| Topic | Immunodeficiencies |
| Author | Ravi Mistry |
| Expert Reviewer | Sanjay Patel |
| Facilitator Level | ST4+ |
| Learner level | Case 1: Foundation doctors, paediatric trainees, paediatric nurses, GPs; Cases 2+3: Paediatric trainees. |
| Equipment Required | None |
● Background – setting the scene and objectives for this module
● Main session – 3 x 10-15 minute cases covering 3 different cases
relating to immunodeficiencies.
Ideally the cases should be reviewed sequentially as learning points from one are built upon in subsequent cases with a focus on what the general paediatrician should know about immunodeficiencies.
■ Case 1 focuses on a case seen in the emergency department and explores the common parental query of a “weak immune system” in a young child who has had several recurrent upper respirator tract infections back-to-back but is otherwise well.
■ Case 2 focuses on an immunodeficiency case that will more commonly be seen in district general hospitals and their day units for on going care
■ Case 3 focuses on a SCID presentation and outlines their initial investigations in a secondary care setting before tertiary involvement
● Quiz – 5 minutes
● Learning points – 3 minutes
https://www.youtube.com/watch?v=_jBpv9fYSU4
or https://www.youtube.com/watch?v=gR84OJ_EGxk – for those wanting a refresher of key elements of immunophysiology, watch one of these two videos provide an overview. The first video being a little more detailed. (15 mins)
Jeffrey Modell Foundation: 10 warning signs of primary Immunodeficiency in children –https://res.cloudinary.com/info4pi/image/upload/v1662306260/JMF_10_Signs_Generic_Poster_photo_resize_900x1177_60a2a7ce56394_original_411895405a.jpg (1 minute
https://www.paediatricfoam.com/2020/09/immunodeficiency/ (10 mins) a clinically
orientated overview of immunodeficiency in children
Primary immunodeficiencies (PI), or inborn errors or immunity (IEI), are a group of
rare genetic conditions resulting in the abnormal function or complete inactivity
of one or more parts of the immune system. Severe forms of PI can present early
in life and can be life-threatening – for example, a neonate with severe combined
immunodeficiency (SCID). Other PIs are more subtle and result in patients
presenting with frequently recurring infections.
There are many PIs and identifying the affected gene should not be the focus for
a general paediatrician. However, understanding the basic components of the
immune system and how they protect against different pathogens can help the
general paediatrician decide if a child with recurrent infections warrants first-line
investigations for an underlying immunodeficiency.
Early detection is vital for two reasons. Firstly it minimises the scope for ongoing
complications that ensue following recurrent, potentially life-threatening, infections.
Secondly, detecting PIs can allow for the either prophylactic treatment to be
given or potentially a curative option via a bone marrow transplant.
For the general paediatrician it is important to know several pieces of knowledge
in relation to this topic. This includes:
- Having a grasp of what is normal and what is not, so as to know when to
consider primary immunodeficiency. - Knowing factors that increase the chances of there being an underlying
primary immunodeficiency. - Knowing what first-line investigations to order when evaluating a child for
primary immunodeficiency.
This module aims to cover the above three points with cases a general
paediatrician may encounter.
A 3 year old boy is brought to emergency department and treated for viral
induced wheeze. This is fifth episode in the last six months. His parents report he seems to “constantly” have infections and are struggling to recall a stretch of time recently where he hasn’t been unwell. She wonders if he has a “weak immune system”. In the last year, he has had multiple attendances to the emergency department and to his GP, and been prescribed two courses of oral antibiotics. He is gaining weight along the 50th centile. His birth history was unremarkable, with no input from the neonatal team after he was born. His immunisations are also all up-to-date.
What is your current impression and what would you like to ask the parents?
Based on the above information, what would say to the parents?
