Mercy Juma Flashcards
(165 cards)
1
Q
Categories of PUO
A
A.Classic PUO – an update of the original PUO definition
PUO is a fever >38o C for over 3 weeks despite being investigated on 2 visits at the outpatient’s or for 3 days in hospital
B. Nosocomial PUO – Fever >38o C for 3 days not present or incubating on admission
C. Immunodeficient PUO –(caused by illness eg malignancy or of treatment such as steroids – neutropenia or defective cell mediated immunity)
Fever >38oC for >3 days for outpatients or >3 days with neg blood cultures after 48 hrs
D. HIV patients – Fever >38oC for >3 wks for outpatients or >3days for inpatients
2
Q
What are the 5 main catergories of causes of classic PUO
A
- Infection 30-50% ( abscesses, endocarditis, tuberculosis, complic UTI)
- Neoplasm 20-25% (lymphoma)
- Connective tissue disorder / vasculitis 15-20% (juvenile rheumatoid arthritis Still’s, other rheumatoid arthritis, SLE, temporal arteritis in elderly)
- Miscellaneous disorders 10-20% (FMF, pulmonary emboli, drug induced, Behcet’s syndrome)
- Undiagnosed 10-20%
3
Q
Where is meliodosis found?
A
SE asia
Melioidosis is an infectious disease caused by a Gram-negative bacterium, Burkholderia pseudomallei, found in soil and water
4
Q
Which infections are found in the mediterranean
A
Leishmaniasis, Ricketsial illness, brucellosis, Q fever
5
Q
Which infection is commonly found in S America
A
dimorphic fungi
6
Q
Which type of inflammtory disease is commonly seen in children <5 k. How does this compare to that in older children
A
kawasaki disease
Juvenile rheumatoid arthritis (Still’s disease) leading cause in older children
7
Q
Cause of PUO in returning travellers Depending on the incubation period
A
see slide 10 on puo lecture
8
Q
In which diseases are clubbing most commonly seen
A
- Chronic respiratory
2. Heart disease
9
Q
What disease has splinter haemorrhages in nails
A
Endocarditis
10
Q
What are subcutaneous nodules characteristic of
A
rheumatic fever
11
Q
markers of inflammation
A
CRP
ESR
WBC
Ferritin
12
Q
How many blood cultures would you take in first 24 hours
A
3
13
Q
What does mycoplasma cause
A
Pneumonia - can have systemic manifestations
14
Q
How to diagnose leishmaniasis
A
BM Bx
a tropical and subtropical disease caused by leishmania and transmitted by the bite of sandflies. It affects either the skin or the internal organs.
15
Q
How to differentiate falciparum on a film from all of the other plasmodiums?
A
Two dots on the ring on the film
16
Q
Use of MRI in PUO
A
very useful for CNS and spleen and lymph nodes
17
Q
Use of radiolabelled leucoyte scans?
A
leucoytes accumulate in sites of accumulation so radiolabelled leucocytes will show us where there is inflammation
abscesses or malignancy
18
Q
Use of PET CT
A
81% sens and 87% specificity (mainly for malignancy)
19
Q
25yr F born Pakistan
UK 1 year
Lives alone
Travelled to Pakistan for 2 weeks and returned one week ago.
PC:
abdominal pains
fevers for over 1 month
Weight loss
HPC:
Eating well but wt down
Sweating at night; has to change the sheets
Abdo pain all the time, all over colicy, possibly worse in the RIF
Been to GP for
A
Think of lymphoma (due to night sweats)
20
Q
What is the cause of typhoid
A
Salmonella typhi
21
Q
What abdo features does salmonella typhi cause?
A
Constipation whereas normally salmonella causes diarhhoea
22
Q
What abdo features does salmonella typhi cause?
