8. Immunocompromised Host Flashcards
immunocompromised host - definition
– “State in which the immune system is unable to respond appropriately and effectively to infectious microorganisms”
4 components of immune system that can be defective
- WBC
- Lymphocytes
- Complement system
- antibodies
2 types of immunodeficiencies
- Primary Immunodeficiency
- You actually have a genetic deficiency
- Secondary Immunodeficiency
- Is as a result of domething
Primary immunodeficiency
- Intrinsic or congenital defect
- Single gene defect
- Pass on from generation to generation (so families can have immunodeficiencies)
- Random error during development
Problems with
• B cells – can lead to problems with antibodies
• T cells
• Both
• Complement
• Phagocyte – phagocytosis
Defects in any of these can cause an immunodeficiency
Age of onset for Primary Immunodeficiency Disease (PID)
- Normally in younger people but not identified until later ages
- Onset < 6 months – Likely to be T cell or phagocyte defect
- Onset > 6 months to 5 years – Likely to be B cell, antibody or phagocyte defect
- Onset > 5 years and later in life – Likely to be B cell, antibody or complement or secondary immune deficiency
Secondary immunodeficiency - causes
SID can be caused due to:
• Malnutrition (eg Zinc important in maturation of B and T lymphocytes)
• Stress
• Cancer – as a result of cancer treatment
• Side effect (corticosteroids, chemotherapy, surgery, anaesthetics)
• Infection (HIV)
Why does host have Primary immunodeficiency: congenital
• Due to intrinsic gene defect (aprox 275 genes)
○ Missing proteins – complement, immunoglobulins
○ Missing cell – b cells or t cells
○ Non-functional components
Why does host have Secondary immunodeficiency: acquired
• Due to an underlying disease/ treatment
○ Decrease production/function of immune components
○ Increased loss of catabolism of immune components
3 causes of immunodeficiency
- Immunodeficiency caused by antibody defects
- Immunodeficiency caused by T cell defects
- Immunodeficiency caused by defects in phagocytosis
Immunodeficiency caused by antibody defects
• Defect in b cell development - any defect in b cells = lack in immunoglobulins
• Defect in antibody production
○ IgG2 deficiency – does not deal well with capsular orgamisms
○ Hyper IgM syndrome – IgM is normally the first antibody, IgM increase with no IgG means improper function
Immunodeficiency caused by T cell defects
• T cell defects
○ DiGeorge syndrome – gene deletion, immune system doesn’t work properly
○ Deficiencies in cell markers e.g. MHC-II
Immunodeficiency caused by T cell defects
○ Severe combined immunodeficiency disease = very bad people can die
○ Wiskott-aldrich syndrome = wbc don’t work properly
○ Ataxia telangiectasia = problems with both immune and nervous system
Immunodeficiency caused by defects in phagocytosis
• Defect in respiratory burst
Chronic granulomatous disease
• Defect in fusion of lysosome/ phagosome ○ Chediak- Higashi syndrome – fusing of phagosome and lysosome doesn't work • Defect in neutrophil production and chemotaxis LAD protein deficiencies – leukocyte adhesion deficiency
Chronic granulomatous disease (CGD
▪ Oxygen burst is normally used to kill phagocytosed microorganism – but in this disease that process doesn’t work so microorganisms can’t be cleared = a lot of infections with gram positive infections (specifically staph aureus- as this oxidative burst is normally used to clear it)
Chediak- Higashi syndrome
○ Chediak- Higashi syndrome – fusing of phagosome and lysosome doesn’t work
LAD protein deficiencies
○ LAD protein deficiencies – leukocyte adhesion deficiency lack of the leukocyte means you can respond to infection effectively
Infections suggesting underlying immune deficiency defined as “SPUR”
–S → severe
–P → persistent
–U → unusual causes
–R → recurrent
Limitations of the 10 warning signs of PID
- Patiets with different defects/ presentations
* Patients with non infectious manifestation
Types of organisms causing infection in PID
Complement deficiency
- Neisseria species,
- Haemophilus influenzae,
- streptococci,
- other capsulated bacteria
Types of organisms causing infection in PID
Phagocytic defect – e.g.. CGD
- Staphylococcus aureus,
- Pseudomonas
- Aeruginosa
- Fungal infecions = Candida and Aspergillus species
Types of organisms causing infection in PID
Antibody deficiency
- Streptococci,
- Staphylococci,
- Haemophilus influenzae,
