Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is a primary immune deficiency of the innate immune system. Children with this condition are susceptible to life-threatening bacterial infections. IRAK-4 deficiency results in reduced or absent systemic features of inflammation despite overwhelming infection. We present 2 siblings who died in infancy after rapidly progressive Pseudomonas sepsis and meningitis. There was diagnostic uncertainty in the firstborn infant because of significant intracranial hemorrhages. This was confounded by a failure to mount an inflammatory response. As such, it was difficult to distinguish between possible nonaccidental injuries and an infectious cause. Perimortem genetic analysis of the second-born infant identified a known mutation in IRAK-4. We intend to raise awareness of IRAK4 deficiency, highlight the importance of considering primary immune deficiencies in the differential of unusually severe infection, document progressive intracranial radiologic changes seen in overwhelming Pseudomonas meningitis and discuss the differences in the radiologic features seen in abusive head trauma within this age group.

More than 430 different primary immunodeficiencies have been described with an overall incidence of ∼1:10 000.1  Over recent years, next-generation sequencing has improved the understanding and increased the number of recognized primary immune deficiencies. Autosomal recessive interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is a rare primary immune deficiency first discovered in 2003. The prevalence is unknown, but there is a cumulative mortality of 30% to 40% reported, with meningitis being the most frequently occurring invasive bacterial infection (41.2%).2  IRAK-4 is a protein kinase crucially involved in the signaling cascade induced by toll-like receptors (TLRs) as part of the innate immune system. Patients with IRAK-4 deficiency suffer from recurrent invasive pyogenic infections in childhood. They are particularly susceptible to Streptococcus pneumoniae, Staphylococcus aureus, and, less commonly, Pseudomonas aeruginosa and Salmonella species.3  Diagnosis involves demonstrating an impaired response to TLR agonists and then genetic confirmation.

A 5-week-old boy was referred to the hospital with a 24-hour history of poor feeding, vomiting, and a temperature of 38.3°C. He was born at 39 + 3 weeks without risk factors for infection and was thriving. The parents were not consanguineous.

On admission, observations were normal apart from a raised blood pressure (133/80), thought to be an unreliable recording. The only significant finding was a small red, circular macule of uncertain cause above his right knee. Blood and urine samples were taken for culture, and treatment with intravenous cefotaxime and amoxicillin was started. Initial laboratory results revealed C-reactive protein (CRP) 10.1 mg/L, white cell count (WCC) 3.9 × 109/L, neutrophils 1.4 × 109/L, lymphocytes 2.1 × 109/L, and platelets 339 × 109/L.

Nine hours after admission, he was noted to be hypothermic, grunting, and still hypertensive. He was intubated because of severe apneas. A computed tomography (CT) scan of the head was performed (Fig 1).

FIGURE 1

Selected axial images of an unenhanced CT head from cranial to caudal. (A) Demonstrates a small volume of extra axial blood overlying the convexity of the left frontal lobe (white arrow), (B) Demonstrates a small focus of high attenuation with the left lateral ventricle in keeping with acute intraventricular hemorrhage (white arrowhead), (C) Small area of parenchymal hemorrhage at the gray white matter junction of the left paramedian frontal and right paramedian parietal lobes (black arrow), (D) Extension of the parenchymal hemorrhage into the left parafalcine extraaxial space (black arrowhead).

The gray/white matter differentiation is preserved throughout and there is no evidence of cerebral swelling. There was no hyperdensity within the venous sinuses.

FIGURE 1

Selected axial images of an unenhanced CT head from cranial to caudal. (A) Demonstrates a small volume of extra axial blood overlying the convexity of the left frontal lobe (white arrow), (B) Demonstrates a small focus of high attenuation with the left lateral ventricle in keeping with acute intraventricular hemorrhage (white arrowhead), (C) Small area of parenchymal hemorrhage at the gray white matter junction of the left paramedian frontal and right paramedian parietal lobes (black arrow), (D) Extension of the parenchymal hemorrhage into the left parafalcine extraaxial space (black arrowhead).

The gray/white matter differentiation is preserved throughout and there is no evidence of cerebral swelling. There was no hyperdensity within the venous sinuses.

