Immunology (MedEd) Flashcards
A 19 year old man who has sex with men presents to the GUM clinic three weeks after he has had unprotected sex with another man.
He is extremely worried he may have caught HIV as he usually has protected sex with condoms.
What is the most appropriate test to provide this patient with an accurate diagnosis?
A. Rapid point of care test
B. CD4 count
C. Viral PCR
D. Viral load
E. 4th generation Antigen and antibody test
E. 4th generation Antigen and antibody test
According to the British HIV association (BHIVA) guidelines, the median window period for this test is 17.8 days (ranging from 13-26 days). Therefore, given this patient is three weeks post-exposure , this is the most appropriate test to see if this patient has contracted HIV. It is a serological blood test that requires venepuncture
Not: A. Rapid point of care test
This is known as the finger prick test and only needs a spot of blood to be conducted. However, antibody detection has a three month (90 day) window period and so, if the initial result were negative, would need to be repeated three months after the initial exposure in order to display a true results. Therefore, this would not be an appropriate choice for this patient
A 32-year-old man presents to the emergency department with a 2-week history of shortness of breath, which has worsened to the point that he felt breathless on the short walk into the department this morning. He has noticed a nonproductive cough that started around the same time. On questioning, he reports feeling generally run down, and has experienced night sweats and 4 kg of weight loss over the past month.
On inspection of his chest, a red, vesicular unilateral rash is noted on the left side of his back in a band-like pattern. He describes a slight burning sensation in this area and describes a previous episode of similar presentation on his right side some weeks ago. On further inspection, a collection of small raised pink lesions with central umbilication is visible over his trunk. Palpation of the neck reveals has a unilateral 1-cm soft nontender, mobile cervical lymph node.
A set of observations is taken:
BP 118/83 mmHg
Temperature 38.3 °C
HR 83 bpm
O2 saturation in air was 95% initially, but has improved to 98% on repeat
RR 19 breaths per minute
A chest X-ray is arranged, which shows no obvious abnormalities. What is the most likely underlying cause of this man’s presentation?
A. Community-acquired pneumonia
B. Hodgkin lymphoma
C. Tuberculosis
D. Heart failure
E. Primary HIV infection
E. Primary HIV infection
This man has presented with a 4-week history of progressively worsening shortness of breath consistent with Pneumocystis jirovecii pneumonia. This is a common opportunistic infection in immunocompromised individuals, such as those with untreated HIV. It is important to have a low threshold for suspicion of HIV, even in absence of obvious risk factors. The other factors indicative of HIV infection in this case include a subacute history of weight loss and night sweats, cervical lymphadenopathy, and dermatological features, including recurrent shingles and molluscum contagiosum.
Not C. Tuberculosis
This is a reasonable differential for this man’s presentation; however, tuberculosis would more likely result in a chronic productive cough, with purulent or bloodstained sputum and findings on chest X-ray.
what is p24 antigen test used for? when?
An antigen test checks your blood for an HIV antigen, called p24.
The p24 antigen test is accurate 11 days to 1 month after getting infected
what is seroconversion?
Seroconversion is a sign that the immune system is reacting to the presence of the virus in the body. It’s also the point at which the body produces antibodies to HIV. Once seroconversion has happened, an HIV test will detect antibodies and give a positive result.
HIV clinical progression
when does seroconversion occur?
Up to six weeks after getting HIV, most people experience a short one- or two-week illness called a seroconversion illness eg flu-like symptoms, myalgia
-differential: EBV
What is an allergic reaction?
Immune reaction to something harmless eg nuts
define atopy:
tendency to develop IgE antibodies against innocuous antigens (allergens)
what type of T cells responsible for atopy?
Th2 cells
what is sensitisation?
sIgE antibody presence & binding to mast cells (Fc receptor on surface, irreversible binding) & basophils
-can be sensitised but not allergic
-If two IgE molecules on the surface of mast cells recognise antigen and cross-link, then this will lead to mast cell activation and in servere cases, anaphylaxis.
what are some mediators stored in granules?
- histamine (H1-4R)
- proteases eg tryptase (can be measured in blood)
- proteoglycans eg heparin
- cytokines eg TNFa
what are some consequences of mast cell release?
- vasodilation
- smooth muscle spasm (contraction)
- increased permeability
- nerve endings: itch
define allergy:
sensitisation + typical reaction history &/or positive provocation
what tests can be used to diagnose allergy?
