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Case Report
Revised

Case Report: Pseudomonas can take a toll on a patient

[version 2; peer review: 2 approved]
PUBLISHED 21 Sep 2021
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is an aerobic Gram-negative bacterium that is implicated in the development of severe systemic infections among pediatric patients.  It is identified in hospitalized chronically ill pediatric patients in association with genitourinary, respiratory tract, and skin or soft tissue infections as well as severe and life-threating infection including sepsis.  A variety of immunologic mechanisms play a vital role in the host defense mechanisms against invasive infections with P. aeruginosa. Rarely, specific inborn errors of immune function are implicated in deficiencies that predispose to invasive infections with P. aeruginosa.  Innate immune function including germ-line encoded pattern recognition receptors such as toll-like receptors (TLRs) and their downstream signaling is vital in the host defense against P. aeruginosa through the generation of antimicrobial peptides, cytokines/chemokines, and shaping of adaptive immune responses. Herein, we describe a previously healthy two-year-old female with an invasive skin, soft tissue, and central nervous system infection secondary to P. aeruginosa.  The invasive nature of this infection prompted a careful evaluation for an inborn error of immunity. Decreased cytokine response to agonists of TLRs was documented. Targeted sequencing of interleukin-1 receptor-associated kinase (IRAK)-4 documented a homozygous deletion of exons 8-13 consistent with IRAK-4 deficiency.  This report provides a vital educative message in the existing scientific literature by underscoring the importance of considering inborn errors of immunity in all patients with severe P. aeruginosa infections.  Functional assessments of immune function often in combination with sequencing can accurately assign a diagnosis in a timely fashion allowing for definitive treatment and the use of necessary supportive care.

Keywords

innate immunity, toll like receptors, interleukin-1 receptor-associated kinase-4, case report

Revised Amendments from Version 1

A few details regarding the assay used to evaluate cytokine response to TLR agonists were added.  Additional discussion regarding the role of the CD62L shedding assay as a potential screening test was added.  Additional discussion focusing on explaining why immunoglobulin prophylaxis has a role in IRAK4 deficiency has been added. A brief discussion regarding the importance of screening other family members for the same pathogenic variants was added.  Lastly, a brief comment on the long-term prognosis of patients with IRAK4 deficiency was also added.

See the authors' detailed response to the review by David Hagin
See the authors' detailed response to the review by Shanmuganathan Chandrakasan

Introduction

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic aerobic Gram-negative bacterial pathogen associated with a variety of genitourinary (UTI), pulmonary as well as skin and soft tissue infections (SSTI) in hospitalized pediatric patients often in association with significant morbidity1. Rarely, P. aeruginosa can be associated with severe and life-threatening infections among children without previously recognized associated risk factors2. In these cases, it is vital to consider the possibility of an underlying inborn error of immunity. Invasive P. aeruginosa infections have been described in the setting of inborn errors of immunity including antibody deficiencies (agammaglobulinemia) Bruton (Bruton agammaglobulinemia), combined immunodeficiency disorders (severe combined immunodeficiency, ataxia telangiectasia), defects of phagocytes (chronic granulomatous disease, leukocyte adhesion deficiency), defects in actin-polymerization (Wiskott-Aldrich syndrome, MKL1-deficiency), chronic neutropenia and innate immunity including defects in canonical NFKB-signaling (e.g., NEMO/NFKBIA) as well as those that impair the downstream signaling of toll-like receptors (TLRs), such as defects in interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor 88 (MyD88)2,3. We describe the presence of an invasive soft tissue and central nervous system infection with P. aeruginosa in a previously healthy two-year-old female which prompted evaluation for an inborn error of immunity.