Close modal

The radiology demonstrated small foci of parenchymal hemorrhage at the gray/white matter junction of the cortex with small volumes of extraaxial and intraventricular hemorrhage. There was no evidence of gross cerebral edema or ischemia nor of venous sinus thrombosis.

Eighteen hours after admission, he suffered a cardiac arrest but had a spontaneous return of circulation after epinephrine. A repeat review of CT images raised the additional possibility of abusive head trauma (AHT).

Repeat laboratory results revealed CRP (17.5 mg/L) and WCC (2.2 × 109/L). Given the unremarkable blood results, CT findings possibly consistent with AHT and an unexplained red mark on his right knee, the admitting clinical team commenced safeguarding procedures.

At 19 hours, he had a cardiac arrest and died after cessation of resuscitation. Two hours after death, the blood culture was reported as positive for Pseudomonas aeruginosa. The red mark was retrospectively thought to be ecthyma gangrenosum typically found in Pseudomonas sepsis.

The imaging was subsequently reviewed, and findings were reported to be in keeping with an infectious process and bacterial meningitis, not typical for AHT. An MRI scan of the head would have been more sensitive to evaluate for subtle hypoxic injury.

Eighteen months later, the brother of patient 1 was referred at 5 days of age because of increasing lethargy and emesis. He had been born at term and observed for 12 hours postnatally because of prolonged rupture of membranes (33 hours). His admission temperature was 38°C with a blood pressure of 119/79. He seemed well otherwise but was commenced on cefotaxime and amoxicillin. Initial laboratory results revealed CRP 0.3mg/L and WCC 9.6 × 109/L. Within 6 hours, he developed clinical seizures. A head CT was performed, and gentamicin was added to cover possible Pseudomonas in light of his brother’s history (Fig 2).

FIGURE 2

Selected axial images of an unenhanced CT head (cranial to caudal). (A) Demonstrates a small volume of acute hemorrhage within the lateral ventricles (white arrow demonstrates the hemorrhage within the occipital horn of the left lateral ventricle, (B & C) small volume of hemorrhage within the ambient cisterns (white arrowhead), (D & E) shows acute hemorrhage within the posterior fossa centered on the left cerebellopontine angle (black long arrow). There is also effacement of the fourth ventricle, increasing mass effect on the cerebellum and brainstem and some low attenuation within the left cerebellar hemisphere (short black arrow), (F) select image of a computed tomography angiogram shows a focal area of enhancement post contrast which would be consistent with a small aneurysm of the left PICA(black and white arrow).

FIGURE 2

Selected axial images of an unenhanced CT head (cranial to caudal). (A) Demonstrates a small volume of acute hemorrhage within the lateral ventricles (white arrow demonstrates the hemorrhage within the occipital horn of the left lateral ventricle, (B & C) small volume of hemorrhage within the ambient cisterns (white arrowhead), (D & E) shows acute hemorrhage within the posterior fossa centered on the left cerebellopontine angle (black long arrow). There is also effacement of the fourth ventricle, increasing mass effect on the cerebellum and brainstem and some low attenuation within the left cerebellar hemisphere (short black arrow), (F) select image of a computed tomography angiogram shows a focal area of enhancement post contrast which would be consistent with a small aneurysm of the left PICA(black and white arrow).

Close modal

He was intubated and transferred to the tertiary pediatric hospital, where he deteriorated on arrival. He required hypertonic saline boluses for presumed raised intracranial pressure. A second CT head scan revealed progressive hydrocephalus, and an external ventricular drain was inserted. A cranial MRI was performed (Figs 3 and 4).

FIGURE 3

Selected MRIs from the diffusion weighted imaging (B1000). (A–D) The corresponding ADC map, (Aa–Dd) shows extensive focal areas of restricted diffusion including multiple areas throughout both cerebral hemispheres (long white arrows), the right thalamus (long black arrow), the head of the right caudate nucleus (white arrowhead) and pons (black and white arrow).

FIGURE 3

Selected MRIs from the diffusion weighted imaging (B1000). (A–D) The corresponding ADC map, (Aa–Dd) shows extensive focal areas of restricted diffusion including multiple areas throughout both cerebral hemispheres (long white arrows), the right thalamus (long black arrow), the head of the right caudate nucleus (white arrowhead) and pons (black and white arrow).