- Mycoplasma pneumoniae
- Viral infections – Enteroviruses
- Protozoal infections - Giardia lamblia
Types of organisms causing infection in PID
T cell defect
- Similar to antibody deficiencies but also includes intracellular bacteria eg Salmonella typhi
- All viruses
- Fungal -Candida and Aspergillus species
- Protozoa - Pneumocystis jirovecii Toxoplasma gondii
Supportive treatment PID
- Infection prevention (prophylactic antimicrobials)
- Treat infections promptly and aggressively
- Nutrition support
- Use UV-irradiated CMV negative blood products only – to make sure products are not contaminated
- Avoid live attenuated vaccines in patients with severe PID (SCID)– as the organism can replicate and multiply
Specific treatment PID
- Regular immunoglobulin therapy (IVIG or SCIG) - iv antibodies
- SCID: Haematopoietic Stem Cell Therapy (HSCT, 90% success)
Comorbidities of PID
- Autoimmune disease and malignancies
- Organ damage (lung function assessment)
- Avoid non-essential exposure to radiation
Immunoglobulin replacement therapy
Give immunodeficient patients immunoglobulins
Goal
• Serum IgG> 8g/l
• Life long treatment
Immunoglobulin replacement therapy
Treatment for which conditions
- CVID – common variable immunodeficiency – low antibody in blood
- XLA (Bruton’s disease)
- Hyper-IgM syndrome
Immunodeficiency due to HIV infection
- as amount of virus goes up CD4 levels go down
* HIV can develop into AIDS when CD4 levels are low enough
Patients with haematological malignancies nove
Increased susceptibility to infections
• Chemotherapy-induced neutropenia
• Chemotherapy-induced damage to mucosal barriers
• Vascular catheters (Hickman line)
Suspected febrile neutropenia – patient with fever and not enough immune cells
• Must be treated as an acute medical emergency
• Patients must be given empiric antibiotic therapy immediately
• If untreated, patients are under risk of septic complications
Recognition and diagnosis of immunodeficiency diseases
- When to suspect an immunodeficiency
- SPUR infections (10 warning signs)
- Age at presentation (sex)
- Site(s) of infection(s)
- Type of microorganism(s)
- Sensitivity and type of treatment (surgery)
- Secondary causes of immunodeficiency
- Family history
Suspicion of antibody/B cell deficiency
Lab tests
- IgG, IgA, IgM (+/-IgE)
- IgG1-4 subclasses
- IgG levels to specific previous vaccines
- Measure antibody in response to “test” immunization
Suspicion of T cell deficiency
Lab tests
- Lymphocyte count (FBC)
- Lymphocyte subset analysis (CD4+, CD8+ T, NK & B cells)
- In vitro tests of T cell function
Suspicion of phagocyte deficiency
Lab test
- Neutrophil count (FBC)
- Neutrophil function tests (eg oxidative burst for CGD)
- Adhesion molecule expression (for LAD)
Tests for Complement
- Individual components
* Tests of complement function (CH50 /AP50)
4 Mycobacterium species
Mycobacterium tuberculosis
Mycobacterium bovis
Mycobacterium avium
Mycobacterium leprae
Mycobacterium tuberculosis
•Causes tuberculosis in humans
Mycobacterium bovis
- Causes infection in cows and rarely in humans (eg drinking unpasteurised milk)
- Can lead to the development of extrapulmonary TB, eg bone infections that lead to hunched backs •Cows and humans can serve as reservoirs
Mycobacterium avium
•Causes a TB-like disease especially prevalent in AIDS patients
Mycobacterium leprae
•Causes leprosy
Culture - growing mycobacterium
Medium that you grow mycobacterium on
• Löwenstein–Jensen medium
○ 4-6 weeks incubation (doubling time of M. tuberculosis 15–20 hours) - slow rates of growth
○ Growing mycobacterium on agar plates is too slow to use for diagnosis – use other methods
Properties of mycobacterium tuberculosis
Aerobes
– Cell wall - mostly lipids (60%) including mycolic acid
• microorganism has a waxy outside and so is resistant to certain staining like gram stain (as the stain is lipid)
– These lipids, polysaccharides and peptides form a waxy cell surface which is hydrophobic and resistant to disinfectants, acids and alkali
– The lipids alsoprevent penetration of the cell wall with most chemical dyes for example dyes used in Gram stain
– Classified as acid-fast bacteria
Acid fast stain – stain pink (used instead of gram staining)
– Ziehl-Neelsen stain. Smear is fixed, stained with carbol-fuchsin, decolorized with acid- alcohol and counterstained with methyleneblue. Acid-fast bacilli appear pink in a contrasting background.