A
Constipation and also pea-like diarrhoea whereas salmonella enteriditis causes inflammatory diarrhoea
23
Q
Frequency of btypes of malaaria
A
- Falciparum - 70%
- Vivax - 43%
- Ovale
- Malariae - 7%
24
Q
What are the complications of malaria in pregnancy
A
25% severe maternal anaemia,
10-20% low birth-weight,
5-10% neonatal and infant death
25
Indirect consequences of malaria
Impaired intellectual development, developmental abnormalities, irregular school attendance, loss of productivity
Retardation of economic development of affected countries
26
Why do male mosquitos not transmit malaria
Males feed on plant juices not blood
27
Phases of development in man
Two phases of development
1. Inside the liver (tissue phase)
Pre-erythrocytic schizogony – no clinical symptoms, no pathological damage
Exo-erythrocytic schizogony – cause of relapse
2. Inside the RBCs (erythrocytic phase)
Erythrocytic schizogony – cause of malarial paroxsyms
Gametogony – infects mosquito
28
Which morphological forms of the parasite are found in the liver
Sporozoites
Pre erythrocytic schizonts
Merozoites – infect RBCs
29
Which morphological forms are found in the RBCs
1. Trophozoites – ring form
2. Schizonts
3. Merozoites – released by the rupture of schizonts – infect other RBCs
4. Gametocytes – micro (male) and macro (female) gametocytes
30
Other modes of transmission of malaria
Sporozoite- induced- malaria : injection of an emulsion of salivary glands of mosquito containing sporozoites
Trophozoite- induced- malaria : injection of blood from a malarial patient containing the asexual forms of erythrocytic schizogony e.g.
1. Transfusion malaria – when persons with latent infection are used as donors
2. Congenital malaria – transmission through some placental defects (a healthy placenta acts as a physiological barrier)
3. Drug addicts – by using same syringe
31
Clinical course of Falciparum
1. Asymptomatic parasitaemia (“clinical immunity”)
2. Acute uncomplicated malaria
3. Severe malaria
32
When is asymptomatc falciparum seen
Seen in older children and adults, with acquired natural immunity-living in endemic areas
There are parasites in blood but no symptoms – reservoir
33
Disease LOB MALARIA
SEE NOTES
34
Manifetations of severe and complicated malaria
1. Cerebral malaria
2. Severe malarial anemia
3. Hypoglycemia
4. Metabolic acidosis
5. Acute renal failure
6. Pulmonary edema
7. Circulatory collapse
8. Blackwater fever
35
Difference in clinical features of severe malaria in adults and children
See slide 20 on malaria lecture
36
What is pernicious malaria
Def: refers to a series of phenomena occurring during infection with P. falciparum which, if not effectively treated, threatens the life of the patient within 1 to 3 days
In children & non immune adults, can cause coma & death – Cerebral malaria.
Occurs as a result of capillary blockage.
37
How does cerebral malaria manifest
Falciparum associated
High fever, headache, vomiting, convulsions, delirium, respiratory failure
Hyperpyrexia: T>400C, convulsion, delirium
Children: deep coma, seizures (more common in children), hypoglycaemia
Ataxia, monoparesis, cortical blindness, aphasia/dysarthria, hearing impairment, cortical defects
38
What are the features of malaria acute renal failure and black water fever
Blackwater fever
Reduced perfusion (obstruction)
Acute Tubular Necrosis
Occurs in previously infected subjects
Due to severe hemolysis
Can also occur in non immune adults with severe falciparum malaria, and also as a complication of quinine therapy.
A rare but acute condition characterised by sudden & massive hemolysis of parasitised & non parasitised RBCs followed by fever and haemoglobinuria.
Often fatal due to renal failure
39
How to treat malarial ARF
1. Dialysis
| 2. continue quinine
40
What are the clinical features of black water fever
Difficult to find the parasites in the blood following a hemolytic attack.
Urine appears dark red to brown black due to the presence of free Hb.
Clinical features – fever, rigors, aching pains in the loin, icterus, bilious vomiting, circulatory collapse, haemoglobinuria & acute renal failure
41
Treatment of black water fever
1. Chloroquine,
2. blood transfusion,
3. peritoneal dialysis in ARF.
42
What is the cause of hypoglycemia in malaria
Parasites use up lots of glucose
43
metabolic consequences of malaria
1. Hypoglycemia
2. Lactic acidosis
3. Thiamine deficiency
44
Two types of recurrences of malaria
1. Relapse
| 2. Recrudescence
45
Which type of malaria does recrudescence occur in ?
1. Falciparum
| 2. malariae
46
Cause of recrudescence reccurence
due to persistence of blood infection (some erythrocytic forms evade host immunity) even after clinical illness has subsided.
The numbers may increase later, leading to reappearance of clinical symptoms
Occur mostly up to one year or so but in P. malariae, it can occur even after decades
47
Which type of parasite does relapse recurrence occur in ?
