MINOR
PEDIATRIC INFECTIOUS DISEASES
PART 3+4
Complete samenvatting van de modules
- Immunode ciencies
- Vaccines
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, Immunode ciencies - Pediatric infectious diseases
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Inherited defects in genes for components of the immune system cause primary
immunode ciency diseases (PID). Primary immunode ciency diseases are distinguished from
secondary immunode ciency diseases, which are due not to defective genes, but to
environmental factors, such as immunosuppressive drugs, chemotherapy or HIV. Secondary
immunode ciencies have a much higher prevalence than primary immunode ciencies. Primary
immunode ciency diseases are of three types: dominant, recessive or X-linked.
Primary immunode ciencies are rare. Pattern recognition is the key to discover a PID is a patient.
Clinical manifestations of a PID can be:
- Infections: Everyone can su er from an infection, but when there are recurrent infections, the
infection follows an atypical course or when opportunistic pathogens are found, then it is
suggestive for PID.
- Auto-immune disease
- Malignancies
- Family members with a known PID or with the same symptoms
- Other symptoms: e.g. dysmorphic features, skin/mucusal manifestation, bleeding tendency,
poor wound healing, etc.
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, As sad a PID can be recognised when a child has an infection. In children with an
immunode ciency, the following infections are the most common present:
- Respiratory tract (91%)
- Gastro-intestinal (21%)
- Central nervous system (13%)
- Urinary tract (5%)
- Osteomyelitis (5%)
Besides recurrent infections, infection with an opportunistic pathogen is also a clue to think of a
PID. The most common opportunistic microbes are:
- Pneumocystic jiroveci: a funghi that causes a pneumonia
- Cytomegalovirus: causes a severe disseminated infection in immunocompromised patients with
often interstitial pneumonia and hepatitis.
- Candida: a yeast that can cause candidiasis. Healthy patients can develop a candidiasis in the
mouth but that is rare. Especially when the infections spreads other tissues such as the
oesophagus, then that is very suggestive for immune compromission.
- Aspergillus: Can cause respiratory tract infections and pneumonia in immunocompromised
patients
- Mycobacterium: a species of bacterium most known for causing tuberculosis and lepra. Latent
tubercolosis can reactivate in immunocompromised patients and follows a more severe course.
Mycobacteria are intracellular bacteria.
- Nocardia: an opportunistic bacterium that can give rise to a pneumonia with often empyema.
When a patient is treated for a longer period with antibiotics to recover from the infection, but the
antibiotics only have little e ect, than that is also suggestive for an immunode ciency. Same story
for when intravenous antibiotics are required to clear an infection that would under normal
circumstances also have been cleared with oral antibiotics.
From all the primary immunode ciencies, more than half of them are antibody disorders. These
are called humeral immunode ciencies and are thus the most frequent.
PID’s should be treated well. First of all an infection may become fatal which must of course be
prevented at all costs. Besides that the amount of infections should be kept as low as possible,
because the recurrent infections can damage the organs. Examples of this regarding the lungs are
bronchiectasis, lung brosis and cor pulmonale.
Recessive and dominant mutations in the IFN-y receptor cause diseases of di ering severity. IFN-
y, the major cytokine that activates macrophages, is made by NK-cells during the innate immune
response and by TH1 and CD8 cells during the adaptive immune response. When IFN-y binds to
receptors on a macrophage, it becomes better at killing bacteria. The response of macrophages
to IFN-y is crucial for defense against intravesicular bacteria such as mycobacteria.
Antibody de ciency leads to poor clearing of extracellular bacteria. The major threat to patients
lacking antibodies is infection by pyogenic (pus forming) bacteria. These encapsulated bacteria,
which include haemophilus in uenzae, streptococcus pneumoniae, streptococcus pyogenes
(GAS) and staphylococcus aureus, are not recognised by the phagocytic receptors of
macrophages and neutrophils, so they frequently escape immediate elimination by the innate
immune response. Such infections are normally cleared when the bacteria are opsonized by
speci c antibody and complement and then taken up and killed by phagocytes. For patients
lacking antibodies, infections with pyogenic bacteria tend to persist unless treated with
antibiotics. Patients with problems in antibody production often also receive regular intrusions of
intravenous immunoglobulins.
