Alasdair Munro. He’s always sick: ENT infections and immunodeficiency, Don't Forget the Bubbles, 2019. Available at:
https://doi.org/10.31440/DFTB.20243
Otis is a 3yr old boy presenting to the emergency department with fever, and purulent discharge from his left ear. He otherwise looks well, however, his mother mentions this is his third ear infection since he was born, and he always seems to have a cough and a cold. She asks you if there could be a problem with his immune system?
Some children seem to have constant ear, nose or throat infections during childhood. We know that for a small, but important minority of children this may be the presenting feature of a primary immunodeficiency. Let’s look at how these may present, when to think of it, and what to do about it.
Primary immunodeficiency is rare
It’s worth stating from the outset, that the majority of children with recurrent ENT infections will not have a primary immunodeficiency. There is a relatively common phenomenon called “physiological immunodeficiency of infancy”, where-by there is a natural nadir in immunoglobulin levels as maternal immunoglobulin fades, and the child’s own immune system has only just become able to produce immunoglobulin for itself. This is at its lowest between 3-6 months and normally resolves by age 1. However, fully developed protection against encapsulated organisms doesn’t reach maturity until between 2-5 years, and IgA production doesn’t reach adult levels until adolescence. It can be completely normal for young children to suffer 4-11 respiratory infections a year (depending on exposure, e.g. siblings, nursery, etc.)
When should I suspect immunodeficiency?
When considering the characteristics of infections that should trigger suspicion for immunodeficiency, we should be thinking about:
More severe infections than is usual
Combined immunodeficiency disorders (affecting both cellular and humoral immunity), such as severe combined immunodeficiency (SCID), present in the first 3-6 months with severe, life-threatening infection. Unusually aggressive infections should prompt further investigation
Infections with unusual organisms
Infections with certain pathogens can point towards specific diagnoses, including respiratory infections with Pseudomonas aeruginosa (think cystic fibrosis or primary ciliary dyskinesia), oral/oesophageal candidiasis (think HIV or chronic granulomatous disease), upper respiratory infections with Pneumocystis carinii (think HIV or other T cell deficiencies) or recurrent otitis/sinusitis with Neisseria meningitidis (think complement deficiency).
Finally, to a lesser extent:
Frequency of infection
This is the least predictive of immunodeficiency, given the discussion above. Very frequent sinopulmonary infections in younger children with encapsulated bacteria can be the presenting feature of the rare condition X-linked agammaglobulinaemia (XLA: boys who produce no immunoglobulins). In late childhood and adolescence, the same presentation in a milder form may be a sign of combined, variable immunodeficiency (CVID), which is a heterogeneous group of disorders of antibody production.
Other, rare conditions include chronic granulomatous disease (CGD) which may present with deep abscesses of the outer ear or mastoid, or HIV presenting with recurrent otitis media (normally with other associated features)
When to refer
Some general guidelines have been produced by the Jeffrey Modell foundation for when to consider referral for immunodeficiency workup:
- Four of more new ear infections within 1 year
- Two or more serious sinus infections within 1 year
- Two or more months on antibiotics with little effect
- Two or more pneumonias within 1 year
- Failure of an infant to gain weight or grow properly
- Recurrent, deep skin or organ abscesses
- Persistent thrush in the mouth or fungal infection on skin
- Need for intravenous antibiotics to clear infections
- Two or more deep-seated infections including septicaemia
- A family history of primary immunodeficiency
Although having a low specificity, they provide a useful framework when thinking of children with more severe infections than usual.
Should I do some tests?
If considering referral, there are definitely some basic tests are useful to do first (if the child is severely unwell, don’t wait for tests to refer).
Full blood count
This is useful for ANY suspected immunodeficiency. Persistent lymphopaenia in a child <2yrs should prompt screening for SCID.
NB: It can be normal to have transient lymphopaenia or neutropaenia in isolation in young children following a viral illness. Incidental neutropaenia does not need repeat testing if there are no concerns about underlying immunodeficiency.
Immunoglobulins
IgG, IgM and IgA levels are useful to investigate children with recurrent ENT/airway infections.
It is also worth considering an HIV test if symptoms are consistent, but ensure you have a discussion with parents before testing.
If both FBC and immunoglobulins are normal in the setting of recurrent infections, it is perfectly acceptable to wait for 3 -6 months to see if the condition improves before referral.
