PBL Learning Objectives

Question 1

Classification and causes of immunodeficiency (9.1)

Answer 1

Primary: A congenital immunodeficiency. Arise due to genetic mutations in genes involved in immune function - most rae autosomal recessive.

• Antibody abnormalities
• Lymphocyte e.g. SCID
• Leukocytes e.g. leukocyte adhesion deficiency
• Innate: Complement, phagocytes
• Developmental defect e.g. of brachial arches (DiGeorge - 3rd and 4th brachial arches)

Secondary: Acquired (infection/disease/aging/malnutrition/iatrogenic causes): Arise due to environmental insults and/or as a consequence of other illnesses.

• AIDS (following HIV infection)
• Immunosuppression for transplant

Consequences of immunodeficiency:

Leaves individuals more susceptible to infection. These infections are often Serious Persistent Unusual (opportunitsic) and Recurrent (SPUR). The immune defect often corresponds to the type of infection seen, e.g. bacterial infections are often associated with complement, phagocyte and antibody defects whilst fungal and viral infections are associated with T cell defects.

Question 2

HIV (9.1)

• Types, infection, routes of transmission, sequence of infection, pathogenesis, outcome of infection, sequelae*
• (draw course of infection diagram)*

Answer 2

HIV - Human immunodeficiency virus

A retrovirus.

Types:

HIV-1: Very pathogenic

HIV-2: Not as pathogenic. Predominantly seen in Africa. Previous HIV 2 infection may ‘protect’ against HIV-1 infection

Infection:

Viral gp120 binds to cellular CD4⁺ receptors alongside co-receptors (CCR5 and CXCR4 = chemokine receptors). Fusion of the virus particle and the cell is dependent upon the hinge activity of the gp41 fusion domains, which allows for membrane fusion.

Cells which express CD4⁺: Helper T cells, macrophages, monocytes, dendritic cells

CCR5: Macs., DCs, T cells

CXCR4:

Once inside the cell HIV uses reverse transcriptase to synthesise cDNA from its RNA genome. dsDNA is subsequently formed and integrated into the host genome, by integrase. As cellular DNA replication proceeds the cell inadvertently synthesises viral DNA, allowing for viral protein synthesis.

Viral protein translation produces a polyprotein which must be cleaved into individual proteins by a protease. Polycistronic RNA

Viral RT allows for rapid replication but is highly error prone - leading to the development of mutations and subsequent resistance.

Routes of transmission:

Sexual, mother to baby (placental, peri-natal and breast milk), blood or blood products (e.g. transfusion, sharing needles)

Sequence of infection:

Primary/acute infection a.k.a. serum conversion phase →assymptomatic infection → symptomatic infection

Pathogenesis:

Characterised by the continual loss of CD4⁺ cells, with ultimate failure to regenerate CD4⁺ T cells. Loss of immune function results leaving the host susceptible to opportunistic infection.

Outcome of infection:

Outcome is dependent upon viral set point, also upon a range of host and viral factors.

Anti-retrovirals look to decrease viral set point and subsequently improve prognosis/decrease progression

Host factors: CCR5 delta 38 mutations. Homozygous leads to decreased susceptibility to infection (loss of viral co-receptor binding abilty)

Viral factors: Nef

Sequelae

Immunocompromised - Below CD4⁺ T cell count of 400 cells per uL. Allows for opportunistic infection.

AIDS - A HIV patient with an AIDS defining diseases e.g.

Question 3

Innate, humoral and cellular immune responses (9.1)

Answer 3

Innate: Complement, neutrophils, phagocytes, NK cells

Humoral: Complement, Igs. IgM is the first Ig produced during infection - class switching to a different subtype then follows, through gene switching of the heavy chain.

Cellular: T and B lymphocytes (adaptive), neutrophils + macrophages + NK cells (innate)

Question 4

Skin pathology (9.1)

Blistering conditions, inflammation, infection, cancer

Answer 4

Question 5

RTIs in immunocompromised or deficient patients (9.1)

Answer 5

• Common cause of mortality, morbidity and health-care costs
• Mucosal barrier is most common entry point for pathogens, even in immunocompetent individuals
• Increased susceptibility to infection → opportunistic infectious agents
• Aspergillosis and candidiasis

Question 6

Viral latency and pathogenesis of viral infections (9.1)

Outline the viral life cyle

Answer 6

Latent viral infection: The full viral genome is retained within the host cell but expression is dramatically reduced such that very few viral antigens and no viral particles are produced. The virus must be persistent and reversible (able to reactivate the viral genome) to be classified as latent.