Case report

A previously healthy two-year-old Hispanic female was evaluated for left hip and knee pain associated with a fever and a refusal to ambulate. She had been given cephalexin for presumed insect bites on her back and legs. Her past medical history was non-contributory. She was fully immunized. Her family history was negative for consanguinity and inborn errors of immunity. She was afebrile and her physical examination demonstrated a 3 cm circular erythematous lesion on her mid left back which was non-indurated. Her left knee was minimally swollen, warm to touch, and non-erythematous. Her hips and knees remained in flexion with demonstrated resistance to knee extension. A nodular 1.5 cm mass in her popliteal fossa was also documented with tenderness upon palpation and she was unable to walk. Her laboratory investigation demonstrated a white blood cell count of 17.2 × 103/uL (normal range: 3.9-13.7), Hgb 10.4 g/dL (normal range:10.2-15.4), platelets 319 × 103 (normal range: 150-450), 64% neutrophils (normal range: 25-72), 26% lymphocytes (normal range: 24-71), 9% monocytes (normal range: 0-14), 0.6% eosinophils (normal range: 2-10), 0.3% basophils (normal range: 0-2), erythrocyte sedimentation rate (ESR) 126 mm/hr (normal range: 0-20), and C-reactive protein (CRP) 68.8 mg/L (normal range: 0-10). A blood culture was negative. Magnetic resonance (MR) imaging of her lower extremity demonstrated myositis and fasciitis involving the soft tissues of the distal left thigh, but no abscess (Figure 1A–C). Likely pathogens included methicillin sensitive Staphylococcus aureus, methicillin resistant Staphylococcus aureus, and group A Streptococcus.

f57b165c-0d3c-46fc-a0dd-eede8c362258_figure1.gif

Figure 1.

Axial (A) and sagittal (C) Short-TI Inversion Recovery (STIR) magnetic resonance imaging (MRI) images of the bilateral lower extremities demonstrate edematous signal involving the left lower extremity vastus medialis, vastus intermedius, soft tissues of the popliteal fossa, and overlying subcutaneous soft tissues. Axial fat-saturated T1-weighted postcontrast MRI of the bilateral lower extremities (B) demonstrates associated enhancement of the vastus medialis, vastus intermedius, and soft tissues of the popliteal fossa. Findings are compatible with myositis with overlying cellulitis.

Empiric antibiotic therapy began with vancomycin (60 mg/kg/day intravenously divided every 6 hours for 3 days) and ceftriaxone (75 mg/kg/day intravenously every 24 hours for 3 days) which was then transitioned to cefazolin (100 mg/kg/day intravenously divided every 8 hours for 7 days), clindamycin (30 mg/kg/day intravenously divided every 8 hours for 7 days), amoxicillin-clavulanate (50 mg/kg/day orally divided every 12 hours for 4 days), and then to linezolid (30 mg/kg/day intravenously divided every 8 hours for 6 days) due to a lack of clinical and laboratory improvement. A lesion on her back was biopsied and demonstrated acute suppurative panniculitis and suppurative necrosis (Figure 2). Cultures were obtained with growth of P. aeruginosa and a 3-week course of cefepime (150 mg/kg/day intravenously divided every 8 hours) for SSTI was completed. Clinical and laboratory improvement occurred as demonstrated by an ESR 57 mm/hr (normal range: 0–20) and CRP <5 mg/L (normal range: 0–10). The patient was discharged while awaiting results of a workup for an inborn error of immunity.

f57b165c-0d3c-46fc-a0dd-eede8c362258_figure2.gif

Figure 2. Skin punch biopsy demonstrates acute suppurative panniculitis with suppurative necrosis (20×, Hematoxylin and Eosin).

She then returned approximately 3 weeks later with malaise, an inability to stand upright, irritability, and pain on palpation of her back as well as a refusal to ambulate. On re-admission she was afebrile, and her laboratory investigation demonstrated an ESR 89 mm/hr (normal range: 0-20), and CRP <5 mg/L (normal range: 0-10). MR imaging of her spine demonstrated enhancement of T9-T11 with an epidural abscess (Figure 3A–B). A culture was obtained by computed tomography (CT)-guided needle aspiration and empiric therapy with meropenem (120 mg/kg/day intravenously divided every 8 hours for 2 days) was begun. Growth of P. aeruginosa was documented and a 6-week course of cefepime (150 mg/kg/day intravenously divided every 8 hours) was completed. Clinical improvement occurred; however, her laboratory investigation demonstrated an ESR 80 mm/hr (normal range: 0–20) and CRP <5 mg/L (normal range: 0–10) at the completion of therapy.

f57b165c-0d3c-46fc-a0dd-eede8c362258_figure3.gif

Figure 3.

Axial (A) and sagittal (B) fat-saturated volumetric interpolated breath-hold examination (VIBE) postcontrast magnetic resonance imagery (MRI) images of the thoracic spine demonstrate multilevel thoracic osteomyelitis and discitis with associated epidural and paravertebral abscesses.