- Skin prick tests
-positve response: wheal >2mm greater than negative control (negative control: dilutant, positive control: histamine) - Quantitative specific IgE to pollutant allergen (blood RAST: (Radioallergosorbent test):
-measure levels of IgE in serum against a particular antigen
name of swelling over the skin
urticaria (itchy, bumpy rash)
name of swelling over mucosal surfaces/softer tissues (eg eye, lips, tongue, throat)
angioedema
how does allergy affect different bodily systems?
- skin/mucosal surface; urticaria, angioedema
- GI system: oedema of intestines; vomiting, cramps, diarrhoea
- Heart: vasodilation–> low BP–> compensatory tachycardia, palpitations, pre-sycope, LOC, empty ventricle syndrome; pulmonary vasospasm, a decreased left ventricular preload, and decreased cardiac output (obstructive shock). It is theorized that all of these effects on the CV system come together to cause an “empty ventricle syndrome” when a patient in anaphylaxis is placed in an upright position (don’t put patients in upright posture
- Resp system: bronchoconstriction (smooth muscle contraction–> SOB, wheeze), itch, sneezing, nasal discharge, voice changes, stridor, asphyxiation
why is it not recommended to put patients in upright position during empty ventricle syndrome?
this can increase the workload on the heart and worsen their condition. In an upright position, blood is pulled downward by gravity, which can cause blood to pool in the lower part of the body, decreasing the amount of blood returning to the heart. This can put additional strain on the heart, which is already struggling to pump effectively.
define anaphylaxis
skin changes (urticaria/angioedema) + A, B & C problem
what are the 2 things needed to treat anaphylaxis (updated guidelines)?
- Adrenaline
- Fluids
(no steroids, no antihistamines, no bronchodilators)
how does adrenaline treat anaphylaxis (mechanisms)
a1: vasoconstriction (increases peripheral vascular resistance, decreases mucosal oedema
b1: inotropy, chronotropy
b2: bronchodilation, decreases exocytosis (stops release of granule contents)
how to treat anaphylaxis in outpatient?
-lift legs up (returns blood to right ventricle)
-epipen
anaphylaxis algorithm:
why does someone need to be kept in hospital for 6 hours after anaphylaxis?
biphasic reaction
what happens when allergen cross-links the antibodies/after triggering exocytosis from mast cells?
from phospholipid bilayer synthesises new mediators eg leukotrienes. prostaglandins/cyclines
(minutes/hours vs mast cells: seconds/minutes)
symptoms of early phase reaction vs late phase reaction:
early; itching, sneezing, rhinorrhoea, congestion
late; nasal congestion, hyperreactivity
hospital discharge plan (mnemonic):
AAAE
-avoid allergen
-educate on allergy
-action plan
-allergy referral
-no epipen given to penicillin allergy: only to accidental exposure eg nuts
differentials for allergy:
-anxiety
-vasovagal episode
-asthma attack & skin flushing
-spontaneous urticarfia/asthma
-inducible laryngeal obstruction
-sepsis
-scombroid poisoning (fresh, canned, smoked fish)
-drug side effect eg penicillin
how can allergy be diagnosed in A & E
tryptase levels
-at baseline and then >-1.2 x baseline level + 2 (eg if tryptase is 0, then positive would be 14)
what is the protein associated with peanut allergy?
Ara H2
what is PR-10
a pollen protein (pollen food syndrome, not anaphylaxis to that certain nut) ; avoid raw/in large quantities but when cooked it should be fine
how to use epipen (mnemonic)
blue to the sky, orange to the thigh (lateral)
-blue=lock, remove lock–> once clicked=injection given (hold for 10 secs), remove it–> can’t reuse it
-if not responded to 2 injections–> ITU team (think about adrenaline infusions)
-everyone that’s used an epipen should go to hospital to get 6 hour monitoring (& get epipen replaced before discharge)
what disorders are associated with recurrent meningococcal septicaemia?
- Immunological
a) Complement deficiency
Recurrent infection with encapsulated organisms
Neisseria meningitis,
Gonococcus, H influenza B, pneumococcus
b) Antibody deficiency
Recurrent bacteria infections, especially of upper and lower respiratory tract
-eg XLA (X-linked agammaglobulinaemia) deficiency where you don’t produce mature B cells
- ## NeurologicalAny disruption of blood brain barrier
Occult skull fracture
Hydrocephalus
what is XLA?
(X-linked agammaglobulinaemia) where you don’t produce mature B cells
questions in history of someone presenting with meningococcal disease? (mnemonic)
- History of other infections (SPUR)
*Serious
*Persistent
*Unusual
*Recurrent - Past medical history
-Specifically ask about neurological disease and head injury - General health and wellbeing
-Energy, weight loss, sleep, work status (eg HIV) - Family history
-Consanguinuity
-History of meningitis
what immunological investigations to perform for meningococcal septicaemia (especially if recurrent)?