This 3 year old boy appears to have had a number of viral upper respiratory tract
infections, resulting in recurrent episodes of viral induced wheeze. Although he
has been prescribed 2 courses of oral antibiotics, it is unclear whether these were
indeed required. He has had no serious invasive infections requiring intravenous
antibiotics or hospitalisation. It is encouraging that he is thriving. Parents should
be advised that it is normal for young children to get approximately 10 upper
respiratory tract infections each year. These will usually be concentrated in the
winter months and may make it seem like their child is constantly unwell.
Is there any evidence behind this?
Two studies can help evidence this. The first is by Gruber et al (2008) where parents kept a symptom diary for 12 years tracking the number of symptomatic episodes their children had. Their data shows the upper limit of what can be a ‘normal’ number of annual URTIs in children aged under 5 years is approximately 11. This drops markedly as children go through primary school, falling to 4 per year.
Another useful study showing the distribution of viral infection in different ages
and household setups comes from the BIG LoVE study (2015) where households
had viral PCR swabs completed weekly for a year. Children under 5 years of age
had virus detected 50% of the time and households with 2 children or more also
tested positive over 50% of the time too. The detection rate halved for children
aged over 5 years old. This is summarised in Figure 1. This study does have limitations in that swab PCR positivity doesn’t necessarily indicate active infection and in some cases patients were asymptomatic. But it nonetheless can serve as a useful aid in highlighting the burden of viruses young children compared to those who are older.
Figure 1. Prevalence of virus detection in (a) patients by age, and (b) number of children per household. Adapted from: Byington et al (2015, Clinical Infectious Disease, https://doi.org/10.1093/cid/civ486)
When to think about primary immunodeficiency?
In terms of thinking about whether there is an underlying immunodeficiency,
it is useful to think of the SPUR acronym. Has the child had any:
- Severe infections
- Persistent infections
- Unusual infections
- Recurrent infections
In terms of exploring other risk factors, there’s the ten signs of primary immunodeficiency from the European Society of Immunodeficiencies which includes some of the above and a few more. Having two of more should prompt clinicians to consider whether the patient has a primary immunodeficiency. These are:
- ≥ 4 ear infections in one year
- ≥ 2 severe sinus infections in one year
- ≥ 2 months treatment of antibiotics with little effect
- ≥ 2 pneumonias within one year
- Faltering growth
- Recurrent deep skin or organ abscesses
- Persistent thrush in mouth or fungal infection on skin
- Need for intravenous antibiotics to clear infections
- ≥ 2 deep seated infections (meningitis, septicaemia, osteomyelitis)
- Family history of a primary immunodeficiency
How well evidenced is this?
This list is not exhaustive and should be viewed as a screening tool. Several papers
have identified the most common features from the classical warning signs are
having a family history of a PI, faltering growth, and the need for intravenous
antibiotics. Additionally, parental consanguinity increases the risk of a primary
immunodeficiency 6-fold.
A retrospective review of patients with PI found that having one warning sign had
a sensitivity of 100%; that is, every patient with a PI had at least one warning sign.
However, 72% of control patients in the study also had one warning sign. With
two warning signs, the sensitivity falls to 94%, with a specificity of 64% and a positive predictive value and negative predictive value of 68% and 92% respectively.
Back to our patient…
From the history we have so far on the patient, there’s no red flags to consider
a primary immunodeficiency. Parents of young children will regularly pose the
question of whether their children have a “weak immune system” in view of lots of
repeated upper respiratory tract infections in particular. In this case, it would be
sensible to try to reassure the parent that if they don’t have any worrying signs;
that as frustrating and difficult as it may seem, these recurrent ‘simple’ infections
are within normal limits of childhood; and that as the child grows up, we’d expect
him to have fewer infections.
A 2 year old boy is referred to the paediatric clinic. His parents and GP are
concerned about him having recurrent infections. He was born at term with an
unremarkable antenatal and postnatal course. His growth and development
have been satisfactory and he has received his routine immunisations to-date. Of concern is the recurrent number of ENT and respiratory tract infections he had which have required antibiotics. He has been treated four times for pneumonia, two of which were confirmed radiologically and required hospitalisation, and he has also experienced recurrent bouts of otitis media. His parents are non-consanguineous and there’s nobody else in his wider family with recurrent infections.