The herpes simplex virus (lytic) and retrovirus families are capable of latency.

Pathogenesis of viral infection

The virus infects host cells. The virus then uses host cell machinery to synthesise its own genome and proteins. The virus may cause cell lysis, chronic infection, transformation or return latent.

Question 7

AIDS and AIDS defining illnesses (9.1)

Answer 7

Diagnosis requires HIV infection and the presence of an AIDS defining illness.

AIDS defining illnesses emerge when CD4⁺ cells are < 200 cell/mm³

AIDS defining illnesses:

• Candidiasis of the oesophagus, bronchi, trachea or lungs (NOT mouth)
• CMV disease
• CMV retinitis
• Kaposki sarcoma: Low-grade vasoformative neoplasm (growth of inner lining of blood vessels). Sees the formation of skin lesions. May affect lymph nodes and internal organs.
• Toxoplasma gondii: Brain abscess
• EBV: Lymphoma
• Pneumocystis jiroveci: Pneumocystis pneumonia

Question 8

Causes of RTIs in immunocompromised or deficient patients (9.1)

Answer 8

• Pneumocystis jirovecii → pneumocystsis pneumonia
• Mycobacteria tuberculosis → TB
• Bacterial pneumonia (strep pneumonia/staph aureus/H. influenza) → TB
• Candida albicans → Eosophagitis

Question 9

HIV - Clinical presentation and staging (9.1)

Answer 9

Clinical presentation:

• Consider risk factors: IV drug use, sexual transmission, blood products (needle stick injury/tranfusion?)
• Fatigue
• Recurrent infection e.g. herpes
• TB/shingles/Kaposki’s sarcoma
• Fever and night sweats: Unexplained, lasting > 1 week
• Weight loss
• Diarrhoea

Staging:

Primary infection/serum conversion phase: Flu-like symptoms may be experienced. High levels of viral replication until the infection is brought under control

Assymptomatic/latent phase: No outward sign of disease but CD4 count declines. Very active viral replication. May persist for 10 + years

Symptomatic HIV infection and AIDS: Immune system failure and disease progresses.

Question 10

HIV - Laboratory diagnosis (9.1)

Answer 10

Immunoassays: Very sensitive and specific

• Detect viral p24 Ag capsid protein
• IgG Abs to HIV1/2

Viral load tests: > viral load indicates poorer prognosis

• May be performed in the early stages due to lack of Ig presence
• Recommended for babies with suspected HIV due to maternal antibody transfer

Question 11

HIV - Pathogenesis of immunodeficiency (9.1)

Answer 11

> viral load indicates poorer patient prognosis.

A continual loss of CD4⁺ (T) cells and the ultimate failure to replace the cells leads to a loss of immune function - leaving the patient susceptible to infection, particularly opportunistic infection e.g. candidia

Through the integration of viral DNA into immune cell nuclei the virus is able to utlise host cell ‘machinery’ to perform its replication - allowing for further increase in viral load.

Question 12

HIV -Routes of spread (9.1)

Answer 12

Sexual transmission: Virus present in mucosal secretions. Transmission is greatest from men.

Maternal-foetal transfer: Placenta, during birth (via blood) or breast milk

Blood products: Sharing needles, blood transfusion, needle stick injury

Question 13

Opportunistic infection (9.1)

Answer 13

An infectious agent that would not cause infection/illness in an healthy individual but is able to in an immunocompromised individual.

Examples:

• Candida albicans
• HSV (cold sores)
• CMV (retinitis)
• Toxoplasmosis (brain lesions)
• TB
• Cryptosporidosis (chronic diarrhoea)
• Cryptococcus (meningitis)

Question 14

Anaemia (9.2)

Outline types (draw diagram)

Answer 14

An abnormality in the number of red blood cells or the amount of haemoglobin within red blood cells.