- Complement (blood)
-C3 and C4
-CH50
-AP50 - Immunoglobulins
-Serum IgG, IgA and IgM
-Protein electrophoresis
what is ch50?
a functional test of the integrity of the classical complement pathway
what is ap50?
a functional test of the integrity of alternative complement pathway
what does normal c3/c4 but absent CH50/AP50 show?
Indicates deficiency of component in final common pathway (C5-9)
how is someone with complement deficiency managed?
- Meningococcal vaccination - tetravalent meninogococcal conjugate vaccine covering serogroups A,C,W,Y (MenACWY vaccine) and the meningococcal V vaccine (Men B vaccine)
- Pneumococcal vaccination – pneumococcal conjugate vaccine (Prevenar 13, PCV)and pneumococcal polysaccharide vaccine (Pneumovax 23, PPV-23)
- Haemophilus influenza vaccination – Haemophilus influenza type b vaccine (HIB vaccine)
- Daily prophylactic penicillin
- Close monitoring
what can be detected in SLE?
The indirect immunofluorescence assay (IIFA) on HEp-2 cells is widely used for detection of antinuclear antibodies (ANA).
what tests is specific for SLE?
anti-double stranded DNA (dsDNA) and anti-SM
when can Ro, La, Sm, RNP (all=ENA) antibodies be positive?
SLE, Sjogren’s
what can assess disease activity in SLE?
Immune complexes bind to
C1q and activate classical
pathway
Complement is consumed
Low levels of C4 (first) and C3 (shows activity, goes down later) complement
suggest SLE is active
-ESR and dsDNA Ab titre also reflect
activity of disease
what do immune complexes bind to in SLE?
Immune complexes bind to
C1q and activate classical
pathway
what abs are present in diffuse cutaneous scleroderma?
SCL70 (& RNA polymerase, fibrillarin)
what abs are present in diffuse cutaneous scleroderma (CREST syndrome)?
centromere
Summary of Abs in SLE:
what should you screen all lupus patients for?
anti-phospholipid antibody syndrome (Hughes syndrome)
clinical criteria for anti-phospholipid antibody syndrome (Hughes syndrome):
- Intravascular thrombosis (arterial or venous)
- Recurrent miscarriage (=> 3):
what are some signs/symptoms of anti-phospholipid antibody syndrome (Hughes syndrome):
- mild thrombocytopenia
- prominent livedo reticularis
- libmann sachs endocarditis
commonest preventable cause of recurrent miscarriage:
anti-phospholipid antibody syndrome (Hughes syndrome):
autoimmune hepatitis antibodies:
anti smooth muscle antibody, anti LKM-1 (liver kidney microsomal-1, anti-SLA (anti-soluble liver antigen)
autoimmune thrombocytopenic purpura antibodies
anti-glycoprotein 2b/3a or Ib-Ix antibody
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
- Pernicious anaemia (anti parietal cell antibodies)
- Graves’ disease (anti-TSH receptor)
- Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
- Goodpasture’s syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
- Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
- Pemphigus Vulgaris (anti-cadherin)
Lab criteria for anti-phospholipid antibody syndrome (Hughes syndrome):
- antibodies to anionic phospholipids (anti-cardiolipin antibodies)
- Antibodies to beta-2-glycoprotein 1
- Lupus anti-coagulant test
(clotting assay-prolonged APTT or DRVVT that does not correct with normal pooled plasma but corrects with phospholipids)
what is paradoxical about anti-phospholipid antibody syndrome (Hughes syndrome) testing?
-APTT is prolonged in vitro (implying it takes longer to clot, ie anticoagulant, however the syndrome is pro-thrombotic in vivo)
what is the best test to look for renal disease in lupus patients?
- urine analysis (dipstick urine to look for proteinuria, microscopic haematuria) before creatinine goes up
- Urine microscopy (red cells, red cell casts)
- Renal biopsy
-diffuse proliferative nephritis
-immune complex and complement deposition
Summary of pathophysiology of lupus:
- Increase in cellular death pathways and impaired clearance of apoptotic cells
- Formation of immunostimulatory nucleic acid complexes
- Uptake of nucleic acid complexes by pDC and generation of Type 1 interferon immune responses
- Stimulation of T and B cells, development of plasma cells, generation of anti-nuclear antibodies, with formation of anti-nuclear antibody immune complexes
- Deposition of immune complexes in renal glomeruli, joints and the skin
- Neutrophil, and macrophage recruitment: innate cell and complement activation resulting in tissue damage (Type III Gel and Combs response)
summary of drugs in SLE”:
-not allopurinol (Xanthine oxidase inhibitor used in gout)
- not adalimumab (iAnti-TNF alpha antibody.
inflammatory arthritis, not lupus as may precipitate cutaneous lupus)
-not colchicine (gout, inhibits neutrophils)
at antibodies are seen in Sjogren’s ?