Secondary to the invasive nature of her P. aeruginosa infection, evaluation for an inborn error of immunity was completed. A normal neutrophil oxidative burst was noted. Additional laboratory assessments included a serum IgG 1331 mg/dL (normal range: 407-1009), IgA 85 mg/dL (normal range: 22-220), an elevated IgM 362 mg/dL (normal range: 43-163), and a IgE 3.8 kU/L (normal range: <97). Antibody responses documented a non-protective Haemophilus influenza type b antibody titer (0.30 mcg/L), a tetanus antibody titer which was protective (0.21 IU/mL), and pneumococcal titers which were protective (> 1.3 mcg/L) for nearly all serotypes covered by Prevnar 13. Lymphocyte immunophenotyping demonstrated a CD3+ count of 1340/ uL (normal range: 1484-5327), CD4+ count of 633 / uL (normal range: 733-3181), CD8+ count of 628/ uL (normal range: 370-2555), CD19+ count of 493/ uL (normal range: 370-2306), CD16/56+ count of 109/uL (normal range: 43-526). Decreased cytokine response to TLR agonists were documented by a commercial lab (ARUP Laboratories) using peripheral blood mononuclear cells (Figure 4). LPS-induced CD62L shedding in neutrophils is an additional potential screening test for TLR defects, but was not completed in this case4. Targeted sequencing of IRAK-4 and MyD88 was performed. A homozygous deletion of exons 8-13 was documented in IRAK-4 consistent with a diagnosis of IRAK-4 deficiency. There were no siblings; however, it is important to underscore the importance of screening other family members for the same pathogenic variants.

f57b165c-0d3c-46fc-a0dd-eede8c362258_figure4.gif

Figure 4.

Decreased cytokine response to toll-like receptor (TLR) agonists: A) TNF alpha, B) IL-1b, and C) IL-6 was measured following peripheral blood mononuclear cell (PBMC) stimulation with PAM3CSK4 (TLR2 and TLR1), zymosan (TLR2 and TLR6), Poly (I:C) (TLR3), flagellin (TLR 5), CLO97 (TLR7 and TLR8), and LPS (TLR4).

Following the diagnosis of IRAK-4 deficiency she was start on prophylaxis with intravenous immunoglobulin (0.5 g/kg/dose intravenously every 4 weeks) as well as amoxicillin (250 mg orally each day). From her diagnosis at 2 years of age until 4 years of age she continued to experience infrequent infectious complications including a urinary tract infection (Escherichia coli), left knee swelling in association with a abscess (methicillin-susceptible Staphylococcus aureus), and a single admission for fever, cough, and post-tussive emesis. She is now 6 years of age and doing well without any recent infectious complications. She remains compliant with her prophylaxis therapy with intravenous immunoglobulin therapy and amoxicillin which she has tolerated without complications.

Discussion

Detection of lipopolysaccharide and flagellin by TLRs results in the elaboration of pro-inflammatory cytokines3. TLRs possess an intracellular domain known as the Toll–IL-1R domain (TIR). Upon activation of TLRs, the recruitment of TIR-containing cytosolic adaptors such as MyD88 occurs. The adaptor MyD88 then recruits cytosolic kinases, including the IRAK complex. The IRAK complex includes two kinases including IRAK-4 and two non-catalytic subunits. This results in the activation of downstream effectors including nuclear factor κB (NF-κB) and mitogen-activated protein kinases which support the synthesis of pro-inflammatory cytokines and chemokines, such as IL-1β, -6, -8, and -12 and tumor necrosis factor alpha.

IRAK-4 deficiency is an autosomal recessive disorder which requires that affected patients have homozygous or compound heterozygous mutations in the IRAK-446. IRAK-4 deficient patients typically have normal basic immunological evaluations46. Importantly, inflammatory responses are markedly blunted as demonstrated by the severe and life-threatening invasive bacterial infection with P. aeruginosa in our patient accompanied by an absence of CRP elevation. In these patients, CRP concentrations can be strikingly misleading as IRAK-4 deficient patients demonstrate impairment in the ability to increase CRP concentrations and to mount fever responses.

Among IRAK-4 deficient patients with invasive bacterial infection, S. pneumoniae is the most frequently (~50% of episodes) implicated organism6. S. aureus and P. aeruginosa are less frequently (~20% of episodes) implicated organisms6. Patients with IRAK-4 deficiency may also experience a variety of minor non-invasive bacterial infections such as upper respiratory tract infections (otitis, sinusitis, pharyngitis) as well as SSTI (furunculosis, folliculitis cellulitis)6. Once again, the most frequently implicated organisms in these non-invasive bacterial infections among IRAK-4 deficient patients are S. pneumoniae, S. aureus, and P. aeruginosa.

