Session 9: The Immunocompromised Host Flashcards
Why is immunodeficiency a clinical problem? Consequences?
Because of the large spectrum of different primary immunodeficiency diseases (PIDs) where there are different phenotypes (>300 diseases) and little knowledge about them. There is also a failure to recognise and diagnose the PIDs where a lot of the diseases might get mixed up as other diseases or just a series of infections. It takes around 8-12.4 years from onset of symptoms for someone to get diagnosed with PID. About 60% or more of the patients will be 18 years old or older when diagnose is made. A consequence of this is that 37% will have permanent tissue/organ damage by this point.
Define immunocompromised host.
State in which the immune system is unable to respond appropriately and effectively to infectious microorganisms. Due to a defect in one or more components of the immune system.
What are the two main categories of immunocompromisation?
Explain them very briefly. (Cause)
Primary immunodeficiency also called congenital.
Due to intrinsic gene defects like missing proteins, missing cells or non-functional components of the immune system.
Secondary immunodeficiency also called acquired. This is due to an underlying disease/treatment like a decreased production/function of immune components or increased loss or catabolism of immune components.
When do you suspect an immunodeficiency?
(What kind of signs are you looking for? (Mnemonic))
Infections defined as SPUR
Severe (infection)
Peristent (infection, won’t go away)
Unusual (infection where the site of infection or type of infection is rather unusual in a healthy individual)
Recurrent (Infection keeps coming back even though it has been cleared)
10 warning signs of PID in children.
4 or more new ear infections within 1 year
2 or more serious sinus infections within 1 year
2 or more months on antibiotic with little effects
Two or more pneumonias within 1 year
Failure* of an infant to *gain weight* or *grow normally
Recurrent, deep skin* or *organ abscesses
Peristent thrush* in *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 PID
10 warnings signs of PID in adults.
2 or more new ear infections within 1 year
2 or more new sinus infections within 1 year in absence of allergy
1 pneumonia per year for more than 1 year
Chronic diarrhoea + weight loss
Recurrent viral infections (colds, herpes, warts and condyloma)
Recurrent need for intravenous antibiotics to clear infections
Recurrent deep abscesses of skin or internal organs
Persistent thrush or fungal infection on skin or elsewhere
Infection with normally harmelss tuberculosis-like bacteria
A family history of PID
Give limitations to the 10 warning signs.
Lack of population-based evidence:
Family history only proven that it is present in 25% of people with PID.
Failure to thrive
Diagnosis of sepsis treated with IV antibiotics
PID patients with different defects may present differently
Infections with a subtle presentation
PID patients with non-infectious manifestations.
Give example of PID patients with non-infectious manifestations.
Autoimmunity
Malignancy
Inflammatory response
Give subgroups of PIDs. (Remember primary)
Which is the most common?
Immunodeficiency due to antibody defects (65%)
Immunodeficiency due to T cell defects (15%)
Immunodeficiency due to phagocytic defects (granulocytic) (10%)
Explain what the problem is in immunodeficiency caused by antibody defects. (Two types)
Give examples.
It can either be a defect in the development of B cells.
E.g. X-linked* agammaglobulinaemia also called *Bruton’s disease
It can also be due to a defect in antibody production
E.g. Common Variable Immunodeficiency CVID, Selective IgA deficiency, IgG subclass deficiency (IgG2), Hyper-IgM syndrome
In the case of the PIDs due to defect in antibody production, what are the most common.
Give a brief description of each.
Common Variable Immunodeficiency is the most common PIDs of this sort that requires treatment.
However Selective IgA deficiency is the most prevalent/common but it is usually asymptomatic and doesn’t require any treatment.
Although if Selective IgA deficiency is associated with IgG subclass deficiency IgG2 patients will require treatment. There is a risk if you have this deficiency that there is a risk of blood transfusion reaction.
Hyper-IgM syndrome has a deficiency in the CD4+ protein that is required from T cells to signal to switch from IgM to IgG. Keeps producing of IgM instead. Requires treatment.
Note that Selective IgA deficiency or IgG subclass deficiency (IgG2) do not need treatment on their own.
Explain what the problem is in immunodeficiency caused by T cell defects. (Two types)
Give examples, explain them very briefly.
Combined B and T cell defects:
Severe combined immunodeficiency (SCID)
Wiskott-Aldrich syndrome
Ataxia telangectasia
T cell defects alone: Di George syndrome (thymus) CD3 deficiency MHC class II deficiencies (not gonna activate CD4+ T cells) Tap-1 or -2 deficiency (MHC class I, not gonna activate CD8+ T cells)
Explain what the problem is in immunodeficiency caused by phagocytic (granulocyte) defects. (3 types)
Example and explain briefly.
Defects in respiratory burst:
Chronic granulomatous disease (CGD)
Defects in fusion of lysosome/phagosomes:
Chediak-Higashi syndrome
Defect in neutrophil production and chemotaxis:
Cyclic neutropenia
LAD protein deficiencies
How could you easily differentiate between types of phagocytic defects PIDs?