Conclusions
- Primary immunodeficiencies are rare but important, and ENT infections may be the presenting feature
- The severity of infection and presence of opportunistic pathogens are a much stronger predictor than the frequency of infections
- Basic tests such as FBC and Immunoglobulins should be performed in children prior to/pending referral if they are not severely unwell
- Consider investigation and referral for primary immunodeficiency early in children with severe infections and failure to thrive, or those with family history
Further reading: https://www.entmasterclass.com/ENT_Journal_2019_Interactive.pdf page 9
Guillain-Barre Syndrome
Aoife Fox. Guillain-Barre Syndrome, Don't Forget the Bubbles, 2020. Available at:
https://doi.org/10.31440/DFTB.25051
A 2-year-old girl, Amy, attends the emergency department. Her father says that for the last 24 hours she has been refusing to walk. Prior to this, she was running amuck without difficulty. In the ED, you notice that she is now having difficulty crawling. She has no significant medical history but did have fever along with a runny nose and cough 2 weeks prior to her attendance which her parents managed with paracetamol at home.
What is Guillain-Barré Syndrome?
Guillain-Barré Syndrome (GBS) is a group of acute immune-mediated polyneuropathies. It most commonly presents as an acute monophasic, paralyzing illness provoked by a preceding infection.
It is the most common cause of acute flaccid paralysis in children. The annual incidence is 0.34 to 1.34 cases per 100,000 in under the 18s, which makes it less common in children than in adults. It rarely occurs in children younger than 2 years, but when it does affect younger children because GBS is way off our radars, this can make it really tricky to diagnose. Boys are affected more often than girls.
What causes it?
It’s thought that an immune response cross-reacts with the myelin or axon of peripheral nerves due to molecular mimicry. Similar peptide sequences between the body’s own peptides and foreign peptides sometimes cause the immune system to get confused and attack its own tissues. You probably knew that myasthenia gravis is due to auto-antibodies against the acetylcholine receptor but did you know that the receptor shares a 7 amino acid sequence with HSV, the herpes simplex virus? It’s thought that exposure to HSV may be the precipitant for myasthenia gravis.
Approximate 2/3 of patients give a history of an antecedent respiratory tract or GI infection. Campylobacter infection is the most commonly identified precipitant and can be demonstrated in as many as 30% of cases. Other infectious precipitants include CMV, EBV, Mycoplasma pneumoniae, and influenza-like illnesses.
Other suggested triggers include immunization, although there is no clear causal relationship several cases suggest an association, as well as one with trauma and surgery.
What about Guillain Barre and COVID?
There have been several case studies reporting GBS associated with SARS-CoV-2 during the COVID-19 pandemic. Given the small number of cases, it is unclear whether severe neurological deficits are typical features of COVID-19 associated GBS. An answer to the diagnostic conundrum of whether the respiratory compromise in COVID19-associated-GBS is due to coronavirus or muscle weakness is yet to be answered.
How can I recognize it?
GBS classically begins with paraesthesia in the extremities – fingers and toes – followed by lower extremity symmetric, or modestly asymmetric, weakness that ascends up the body. In severe cases, the muscles of respiration are affected, in about 10-20% of children.
Cranial neuropathy can also occur, most commonly affecting facial nerves, causing bilateral facial weakness.
Autonomic dysfunction occurs in approximately half of children with GBS: cardiac dysrhythmias, orthostatic hypotension, hypertension, paralytic ileus, bladder dysfunction, sweating.
Physical exam typically reveals:
Generally, children have shorter clinical courses and more complete recoveries in comparison to adults. A child’s function typically deteriorates for 2-4 weeks followed by a slow return of function over the coming weeks to months.
On examination, you find a quiet child who is otherwise acting appropriately. She is afebrile and the rest of her vitals are within normal limits. No bruises or rashes are observed on her skin and there is no evidence of trauma. Cardiovascular, respiratory, abdominal and ENT exams are unremarkable. Her extremities are warm and well perfused with normal pulses. There is no bony tenderness or deformities on palpation of her limbs. On neurological examination, she is moving all 4 limbs spontaneously. However, she will not bear weight or stand. Both her lower limbs are weak on exam. Her grip strength is reduced and when given a toy, it falls. Both upper and lower extremity reflexes are absent.
Subtypes
GBS most commonly presents in the classical way above: a mixed motor and sensory polyneuropathy with lower limb pain and ascending weakness. This is the classic Acute Inflammatory Demyelinating Polyradiculopathy (AIDP), which accounts for 85 to 90% of cases in the developed world. But, there are a few other subtypes of GBS you should be aware of.
Acute Motor Axonal Neuropathy (AMAN), is a purely motor from of GBS, occurring mainly in Asia, Central and South America and associated with a preceding Campylobacter infection. Its clinical features are similar to AIDP, but respiratory failure is more common.
