Mahreen Sohail and Arwa Othman

Children fall sick…a lot! But how sick is too sick for a normal child? At what point do you need to step back and think, ‘hang on a minute, this child is falling too sick, too often’?

This article serves as guide to help you understand the basics of immune system defects in children. Whilst an exhaustive list of all paediatric immunodeficiencies is beyond the scope of this article, we will discuss a simple approach to a child with suspected immunodeficiency. But to understand the abnormal, first we have to think about….

What is ‘normal’, anyway?

• Well children have normal growth and development, respond quickly to appropriate treatment, recover completely, and appear healthy between infections.
• Children vary quite a bit as to the number of infections experienced. One study, which recorded respiratory infections in a cohort of 760 children from birth to age 12, stuggested that up to 11 infections (per year) in infancy, 8 infections for pre-school children and 4 infections in school age children can be considered normal
• A viral URTI usually lasts 8 days long. However, the normal range can extend beyond two weeks, which means that the “normal” child with over 10 viral respiratory infections can have symptoms for nearly half of the year!
• Most of the respiratory infections are viral.
• Healthy children generally do not have more than one episode of pneumonia or more than two episodes of uncomplicated otitis media in the first three years of life and most of these infections tend to be viral in aetiology.

So, as we said at the start, children get sick, a lot! But it is when they are exceeding these limits that we have to think about immunodeficiencies.

There are two types of immunodeficiency: primary and secondary immunodeficiencies.

Primary immunodeficiencies (PID): refer to inherited disorders affecting the functioning of the immune system. Children and adults with PID are predisposed to infection as well as autoimmune disease.

Secondary immunodeficiencies (SID): are immune deficiencies secondary to other conditions (for example, viral infections, radiation, malignancies, or malnutrition).  The list of conditions causing secondary immunodeficiencies is exhaustive but always remember HIV as one of the most important ones to test a child for. This article will mainly be focusing on PID.

Primary Immunodeficiency

Primary immunodeficiencies are rare. It is estimated that PID occur in about 1: 16,000 to 1:50,000 live births. They can present at any age and they do not always present with severe infections. Before we jump into the details of individual diseases, it’s important to revise some basics of the immune system. In healthy individuals the immune response comprises two phases:

• The first line of defence is the innate system: it is made up of specialised cells that provide a rapid response that is not tailored to the specific microbe that has infiltrated the body.
• The adaptive response is the second line of defence. This response is specific to the microbe and leaves a lasting immune memory, which makes the response to a repeat reinfection more efficient.

Special mention should also go to the complement system at this point. This is a collection of proteins (C1-9) which, when activated by pathogens or immune complexes, trigger each other (heard of the ‘cascade’?). The byproducts of this cascade assist the immune response in a number of ways.

The adaptive immune system consists of T-cells and B-cells. These calls are formed from stem cells which proliferate from the thymus and the bone marrow respectively.

Disorders in adaptive immune responses can be tricky to recall. The best way to remember them is to understand the differentiation of the cells and know where in the pathway the defect in immune response is. The diagram below depicts common differentiation pathway defects (shown by the orange dotted lines) as well as the immunodeficiency disease it is associated with:

There are, of course, defects in the innate immune system as well, but that is beyond the scope of this article.

Now, let’s tackle a case

You’re the Paediatric SHO on call and the GP rings you with an urgent referral. She gives a history of a 9-month-old boy who had been unwell over the past few days with a runny nose and loose stools. Overnight, his breathing has become increasingly laboured and he has become increasingly lethargic. He has also been vomiting in between feeds for the past 24 hours. She’s worried and wants to send him over to A&E for management.

When you see the patient in A&E, his mother is extremely anxious. She says that he has “never really been right” since about 6 months of age. She describes a child with recurrent fevers, chronic dermatitis and faltering growth. He’s also had a previous hospitalization for a pneumonia. The child is a son of consanguineous parents and had a female sibling who died after ‘recurrent severe infections’. On a physical examination, his weight, height, and head circumference were all less than the 0.4^th percentile. He has oral thrush and a diffuse brownish coloured macular rash on the trunk. Chest auscultation reveals bilateral crackles at the lower zones. He is significantly tachypnoeic, has marked sternal recessions and has shallow breath sounds throughout his lung fields. He is tachycardic and poorly perfused. Examination of his abdomen reveals a 2cm liver. His blood gases show a significant respiratory acidosis. With his respiratory effort deteriorating and oxygen requirement increasing, you put out a ‘crash call’ and he is intubated by the anaesthetic team. Mum is understandably distraught at this point and discloses that he has been intubated before in similar circumstances….