Question 15

Blood cell production and turnover (9.2)

Answer 15

Life span of RBC: 120 days

Life span of platelet: 7 days

Question 16

Leukaemias (9.2)

Symptoms, AML, ALL, CML and CLL

Answer 16

Question 17

Spleen: Function and splenomegaly (9.2)

Answer 17

Functions of the spleen:

• Sequestrates platelets (storage for when required)
• White pulp: Immune processes - antigen recognition, Ig production
• Red pulp: Removal of defective RBCs from circulation
• Extramedullary haematopoiesis (pathology)

Splenomegaly

Causes:

• Storage diseases
• Autoimmune : SLE
• Congestive: Cirrhosis, portal hypertension
• Infection/inflammation: Acute, RA,
• Neoplasm:

Consequences:

Panocytopenia: Deficiency of RBCs, WBCs and platelets

Haemolysis

Increased plasma volume

Question 18

What are biological medicines? (9.2)

Answer 18

A substance made from a living organism or its products.

Include hormones, enzymes, clotting factors and antibodies

Question 19

Bone marrow donation and compatability (9.2)

Answer 19

Allogenic stem cell transplantation

Bone marrow donation matching is based upon HLA tissue antigen.

Question 20

Bone marrow transplantation (9.2)

Harvesting, conditioning treatment

Answer 20

Harvesting of stem cells:

• From blood: Separation of stem cells from the blood using a machine to do so
• From bone marrow: Collection of bone marrow from the pelvis (iliac bone). Uses a syringe, performed under general anaesthetic.
• From cord blood: Blood from the placenta and umbilical cord of a newborn baby is used as a source of stem cells

Conditioning treament:

The recipient must undergo high doses of chemotherapy, and sometimes radiotherapy prior to receiving the transplant.

This ensures that the existing bone marrow cells are destroyed, destroys cancer cells and causes immunosuppression (preventing rejection).

Question 21

Chemotherapy and radiotherapy (9.2)

Question 22

CML chromosome rearrangements (9.2)

Answer 22

Chronic myeloid leukaemia - Increased levels of mature cells within the bone marrow and blood.

Associated with the Philadelphia chromosome.

BRC-ABL translocation between chromosomes 9 and 22 leads to the generation of a functional fusion protein (changed chromosome 22 forms the Philadelphia chromosome). The protein produced has tyrosine kinase activity, allowing it to phosphorylate proteins. This phosphorylation activity drives proliferation - but does so quite sedately.

Question 23

Graft versus host disease (9.2)

Answer 23

A type IV hypersensitivity reaction

Grafted immunocompetent T cells proliferate within the immunocompromised host and reject host cells with ‘foreign’ proteins. Can cause severe organ dysfunction.

May be advantageous in bone marrow transplant for leukaemia - graft vs tumour effect.

Question 24

Current treatment for CML (9.2)

Answer 24

Treatment for chronic, accelerated and blast phases:

Tyrokine kinase inhibitor - Imatinib

• Not very successful in the blast phase of CML (not used)

Chemotherapy and allogenic bone marrow transplant (Haematopoietic Stem Cell Transplant - HSCT)

Question 25

Abnormal gut structure and meconium ileus (9.3)

Answer 25

Question 26

Coping and QoL in cystic fibrosis (9.3)

Answer 26

**Coping** plays a huge part in CF outcomes, QoL and how patients live their lifes. Severity of disease does not correlate to QoL and activities (e.g. employment). ## Footnote Huge **treatment burden** associated with CF. Also, stigma Disease specific measurements provide a better assessment of QoL **CFQoL** assesses 9 domains QoL looks at paremeters which are more important to patients than those to clinicians e.g. FEV1 **Transition** to adult services can be particularly **difficult** for young adults.