On examination you hear right sided inspiratory crackles and his parents inform you he has just finished a course of oral antibiotics for a chest infection. He is afebrile.
What investigations would you like to request and why?
His investigations show the following:
| Haemoglobin: 128 g/L | [110 – 140 g/L] |
| Platelets: 260 x 109/L | [150 – 450 x109/L] |
| WCC: 6.6 x 109/L | [5.0 – 12.0 x109/L] |
| Neuts: 2.2 x 109/L | [2.0 – 6.0 x109/L] |
| Lymph: 3.8 x 109/L | [1.5 – 7.0 x109/L] |
| Mono: 0.4 x 109/L | [0.3 – 2.1 x109/L] |
| Eos: 0.2 x 109/L | [0.1 – 0.8 x109/L] |
LFTs: normal liver enzymes, normal albumin and total protein
| U&Es: normal | ||
| CRP: 22 mg/L | [<5 mg/L] | |
| IgG: 0.8 g/L | [5 – 12 g/L] | |
| IgA: 0.04 g/L | [0.4 – 1.3 g/L] | |
| IgM: 0.06 g/L | [<5 mg/L] |
Tetanus vaccine response: reported markedly low by laboratory
HIV: Not detected
Blood film: no abnormalities reported
What is the most likely diagnosis, how is it managed and what is its prognosis?
Investigations:
This child should be investigated for a primary immunodeficiency given his history.
A useful starting point would be the following investigations which could help
localise which compartment(s) of the immune system may be properly functioning.
More advanced investigations can take place subsequently which can be more
targeted, and also include various genetic analyses to confirm a molecular
diagnosis. First-line investigations can include:
- FBC and blood film – allows for gross inspection of total white cell counts
and key lineages. Platelet count and mean platelet volume can help identify
microthrombocytopaenia (for Wiskott Aldrich Syndrome). A blood film can help
provide evidence of hyposplenism if Howell-Jolly bodies are present.
It is also useful for consider whether there could also be a malignancy present
which could also present similarly. - Immunoglobulin profile (IgG, IgA, IgM) – these are helpful in evaluating
B-cell function - Vaccine responses – these are helpful in evaluating B-cell function.
Before performing this test, it is important to ensure the patient has in fact
had the vaccine being tested for. - Lymphocyte subsets – this allows for evaluation of different types and stages
of lymphocytes using flow cytometry. The test gives absolute counts and relative
(percentage) counts of different lymphocyte populations differentiated by
expression of particular transmembrane proteins. B-cells of all stages of maturity
express CD19. T-helper cells express CD4, cytotoxic T-cells express CD8.
T-regulatory cells can be identified by their expression of FoxP3. Natural killer
cells express CD56/16. - HIV test – while HIV is an acquired (secondary) immunodeficiency, it is important
not to miss this in cases of suspected immunodeficiency. Similar to PIs, early
detection allows for minimisation of complications from infections and for early
treatment. - Complement function – patients with abnormal complement function or
complement deficiencies are at higher risk of infections with encapsulated
organisms such as Neisseria, Streptococcus and Haemophilus. However, tests
such as complement function and neutrophil oxidative burst are more complex
and you may consider discussing the case with a paediatric immunologist or
referring the patient to them.
It is important to remember that a lot of the above laboratory tests’ normal ranges
will vary with in accordance with the child’s age. If in doubt with reference ranges,
it is best to speak to the laboratory the test gets sent to as a starting point.
Abnormal results, especially with lymphocyte subsets, may need repeating several
weeks after a child recovers from their acute episode; many viral illnesses can
result in a suppressed leucocyte count. It is also important to review whether
any medicines the child may have taken could have resulted in a suppressed
cell count. However it is always important to notice a lymphopaenia and follow
it up as it could indicate a low T-cell count, which can point towards more severe
immunodeficiencies if persistently low.
