Infectious diseases/immunology Flashcards

Question

Nathaniel is a 3-month-old Afro-Caribbean baby who is brought to A&E by his parents after developing a fever. They tell you that Nathaniel is off his feeds and is unusually sleepy. His crying has become high pitched - 4 dd, 12 hist, 11 exam, 8ix, 3mx

Answer 1

dd - Meningitis. 2 Encephalitis. 3 Other focal bacterial infection, e.g. pneumonia, UTI, otitis media. 4 Viral infection hist - when/what was wrong first? what have temps been? any vomiting? any loc/convulsions? any rash/cough/dyspnoea or ear pulling? how much feed in last 24h? wet nappies? had other illnesses, any vaccinations? obs/labour history; any infectious contacts at home? look for avpu, rash, behaviour eg drowsy, irritable; signs of dehydration, raised icp (ant font, unequal pupils, hypertens w bradycard (cushing), rarely papillo); kernigs, brudzinskis, lying with arched back; do resp and ent system exam blood cultures and PCR, FBC, U&Es, blood glucose, MSU, rapid antigen test on blood/csf or urine, then when stable LP sending csf for cyto, micro, biochem broad spectrum abx (with listeria cover if <1mo), iv fluid resus, dexameth

Answer 2

non-blanching rash” that everybody worries about as it indicates the infection has caused disseminated intravascular coagulopathy (DIC) and subcutaneous haemorrhages. NICE recommend lumbar puncture as part of the investigations for all children: Under 1 months presenting with fever 1 – 3 months with fever and are unwell Under 1 years with unexplained fever Steroids are also used in bacterial meningitis to reduce the frequency and severity of hearing loss and neurological damage. Dexamethasone is given if the lumbar puncture is suggestive of bacterial meningitis

Answer 3

Antibiotics < 3 months: IV amoxicillin (or ampicillin) + IV cefotaxime - note no ceftriaxone if <3mo as it displaces bilirubin from albumin binding sites, resulting in higher levels of bilirubin that accumulate in the tissues > 3 months: IV cefotaxime (or ceftriaxone) 2. Steroids NICE advise against giving corticosteroids in children younger than 3 months dexamethsone should be considered if the lumbar puncture reveals any of the following: frankly purulent CSF CSF white blood cell count greater than 1000/microlitre raised CSF white blood cell count with protein concentration greater than 1 g/litre bacteria on Gram stain 3. Fluids treat any shock, e.g. with colloid 4. Cerebral monitoring mechanical ventilation if respiratory impairment 5. Public health notification and antibiotic prophylaxis of contacts: ciprofloxacin is now preferred over rifampicin also: If you're treating empirically for suspected bacterial meningitis (either contracted abroad or from a patient who has spent extended duration abroad in recent history or have had prolonged or multiple exposure to antibiotics (within the past 3 months)) and you haven't yet identified the causative organism, you need to take into account the possibility of penicillin-resistant Streptococcus pneumonia and add vancomycin. this is because because in the UK Pneumococcal penicillin resistant is exceedingly rare, whereas around many other parts of the world it is common enough that you can't afford to not cover for it in the case of meningitis. This is largely driven by the over-use of penicillin-based antibiotics (both by prescribers and over-the-counter). once cultures and sensitivities are back you can stop the vanc

Answer 4

proph abx for all members of household and other close contacts (rifampicin - cipro now preferred) notifiable disease - let consultant in communicable disease control know complications: * Deafness: Due to inflammatory damage to the hair cells. All children with meningitis should have their hearing checked after recovery. * Cranial nerve palsies: Due to local vasculitis. * Cerebral abscesses: Cause rapid deterioration with a high fever and features of raised intracranial pressure. They require surgical drainage. * Epilepsy: May be caused by an abscess or local infarction. * Hydrocephalus: The presence of inflammation and exudates may block the reabsorption of CSF. A ventriculoperitoneal shunt may be needed. * Mental impairment: Permanent brain damage may result, although this is much less common with meningococcal rather than pneumococcal meningitis

Answer 5

Signs of raised intracranial pressure, e.g. papilloedema. * Cardiorespiratory instability. * Local infection at the site of the lumbar puncture. * Coagulation disorder or thrombocytopaenia

Answer 6

coagulase negative staph (CONS) egs: S. epidermidis, S. capitis, S. hominis, S. warneri, and S. haemolyticus