What in this case should lead to a high suspicion of immune deficiency?

• Aged 6 months onward – This is generally the age when an infant’s immunoglobulin levels fall, meaning it is also the age when children may present with symptoms typical of immunodeficiency
• Anxious mother – Parents usually know their children! Listen to them!
• Parents are first cousins – A lot of immunodeficiencies are inherited so a history of consanguinity is a high-risk factor for genetic diseases
• Faltering growth – When there’s any concerns about faltering growth, remember to rule out common causes first! PID is a rare, but important, cause
• Persistent oral thrush – Prolonged oral thrush suggests a weakened immune system and development of opportunistic infections
• Recurrent, severe infections – This is the second time this child has been intubated!

As with any case, it’s important that you formulate a differential diagnosis. While this article is about immunodeficiencies, remember the old gambit that ‘common things are common‘ so, before jumping to immunodeficiency, consider other more common diagnoses, as well as differentials such as TB or malignancy. However, there are some ‘red flags’ that should trigger you to consider immunodeficiency….

The RED FLAGS

Primary Immunodeficiency UK (PID UK) have issued a list of 10 warning signs and suggest that having two or more should prompt consideration of PID. They are:

However, trying to remember those during a busy shift with a patient in front of you can be difficult. So an alternative is using the mnemonic, SPURR:

Severe
Persistent
Unusual (uncommon organism)
Recurrent
(PID) Running in the family

Ok, so now your immunodeficiency spidey-senses are tingling. What else should you ask about in the history to lend further weight towards your diagnosis?

Further History

• Birth history – maternal illnesses which might risk secondary immunodeficiencies
• Antenatal and Neonatal Hx –  ask about antenatal scans or dysmorphic features suggesting syndromes. What was the birth weight? Was cord separation delayed?
• Family hx – autoimmune disease or anyone else with an immunodeficiency?
• History of miscarriage or still birth or deaths in early infancy.
• Feeding Hx in infancy – consider alternative diagnoses like reflux or an unsafe swallow causing recurrent aspiration pneumonia.
• Growth and developmental Hx- check their growth charts!
• Immunisation history.
• Medications – immunosuppressive, maternal meds in pregnancy.
• Chronic diarrhoea.
• Atopy – There is a noted co-existence of atopy and immunodeficiency (such as Wiskott Aldrich, hyperimmunoglobulin E syndromes and Omenn syndrome), but also atopy related infection mistaken for immunodeficiency.
• Other weird and wonderful things to keep an eye to include chronic osteomyelitis, structural damage e.g. bronchiectasis or any features of autoimmune diseases in a child.

Examination

• Look at the child’s overall appearance, demeanour, and activity. Are there some clues about the child’s general health.
• Mouth ulcers, gingivitis, mucosal candidiasis, and poor dentition can suggest immunodeficiency.
• Diminished or absent tonsils and cervical nodes in the presence of recurrent respiratory infections can suggest an antibody deficiency.
• If the child is a bit older, ask him to cough.- A ‘wet’ cough suggests bronchitis, pneumonia, or bronchiectasis. Take a note of any crackles, wheezes, and abnormal breath sounds
• Cutaneous granulomas, impetigo, or non-healing sores may suggest a phagocytic immunodeficiency
• Look for signs of autoimmunity such as facial rashes, vitiligo, alopecia, and vasculitic lesions
• Adenopathy and hepatosplenomegaly are frequently seen in certain forms of B cell immune defects
• Common constellations of symptoms to bear in mind include:
  • Ataxia, telangiectasia, and developmental delay in ataxia-telangiectasia
  • Easy bleeding, eczema, and recurrent infections in Wiskott-Aldrich syndrome
  • Congenital heart disease, developmental delay, and abnormal facies (low-set ears, hypertelorism, down-turning eyes, and micrognathia) in DiGeorge syndrome
  • Oral ulcers, gingivitis, and impetigo in CGD or leukocyte-adhesion defects
  • Oculocutaneous albinism in Chediak-Higashi disease

What kind of tests can be done?