Careful institution of aggressive supportive care measures is necessary for IRAK-4 deficient patients. Vaccines should include conjugated and nonconjugated vaccines for S. pneumoniae and N. meningitidis. Haemophilus influenzae type b conjugated vaccine should also be provided. Lifelong antibiotic prophylaxis with cotrimoxazole in combination with penicillin should be administered. Prophylaxis with intravenous or subcutaneous IgG should also be provided as a significant proportion of IRAK-4 deficient patients have impaired responses to glycans. Empiric parenteral antibiotic therapy against S. pneumoniae, S. aureus, and P. aeruginosa is critical whenever an infection is suspected or if the patient develops a fever. Inflammatory markers such as CRP should be considered unreliable. Importantly, patients may die from invasive bacterial infection despite prophylaxis even in the absence of fever or laboratory evidence of inflammation. The long-term prognosis of IRAK-4 deficient patients is positive as the risk of invasive infections tend to improve with age.

Although the occurrence of invasive P. aeruginosa infections in IRAK-4 deficiency is not novel, there is a vital and important educative message that bears repeating. Astute clinical judgment is necessary in the evaluation of patients with a potential inborn error of immunity. Clinical findings such as severe infections with P. aeruginosa should support the consideration of inborn errors of immunity including IRAK-4 deficiency.

Data availability

All data underlying the results are available as part of the article and no additional source data are required.

Consent

Written informed consent for publication of their clinical details and/or clinical images was obtained from the parent of the patient.

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Buchbinder DK, Singh J, Dao T et al. Case Report: Pseudomonas can take a toll on a patient [version 2; peer review: 2 approved]. F1000Research 2021, 10:526 (https://doi.org/10.12688/f1000research.53424.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 01 Jul 2021
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Reviewer Report 29 Jul 2021
Shanmuganathan Chandrakasan, Division of Bone Marrow Transplant, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA 
Approved
VIEWS 14
Very well-written case report of a child with IRAK4 deficiency. I have no major comments, few minor comments include:
  • Briefly discuss the role of CD62L shedding assay as another screening test.1
     
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Chandrakasan S. Reviewer Report For: Case Report: Pseudomonas can take a toll on a patient [version 2; peer review: 2 approved]. F1000Research 2021, 10:526 (https://doi.org/10.5256/f1000research.56805.r88939)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 21 Sep 2021
    David K. Buchbinder, Department of Hematology, CHOC Chidren's Hospital, Orange, 92868, USA
    21 Sep 2021
    Author Response
    Reviewer #2:

    Comment #1:
     
    Briefly discuss the role of CD62L shedding assay as another screening test.

    Response #1:

    Thank you for this excellent and important suggestion. ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 21 Sep 2021
    David K. Buchbinder, Department of Hematology, CHOC Chidren's Hospital, Orange, 92868, USA
    21 Sep 2021
    Author Response
    Reviewer #2:

    Comment #1:
     
    Briefly discuss the role of CD62L shedding assay as another screening test.

    Response #1:

    Thank you for this excellent and important suggestion. ... Continue reading
Views
14
Cite
Reviewer Report 05 Jul 2021
David Hagin, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 
Approved
VIEWS 14
I had a pleasure reading this case report. The authors nicely describe a rare case of IRAK-4 deficiency in a female patient with invasive pseudomonal infection.

The case report highlights several important issues. First, and most important, ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Hagin D. Reviewer Report For: Case Report: Pseudomonas can take a toll on a patient [version 2; peer review: 2 approved]. F1000Research 2021, 10:526 (https://doi.org/10.5256/f1000research.56805.r88936)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 21 Sep 2021
    David K. Buchbinder, Department of Hematology, CHOC Chidren's Hospital, Orange, 92868, USA
    21 Sep 2021
    Author Response
    Reviewer #1:

    Comment #1:

    Decreased cytokine response to TLR agonists: Was that performed by a commercial lab? If so, I think I would mention it so readers would ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 21 Sep 2021
    David K. Buchbinder, Department of Hematology, CHOC Chidren's Hospital, Orange, 92868, USA
    21 Sep 2021
    Author Response
    Reviewer #1:

    Comment #1:

    Decreased cytokine response to TLR agonists: Was that performed by a commercial lab? If so, I think I would mention it so readers would ... Continue reading

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 01 Jul 2021
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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