Answer 7

crp: CRP is recommended over ESR to detect acute phase inflammation in patients with undiagnosed conditions because it is more sensitive and specific than ESR; concentrations change rapidly within the first 6-8 hours after injury, peak after 48 hours, and return to normal levels once the issue has resolve; CRP levels fall quickly once the cause of inflammation has resolved, CRP is a useful marker for monitoring disease activity: levels should decrease during the first 48 hours if treatment is adequate; increases in CRP concentrations during the first 48 hours suggest inadequate therapy - wait at least 24 hours to repeat esr: fibrinogen released in blood causing RBCs to stick together which raises esr; Because the ESR depends on several proteins with varying half-lives, the rate rises and falls more slowly than do CRP concentrations; useful for select conditions, esp to do with bone, PMR, temp arteritis etc: presence of an ESR/CRP mismatch - you see this in SLE where a massive ESR and a modest CRP would push me towards disease activity rather than infection. You don't tend to get mahoosive CRPs in SLE unless they have infection/serositis. Obviously the usual caveat of "never say never" in medicine applies here. You may also see a disproportionately high ESR in conditions like Sjogren's or myeloma due to hypergammaglobulinaemia (polyclonal in Sjogren's, monoclonal in haem issues); very unusual to have PMR, and even more so GCA when both ESR and CRP are normal (but can have it if only a mild raise in one or both) procalcitonin: newer, more selective for bacterial cause: most often induced by bacterial infection; however, increases can also result from other causes, including severe viral infection, pancreatitis, tissue trauma, and certain autoimmune disorders; PCT levels halve daily when the infection is controlled, and levels correlate well with disease burden; rise over 2 tests suggests bacti infection and if not suggests other cause but not definite; main uses: To differentiate systemic bacterial infection from non-infectious systemic inflammatory response syndrome (SIRS) (diagnostic marker) or suggests eg septic arthritis in face of equivocal aspirate vs rheumatic cause like reactive arth that would also inc CRP * To ascertain the severity of illness of bacterial sepsis (prognostic marker) * To monitor response to therapy of systemic bacterial infections * To guide discontinuation of antibiotics during systemic bacterial infections - different guides exist based on different studies but eg withhold antibiotics for patients with procalcitonin values of ≤0.25 µg/L or stop antibiotics if procalcitonin levels decreased by ≥80% when the initial procalcitonin was >5–10 µg/L * For cases of CAP and acute exacerbations of COPD to exclude a bacterial aetiology

Answer 8

LDH is general marker of cell damage/death which may be raised in wide variety of conditions: liver disease, heart attack, anemia, muscle trauma, bone fractures, cancers, and infections (esp serious) CK generally is muscle damage which can be from a direct damage to the muscle inc myopathies, or can result from eg infection causing damage; can be raised in various electrolyte abnorms and endocrine problems, due to medications, or due to surgery or exercise other markers may inc GGT, AST/ALT, troponins etc

Answer 9

in DH ask if had chemoprophylaxis on recent trip occupation may be relevant; any close contacts ill; travel: when and for how long? move between countries? rural or urban? what kind of accom eg hotels, camping etc; what purpose, what activities while there; do pt have idea where may have come from - ask about tattoos, sexual activity, contact with sick person, drug use; what did they eat/drink? prophylaxis? sexual history inc when last std check, ever positive? freshwater - schisto, lepto; mosquito bites - malaria, dengue; animal bites -rabies; tick bites - lyme disease; rocky mountains - rickettsia contaminated water - giardia, enteric fever, salmonella and campylobacter; unpasteurised milk - salmonella, listeria; cruises, air-con - listeria sex contacts - HIV, hepatitis, chlam, gon, syph, warts etc work in healthcare - TB, HIV, hepatitis damp conditions or prison - TB FBCs (differential white cell count)/U&Es/LFTs/CRP; if malaria then thick and thin blood films; HIV +/- viral hep test; cultures; PCR for some viruses; urine and stool for culture; CXR; if seizures or focal neuro then CT head; organomegaly then USS of these organs for eg abscess/amoeba

Answer 10

common + serious (30%): HIV, TB, malaria common bacti (30%): Staphylococcus aureus bacteraemia, Streptococcus pneumoniae bacteraemia/meningitis, Neisseria meningitidis bacteraemia/meningitis common viral (30%): EBV, flu etc rare: haemorrhagic fevers, salmonella typhi or paratyphi, brucella, ricketssia, spirochaetes, dengue, amoebic liver abscesses, helminths high fever without local symptoms or signs is often intracellular infection in general CRP 100-130 is equivocal with over this more likely bacti, lower could also be either; can be useful to see how fast it is going up -> bacti tends to rise much quicker if neutrophil leucocytosis then extracellular organisms more likely (bacti, spirochaetes, amoeba); if not then is CRP >100 (think eg salmonella, brucellosis), <30 (usually viral), 30-100 (almost anything)