Hypnozoites
- Activated from time to time to initiate pre- erythrocytic schizogony - Exoerythrocytic schizogony
48
Malaria protective factors
- P. vivax
Uses RBC duffy receptor not present in sickle cell anemia therefore these patients are protected from P vivax
- Thalassemia and G6PD deficiency
Make parasite-exposed RBCs more susceptible to apoptosis from oxidative stress therefore malaria is unable to undergo its life cycle in these individuals
- Hence a natural selection advantage for the above diseases
- HLAB53 alleles enable T cells to kill parasite-infected hepatocytes in non-Europeans.
Newborn infants and B thalassemia
High levels of HbF
49
Elevated CKs in malaria
TNFa (Plasma TNFα higher in fatal cases)
| IL-1
50
How long does falciparum last in absence of treatment
1 year but reinfection possible by other strains
51
How long could hypnozoites last
Can have periodic relapses up to 5 years
Malariae may last up to 40 years
52
Diagnosis of malaria?
Thick: located parasites sitting in RBCs
- More sensitive as they allow a greater amount of blood the be examined
Thin: directly identifies the plasmodium species
- Species identification and parasitemia (% of parasitised RBCs)
>2% parasitemia is a sign of more severe disease although severe disease can occur at any %
- Patients with schizonts at higher risk of sudden deterioration - 3rd stage of the erythrocytic phase (replicative phase
Most common form seen is the trophozoite (after merozoite has differentiated in the erythrocytic phase)
53
Other diagnostic methods for malaria
1. Antigen detection
Immunochromatographic, dipstick or
cassette format
Fast, 2-15 mins
2. Serology
Detection of Abs (IFA or ELISA)
Past infection related
3. PCR
Detection of NAs
54
Antimalaria Tx for causal prophylaxis
1. Pyrimethamine
| 2. Primaquine
55
Antimalaria Tx for blood schizonticides (terminate atacks)
1. CHoloroquine and artesmisinine
56
WHO recommendations for malaria treatment
WHO recommendations
Artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the P. falciparum parasite.
Atovaquone-proguanil is a combination of two drugs, atovaquone and proguanil, in a single tablet – for patients returning from endemic areas.
Do not use artemisinin monoterapy – resistance.
57
Treatment for tissue schizonticides (prevent relapse)
1. Primaquine
| 2. Tafenooquine
58
Treatment for gametocytocides (block transmission)
1. Primaquine
| 2. Tafenoquine
59
Treatment for sporozoitocides (ablate transmission of mosquito)
1. Primaquine and progaunil
60
Which type of malaria is common in monkeys?
Knowlesi
61
Risk factors for malaria
Travel to endemic areas
Lack of chemoprophylaxis
Low host immunity
Pregnancy
<5 years old
Immunocompromised (underlying HIV)
Old age
62
Pathophysiology of malaria
See disease LOB in PBL notes
63
Incubation time of falciparum
7-10 days
64
Incubation time of vivax
10-17 days
65
Incubation time of malariae
18-40 days
| - may ‘lie low’ in the blood to recrudesce after 1–52yrs.
66
What causes the paroxysms of fever in malaria
Release of TNF alpha and inflammatory cytokines cause fevers that correspond to the rupture of the RBC (waves of reproductive cycles)
These paroxysms of fever are specific to each type of plasmodium
67
Three stages of malaria fever?
1. Cold stage Shivering (1h): “I feel so cold.”
2. Hot stage (2–6h): T ≈41°C, flushed, dry skin; nausea/vomiting; headache.
3. Sweats (~3h) as T° falls. 95
68
Time between fever paroxysms in malariae
72 hours - quartian fever
69
Time between fever paroxysms in vivax and ovale
48 hours - tertian
70
Time between fever paroxysms in knowlesi
24 hours
71
Time between fever paroxysms in falciparum
Variable 24-48 hours - malignant tertian fever
72
How does falciparum cause complicated malaria
Falciparum coats RBCs with a sticky protein which looks like knobs or little bumps on the RBC