Remember to investigate the presentation appropriately first, before jumping to uncover the underlying immunodeficiency. The patient presents with cough and respiratory distress, you gotta xray that chest! The patient comes with urinary symptoms, you better get a (clean) urine sample! But how can you start to investigate for PID?

• Full blood count – let’s start simple!
• Lymphocyte subsets
  • These are marker tests to indicate roughly the percentage of certain types of lymphocytes in the blood. The absence or excess of a certain subset marker may indicate and absence or excess of that particular cell line.

• Immunoglobulins – may indicate a selective deficiency of a certain immunoglobulin, hyper-IgM syndrome, or complete deficiency of all immunoglobulins
• Specific antibodies to vaccine responses – this is really helpful as it helps in identifying the functionality of circulating B cells and immunoglobulins. A child could have perfectly normal cell counts and immunoglobulin levels, but the cells and antibodies just don’t work! (Pro tip – make sure the patient has actually HAD the vaccine you are checking the antibody for, to avoid embarrassment in handover)
• If the history is suggestive, consider:
  – complement function (C3, C4, CH50, AP50) in recurrent invasive bacterial infections, including bacterial meningitis
  – neutrophil oxidative burst in recurrent skin and soft tissue infections, or fungal infections
  – HIV test – remember to council and consent the parents of the patient before sending this!

Management of Immunodeficiency

The kind of management and follow-up a child with an immunodeficiency needs is a large, complex area and very much guided by the specific condition that they have. The exact treatment and follow-up will be led by a specialist immunologist, but these are some of the treatment strategies to know about:

Emergency Treatment: PID patients need an emergency treatment plan when things go wrong. Every patient should have an individual plan for specific therapy, antimicrobial choice and tertiary contact centre.

Antimicrobial Measures: Treatment of infection in PID patients is complex, often requiring one or more broad-spectrum antimicrobials and for prolonged time. Prophylactic antimicrobials may be given in some cases as well. Consult your local ID team for more advice.

Immunoglobulin replacement therapies: There are several types of human immunoglobulin in blood; these include IgG, IgA, and IgM. IgG has the highest concentration in blood and is critical for protection against infection. Such IgG replacement treatment is life-saving for PID patients and usually needs to be continued for life to prevent bacterial infections and avoid organ damage that leads to chronic disease and poor quality of life.

Hematopoietic Stem Cell Transplantation: This is the only cure for severe, fatal PIDs that present in infancy or early childhood 

Vaccines: In general, live attenuated vaccines including BCG and rotavirus, must be avoided in all the severe forms of PID (SCID, CGD, T-cell defects), as there is a clear risk of developing the disease. Inactivated vaccines are safe for use in most PID patients but are ineffective if there is no immune response, depending on the type of immune defect.

Other Treatments

• Granulocyte-colony stimulating factor (G-CSF) to stimulate the production of neutrophils
• Gamma interferon in patients with defective neutrophils.
• Anti-inflammatories such as corticosteroids, and immunosuppressive agents are useful for certain complications
• Nutritional supplements, physiotherapy and psychotherapy

Gene Therapy: Novel approaches to replacement of faulty genes has been developed in recent years, though research is ongoing….

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And there we have it! Those are the guiding principles behind approaching and treating children who are ‘too sick, too often’. Armed with this, we hope you now feel more confident in looking after any such children who may stumble unexpectedly into your local A&E department. But don’t forget, if you have any concerns at all, discuss with your friendly local immunologist for advice. Good luck!

Additional reading

https://www.nice.org.uk/guidance/ng75/chapter/Recommendations#faltering-growth-after-the-early-days-of-life

piduk.org/whatarepids/symptomsanddiagnosis

https://www.frontiersin.org/articles/10.3389/fimmu.2014.00627/full#B12

http://www.info4pi.org/library/educational-materials/10-warning-signs

https://www.immunology.org/policy-and-public-affairs/briefings-and-position-statements/immunodeficiency

http://www.ukpin.org.uk/guidelines/publications-and-guidelines-contributed-to-by-ukpin