Answer 11

eosins >0.6x10^9/L (obtain previous FBCs if you can to see when it started) if pt has atopy or urticaria identify provoking allergens, if asthma + skin/renal/nerve involvement consider churg strauss (ANCA test) it no atopy/urti did it occur after pt took a drug? document history of drug exposure -> eosin, if poss discontinue drug and monitor eosin if not then did occur after travel to developing country? if yes investigate for helminths, discuss with infectious disease; CXR, stool microscopy; if fresh water exposure then schisto so urine micro; if soil exposure then toxocara, stronglyoides so duodenal biopsy; if undercooked pork then trichinella or cysticercosis so CPK; if dogs then echinococcus so liver uss; if mosquitoes then filariasis so blood film, skin biopsy, opthalm assessment if not then blistering skin rash? (biopsy for pemphigus or dermatitis herpetiformis) if not then B symptoms? (lymphoma) if not then renal/urine symptoms or purpura? (polyarteritis nodosa) if not then abnormal CXR? (pneumo/haemothorax, sarcoidosis, lung helminths, drug induced pulm eosin) if not consider rare causes: hypereosin syndrome, eosin leukaemia, coccidioidomycosis, hypoadrenalism

Answer 12

many actions inc: decrease glucose uptake by muscle/fat, inc gluconeogensis, inc protein metabolism, dec protein anabolism, redistribution of fat also antiinflam actions inc: dec activity/influx of leucocytes, dec activity of monocytes, dec clonal expansion of T/B cells, switch from Th1 to Th2, dec pro-inflam cytokine production, dec eicosanoid production, inc release of antiinflam factors; will get reduced healing bind to glucocorticoid receptor in cytoplasm which is bound to hsp90 (and other proteins), ligand binding causes hsp90 to dissociate and r's to form homodimers which translocate to nucleus to transactivate/repress up to 1% of genome, thus drugs very broad spectrum with side effects; either binds to positive glucocorticoid response element within promoter, bind to negative GRE to displace tfs etc also rapid non-genomic effects that arent well understood eg hydrocortisone rapidly inhibs neutrophil degranulation and GR antags dont stop this, same for IgE mediated mast cell degranulation and IV betamethasone reduces nasal itching after pollen applied within 10 mins, too fast to be genomic effects

Answer 13

oppurtunistic infection due to suppressed immune system, thinning of skin and impaired wound healing, oral thrush due to local anti-infection mechanisms suppressed when taken orally, osteoporosis due to severeal reasons including inc osteoclast and dec oestoblast activity, hyperglycaemia, muscle wasting, stomach ulcer, avascular necrosis of femoral head (rare, need hip replacement); long term use can get cushings syndrome + suppression of HPA so sudden withdrawal after >1week of use can result in acute adrenal insufficiency other drugs given to reduce eg PPI and a bisphosphonate to protect bone for bisphos: (In all men and women aged > 65 years who take corticosteroids of any dose for more than 3 months, including high dose inhaled corticosteroids or patients on 3/4 courses of prednisolone in a year.) for PPI: if older, pmh of GI ulcer/bleed, or other meds/risk factors for upper GI problems present (antigoags/plats, SSRIs, NSAIDs, cav blockers)

Answer 14

As a general principle, short courses of oral corticosteroids (less than 3 weeks) can be stopped abruptly as long as underlying symptoms allow. Gradual withdrawal should be considered for people whose disease is unlikely to relapse and who have: Taken more than 40 mg oral prednisolone daily or equivalent for more than 1 week. Taken repeated evening doses of corticosteroids. Received more than 3 weeks of corticosteroid treatment. Recently received repeated courses of corticosteroids (especially if taken for longer than 3 weeks), such as short courses repeatedly prescribed for the treatment of acute exacerbations of asthma. A history of previous long-term therapy (months or years). Other possible causes of adrenal suppression, such as excessive alcohol consumption or stress. If stress, for example caused by infection, trauma, or surgery, occurs up to 1 week after stopping the corticosteroid, additional corticosteroid cover should be prescribed to compensate for any potential adrenal suppression. During withdrawal, the dose of oral corticosteroids may be reduced rapidly down to physiological doses (about 7.5 mg of prednisolone or equivalent (as this is roughly equiv to normal physiological dose of 10mg/m^2 hydrocortisone a day ie should prevent adrenal suppression) and reduced more slowly thereafter. Unlikely to have adrenal suppression if less than 2-3 weeks course even higher doses, and so generally no need to wean (or fast taper eg 25% per day); nevertheless be wary of adrenal insufficiency sx Normal secretion generally takes 6-8 weeks to resume but may take 6-12mo; different tapering plans and no strict rules could eg wean to 10mg/m^2 hydrocort a day over eg 4-6 weeks or as sx allow then by a further 10-20% ie initially 2mg/m^2 every 1-2 weeks; when at physiological dose switch from dex/pred to hydrocort, shorter half life may help adrenal function recover lethargy/depression suggests go back up and switch to slower wean over eg 6 months Check early morning serum cortisol 24-48 hours after stopping hydrocortisone - if adrenal insuff present restart and get endo advice for prolonged wean, and if borderline result seek advice likewise; for one year after still have clinical suspicion for adrenal crisis as gland function may not be fully recovered even with normal morning levels