Diagnosis
The patient’s results show low levels of all types of antibody (hypogammaglobulinaemia). The most likely diagnosis here is X-linked agammaglobulinaemia.
X-linked agammaglobulinaemia (XLA) is a genetic disorder which primarily affects
males due to being a defect on the X chromosome. Depending on the population
studied, the literature indicates that around half the cases of XLA occur from a de
novo mutations. Mutations affect the BTK gene that producing the BTK protein
which has a role in B-cell development. It ultimately results in diminished levels of
antibodies as a result of early B-cells not maturing and subsequently not entering
the systemic circulation.
Patients usually present with recurring bacterial infections, notably in the respiratory
tract and ears. These can be severe and challenging to treat, leading to chronic
lung complications if not managed effectively.
Management entails lifelong replacement therapy with intravenous immunoglobulin
(IVIg) or subcutaneous immunoglobulin (SCIg) infusions. These infusions confer
passive immunity by providing a supply of the absent antibodies, thus
diminishing the frequency and severity of infections. You may encounter these
patients on paediatric day units, although the majority self-administer their
subcutaneous immunoglobin at home.
It is important to highlight the immunoglobulin infusions are a lifesaving intervention as it prevents severe infections from taking hold, as well as a life-improving intervention due to the reduction in number of illness episodes and hospital admissions. Their prognosis is typically good provided they regularly have their immunoglobulin infusions regularly.
A 4 month old boy is admitted to the ward with pneumonia. On a wider review,
his parents report him having persistent diarrhoea for two months. Examination additionally reveals oral thrush. His growth chart demonstrates faltering growth, having originally being born on the 50th centile for weight and now is below the 2nd centile. He is parents are consanguineous and he is their first child. There was one previous pregnancy with miscarriage. Pregnancy with him was uncomplicated, with normal scans, an elective C-section delivery and no neonatal input following birth. Both his parents were born in the UK and was not indicated to receive the BCG vaccine. He has had his two and three month immunisations as per the UK schedule. His parents are both fit and well and there is no family history of any medical conditions.
His bloods show the following:
| Hb 105 g/L | [110 – 140 g/L] |
| WCC 14.1 x 109/L | [6.0 – 15.0 x 109/L] |
| Lymph 1.1 x 109/L | [4.0 – 10.0 x 109/L] |
| Neuts 11.3 x 109/L | [1.5 – 8.0 x 109/L] |
| Mono 1.3 x 109/L | [0.3 – 1.1 x 109/L] |
| Eos 0.4 x 109/L | [0.1 – 1.0 x 109/L] |
| CRP 16 mg/L | [<5 mg/L] |
What diagnosis needs to be ruled out?
What further investigations would be helpful?
From his investigations, the following results are seen:
| CD3+ 309 x 106/L | [2284 – 4776 x 106/L] |
| CD4+ 173 x 106/L | [1523 – 3472 x 106/L] |
| CD8+ 136 x 106/L | [524 – 1583 x 106/L] |
| CD19+ 331 x 106/L | [776 – 2238 x 106/L] |
| CD56/16+ 468 x 106/L | [230 – 801 x 106/L] |
HIV Test: Negative
Which team should this patient be referred to and what might they offer?
What possibilities exist for potentially detecting this earlier?
Diagnosis and investigations
Severe combined immunodeficiency (SCID) needs to be ruled out. He is presenting
with recurrent and severe infections, as well as faltering growth, alongside a low
absolute lymphocyte count. A reasonable starting point would be to perform
a HIV test and check his lymphocyte subsets and immunoglobulin levels (IgGAM).
Linking this case back to the discussion from the first case, warning signs for
PID here include a persistent infection and faltering growth on a background of
consanguinity. Another useful piece in the history is that of a miscarriage, which
could potentially have been due to a non-viable foetus, the chances of which
are increased due to consanguinity
In addition to evaluating for a pneumonia and its complications, a chest radiograph
can also be used in very young children to see if the thymus is absent which
could indicate various forms of SCID or a condition like DiGeorge Syndrome.