– Need in excess of 10,000 organisms per ml of sputum to visualize the bacteria (1000X mag) (a lot of organisms needed for staining)
Transmission off Tb
- Person to person by inhalation of droplets in the air containing bacteria from cough, sneeze, spit of infected person
- Organism in sputum, spit, cough are spread
Tb Infection -specifics
- Mycobacterium tuberculosis is phagocytosed by alveolar macrophages
- M.tuberculosis survive in the macrophages by producing sulfolipids which inhibit fusion of phagocytic vesicles (phagosomes) with lysosomes
- The presence of M.tuberculosis initiates an inflammatory response causing new lymphocytes and macrophages to migrate to the area where they surround the area of infection forming a granuloma in an attempt to wall off the bacteria and prevent spread
- After 3-4 weeks many macrophages within the granuloma die releasing the bacteria and forming a caseous centre surrounded by macrophages and lymphocytes.
Latent TB can be reactivated
• Tissue damage occurs due to the destruction of the organism and phagocytes which release degradative enzymes and reactive oxygen species such as superoxide radical
General Tb infection
Primary disease – granuloma formation (centre of macrophages with bateria, wbc all surounding the area)
Inhale the organism
Latency
—> latent bacteria can be reactivated an cause infection
Affected individuals may be asymptomatic or have mild flu like illness
• Once latent, most people remain non-symptomatic and are not contagious
• 5-10% go on to active infection and are contagious
In some individuals, the bacteria keep multiplying in the centre of the granuloma which may rupture releasing the bacteria into the bronchiole resulting in respiratory infection and haematogenous spread to other systems of the body
Latency
—> latent bacteria can be reactivated an cause infection
Affected individuals may be asymptomatic or have mild flu like illness
• Once latent, most people remain non-symptomatic and are not contagious
• 5-10% go on to active infection and are contagious
In some individuals, the bacteria keep multiplying in the centre of the granuloma which may rupture releasing the bacteria into the bronchiole resulting in respiratory infection and haematogenous spread to other systems of the body
Reactivation
- Mainly occurs in granulomas in the lungs although can happen at any site
- M. tuberculosis growth causes caseation necrosis (destruction of lung tissue resulting in cavities where bacteria grow)
- Large numbers of bacteria are present in the lungs and as a result are shed when the person sneezes or coughs.