Causes RBC to clump and clog vessels: cytoadherence
Cells cannot flow into spleen
Causes end organ damage via ischemia
Resulting in organ failure
73
Organs affected by complicated malaria
Brain affected: cerebral malaria
Altered mental status, seizure and coma
Liver affected: bilious malaria
D&V
Jaundice
Liver failure
Lungs, kidneys and spleen commonly affected
Created sepsis like clinical picture that can result in death
74
Signs and symptoms of malaria
No rash or lymphadenopathy
Presence of risk factors
Paroxysmal fever
Headache
Weakness
Myalgia
Anorexia
Diarrhoea
75
What are the five grim signs of malaria
1. Consciousness/coma (cerebral malaria p397)
2. Convulsions
3. Co-existing chronic illness
4. Acidosis (eg esp bad if HCO3– <15 mmol/L)
5. Renal failure (eg from acute tubular necrosis).
76
Investigations of malaria - principles of blood smears
Thick: locates parasites sitting in RBCs
More sensitive as they allow a greater amount of blood the be examined
Thin: directly identifies the plasmodium species
- Species identification and parasitemia (% of parasitised RBCs)
- >2% parasitemia is a sign of more severe disease although severe disease can occur at any %
77
Presence of which type of reproductive phase of the plasmodium increase the risk of sudden deterioration?
Schizont
78
What is the most common form of plasmodium seen on film
trophozoite
79
Which form of plasmodium can persist int he blood after treatment has ended
Gametocyte
80
Usefulness of rapid diagnosis malaria test?
- Detect presence of malaria antigen or enzyme
- Poor detection of species that aren’t falciparum
- Rapid diagnosis in health resource limited areas where microscopy is not available
- Unable to distinguish between active and recently cured infection
81
What would FBC show in malaria?
- Thrombocytopenia in falciparum
Despite this, bleeding complications are rare
- Anemia
Normochromic normocytic
More common in children due to a combo of RBC destruction, AI hemolysis and disturbed marrow fx
82
Other significant biochemical abnormalities in malaria
1. Elevated lactate dehydrogenase (due to cell lysis)
| 2. Hypoglycemia since malaria consume lots of glucose
83
Treatment principles for malaria
1. If patient has taken prophylaxis do not use the same drug for treatment
2. If plasmodium species is unknown treat as falciparum
3. Nearly all falciparum is resistant to chloroquine and Fansidar (pyrimethamine and sulfadoxine
4. Chloroquine if 1st choice for benign malarias
84
Treatment for uncomplicated malaria (vivax, ovalae and malariae)
1. Chloroquine
2. If resistant to chloroquine try malarone, quinine or riamet
3. Primaquine in vivax given after chloroquine to treat liver stage and prevent relapse
4. The above are contraindicated in pregnancy
85
Treatment for Uncomplicated falciparum malaria (or if species uncertain)
1. Combination therapy is required since multidrug resistance exists
2. Choose combo therapy that contains artemisinin derivative
3. Artemisinins are ok in children and pregnancy from 13 weeks but use quinine and clindamycin in 1st trimester
86
Prophylaxis for travellers
1. Mosquito nets
2. Proguanil and chloroquine
- If chloroquine resistant area use mefloquine from 18 days before until 4 weeks after trip
Or
Doxycycline from 1 day before tip until 4 weeks after
Or
Atovaquone and proguanil (malarone) from 1 day before travel to 7 days after
87
Structure of HIV
1. Envelope
- Lipid bilayer (host cell)
- Surface glycoprotein
120 (gp120)
- Transmembrane gp41
2. Matrix
- matrix protein
beneath envelope
3. Core
- Viral capsid – p24
- Viral nucleocapsid – p9
- Integrase
- Genome : Single stranded RNA - +ve
polarity - Two copies
Protease is outside of the capsid
88
Non structural proteins of HIV
Protease
Integrase
Reverse transcriptase
89
Regulatory proteins of HIV
Tat, Rev, Vif, Vpr, Nef, Vpu,
90
Mode of HIV entry into the cell
- HIV gains entrance to the CD4 cell by:
Binding to CD4 receptor via its gp120 envelope protein
- Binding co receptor (CCR5, CXCR4) via its gp120 envelope protein
CXCR4 on:
T cells
```
CCR5 on:
Monocytes
Macrophages
Dendritic cells
T cells
```
91
Other modes of entry of HIV into the cell
The gp120 - CD4 interaction not the only way of virus entry
1. gp120 + antibodies via Fc receptors
2. gp120 + antibodies with complement domain + complement receptors
92
5 'H's of high risk people for HIV
Homosexual men
Haemophiliacs
Haitians
Heroin users
(Healthcare workers)
93
Which species can HIV be found in?