Who should he be referred to and what treatment might they offer?
His results show a lymphopaenia that is characterised by profoundly low numbers
of T and B cells. This is in keeping with SCID. By definition, SCIDs are T-cell negative (T-). They can then be classified by the presence/absence of B-cells (B-cell positive, B+; B-cell negative, B-), followed by the presence of natural killer cells (NK+/NK-). This patient has a T-/B-/NK+ SCID. He will require genetic analyses to determine if there is a known mutation that underpins his phenotype. One potential cause for this could be a RAG1/RAG2 mutation, which is a commoner cause for this phenotype but still rare overall. He will need to referred to a paediatric immunology team who can lead these investigations and begin the work-up for a bone marrow
transplant.
Bone marrow transplantation reconstitutes the patient’s immune system and
can be curative for patients with SCID. It is long and physiologically challenging,
for which patients need to be medically optimised prior to commencing treatment.
Following the transplant, engraftment takes approximately four weeks, during
which patients are very closely monitored. Life threatening complications from
bone marrow transplant include infections during their immunosuppressed state,
graft versus host disease, and veno-occlusive disease. Patients are initially on a prophylactic combination of antibiotics, antivirals and antifungals as well as
replacement immunoglobulin, which may rapidly need to be escalated if there
is suspicion of an infection especially in the earliest stages post-transplant.
Detecting SCIDs
Depending on whether this patient had presented to services previously, it might
have been possible with careful history taking and a high degree of vigilance to
have detected this earlier.
However there also could be a possibility of detecting SCID cases and several
other primary immunodeficiencies earlier through screening. SCID is identifiable
from birth, is life-threatening and also treatable. This makes it a good candidate for
screening. Furthermore, detection of a biomarker, T-cell receptor excision circles
(TRECs) suitable for analysis from a dried bloodspot, means there is potential for
this to take place. TRECs are a by-product of T-cell receptor (TCR) recombination
process which results in diversifying the host’s TCRs. A low number of TRECs
indicates there could be a low number of T-cells, which in turn could heavily point
towards SCID.
Using TRECs to screen for SCID has been used in the USA since 2018 and UK is
currently undertaking a pilot of whether to include it as part of the day 5 newborn
bloodspot screen. Patients with a low number of TRECs would then get invited for
further testing, which would include checking lymphocyte subsets.
Not only would early detection minimise complications of infections and facilitate
early transplantation, it would also ensure that babies with SCID are not given
live vaccines such as the rotavirus or BCG vaccines, avoiding an iatrogenic
life-threatening infection.
Question 1
In otherwise healthy children, how many simple upper respiratory tract
infections are considered to be normal within one year?
- One
- Four
- Ten
- Fifteen
Answer 1
The correct answer is (3) .
Question 2
Which of the following features should prompt a consideration for whether a child has an underlying primary immunodeficiency?
- Five episodes of bronchiolitis in 2 years
- Six episodes of upper respiratory tract infections 6 months
- Two episodes of pneumonia in 3 months
- One episode of bacterial meningitis across their life
Answer 2
The correct answer is (3).
Question 3
Which of the following results would be expected in a patient with X-linked Agammaglobulinemia?
- . Reduced WCC
- Reduced vaccine responses
- Small platelet volume
- Elevated CD19 (B-cell) count
- Elevated CD3 (T-cell) count
Answer 3
The correct answer is (2).
Question 4
What marker could be used to screen for SCID as part of the newborn blood spot test?
- CD3
2. CD19
3. CD4:CD8 ratio
4. TREC
5. HLA typing
Answer 4
The correct answer is (4) .
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https://esid.org/Working-Parties/Clinical-Working-Party/Resources/10-Warning-Signs-of-PID-General
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Subbarayan A, Colarusso G, Hughes SM, et al. Clinical features that identify
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