What pathogens are normally found in the neutropenic patient
- Neutrophil count less than 0.5x109, or less than 1x109 and falling
- Fever develops in almost all patients
- S.Aureus, enterococci, E.coli and especially fungi
Define chronic granulomatous disease
- An X-linked inherited cause of innate deficiency
- Defect in NADPH oxidase = reduced O2 radical production in macrophages
- Causes recurrent gram +ve and fungal infections
What is the significance of lymphopenia?
- It affects humoral immunity as well as adaptive
- Leads to infection by most types of pathogen
Why does a splenectomy cause immunodeficiency?
- Splenic macrophages eliminate non-opsonised microbeds, including encapsulated organisms
- Site of primary Ig response
- All phagocytic cells impaired
When did HIV arise in the human population?
What is the wordwide and national epidemiology of HIV?
- Small IVDU population, mainly found in london
- MSMs largest population in UK
- Heterosexual disease in other counties, especially africa
Outline common presentations of HIV infection
- Mucosal ulceration
- Flu-like symptoms
- Pseudo-membranous candida
- Oral hairy leukoplakia (EBV infection)
- Skin disease
List some characteristics of AIDS?
- CD4:lymphocyte ratio >0.15
- Polycystic pneumonia (P.jirovecii)
- Kaposi's sarcoma
- Cerebral toxoplasmosis
Outline the genome of HIV virus and its replication in cells
- Retrovirus, ssRNA
- Integrated into T4 host lymphocyte chromsome, causing latent infection and incurability. Also infects macrophages and dentritic cells
What processes can HIV antivirals inhibit?
- Entry into cell via CCR5 receptor
- Envelope fusion with membrane via GP41
- Reverse transcription via reverse transcriptase
- Chromosome entry via integrases
- Replication via nucleotides
What characteristics of HIV make it difficult to treat?
- Intracellular replication
- Most enzymes used for replication are cellular not viral
- Reverse transcriptase has a high mutability; inhibits treatments
What is HAART?
- Highly active anti-retroviral therapy
- A regimen of 3 or more drugs used to treat HIV
What problems imitate HIV drug resistance?
- Insufficient drug dosage
- Weak antiviral regimen
- Drug interactions reducing half life
- Pregnancy (changes metabolism)
What resistance tests for HIV are available?
- Phenotypic: Virus grown in changing concentrations of drugs. Expensive and lengthy
- Genotypic: Multiple RT-PCR primes used to sequence protease, RT, integrase or envelope genes
Give examples of immunosuppresants
- Anti-metabolic agents
- Celcineurin inhibitors
- Biologic therapies
What is the mechanism of action of azathioprine? What are its adverse affects?
- Purine analogue
- Prevents DNA synthesis, especially in lymphocytes, causing apoptosis
What is the mechanism of action of glycophenolate mofetil? What are its indications?
- Inhibits purine biosynthesis and so lymphocyte proliferation (other cells can scavenge purines)
- Transplantation and vasculitis
What is the mechanism of action of methotrexate?
Inhibit folate synthesis to prevent thymine/purine synthesis
Define a biologic therapy
A medication tailored specifically to target an immune or genetic mediator of a disease
Give examples of some biologic therapies
What is the mechanism of action of rituximab?
Regulates immunosuppression by inducing B cell apoptosis via CD20 binding
What is the mechanism of action of cyclosporine?
- Inhibits calceneurin pathway, preventing calcium metabolism and influx into nucleus
- Prevents IL-2 transcription (lymphocyte chemokines)