in the nasopharynx by P. aeruginosa, there were no observed upper respiratory infections by this organism, but the first infection was invasive and fatal. The sign of possible Pseudomonas sepsis was the appearance of ecthyma gangrenosum. This cutaneous lesion has been described as the initial manifestation of invasive infections in infants with PIDs or leukemia by Gram-negative bacteria (P. aeruginosa, Escherichia coli), Gram-positive bacteria (Staphylococcus aureus), viruses (Ηerpes simplex virus) and fungi (Mucorales and Aspergillus fumigatus).8

Umbilical cord separation in our patient was observed between 21 and 28 days postpartum. This concurs with the definition that the upper limit of separation is more than 25 days.9 Delayed umbilical cord separation was reported in children with IRAK-4 deficiency in previous publications.3 Thus, IRAK-4 deficiency can be considered among other PIDs if delayed umbilical cord separation is observed. The mother, who was a Russian descent, is heterozygous for the splice mutation 1189-1G>A. This mutation is demonstrated for the first time, whereas the 831+5G>T mutation that was transferred by the father has been previously described in a French patient.10 The death of the patient’s sibling by Pseudomonas sepsis strongly suggests that she was suffering from the same immunodeficiency. It is striking that both children of the same family died of similar events at the same age.

In conclusion, Pseudomonas sepsis in early childhood of a previous healthy child signifies the possible presence of a PID, particularly defects of the TIR1 signaling pathways such as IRAK-4 deficiency, and an appropriate genetic investigation should be initiated. The presence of ecthyma gangrenosum should alert physicians for anti-pseudomonas antibiotic treatment. IRAK-4/MyD88 deficiency should be considered a part of the differential diagnosis of primary Pseudomonas sepsis in children with diverse national backgrounds.


1. Yang MA, Lee J, Choi EH, et al. Pseudomonas aeruginosa bacteremia in children over ten consecutive years: analysis of clinical characteristics, risk factors of multi-drug resistance and clinical outcomes. J Korean Med Sci. 2011;26:612–618
2. Huang YC, Lin TY, Wang CH. Community-acquired Pseudomonas aeruginosa sepsis in previously healthy infants and children: analysis of forty-three episodes. Pediatr Infect Dis J. 2002;21:1049–1052
3. Picard C, von Bernuth H, Ghandil P, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010;89:403–425
4. Cardenes M, von Bernuth H, García-Saavedra A, et al. Autosomal recessive interleukin-1 receptor-associated kinase 4 deficiency in fourth-degree relatives. J Pediatr. 2006;148:549–551
5. Ku CL, von Bernuth H, Picard C, et al. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007;204:2407–2422
6. Bouma G, Doffinger R, Patel SY, et al. Impaired neutrophil migration and phagocytosis in IRAK-4 deficiency. Br J Haematol. 2009;147:153–156
7. Zhang Q, Smith JC, Zhu Q, et al. A five-year review of Pseudomonas aeruginosa bacteremia in children hospitalized at a single center in southern China. Int J Infect Dis. 2012;16:e628–e632
8. Pathak A, Singh P, Yadav Y, Dhaneria M. Ecthyma gangrenosum in a neonate: not always pseudomonas. BMJ Case Rep. 2013
9. Kemp AS, Lubitz L. Delayed umbilical cord separation in alloimmune neutropenia. Arch Dis Child. 1993;68(1 Spec No):52–53
10. Hoarau C, Gérard B, Lescanne E, et al. TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway. J Immunol. 2007;179:4754–4765

interleukin-1 receptor-associated kinase 4; Pseudomonas sepsis; primary immunodeficiency; ecthyma gangrenosum; delayed umbilical cord separation; ecthyma gangrenosum

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.