Diminished production of antibodies is not always the result of defective B cells, but also results
from inherited defects in T cell help. Diminished production of antibodies is also a symptom of
defective genes encoding the membrane associated cytokine CD40 ligand. Interaction of CD40
ligand on activated T cells with B cell CD40 is a crucial part of the T cell help given to B cells. This
stimulates B cell activation and isotype switching. In the absence of CD40 ligand, virtually no
speci c antibody is made against T cell dependent antigens. Patients with this immunode ciency
are inherently susceptible to infection with pyogenic bacteria. Macrophage activation by CD4 TH
cells also depends on the interaction of CD40 on the macrophage with CD40 ligand on the T cell.
If this interaction does not occur, it impairs the macrophage production of granulocyte
macrophage colony stimulating factor (GM-CSF), a cytokine that stimulates the development of
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, neutrophils in the bone marrow and their release into the circulation. The patients su er from
neutropenia and can not create a leukocytosis.
Antibody de ciencies generally present with recurrent ear, nose and throat (ENT) and airway
infections, but may also present with severe bacterial infections in other organ systems.
Complement defects impair antibody-mediated Complement E ects of de ciency
immunity and cause immune-complex disease. All protein
the e ector functions that antibodies recruit to clear
pathogens and their antigens are facilitated by C1, C2, C4 Immune-complex disease
complement activation. Consequently, the spectra
of infections associated with de ciencies in C3 Susceptibility to
complement and antibody production overlap encapsulated pyogenic
substantially. Defects in the activation of C3 result in bacteria
susceptibility to a wide range of pyogenic
infections, emphasising the importance of C3 as an C5-C9 Susceptibility to Neisseria
opsonin that promotes the e cient elimination of
bacteria by phagocytes. In contrast, defects in C5-C9, the terminal complement components of
the membrane attack complex, have few e ects. Of these susceptibility Neisseria is the best
example (so Neisseria is a gram negative bacteria).
An immune complex is a protein complex formed by the binding of antibodies to soluble antigens.
Large immune complexes are cleared by phagocytes bearing Fc-receptors. Small soluble immune
complexes tend to be deposited on the walls of small blood vessels, where they activate
complement and cause damage. The attachment of complement components to soluble immune
complexes allows them to be transported, or ingested and degraded, by cells bearing
complement receptors. Immune complexes are mainly transported by erythrocytes, which capture
the complexes with their CR1 complement receptor that binds to C4B and C3B. De ciencies in
complement components C1-C4 impair the formation of C4B and C3B and lead to the
accumulation of immune complexes in the blood, lymph, and extracellular uid and to their
deposition within tissues. In addition to directly damaging the tissues in which they deposit,
immune complexes activate phagocytes, causing in ammation and further tissue damage. This
condition is called immune-complex disease.
De ciencies in the proteins that control complement activation can also have major e ects.
Defects in phagocytes result in enhanced susceptibility to bacterial infection. Phagocytosis
mediated by macrophages and neutrophils is the principal method by which the immune system
gets rid of infecting bacteria and other microbes. The defect of the phagocyte can lay in his ability
to bind to the pathogen, but can also be caused bij a disabled capacity of phagocytes to kill
ingested bacteria. An example of PID based on a defect in phagocytes is chronic granulomatous
disease. Defects in phagocytes predispose patients to pyogenic infections and recurrent ENT and
airway infections.
Defects in T-cell function result in severe combined immune de ciencies. Whereas B cells
contribute only to the antibody response, T cells function in all aspects of adaptive immunity. This
means that inherited defects in the mechanisms of T cell development and T cell function have a
general depressive e ect on the immune system’s capacity to respond to infection. Those
patients who make neither T cell dependent antibody responses nor cell mediated immune
responses are said to have severe combined immune de ciency (SCID). T cell development and
function depend on the action of many proteins, so the SCID phenotype can arise from defects in
any one of a number of genes.
Disorders of granulocyte number and function often concerns a neutropenia. Recurrent non-
super cial pyogenic infections and recurrent ENT and airway infections can both point towards a
granulocyte disorder. A third, much rare presentation consist of opportunistic infections with
Aspergillus and other fungi.
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, Opsonisation defects
Opsonisation defects Pathogens
IgA or IgG de ciency H. In uenzae, S. Pneumoniae
Agammaglobulinemia H. In uenzae, S. Pneumoniae, M. Pneumoniae
De ciency C2, C3, C4, MBL H. In uenzae, S. Pneumoniae, Meningococcus
Defects in opsonisation result in an increased vulnerability to extracellular bacteria. For these
pathogens opsonisation is very important. De ciencies in the complement system typically
increase the vulnerability for pathogens with a cell wall such as the gram positive H. In uenzae
and S. Pneumonia and to pathogens requiring a MAC such as the gram negative meningococ.