- Haematogenous spread to other parts of the body and miliary tuberculosis (immunocompromised)
Milliary tuberculosis
• Milliary tuberculosis = tuberculosis all over
Reasons for reactivation
- Immunocompromised (medication/infection for example HIV
- Elderly – reduced immune competency
- Severe stress
- Malnutrition
- Alcoholism
- Migration – person wiht latent tb may move to another country and tb can be reactivated
Incidence of Extrapulmonary TB
—> TB in a lot of different areas of the body
•Only 10% of immunocompetent individuals who have latent TB develop active infection
– Extrapulmonary TB accounts for 15-20% of the active TB cases
•In HIV positive individuals
– Extrapulmonary TB accounts for 50-60% of the active TB cases
Extrapulmonary TB – examples
- Meninges – meningitis
- Kidneys – sterile pyuria (elevated WBC in urine)
- Liver – hepatitis
- Lumbar vertebrae – Pott’s disease
- Miliary tuberculosis (normally in immunocompromised individuals – tb all over body)
Common symptoms of TB
- Fever
- Night sweats
- Cough
- Haemoptysis - coughing up blood
- Chest pain
- Weakness
- Weight loss
Diagnosis of TB
• Chest X-ray
• Sputum sample (Ziell Neilsen stain is also called Acid Fast stain)
• Sputum culture (Lowenstein Jensen culture) - can take a long time 4-6 weeks
• Bronchoalveolar lavage (culture)
• PCR – specific and sensitive, can be used to identify different species and resistance
• Xpert MTB/RIF - diagnoses rifampicin resistance (a surrogate marker for MDR-TB) and takes approx. 90 min
○ The Xpert MTB/RIF assay is a nucleic acid amplification (NAA) test
Mantoux skin test
– Intradermal injection of purified protein derivative from mycobacteria
– Measure size of area of induration (measure radius of red patch) after 48-72 hours
– Positive test = radius >10mm
• Positive result may be due to infection, non-TB Mycobacteria, latent infection or vaccination with BCG
○ Positive test doesn’t differentiate on whether it is latent TB, present Tb of because you are vaccinated
• False negative could be due to immunocompromised status – immune system doesn’t work and so t can’t react to the purified protein mycobacterium
Blood test - Interferon Gamma Release Assay (IGRA)
Fresh blood from the patient is mixed with antigen derived from Mycobacterium tuberculosis. The white blood cells are stimulated from a person with active or latent infection will release interferon gamma which can be measured.
• Level of interferon gamma can show that wbc has been exposed to mycobacterium TB in past or present
– Detects evidence of exposure to Mycobacterium tuberculosis only
– Specific to Mycobacterium tuberculosis – Indicator of latent infection as well as active infection with Mycobacterium tuberculosis
Blood test - Interferon Gamma Release Assay (IGRA)
Limitations
– IGRA test does NOT distinguish between latent and active infection
– IGRA does differentiate between if you are vaccinated or not vaccinated = as vaccine uses mycobacterium bovis but the IGRA test uses mycobacterium TB
• Negative in subjects who have received BCG vaccine as this is an attenuated strain of Mycobacterium bovis which is different from Mycobacterium tuberculosis
Respiratory TB treatment
– 2 months treatment (killing phase) with - Rifampicin, Isoniazid, Pyrazinamide, Ethambutol
(patient may be non-infectious in 2-3 weeks)
– 4 months treatment (kill remaining bacteria and stop relapse) with
– Rifampicin and Isoniazid
Longer treatments may be needed for resistant bacteria
• Problem of compliance with long term treatments or combination treatment
Antibiotic resistance
• Resistant to one first line antibiotic (Rifampicin/Isoniazid)
– Treat for longer than 6 months
• Multi drug resistant TB (MDR-TB) resistant to 2 first line antibiotics
– Add a second line antibiotic eg Flouroquinolone
- Extensively drug resistant TB (XDR TB) resistant to first and second line antibiotics = High mortality
- As disease can’t be treated
Notifying disease
TB is a notifiable disease
• Must let health authorities know when patient has TB
- Contact tracing = make sure patients close contacts don’t have TB or are vaccinated
- Outcome – notify government about patient outcome, did they survive or not
Prevention of TB
- Vaccination – BCG vaccine
- Reporting – to health authorities
- Contact tracing
- Chest X-ray (for pulmonary TB)
BCG vaccine
—> Live attenuated strain of Mycobacterium bovis (Bacillus Calmette Guerin)
• BCG vaccination was routine in the UK as the death rate due to TB was high.
Who receives BCG vaccine
- BCG vaccination is now recommended for all babies up to one year old who are born in areas in the UK where the rate of TB is high or they have parents or grandparents who were born in areas of the world with high TB rates.
- BCG is also recommended for children and adults under the age of 35 years who are at risk of catching TB
Where is c reactive protein produced
The liver
Fungi do not respond to standard antibiotics
Because their cell walls are made of chitin not peptidoglycar