Human
Primates
Cats
94
What are the four groups of HIV - 1
M
N
O
P
95
Difference between HIV -1 and HIV -2
HIV-1 and HIV-2 are:
* Transmitted through the same routes
* Associated with similar opportunistic infections
HIV-1 is more common worldwide
HIV-2 is found in West Africa, Mozambique, and
Angola
HIV-2 is less easily transmitted
HIV-2 is less pathogenic
MTCT is relatively rare with HIV-2
96
Natural history of HIV
See graph in PBL notes
97
What occurs in the first 12 weeks (Acute phase)
In the acute phase a.k.a seroconversion (primary infection) the numbe
r of t cells drops rapidly while the viral load rapidly increases
This manifests as flu like symptoms and persistent generalised lymphadenopathy in the first 12 weeks
PGL defined as >1 cm nodes in >2 extrainguinal sites persisting 3 months or longer
98
What occurs after the first 12 weeks of HIV infection (chronic)
After 12 weeks, you enter the counterattack phase where T cells mount a response against the virus
Reduction in viral load and increase in T cells
However, as chronicity progresses, HIV eventually overtakes the T cell response
About 1-2 billion T cells die per day
Usually remain >500 cells/mm3
Can fight off most infection but some infections like TB can become more severe
99
What pathologies occur when T cell levels are between 200-500 cells/mm3
- Swollen lymph nodes
- Hairy leukoplakia
White patch on tongue caused by EBV
- Oral candidiasis
100
What occurs when T cell levels <200?
When T cells <200 T cells/mm3 patients are classified as severely immunocompromised and are said to have AIDS which manifests as the “AIDS related complex (ARC)”:
1. Persistent fever
2. Fatigue
3. Night sweats
4. Weight loss
5. Diarrhoea
101
What are the 'AIDS defining illnesses'
1. Recurrent bacterial pneumonia
2. Pneumocystis pneumonia
3. Fungal infections
4. Candidiasis of esophagus
5. Tumours
6. Kaposi sarcoma
7. Skin lesions
8. Primary lymphoma of the brain
102
What is AIDs diagnosis commonly accompanied by?
1. CD4 count <200
2. Mycobacterium Avium Intracellulare complex
3. CMV retinitis
103
Which signs correlate most with HIV progression
1. Persistent generalised lymphadenopathy
2. Chronic fever
3. Cough >1 month
4. Chronic diarrhoea
5. Oral thrush
6. Weight reduction by 10% in one month
7. TB
8. Zoster
104
Pathogenesis of HIV
1. Infected cells undergo apoptosis
2. APCs present viral peptides to Th cells – cytokine production
3. Activated B cells produce antibodies – block virus attachment to receptor
4. Specific CD8+ T cells – kill infected cells
5. NK cells engage in ADCC:
- Kill infected cells coated with Ab
- Kill uninfected cells that take up gp120+Ab
6. Cytokine production:
- Protective role, but stimulate replication of HIV in mΦ
105
What is HIV progression measured by ?
1. CD4 count
| 2. Viral load
106
Which organs can HIV directly affect
1. Brain (HIV dementia)
2. Gut (wasting)
3. Heart (cardiomyopathy)
107
Chronological presentation of common AIDS related conditions
From early to late after onset of HIV infection:
1. Thrush
2. Oral hairy leukoplakia
3. TB
4. Pneumocytis carinii (jiroveci)pneumonia
5. Histoplasmosis
6. Coccidiomycosis
7. Cryptococcosis
8. Toxoplasmosis
9. Atypical HSV disease
10. Cryptosporidioisis
11. CMV disase
12. Mycobacterium avium complex disease
Also
- Kapsis
- CMV ritinitis
- Oesophageal candiadsis
108
Treatment of pneumocystisis jiroveci
Causes pneumocystis pneumonia
Treatment: co-trimoxazole (combination antibiotic) 14-21 days
Or… pentamidine isetionate (antifungal) 14-21 days
109
Treatment for candidiasis
Local; nystatin (antifungal)
Systemic: Fluconazole (antifungal)
110
Treatment for Kaposis sarcoma
1. ART
| 2. Liposomal daunorubicin (chemotherapy)
111
Treatment of herpetic ulcer >1 month
aciclovir (antiviral)
112
Treatment of cerebral toxoplasmosis
Parasitic disease
Pregnant women with cats are susceptible
Pyrimethamine (antiparasitic) + sulfadiazine (antibiotic) + leucovorin (folinic acid)
113
Treeatment of cyrptococcal meningitis
1. Amphotericin IV (antifungal) and 5 - flucytosine (fluconazole) (antifungal)
114
Treatment of TB
Commonest and most lethal
| Treatment: isoniazid (antibiotic) +/- RIFAMPICIN and pyridoxine (vitamin B6)
115
Treatment of CMV reitinitis
Ganciclovir (valganciclovir) eye implant (antiviral)
116
HAART Principles
See PBL notes too
Triple therapy
Two nucleoside analogues + Protease inhibitor or NNRTI
or three nucleoside analogues
117
Investigation of HIV
1. 4th-generation kits can test for HIV-Ab and p24-Ag.