Cellular defects
Cellular defects Pathogens
Phagocyte dysfunction S. Aureus, Candida spp (deep seated infections)
T Lymphocyte dysfunction Mycobacteria, viruses, Candida spp (super cial
infections), Pneumocystis jiroveci
Dysfunction of phagocytes increase vulnerability to pathogens that live outside the cell. So this
will not signi cantly impact intracellular pathogens such as viruses and mycobacteria.
Example of PID and the relation with clinical presentation:
- Recurrent infections of the respiratory tract and the ear, nose and throat: Opsonisation defects
(See pathogens above)
- Unusual or opportunistic infections and general malaise, loss of weight and failure to thrive: T
cell dysfunction
- Severe recurrent infections of the skin, oral cavity and mucosa, and of the internal organs (lungs
and liver) and the skeleton: Phagocyte dysfunction
Complement
- Meningococci
- Pyogenic bacteria (encapsulated bacteria, which include haemophilus in uenzae,
streptococcus pneumoniae, streptococcus pyogenes (GAS) and staphylococcus aureus, they
require opsonisation because the phagocytic receptors can not recognise them on their own)
Phagocytes
- Bacteria:
- S. Aureus
- Gram-negative bacteria (meningococ)
- Fungi:
- Aspergillus
- Candida
Antibody de ciencies
- Pyogenic bacteria (encapsulated bacteria, which include haemophilus in uenzae,
streptococcus pneumoniae, streptococcus pyogenes (GAS) and staphylococcus aureus, they
require opsonisation because the phagocytic receptors can not recognise them on their own)
- Some viruses
T lymphocytes
- Viruses: CMV and other herpes viruses
- Fungi: Aspergillus, Candia and Pneumocystis jiroveci
- Bacteria: Mycobacteria
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, Immunodiagnostiek
De diagnostiek is tweeledig. Bij een vermoeden van een afweerstoornis, bijvoorbeeld neutropenie
of een fagocytair functiedefect, is het nuttig en in sommige gevallen zelfs noodzakelijk om
geïnformeerd te zijn over de verwekker. Maar ook is informatie over de werking van het
immuunsysteem nodig. Wat dat laatste betreft kunnen zeer veel tests verricht worden. Sommige
tests worden routinematig uitgevoerd, andere alleen in gespecialiseerde laboratoria of in het kader
van wetenschappelijk onderzoek. In het kort zijn de volgende laboratoriumtests van toepassing bij
afweerstoornissen:
- Leukocyten en di erentiatie in perifeer bloed
- Telling van subpopulaties van lymfocyten (T/B/NK)
- Spectrum van immunoglobulinen
- Functioneel fagocytoseonderzoek
- Complementactivatie onderzoek
Onderzoek Waarde Eenheid
Leukocyten totaal 4-10 x10^9/L
Neutro ele granulocyten 1,5-9,0 x10^9/L
Lymfocyten 1,0-4,0 x10^9/L
Eosino ele granulocyten < 0,4 x10^9/L
Baso ele granulocyten < 0,2 x10^9/L
Monocyten 0,2 – 0,8 x10^9/L
Antisto en
Bij sommige ziektebeelden is het belangrijk een screening van de hoeveelheid antisto en te doen.
Met een immunoglobuline (Ig)-spectrum van totaal IgM, IgA en IgG is een eerste indruk van de
humorale afweer snel verkregen, vooral als er sprake is van recidiverende (luchtweg)infecties met
gekapselde bacteriën (onder andere pneumokokken en Haemophilus in uenzae). Bij onderzoek
naar antisto en moet in het eerste levensjaar rekening worden gehouden met lagere waarden
volgens de ‘window of vulnerability’. Bij jonge kinderen gelden dus andere referentiewaarden. Van
de antistof IgG zijn er vier verschillende subtypen. De subtypen hebben verschillende functies
zoals neutralisatie, opsonisatie, complementactivatie en ADCC. Wanneer het totaal IgG normaal
is, dan kan er nog een steeds een immuunde ciëntie spelen, namelijk één type IgG dat de ciënt
is. Ook deze verschillende subtypes kunnen worden doorgemeten. Wanneer de concentratie
antisto en in het bloed te laag zijn spreekt men van hypoglobulinemie.
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