Question 27

Cystic fibrosis as a multi-system disease (9.3)

Answer 27

A s**pectrum of disease** is seen in CF. Severity of the condition is **dependent upon** the **causative mutation/alleles.** **Pancreatic:** * Pancreatic secretions are interrupted leading to blocking of the pancreatic ducts * The enzymes contained within the pancreatic secretions become unappropriately activated and damage the pancreatic tissue * Loss of pancreatic secretion leads to decreased ability to digest and therefore absorb food and subsequent malnutrition, deficiencies in fat soluble vitamins and may also lead to Islet destruction - CF-related diabetes. **Reproductive system:** * **Males:** Infertile. Failure of Vas Deferens formation from the Wolffian ducts. * **Females:** Often subfertile. Unusually thick cervical mucous causes difficulties conceiving. **Intestinal:** * Unusually thick intestinal mucous causes obstruction in infants - **meconium ileus** (failure to pass the first stool). * Wasting and meconium Ileus scar **Lungs:** * Presents as **barrel chest, clubbing, bronchiectasis** on CXR * Mucus within the respiratory tract is thickened * The mucocilliary apparatus find it difficult to transport the thickened mucous * Bacteria accumulate - increasing infection risk * Staph. aureus in children and P. aeruginosa in adults **Liver:** * **Interrupted** secretion of **bile** from the liver (and gall bladder) * Cystic fibrosis can lead to **cirrhosis** of the liver which in turn may cause **portal hypertension** → **oesophageal varices**

Question 28

Molecular genetics of cystic fibrosis (9.3)

Answer 28

Mutation in the apical CFTR (cystic fibrosis transmembrane conductance regulator) ion channel, chromosome 7q31.2. An ABC superfamily member. Mutations may cause decreased production of the protein or reduced functioning of the protein (nucleotide binding domain or chloride channel dysfunction). 6 possible classes of mutation: (CARDSS) 1. Improper Cl^_ transport 2. Improper Assembly 3. Imporper Regulation 4. Dysfunction 5. Imporper Synthesis 6. Lack of Synthesis The most common mutation is deltaF508 (deletion of phenylalanine at 508). **Consequences:** Inabilty to transport chloride across the membrane to create an electrochemical gradient. Sodium and water movement into the cell are increased. This prevents movement of H₂O into mucus. Mucus becomes abnormally viscous.

Question 29

Screening (9.3) ## Footnote *Principles*

Answer 29

* Disease must have a known natural history which is understood * The screening test must be acceptable to the population * There must be a treatment available * Cost of screening should be economically balanced * The screening test should have a high level of accuracy

Question 30

Structure and function of foregut (9.3)

Answer 30

**Structure:** Extends from the mouth to the second part of the duodenum Oesophagus, stomach, first 2 sections of the duodenum, liver, gallbladder, pancreas, spleen Supplied by the **coeliac trunk** Pain is referred to the **epigastric region** **Function:** * Acts to allow transport of ingested nutrients * Allows for digestion - amylase, proteases, lipases * Allows for absorption of nutrients - diffusion, facilitated diffusion, active transport

Question 31

Structure and function of pancreas, including exocrine secretion (9.3)

Answer 31

**Structure:** ## Footnote Located within the C of the duodenum, on the **transpyloric plane.** Can be divided into **5 parts**: Head, neck, body, tail, uncinate process **Retroperitoneal,** **except** the head of the pancreas. Blood supply from the CT via the splenic artery. Venous drainage to to superior mesenteric vein or hepatic portal vein. **Function:** **Endocrine:** Various cell types contained within the **Islets of Langerhan's** perform the endocrine functions of the pancreas _Alpha:_ Glucagon _Beta:_ Insulin and amylin _Gamma:_ Pancreatic polypeptide _Delta:_ Somatostatin _Epsilon:_ Grehlin **Exocrine:** The **pancreatic duct** unites with the **commone bile duct** to form the hepatopancreatic ampulla of Vater - opening into the duodenum. **Acinar cells** ⇒ synthesis, storage and secretion of digestive enzymes Proteases, lipases, amylase Zymogens are packaged alongside a trypsinogen inhibitor, preventing activation. Enterokinase activates trypsin at the brush border. Trypsin then cleaves other zymogens, allowing for activation. Stimulated by the release of **cholecystokinin (CCK)** from **I cells.** **Duct cells** ⇒ synthesis and secretion of HCO₃^- Secretion of HCO_3^- allows for neutralisation of acidic chyme as it enters the duodenum. Triggered by the release of **secretin** from **S cells.**

Question 32

Assessing nutritional status (9.3)