- Can reduce window period to 2-4 weeks
2. Serum (or salivary) HIV-Ab by ELISA, eg confi rmed by Western blot.
- In recent infection, HIV-Ab might be –ve (window period ~1–3wks after exposure); here, checking HIV RNA (PCR) or core p24 antigen in plasma, or repeating ELISA at 6wks and 3 months confirms diagnosis
- Western blot is expensive so is only used as a confirmatory test after ELISA
3. Rapid test kits (serum HIV)
- Can give results within 30 minutes but results must be confirmed by ELISA
- Positive test should be confirmed with a second rapid test
118
Types and exmaples of HAART therapy
```
1. Nucleoside reverse transcriptase inhibitor (NRTIs)
Abacavir
Lamivudine
Didannosine
Tenofovir
```
2. Integrase inhibitors
- Raltegravir
```
3. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Delaviridine
Efavirinez
Etravirine
Nevirapine
Protease inhibitors
Rotanavir
Lopinavir
```
4. Pharmacokinetic
enhancers/boosters
5. CCR5 antagonist
mARAVIOC
119
Which factors enhance the toxicity of antiretroviral therapy
1. Lipodystrophy
2. Lactic acidosis
3. Mitochondiral toxicities
4. Drug interractions
120
What may cause virological failure
1. Viral resistance
2. Poor adherence
3. Intercurrent illness
4. Pharmacokinetic problems
- Absorption
- Intracellular metabolism
121
New drug classes in ART?
Fusion inhibitors - T20
CCR-5 Antagonists - Maraviroc
Integrase inhibitors
122
ART targeting immune manipulation
IL-2, IL-7
Treatment vaccines
123
Preventing MTCT
1. C seciton
- Elective or planned C-sections are done before labor begins and before the mother's "water" (the membranes that surround the baby) breaks. This reduces the baby's contact with the mother's blood. (Emergency C-sections, those done after the membranes break, do not reduce HIV transmission.)
C sections reduce vertical transmission of HIV to the bebe
2. ART
3. Bottle feeding
124
Which factors mean a person is unable to transmit HIV through sexual contact
The person adheres to antiretroviral therapy and
monitoring
The viral load <40 copies/mL for at least six
months
There are no other sexually transmitted infections
125
Can vaccinations be given in HIV
- Given as early as possible or once immune system has recovered from ART
- Live vaccines should be used selectively
- BCG, yellow fever, oral polio, typhoid and MMR vaccines are contraindicated
126
HIV monitoring
1. CD4 count every 3-6 months
- Expensive so can also do a total lymphocyte count (TLC)
- TLC of 1400 microlitres almost equates to a CD4 count of 200 microlitres
2. HIV RNA every 3-6 months
3. Serum U+E, creatinine, Cl, bilirubin and LFT every 6-12 months
4. FBC differential every 3-6 months
5. Fasting lipid profile and glucose annually
127
Immune response to vaccination
1. Primary exposure: 5-7 days = antibody response (two weeks for a full response to switch from IgM to IgG and memory B a and T cells
2. Secondary response = 2 days for full protective response when recipient has been previously exposed
128
General principles of vaccine
1. Induce RIGHT TYPE of response
- Antibodies e.g.Hep B
- Cell mediated immunity e.g.Tuberculosis
2. Induce response in RIGHT PLACE
- Mucosal - sIgA e.g.Flu; polio
- Systemic e.g. Yellow fever
3. Response in RIGHT TIME frame
- Short-term (travel) antibody sufficient
- Long-term - memory essential
4. Vaccinated at RIGHT AGE
- Maternal antibodies in neonate neutralise vaccine
- sIgA in milk last 6 months e.g. MMR vaccine > 9 months
129
Describe the pneumococcal conjugate vaccine
- PCV7
- Polysaccharides from 7 most common capsule types
- Conjugated to T/D toxoids + OMP (as for Hib and MenC)
- improvement on old PPV23 polysaccharide
- poor IgG2 responses <2 years
130
Aims of immunization
To protect those at highest risk
Reduce disease - moderate and severe