Close modal
FIGURE 4

(A & B) selected axial T2 MRIs, (C & D) selected axial T1 images.

These demonstrate small areas of hemorrhage within the ventricles (black arrow), within the left cerebellopontine angle and overlying the cerebellar hemisphere (short white arrow c and d respectively). There is multifocal abnormal T2 hyperintensity, several of which correspond to the areas of restricted diffusion, such as the head of the right caudate nucleus (long white arrow).

FIGURE 4

(A & B) selected axial T2 MRIs, (C & D) selected axial T1 images.

These demonstrate small areas of hemorrhage within the ventricles (black arrow), within the left cerebellopontine angle and overlying the cerebellar hemisphere (short white arrow c and d respectively). There is multifocal abnormal T2 hyperintensity, several of which correspond to the areas of restricted diffusion, such as the head of the right caudate nucleus (long white arrow).

Close modal

Despite ongoing intensive care, he died 12 hours later. Postmortem findings revealed the cause of death to be sepsis secondary to Pseudomonas aeruginosa, isolated in cerebrospinal fluid.

Pediatric immunologists advised perimortem blood to be sent for whole exome genomic sequencing. This identified a pathogenic homozygous nonsense variant in exon 8 of the IRAK-4 gene (NM_016123.3:c.877C>T p.(Gln293Ter), location:Chr12:g. 44172041C>T) consistent with the diagnosis of IRAK-4 deficiency.4,5  The parents were subsequently confirmed as carriers. Antenatal diagnoses have since supported the birth of a daughter in good health (carrier) and then a further affected son. Experts were consulted and a multidisciplinary management plan was initiated for the further affected son. Antibiotic prophylaxis was to start after delivery. This needed to include gram-negative coverage until the infant achieved protective antibody levels. He received amoxicillin and ciprofloxacin from birth. At 2 weeks of age, immunoglobulin supplementation was commenced, and routine were vaccines given. At 4 weeks of age, cotrimoxazole replaced ciprofloxacin for longer-term prophylaxis. He remains healthy at 14 months of age. It is presumed the first sibling had the same IRAK-4 gene mutation.

Surface membrane TLRs recognize pathogen-associated molecular patterns from a variety of microbes. Recognition leads to the activation of complex signaling pathways, resulting in the induction of the innate immune system and the production of inflammatory cytokines and other mediators.6  TLR signaling pathway defects, including IRAK-4 deficiency, are rare but important to consider because of the life-threatening consequences. Those with such signaling pathway deficiencies have an impaired ability to mount an inflammatory response.7  This is reflected by a minimal rise in temperature and inflammatory markers in the presence of invasive bacterial infection.

In those with IRAK-4 deficiency, the first invasive infection usually occurs before 2 years of age (88%), with 33% occurring in the neonatal period.2  The mainstay of treatment in IRAK-4 deficiency is antibiotic prophylaxis and immunoglobulin replacement.7  Although the rate of infections is thought to decrease with age, a 31-year-old is reported to have had ongoing infections due to IRAK-4 deficiency.8  The duration of immunologic supportive treatment may need to be lifelong pending further knowledge.

Empirical antibiotic regimens in sepsis balance the need for broad-spectrum coverage against antibiotic toxicity and potentiating antibiotic resistance.9  It should be remembered that uncommon organisms, such as Pseudomonas, may not be covered by empirical antibiotic regimes for immunocompetent children. In critically ill children, further consideration should be given to patient-specific risk factors that may necessitate broadening antibiotic coverage,9,10  including a potential underlying immune deficiency or possible resistant organism.

Pseudomonas is a rare cause of meningitis,11  particularly in those without intraventricular catheters or previous neurosurgical procedures.12  The presence of an unusual organism causing severe infection should raise the possibility of an underlying immune deficiency. An immunologist should be consulted about appropriate laboratory investigations and subsequent clinical management. It is also important to develop plans for future pregnancies by using a multidisciplinary team approach to facilitate prenatal screening, raise awareness of possible postnatal infection risks, and, potentially, commence prophylactic antibiotics at birth in situations of diagnostic uncertainty.