Answer 32

Mass (BMI) Middle upper arm circumference Skin fold thickness U&Es FBC - Anaemia

Question 33

Digestion and absorption of food (9.3)

Answer 33

**Digestion:** * Begins in the mouth through mastication and enzymatic via amylase * Continues within the stomach via stomach acid and pepsin (activated by stomach acid) * Pancreatic enzymes are released into the duodenum to allow further digestion **Absorption:** * Occurs within the small intestine and in the large intestine to a small degree (mainly water) * May be passive, facilitated or active (ATP) * Iron absorption is limited to the duodenum

Question 34

Prophylactic use of antibiotics (9.3)

Answer 34

Prophylactic antibiotic in CF - **Ciprofloxin (P. aeruginosa)** or **flucloxacllin (staph. A.)** Prophylaxis looks to prevent complications associated with bacterial infection. In CF antibiotics are used to keep the bacteria count low, decreasing the likelihood of bacterial associated illness e.g. respiratory tract infection. May provoke antibiotic resistance? Removal of 'protective' commensal bacteria. Adverse effects include oral thrush (due to reduced commensal bacteria) and diarrhoea.

Question 35

Management of cystic fibrosis (9.3)

Answer 35

**Physiotherapy:** Encourages movement of respiratory associated mucus **Mucolytics - DNase**: Digests DNA of neutrophils and macrophages within mucus **Nebuliser:** Decrease mucousal viscosity **Enzymatic and vitamin supplementation:** Supplement pancreatic enzymes (CREON) **Prophylactic antibiotics:** Flucloxacillin (Staph. A), tombramycin (P. aeruginosa) **'Stored' antibiotics to be taken at the first sign of infection**

Question 36

Fertility in CF (9.3)

Answer 36

**Males** - **Infertile** (failure of Vas Deferens development) despite zygote production being uninterrupted **Females** - **Subfertile** (thick cervical mucus) * **Low FEV1** (\< 60) is indicative of inabilty to proceed with pregnancy - reduced respiratory reserve during foetal diaphragm displacement and during delivery Individuals may be referred to **genetic counselling**. Possibility of **IVF**.

Question 37

Impact of gene therapy in the future of cystic fibrosis (9.3)

Answer 37

Potential to have a huge impact of the QoL for patients with CF Delivery of the CFTR gene to allow expression of a functional CFTR transporter. Delivery to multiple organs, as CF is a multi-system disease, is very difficult. There are barriers to delivery (mucosal epithelium, glycocalyx, cilia). Delivery to the lungs is easier, as can be delivered via **inhalation** - **cationic liposomes or viral vectors.**

Question 38

Prognosis in cystic fibrosis (9.3)

Answer 38

A life-limiting disease Related to the increated incidence of respiratory tract infections associated with the condition. Average life expectancy of 43 y/o

Question 39

Blood pressure, haematocrit and fluid replacement (9.4)

Answer 39

**Blood pressure:** 120/80 MAP = TPR x CO Fluid loss leads to a decrease in blood pressure as CO decreases. Baroreceptors detect decreased plasma volume. This triggers arteriolar and venous constriction alongside tachycardia - in at attempt to maintain BP. A significant lactic acidosis is seen in haemorrhagic shock. **Haematocrit:** Volume percentage of RBCs in the blood **Fluid replacement:** Indications: Haemorrhage, dehydration, disturbances of osmolality, shock e.g. burns **Normal saline (9% NaCl):** An isotonic crystalloid. Vomiting, diarrhoea, haemorrhage and shock.

Question 40

Dyspnoea, lung perfusion, cardiovascular compensation (9.4)

Answer 40

**Dyspnoea:** Shortness of breath **Lung perfusion:** **CV compensation:**

Question 41

ECG (9.4)

Question 42

Haematology - anaemia, sickle cell disease, clotting & thrombus formation (9.4)

Question 43

Late stages in embryological development (9.4)

Question 44

Lung vasculature and imaging (9.4)

Question 45

Physiological changes in pregnancy (9.4)

Question 46

Pregnancy and childbirth (9.4)

Question 47

Vitamin K, heparin & warfarin (pharmacology) (9.4)