Immunocompromised Host

Primary Immunodeficiency

As mentioned above, the term primary immunodeficiency refers to congenital immunodeficiencies that are due to intrinsic gene defects. These can lead to a missing or non-functional protein, cell or other component of the immune system, making the immune system weak or dysfunctional.

The main immunodeficiencies that we will focus on are:

• Predominantly antibody deficiencies - account for roughly 50 to 65% of all PIDs, depending on the registry.
  • Common variable immunodeficiency (CVID): the patient has B cells but they produce reduced or dysfunctional antibodies
  • Bruton’s disease (X-linked agammaglobulinaemia, XLA): the gene is on the X chromosome, so mostly boys are affected. The patients lack B cells so cannot produce antibodies
  • IgA deficiency: the most common primary immunodeficiency. Most individuals are asymptomatic (have no symptoms). Prevalence is about 1 in 600 in white people, and estimates range from about 1 in 150 to 1 in 3000 depending on the population. These patients have an increased risk of autoimmune conditions.
  • Hyper IgM: a defect in immunoglobulin class switching (B cells changing from making IgM to making IgG, IgA or IgE), resulting in low IgG, IgA and IgE levels with normal or raised IgM. The X-linked form is caused by CD40 ligand deficiency, a disorder of abnormal T- and B-cell function.
    
• Combined T and B cell deficiencies - represent around 15% of all PIDs and include severe combined immunodeficiency (SCID): as T cells are defective, B cells are not activated
• Phagocytic defects - responsible for about 10% of all PIDs. The most frequently diagnosed is chronic granulomatous disease (CGD), in which phagocytes lack killing machinery and are ineffective as a result
• Other cellular immunodeficiencies - make up 5-10% of all PIDs, the most common being DiGeorge syndrome (22q11.2 deletion syndrome: a deletion in a region on the long arm of chromosome 22), with a hypoplastic (underdeveloped) or, rarely, absent thymus. T cell maturation may be incomplete (partial DiGeorge syndrome) and is absent only in complete DiGeorge syndrome, which was about 1.5% of the patients tested in one large series.
  

A way of differentiating between the different types of primary immunodeficiencies is by looking at the age of onset of first symptoms:

• Onset < 6 months old: most likely a T-cell or phagocyte defect.
• Onset between 6 months and 5 years old: suggests a B-cell/antibody or phagocyte defect (maternal antibodies have now cleared, so antibody defects become clear).
• Onset > 5 years old: most likely a B-cell/antibody/complement or a secondary immunodeficiency.

The type of microbe and the site of infection also help to identify the major immune defects, because specific presentations are associated with specific defects of the immune system:

Figure: Infections associated with the different types of immune system defects

SimpleMed original by Dr. Elena Perez

Management of primary immunodeficiency diseases has three components: supportive treatment, specific treatment and management of any co-morbidities.

• Supportive treatment:
  
  • Infection prevention: prophylactic antibiotics (antibiotics given to prevent infection)
  • Treat infections promptly and aggressively, alongside immunoglobulin replacement where indicated
  • Nutritional support: vitamins A/D
  • Use UV-irradiated CMV -ve blood products only
  • Avoid live attenuated vaccines (made from weakened living microbes, which can cause the disease they aim to prevent) in patients with severe PIDs (e.g. SCID)
• Specific treatment:
  
  • Regular immunoglobulin therapy to replace missing antibodies: intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg)
  • SCID: haematopoietic (blood-forming) stem cell transplantation (HSCT). Survival is 94% in infants transplanted at 3.5 months of age or younger, and 90% in older infants without prior infection
• Treat co-morbidities:
  
  • Autoimmune and malignancy treatment if disease arises
  • Assess organ damage (lung function assessment)
  • Avoid non-essential exposure to radiation, especially in conditions with radiation sensitivity such as ataxia telangiectasia (an inherited condition that includes immunodeficiency and radiation sensitivity)

Secondary Immunodeficiency

Secondary immune deficiencies are the result of extrinsic factors (factors outside the immune system) that decrease the production of immune components or increase their loss. The single most common cause of secondary immunodeficiency worldwide is malnutrition. Other causes include infections (see article on HIV), liver diseases, lymphoproliferative diseases (conditions with excess lymphocytes, such as lymphoma) or asplenia (an absent or non-functioning spleen).