Cranial CT is often the first-line imaging modality employed to assess critically ill children because MRI studies often require sedation or a general anesthetic. However, MRI can better identify patterns of complications due to meningitis caused by specific organisms. In infants, extensive infarcts are reported to be more typical of streptococcal meningitis13  and early hydrocephalus in Escherichia coli meningitis.14  Radiologic patterns of Pseudomonas meningitis are poorly documented. The authors of a single case of an 81-year-old patient report a massive left hemisphere intraparenchymal hemorrhage with midline shift due to Pseudomonas meningitis.15  The serial images we present reveal extensive subarachnoid, parenchymal, and intraventricular hemorrhage, as well as multifocal acute ischemia, in an immunocompromised child with overwhelming Pseudomonas meningitis. The ischemia is due both to perforator infarcts to deep structures, as well as cortical ischemia, which may partly relate to hypoperfusion and cortical vascular inflammation.

Several radiologic findings are typically associated with AHT. The anatomy of the infant brain predisposes them to certain types of injury. They have a large head size relative to their body and weak neck muscles. Their brains have relatively higher water content and reduced myelination compared with adults. Key findings of AHT are described in Table 1. AHT must be considered with multifocal areas of parenchymal and extraaxial hemorrhage. The differential always includes infection, metabolic conditions, and clotting disorders. Evaluating for an underlying coagulopathy is recommended acknowledging that AHT and a bleeding disorder may coexist.16  However, in sibling 1, the pronounced subarachnoid and gray/white matter parenchymal hemorrhages and, in sibling 2, the multiterritory, peripheral infarcts with an absence of subdural hemorrhage and more focal white matter hemorrhages were not consistent with AHT. Intraventricular hemorrhage and punctate parenchymal hemorrhages are relatively rarely seen in AHT and should heighten consideration of another diagnosis. All of the other features revealed on the CT scans of these 2 siblings may be seen in AHT.

TABLE 1

Key Radiologic Findings Found in AHT

Radiologic FindingFurther Description
Soft tissue hemorrhage — 
Skull fractures in the absence of a clear corresponding history of trauma Linear fractures are commonly seen with AHT.
Depressed, comminuted and diastatic fractures of any bone can be seen in AHT. 
Subdural hematomas Especially of differing imaging appearances, which may include traumatic effusions. 
Cortical lacerations (aka shear injuries) hemorrhages involving the white and gray matter Due to tearing of the surface of the brain from shaking AHT.
Cortical contusions directly under impact injuries to the skull or contrecoup contusions are associated with impact AHT. 
Hypoxic ischemic injury Multifocal areas of ischemia not conforming to vascular territories are most commonly associated with shaking AHT. 
Radiologic FindingFurther Description
Soft tissue hemorrhage — 
Skull fractures in the absence of a clear corresponding history of trauma Linear fractures are commonly seen with AHT.
Depressed, comminuted and diastatic fractures of any bone can be seen in AHT. 
Subdural hematomas Especially of differing imaging appearances, which may include traumatic effusions. 
Cortical lacerations (aka shear injuries) hemorrhages involving the white and gray matter Due to tearing of the surface of the brain from shaking AHT.
Cortical contusions directly under impact injuries to the skull or contrecoup contusions are associated with impact AHT. 
Hypoxic ischemic injury Multifocal areas of ischemia not conforming to vascular territories are most commonly associated with shaking AHT. 

—, not applicable.

These cases reveal the importance of considering infection in unwell children and not dismissing it on the basis of a lack of fever and a rise in inflammatory markers. This is particularly important in young infants when an overwhelming infection may be the first presentation of a primary immune deficiency. Broadening the antimicrobial cover may be necessary if this is suspected. Every case of unusual infection should prompt the consideration of a primary immune deficiency and a discussion with an immunologist who will be able to advise on the most appropriate clinical management and diagnostic testing. Although AHT must be considered for all encephalopathic neonates and infants, this must be in parallel with investigations for other diagnoses.

Drs Waruiru and Connolly conceptualized the article and critically reviewed and revised the manuscript; Drs Hardman and Martin helped conceptualize the article, drafted the initial manuscript, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

AHT

abusive head trauma

CRP

C-reactive protein

CT

computed tomography

IRAK-4

interleukin-1 receptor-associated kinase 4

TLR

toll-like receptor

WCC

white cell count

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