selective immunisation strategy
OR/AND
To eradicate, eliminate or contain disease
mass immunisation strategy
Reduce infection incidence
131
Examples of selective vaccination
Travel
e.g. Typhoid
Occupational risk
e.g. Anthrax, rabies
High risk groups
e.g. Hepatitis B vaccine for neonates born to HBV+ve
mothers
Outbreak control
e.g. Hepatitis A vaccine
132
Principle of herd immunity
lots of people immunised so less likelihood of disease in the community
- natural boosting form periodic outbreak of diseases in the community
- allow people who cannot be vaccinated to be protected
133
Methods of acquiring immunity
1. Active : own antibodies via natural exposure or artificial immunisation
2. Passive: ready made antibodies via natural maternal antibodies or artificial antibodies from other sources
134
Describe the graph of passive immunity in infants
Slide 13 on Vaccine PK1 lecture
135
Two types of immune response
1. Innate: (myeloid cells) - resistance to infection and to cancer progression
2. Adaptive (lymphoid) - AI diseases and chronic inflammatory diseases
136
Steps of the immune response
See slide 20 on Vaccines PK1 lecture
137
Difference between extra and intracellular response
1 Intra (often viruses) targeted by cytotoxic T cells
2. Extra )bacteria and parasites) - humoural antibody response
138
Immunological principles of vaccination
1. Adaptive immunity is established before the infection
2. Immunity must be robust and durable
Can form
- Protective antibodies
- CTL memory
139
What do innate immune cells recognise that is the basis for vaccine design?
Innate immune cells recognise PRR that recognise PAMPs expressed by pathogens e.g. TLR - 4 recognises LPS
140
Stimulators of TLRs
Slide 25 on vaccines PK1 lecture
141
Principle of booster immunisations
immune response is always greater after secondary exposure to same antigen
slide 27 on vaccine PK1 lecture
142
Difference between antigen and adjuvant
1. Antigen: any protein peptide subtance that stimulate immine response specific to the pathogen of interest
2. Adjuvant: substance than enhances the immune response to a weakly immunogenic antigen (non specific)
143
Exxamples of live attentuated vaccines
1. BCG,
2. polio (Sabin),
3. MMR,
4. yellow fever,
5. VZV )
6. Rotavirus
144
Examples of killed (whole organisms)
1. Pertussis, flu (old types)
2. polio (Salk type),
3. cholera,
4. Hepatitis A
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Examples of sub-unit vaccines
1. toxoids
(e. g. diphtheria; tetanus)
2. polysaccharide
poor antigens = conjugated
- (toxoid + membrane proteins e.g. MenC; Hib; PCV)
- surface antigens (e.g. Hepatitis B; influenza haemagglutinins)
- virulence determinant (aP-Pertussis:- adhesin + toxoid + OMP)
- virus like particles from recombinant surface proteins - HPV
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How is a virus attenuated
Virus is put into monkey cells in order to acquire lots o mutations that don't allow it to replicate well in human cells
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Adv. and disadv. of live att. vaccines
Adv:
1. minic natural infx - stimulatate PRR
2. Induce anitbodies, CD4 and CD8
3. Fewer doses
4. Long lasting
Disadv
1. May cause Disease in immunocomprimised
2. Maternal Ab's may interfere
3. Special storage
4. Back mutation
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Disadv. of whole organism
1. Inactivation may destroy protective proteins
2. Do not induce CD8
3. May require multiple boosters to adequately stimulate immune response
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Adv. and disadv. of subunit vaccines
Adv:
1. Reduce risk of adverse affects - no risk of infx to unintended bystanders
2. more simple to produce
Disadv.