Acute Motor-Sensory Axonal Neuropathy (AMSAN) is similar to AMAN but with more sensory symptoms. The course tends to be prolonged and severe but is pretty uncommon in children.
Miller-Fisher syndrome is characterized by an external ophthalmoplegia, ataxia and muscle weakness with areflexia. It affects adults more commonly than children but should definitely be on your radar in a child presenting with cranial nerve and lower limb neurology.
How can it be diagnosed?
The initial diagnosis of GBS is based on the history and clinical exam – be suspicious of a child with lower limb weakness, weak reflexes and a preceding illness. Use investigations to confirm your suspicion.
CSF
CSF protein above 45mg/dL with a normal WCC count is present in 50-66% of patients in the first week after symptoms onset and ≥75% of patients in the third week. This disconnect between protein and white cells is called albuminocytologic dissociation.
Gadolinium-enhanced MRI of Spine
MRI will show contrast enhancement of the spinal nerve roots, cauda equina or cranial nerve roots. These changes aren’t specific to the GBS, but can be helpful in the correct clinical setting.
Nerve conduction studies
This is the most specific and sensitive test available for GBS, abnormal in up to 90% of cases. The test can be technically difficult in small children.
Antibodies
Antibodies against GQ1b (the ganglioside component of a nerve) are present in the vast majority of patients with Miller-Fisher syndrome.
In the emergency department, you send baseline bloods (FBC, U&E, LFTs and CRP) which are all normal and organize a CT head under sedation which is unremarkable. After getting consent from her parents you perform a lumbar puncture. The CSF appears clear. It has no red blood cells, 2 white blood cells and CSF glucose is within the normal limits but her protein is mildly elevated. No organisms were seen on gram stain and cultures had no growth after 5-days. You refer her to the neurology team for further investigation.
What else could it be?
The differential diagnosis of GBS is long.
Brain
Spine
Peripheral nervous system
Neuromuscular junction
Muscle
What is the treatment?
The mainstay of treatment is supportive management including close monitoring of motor, autonomic and respiratory function as well as pain management and prevention of immobility complications, such as pressure ulcers. ICU admission for mechanical ventilation will be required in 10-20% of kids. This is more likely to be needed in children with:
In addition IV immunoglobulin (IVIG) and plasmapheresis (plasma exchange) can be used in children with severe, progressive GBS (i.e. worsening respiratory status or need for mechanical ventilation, rapidly progressing weakness, inability to walk unaided or significant bulbar weakness).
IVIG is typically preferred to plasmapheresis in children due to its better safety record and ease of administration
Plasmapheresis can be useful in bigger children where technically it is more feasible to perform. However, there are no reliable studies to suggest one has better efficacy than the other in children.
During her admission, Amy has a Gadolinium-enhanced MRI of the spine and nerve conduction studies which are consistent with the acute inflammatory demyelinating polyradiculopathy (ADIP) subtype of GBS. She is given IVIG. She does not develop any respiratory complications. On discharge after three weeks, her weakness is greatly improved and completely resolves over the next two months.
Bottom line
Selected references
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Yuki N, Hartung H-P. Guillain–Barré Syndrome. New England Journal of Medicine [Internet]. 2012 Jun 14 [cited 2020 Apr 5];366(24):2294–304. Available from: https://doi.org/10.1056/NEJMra1114525
Rudant J, Dupont A, Mikaeloff Y, Bolgert F, Coste J, Weill A. Surgery and risk of Guillain-Barré syndrome: A French nationwide epidemiologic study. Neurology. 2018 25;91(13):e1220–7.
Hicks CW, Kay B, Worley SE, Moodley M. A clinical picture of Guillain-Barré syndrome in children in the United States. J Child Neurol. 2010 Dec;25(12):1504–10.
Dimachkie MM, Barohn RJ. Guillain-Barré Syndrome and Variants. Neurol Clin [Internet]. 2013 May [cited 2020 Apr 5];31(2):491–510. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3939842/
Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. The Lancet [Internet]. 2016 Aug 13 [cited 2020 Apr 5];388(10045):717–27. Available from: https://www.sciencedirect.com/science/article/pii/S0140673616003391
Ryan MM. Pediatric Guillain-Barré syndrome. Curr Opin Pediatr. 2013 Dec;25(6):689–93.
Hughes RAC, Wijdicks EFM, Barohn R, Benson E, Cornblath DR, Hahn AF, et al. Practice parameter: Immunotherapy for Guillain–Barré syndrome. Neurology. 2003 Sep 23;61(6):736.