The spleen is an important organ of the immune system and by understanding its immune functions, one can easily understand how its removal or damage would contribute to secondary immunodeficiency. The spleen has an important role in:

• Removal of blood-borne pathogens: especially in dealing with encapsulated bacteria (bacteria with a protective capsule that makes them harder for phagocytes to engulf).
• Antibody production: during the acute phase response (the body's early reaction to infection) it produces IgM, and for long-term protection it produces IgG.
• Splenic macrophages: removal of opsonised microbes (microbes coated with antibody or complement so that phagocytes can ingest them) and of immune complexes (antibody bound to antigen).

Asplenic or splenectomised patients thus need to be especially careful regarding infections and hospital admissions, so they are often given life-long penicillin prophylaxis and immunisation against encapsulated bacteria (Neisseria meningitidis, Haemophilus influenza and Streptococcus pneumonia). In addition, they often wear a Medic Alert bracelet to inform healthcare professionals in emergencies.

Similarly, patients with haematological malignancies (cancers of the blood and bone marrow) or who have undergone chemotherapy are highly susceptible to infections. This susceptibility is due to chemotherapy-induced neutropenia (a low neutrophil count) and damage to mucosal barriers. Commonly used vascular catheters breach the skin and give bacteria a route into the body. Biofilms (layers of bacteria stuck to a surface and protected from antibiotics) can also form on them, which further increases the risk of infection. Any suspected neutropenic sepsis should be treated as a medical emergency and the patient should be given empirical (started before the cause is known) antibiotic therapy immediately.

Finally, any condition that results in an increased loss or catabolism (breakdown) of immune components can also cause secondary immunodeficiency. Some examples of such conditions include protein-losing diseases such as nephropathy (kidney disease that leaks protein into the urine) or enteropathy (bowel disease that leaks protein into the gut), and burns.

Examples of common manifestations of secondary immunodeficiency:

Shingles (herpes zoster) is caused by reactivation of the Varicella Zoster Virus (VZV) and is an example of a common infection in secondary immunodeficiency. Primary infection with VZV causes chickenpox, a vesicular (blistering) rash. The virus then remains latent (dormant) in sensory dorsal root ganglia (clusters of sensory nerve cells next to the spinal cord). Reactivation of latent VZV is more common in immunocompromised patients and causes shingles. Shingles is a painful, one-sided rash of vesicles (blisters) on red skin (erythema) that usually follows a dermatome (the area of skin supplied by one spinal nerve). It is treated with pain relief and antivirals such as aciclovir. Patients who are severely immunocompromised need hospital admission or immediate specialist advice.

Candida albicans is known as an opportunistic pathogen: it can be commonly found in the normal flora (the microbes that normally live there) of the mouth and gut of healthy hosts. However, in the immunocompromised, it can become pathogenic and overgrowth of the yeast can cause candidiasis. Oral candidiasis is indeed a characteristic sign of HIV development into AIDS.

Finally, Aspergillus is a genus of fungi (moulds that spread by spores called conidia), with species that infect humans and crops. It is commonly found in samples taken from immunocompromised hosts. Aspergillus fumigatus is the most common organism causing aspergillosis. It primarily colonises paranasal sinuses and lungs, potentially leading to necrotising pneumonia. On high-resolution CT (HRCT) scans, the ‘halo’ sign (a ring of hazy, ground-glass change around a lung nodule) is highly suggestive of invasive pulmonary aspergillosis in the right clinical setting, but it is not diagnostic on its own. Diagnosis also uses microbiological tests, such as galactomannan (a fungal antigen) and PCR (a DNA test).

Edited by: Dr. Ben Appleby and Dr. Thomas Burnell

Reviewed by: Dr. Marcus Judge