By blood test.
CGD and Chediak-Higashi syndrome would have normal neutrophil/granulocyte count.
Cyclic neutropenia and LAD protein deficiencies will have a lowered neutrophil count/other granulocytic count.
How would you by age be able to differentiate between the different subgroups of PIDs and SID?
The onset for T-cell or phagocyte defects are usually < age 6 months.
Onset after 6 months and before 5 years of age suggests a B-cell antibody or phagocyte defect
Onset after 5 years of age or later in life usually suggests a B-cell/antibody/complement or secondary immunodeficiency.
Explain why it is possible to categorise the PIDs and SID by age as such.
Early onset before 6 months suggest T cell or phagocyte defect because you still have your mother’s antibodies present in your system. So there shouldn’t be any problems with antibodies.
Onset after 6 months could much more likely be B-cell antibody or phagocyte defect because the mother’s antibodies are now lost and a T-cell deficiency would probably manifest itself before 6 months.
Onset after 5 years of age suggests antibody defect or a secondary immunodeficiency that has been acquired later in life.
Give examples of microbes and infections/conditions associated with complement deficiency. (Complementary cascade from antibodies)
Neisseria spp like meningitidis or gonorrhea
Streptococci
Haemophilus influenzae
or other encapsulated bacteria.
(Think of spleen and try to connect it to white pulp and lymph system.)
Pyogenic infections, meningitis, sepsis and arthritis can happen. Also angiooedema.
Give examples of microbes and infections/conditions associated with phagocytic defects.
Bacteria:
Staphylococcus aureus, Pseudonomas aeruginosa, non-tuberculous mycobacteria.
Fungi:
Candida spp., Aspergillus spp.
Can lead to skin/mucous infections, deep seated infections and invasive fungal infections like aspergillosis.
Give examples of microbes and infections/conditions associated with antibody deficiency.
Bacteria
Streptococci, staphylococci, Haemophilus influenzae, Moraxella catarrhalis, Pseudonomas aeruginosa, mycoplasma pneumoniae.
Virus
Enteroviruses
Protozoa
Giardia lamblia
Can lead to sino-respiratory infections, arthropathies, GI infections, malignancies, autoimmunity
Give examples of microbes and infections/conditions associated with T cell defects.
Similar to antibody deficiencies but also includes the intracellular bacteria Salmonella typhi, Listeria monocytogenes, and non-tuberculous mycobacteria.
Virus
All viruses
Fungi
Candida spp., Aspergillus spp., Cryptococcus neoformans, Histoplasma capsulatum
Protozoa
Pneumocystis jiroveci, Toxoplasma gondii, Cryptosporidium parvum
Can lead to death if not treated, failure to thrive, deep skin and tissue abscesses, opportunistic infections.
Clinical case 1:
6 month-old boy who was born at term physically normal and apparently healthy.
In last 3 months => recurrent fungal (diaper rash, oral candidiasis), viral (upper resp), and bacterial (otitis media) infections, all of which resolved with appropriate pharmacologic intervention.
Below 50% percentile for weight
Routine childhood immunization OK.
Weak IgG response to vaccines
Both sexes of family have been affected by these infections.
Diagnosis? Explain why.
Onset before 6 months tell us it shouldnt be antibody defect. So it is either T-cell or phagocyte.
Oral candidiasis could point to both due to Candida albicans.
However he is below 50% percentile for weight so he has a failure to thrive. This means it is more likely to be T-cell defect.
Most likely diagnosis is SCID Severe combine immunodeficiency
12 month old boy. 4 episodes of severe gram-positive bacterial pneumonia in last 6 months.
Had recurrent diarrhoea (Giardia lamblia) and his tonsils are barely detectable.
Below norm for heigh and weight.
Recommended paediatric immunizations (low IgG, undetectable IgE, IgA and IgM and no B cells)
Patient has three healthy sisters aged 3, 5 and 7. Family lost a boy at 10 months of age to bacterial pneumonia 8 years ago.
Diagnosis. Explain.
Onset after 6 months tells us it’s probably not T-cell. Could still be phagocytic and can also be antibody defect.
Recurrent diarrhoea of Giadria lamblia points towards antibody defect.
Failure to thrive
Pneumonia points towards antibody defect.
No B cells means that the problem isn’t the production of antibodies but rather the production of B cells.
All healthy sisters points towards an x-linked disease.
This means that most likely diagnosis is x-linked recessive agammaglobulinaemia also called Bruton’s disease.
Young patient. Developed since age of 4 weeks multiple staphylococcal abscesses in chest, sin, face and buttock requiring surgical incision and a course of systemic antibiotics for 10 days.
By age of 2 he was admitted to hospital 5 times for Staph infections and pulmonary aspergillosis.
Height and weight below average.
Three elder brothers died of infections at an early age but sisters are healthy.