Ro and La
what HLA subtype is associated with rheumatoid arthritis? (mnemonic)
HLA-DR4 (r letters in “rheum”): only subtypes (Dw4, Sw14, Dw15) & HLA Dr1
Rheum=room=4 walls in a room
what is rheumatoid factor?
- Antibody directed at the Fc region of human IgG
some symptoms of rheumatoid arthritis;
-Peripheral, symmetrical, polyarthritis with stiffness
-Persists for > 6 weeks
-May be associated with RF and/or anti-CCP Ab
-Post-partum presentation frequently described
what do assays for rheumatoid arthritis usually look for?
- Assays usually look for IgM RF although patients may sometimes also have IgG and IgA RF
what is sensitivity/specificity of rheumatoid factor?
60-70%
what is anti-CCP? specificity?
cyclic citrullinated peptides (95%; very specific)
-polymorphism mutation in PADI enzymes (petidyl arginine deiminase eg PADI type 2, type 4 and PTPN 22 also associated with SLE, T1DM)
-smoking & gingivitis ( Porphyromonas gingivalis bacteria) associated with rheumatoid arthritis
what happens in joints of RA?
synovial hypertrophy (more synovial fluid, damage to bone & cartilage: B cells, T cells & macrophages)
what does RA treatment inhibit?
TNFa, Il-6, B cells and T cells
treatment of RA:
- First line treatment – conventional disease modifying anti-rheumatic drugs (DMARDs)
- Methotrexate
- Sulphasalazine, hydroxychloroquine, leflunomide
- Further treatment – biologic DMARDs and Jakinibs
- TNF-alpha antagonists (infliximab, entarcept)
- Tocilizumab. Antibody specific for IL-6 receptor – widespread effects
- Rituximab. Antibody specific for CD20. Depletes B cells (not plasma cells).
- Abatacept. CTLA-4 – Ig fusion protein. Binds to ligands of CD28 (CD80 and CD86) and thereby inhibits T cell activation.
- Jakinibs (targeted synthetic DMARDs) – inhibit signalling via cytokine receptors
what should RA patient do in case of infection (safetynet)?
stop drug & seek advice
-careful sun exposure/photosensitivity (tiny increased risk of melanoma)
what can cause high ESR but low CRP?
-multiple myeloma
-SLE
how can you test for multiple myeloma?
- serum immunoglobulins (usually IgG raised)
- serum protein electrophoresis (monoclonal band in gamma region)
- urine electrophoresis (free light chains detected)
why are MM patients susceptible to recurrent infections?
-Suppression of production of normal immunoglobulin by the malignant clone results in functional antibody deficiency
-Sometimes known as “immune paresis”
why are patients with MM anaemic?
- Space limitation: excess plasma cells (fill up bone marrow)–> crowd out capacity to produce RBCs
- Inhibitors
-Tumour may produce local cytokines which inhibit normal bone marrow function
why is ESR high in MM?
if protein constituents of plasma increase or change
Increases attractant charge
-Causes erythrocytes to clump together
-Clumped erythrocytes fall more quickly through plasma
–> higher ESR (ie rouleaux formation in blood film of ESR)
how does hypercalcaemia cause renal failure?
Hypercalcemia causes reduced glomerular filtration rate, increased sodium excretion and depletion of total body water (dehydration), leading to increased bicarbonate reabsorption and metabolic alkalosis.
-Alkalosis enhances calcium reabsorption in the distal nephron, thus, aggravating the hypercalcemia
what antibodies can be checked to check how well immune system functioning (bonus)?
- Antibodies to tetanus toxoid (T cell depdendent)
- Antibodies to HiB (after 2,3,4 months)
- Antibodies to PCV-13 (conjugate vaccine; after 2 months or 12-13 months)
what test can be used to quantify individual lymphocyte subsets?
-flow cytometry
-CD3: marker for T cells
-CD20: marker for B cells
-natural killer cells don’t express CD3 or CD19
-this one shows: NK cells (bottom left), B cells (top left), T cells (bottom right)
what does this flow cytometry show?