1. Must know which antigen to which protective immunity is directed
2. No CD8 (no presentation to MHC1)
3. require adjuvant
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Recominbant technology for vaccines
1. Hep B - yeast
| 2. Rotavirus - animals
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Active vs passive immunity
Active: recipient forms own Abs from stimulation of an antigen
2. Passive: antibodies put into host
e. g. Ig transfer in patients with X linked agammaglobulinemia
e. g. injection of antiHBV into babies whose mothers have Hep b within 12 hours of birth
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immunisation schedule for children
look up nearer to exam
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Basis of conjugate vaccine
capsule polysaccarides form encapsulated bacteria (e.g. H flu) cross linked to carrier protein (e.g. tetanus toxin protein) -
- carrier proteins induce CD4 response
-Bacterial (e.g. polysaccharides cannot
activate T cells because MHC molecules
cannot present them.
-Without T cell activation B cells cannot make high affinity antibodies.
- Conjugates induce T-cell dependent B cell
responses to polysaccharide antigens
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Functions and examples of adjuvants
e.g. alum, oil and microbial components
- Activate cells (APC, b cells, t cells and tissue cells) via TLRs
- increase expression of costim molecules and MHC molecules
- Induce chemokines to recruit phagocytes
- Activate APCs
- Sustained release of antigens (alum or oil)
- Enhance antigen uptake by APC (alum or oil)
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Routes of vaccines
oral/nasal
im/iv
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Risks of vaccination
1. Live can revert and become pathogenic (has caused polio in three peeps)
2. Immunodeficideent
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Significance of mantoux tuberculin response
A reaction of 6mm or greater, indicates
a response of the immune system due
to either TB infection, infection with
environmental mycobacteria or previous
BCG vaccination
Reactions >15mm more likely to be TB
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Use of hepatitis B vaccine
Infants: several options that depend on status of
the mother
If mother HBsAg negative: birth, 1-2m,6-18m
If mother HBsAg positive: vaccine and Hep B immune
globulin within 12 hours of birth, 1-2m, <6m
Adults
0,1, 6 months
Vaccine recommended in
All those aged 0-18
Those at high risk
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Hep B high risk groups
Persons with multiple sex partners or diagnosis of a
sexually transmitted disease
Men who have sex with men
Sex contacts of infected persons
Injection drug users
Household contacts of chronically infected persons
Infants born to infected mothers
Infants/children of immigrants from areas with high
rates of HBV infection
Health care and public safety workers
Haemodialysis patients
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Features of VZV virus
Varicella (chickenpox)
= Primary infection
Zoster (zoster)
= Reactivation
You cannot catch zoster (shingles)
You can catch chickenpox (from either chickenpox
or shingles)
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Potential epidemic of post-herpetic neuralgia
Widespread varicella vaccine in childhood
Reduction in childhood disease
Reduction in exposure of naturally immune
Reduction in natural boosters
Increase in zoster
Increase in PHN
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High risk and low risk HPV
High risk types (16,18) – lead to cancer
HPV16: 50%
HPV18: 20%
Low risk types (6,11) - warts
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Contraindications to live vaccines
Primary immunodeficiency
Standard and intensive chemotherapy
Haemopoietic stem cell transplant
Solid organ transplant
Systemic corticosteroid use
Immunosuppressive drug therapy
HIV infection
Other conditions
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Who is the influenza vaccine offered to
- all those aged 65 years or over
- all those aged 6 months or over in a clinical risk group
- those living in long-stay residential facilities
- those who care for elderly or disabled persons
- household contacts of immunocompromised individuals
- those working within health and social care settings
- those who work in close contact with poultry
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What is MAC
M avium and M intracellulare; because these species are difficult to differentiate, they are also collectively referred to as Mycobacterium avium-intracellulare (MAI) . MAC is the atypical Mycobacterium most commonly associated with human disease.
MAC is primarily a pulmonary pathogen that affects individuals who are immune compromised (eg, from AIDS, hairy cell leukemia, immunosuppressive chemotherapy). In this clinical setting, MAC has been associated with osteomyelitis; tenosynovitis; synovitis; and disseminated disease involving the lymph nodes, the CNS, the liver, the spleen, and the bone marrow. MAC is the most common cause of infection by nontuberculous mycobacteria (NTM) in patients with AIDS. M avium is the isolate in more than 95% of patients with AIDS who develop MAC infections.