Neutrophils failed to produce oxygen radicals (resp burst).
Diagnosis. Explain.
Before 6 months rules generally out antibody defect.
Staph infections and aspergillosis points towards phagocytic defect.
Failure to thrive
Seems to be x-linked recessive
Normal levels of neutrophils but they can’t produce oxygen radicals.
Most likely diagnosis is x-linked recessive Chronic granulmatous disease.
40 year old woman. Suffering throughout her life of recurrent bacterial respiratory and gastrointestinal infections.
As a child she was hospitalised for pneumonias and GI infetions (Giardia lamblia)
IgG, IgM, IgA below normal. Poor IgG response to pneumococcal vaccines. Number of B cells and T cells normal.
Mother and sister had also poor response to polysaccharide vaccines and died from haemolytic anaemia and non-Hodgkin’s lymphoma.
Diagnosis. Explain.
Unknown onset but does not seem to be acquired.
Pneumonia and GI infection by protozoa Giardia lamblia points towards antibody defect.
IgG, IgM and IgA are all below normal making it more possible to be antibody defect. T cells and B cells are normal. Rules out T cell (quantitative defect). B cell development defect ruled out as well.
Probably a problem with the production of antibodies from B cells.
Haemolytic anaemia and non-Hodgkin’s lymphoma can both arise from CVID.
Most likely diagnosis is antibody defect by non-functional B cells: CVID (Common variable immunodeficiency)
Management of PIDs: Supportive treatment.
Infection prevention like prophylactic antimicrobials
Treat infections promptly and aggressively
Nutritional support with Vitamin A and D
Use UV-irradiated CMVneg blood products only
Avoid live attenuated vaccines in patients with severe PIDs (SCID) like MMR vaccine.
Management of PIDs: Specific treatments.
Regular immunoglobulin therapy (IVIG or SCIG (intravenous or subcutaneous))
In the case of SCID treat with haematopoietic stem cell therapy.
Comorbidites of PIDs.
Autoimmunity and malignancies
Organ damage
Avoid non-essential exposure to radiation
In what conditions are immunoglobulin replacement therapy used?
CVID
XLA (Bruton’s disease)
Hyper-IgM syndrome
(All the antibody defects)
Explain administration of treatment.
(How often, how long, where?)
Either intravenous immunoglobulin (IvIg) or subcutaenous (ScIg)
IvIg needs to be administered every three weeks.
ScIg needs to be administered every week.
It is a life long treatment.
When do you do IvIg and when ScIg?
IvIg in adults
ScIg in children
Causes of secondary immune deficiencies.
Decreased production of immune components like:
Malnutrition
Infection (HIV e.g.)
Liver disease
Haematological malignancies
Therapeutic treatment like corticosteroids or cytotoxic drugs
Splenectomy
Increased loss of immune components:
Protein-losing condition (Nephropathy, Enteropathy)
Burns
Give haematological malignancies which can increase susceptibility to infections.
It can be due to the haematological malignancies or it can especially be due to chemotherapy.
Explain how chemotherapy can increase susceptibility to infections. It might help to explain how most chemo-therapy works.
Most chemo-therapies are anti-mitotic so they target mitosis and hinders it. This is preferential in rapidly dividing cells like malignant cancer cells, but also mucosal cells. So for example in the mouth there will be breakdown of mucosal cells and therefore the mucosal barrier protecting us will be damaged. Bleeding can ensue and microbes can end up in vascular system.
Chemo-therapy can also induce neutropenia.
The vascular catheters used in chemotherapy (Hickman’s line) is a perfect spot for bacterial biofilm to grow (S. aureus and S. epidermidis are good candidates for growth here).
This all can lead to septic complications along with febrile neutropenia which can be life-threatening.
How to recognise and diagnose IDs.
Recognise by SPUR and 10 warning signs.
In spur you can also somewhat diagnose by looking at site of infection and type of microbe.
Look at the age of onset
Sensitivity and type of treatment
Secondary causes in case PIDs don’t tick the boxes
Family history
Lab investigation of IDs.
Suspicion of antibody/B cell defect
IgG, IgA, IgM maybe IgE
IgG1-4 subclasses
IgG levels to specific previous vaccines
Measure antibody in response to test immunization
Lab investigation of IDs.
Suspicion of T cell defect.
Lymphocyte count in FBC
Lymphocyte subset analysis of CD4+, CD8+ T, NK and B cells
In vitro tests of T cell function
Lab investigation of IDs.
Suspicion of phagocytic defect
FBC checking for granulocytes most commonly neutrophils
Neutrophil function test (oxidative burst for CGD or test lysosome and phagosome activity for Chediak-Higashi syndrome)
Adhesion molecule expression for LAD
Lab investigation of IDs.
Suspicion of complement defect
Individual components of C complements (C1-C9)
Tests of complement function (CH50/AP50)
Other tests.
Definitive tests for molecular testing and gene mutations.