-this one shows: NK cells (bottom left), no B cells (top left), T cells (bottom right)
-XLA (Bruton’s tyrosine kinase mutations as it normally causes pre B cells to pro B cells)
what is overexpression of PTK associated with (Bruton’s tyrosine kinase)? drug to target it?
CLL (philadelphia chromosome, (BCR-ABL) , t(9;22). Imatinib: tyrosine kinase inhibitor
what demographic get XLA?
only males
treatment for XLA :
pooled serum immunoglobulin (every 3 weeks; SC or IV, indefinite treatment, against encapulsated bacteria eg pneumococcus/haemophilus)
what is more common B or T cell lymphoma?
B cell lymphoma (T cell eg EATL:Enteropathy-associated T-cell lymphoma, Coeliac disease)
what investigations should be done for osteomyelitis:
- Blood inflammatory markers, Blood cultures, and culture of any expressed pus (but note that samples from sinus tracts are unreliable)
- Imaging:
-X-ray - may be negative early on as periosteal reaction cannot be seen until about 7 days and bone necrosis after 10 days. It is useful in the diagnosis of chronic osteomyelitis.
-MRI - good for viewing bone and soft tissue. Imaging modality of choice*
-CT - good for identifying necrotic bone and for guiding needle for biopsy.
what investigations should be done for osteomyelitis:
- Blood inflammatory markers, Blood cultures, and culture of any expressed pus (but note that samples from sinus tracts are unreliable)
- Imaging:
-X-ray - may be negative early on as periosteal reaction cannot be seen until about 7 days and bone necrosis after 10 days. It is useful in the diagnosis of chronic osteomyelitis.
-MRI - good for viewing bone and soft tissue. Imaging modality of choice*
-CT - good for identifying necrotic bone and for guiding needle for biopsy.
RFs for osteomyelitis:
Diabetes melitis
Peripheral vascular disease
Malnutrition
Immunosuppression
Malignancy
Extremes of age
Local factors e.g chronic lymphedema, vasculitis, neuropathy etc.
A 42 year old male is brought by ambulance to A+E with sudden-onset diarrhoea and visual changes, followed by progressive dysphagia and generalized weakness. He has no past medical history, including no recent history of gastroenteritis or other infections. He takes no regular prescribed medications, though he has been taking intravenous heroin regularly for the past two years.
On examination, he is alert but his eyelids are drooping and his speech is breathy and nasal in quality. Neurological examination reveals hypotonia, reduced reflexes and reduced power in all four limbs; but the upper limbs are more severely affected than the lower limbs. Respiratory examination is unremarkable.
The patient is escalated immediately to ITU and supportive management started. Which diagnostic investigation should be ordered to confirm the diagnosis?
A. Lumbar puncture and CSF analysis
B. Electromyography (EMG)
C. Non-contrast CT head
D. Stool toxin ELISA
E. Tensilon (edrophonium) test
D. Stool toxin ELISA
Recreational intravenous drug use is the commonest cause of wound-associated botulism, and so this is a diagnosis that cannot be missed. The toxin can be identified by ELISA using stool, vomit, serum or urine samples. Once the diagnosis is confirmed, antitoxin should be administered as soon as possible but can still be beneficial even if provided weeks after inoculation or ingestion of the toxin. It can slow progression but has no effect on toxin already bound to the neuromuscular junction
Not:
A. Lumbar puncture and CSF analysis:
Although Guillain-Barre/Miller-Fisher syndrome is an important differential here, the history more strongly points towards botulism due to the patient’s recreational drug use. Classically, in GBS there is raised CSF protein is ‘albuminocytological dissociation’
Not B: EMG
This can be used to assess electrical activity of muscles and is particularly useful in neuromuscular diseases such as Guillain-Barre syndrome. It is not diagnostic
Not E: Tensilon (edrophonium) test
Although this could be a new presentation of Myasthenia gravis, it is uncommon in middle-aged males. It usually presents with more insidious symptoms, which progress over the course of weeks to months. In myasthenic crisis patients develop worsening muscle weakness and respiratory compromise, but this usually occurs in known MG patients with a clear trigger such as a respiratory tract infection
CSF findings in
elevated opening
Tetanus causative agent & treatment
-Clostridium tetanii
-Tetanus immunoglobulin
treatment of VRE (vancomycin resistan enterococci )
oxazolidinone e.g. linezolid
-However, can cause bone marrow suppression, peripheral neuropathy and optic neuritis
staph aureus vs enterococci:
Staphylococcus aureus produces the enzyme catalase and breaks down hydrogen peroxide, whereas Enterococcus faecalis does not produce the enzyme catalase