Answer 15

stress kinase pathways activated by wide range of factors eg osmotic stress, oxidative stress, heat, UV, DNA cleavage) which activate heterodimeric transcription factors eg AP1 that re-programme transcription which may lead to shutdown of protein synthesis, apoptosis or necrosis depending on additional factor heat shock response is reaction to injury in all living cells where stresses cause dissociation of cytosolic heat shock factors (proteins) from complexes which normally keep them inactive, these HSFs translocate to the nucleus and suppress transcription of some genes but promote HSPs, chaperone proteins which refold partially denatured proteins to allow cell to maintain function: HSPs thus responsible for preconditioning where cells exposed to minor injury become resistant to more major stresses unfolded protein response (ER [protein] in active cell can reach 100mg/ml, which can allow unwanted precipitation/aggregation of proteins unless folded correctly and chaperoned), this process ensures rate of protein synthesis doesn't exceed cells capacity to complete the folding process by activating signalling cascades that increase synthesis of folding chaperones, enhance proteasomal protein degradation and slows translation; UPR is usually reversible and part of process called 'host cell shut down', a primitive reversible response that acts within minutes to suppress DNA/RNA synthesis and inhibit many enzyme-catalysed reactions

Answer 16

intrinsic pathway: activated when the cell undergoes stress from the inside due to various factors such as DNA damage from x-ray or UV light exposure, chemotherapeutic agents, hypoxia, the accumulation of misfolded proteins inside the cell as seen in conditions such as Alzheimer's disease, Parkinson's disease, or Huntington disease, among others. When the cell undergoes stress, cytochrome c leaks from the intermembrane space of mitochondria into the cytosol, which leads to the activation of caspases 9. The regulation of this pathway is governed by the Bcl-2 and TP53 genes extrinsic pathway: triggered when the cell receives death signals from the other cells, ultimately activating caspase 8; TNFa is main extrinsic trigger Initiator caspases include caspases 2, 8, 9, and 10. When activated, the initiator caspases activate the effector caspases. Effector caspases encompass caspases 3, 6, and 7. Active effector caspases cleave several proteins in the cell, leading to cell death and, ultimately, phagocytosis and removal of cellular debris

Answer 17

Coagulative necrosis: Ischemia in most organs except the brain can lead to coagulative necrosis. In this type of necrosis, the cell architecture remains preserved. Under the microscope, the cells appear anucleate, eosinophilic, with preserved structure. Eventually, the dead cells are cleared by phagocytosis and leukocytes Liquefactive necrosis: This morphology is most commonly observed in the central nervous system as less connective tissue and many digestive enzymes present. The dying cells are digested by hydrolytic enzymes and hence lose their structural integrity and turn into a viscous mass. This is also typical of bacterial, or sometimes fungal, infections because of their ability to stimulate an inflammatory response Caseous necrosis: The term caseous means "cheese-like," which refers to the whitish appearance of the necrotic area. This necrosis takes place in tuberculous infection, and the necrotic area is surrounded by a granuloma Gangrenous necrosis: This is not a morphological pattern but rather a clinical term for ischemic necrosis of the limbs. It has two types i) dry (ischemia leading to coagulative necrosis), and ii) wet (ischemia with superimposed bacterial infection leading to liquefactive necrosis) Fat necrosis: This type of necrosis occurs in acute pancreatitis. The release of pancreatic enzymes leads to liquefaction of the fat cells in the peritoneal cavity. These liquified fat cells then combine with calcium and are identified as chalky white areas. This process is referred to as saponification Fibrinoid necrosis: This type of necrosis occurs in blood vessels due to the deposition of immune complexes in blood vessel walls leading to leakage of fibrin

Answer 18

PAMPs and DAMPs bind to PRR on macros, DCs, mast cells in tissue which activates them; lysis of host cells releases inflam mediators like atp; neurogenic: stimulating nerve results in APs along central trunk up to brain, and along other branches from central trunk to give inflam; these branches release calcitonin gene related peptide CGRP and substance P, which directly cause vasodilation and SP is potent activator of mast cell degranulation which leads to local production of histamine dermatographic urticaria (2-5% pop) is condition where triple response is exaggerated, is largely idiopathic and treated with H1r antagonists and the monoclonal antibody omalizumab which recognises IgE and acts to decrease mast cell activation factor XII activated by contacting negative substances like collagen, becomes XIIa which produces thrombin (intrinsic pathway), plasmin, fibrin and bradykinin (activates kallikrein); first two hydrolyse C3 to produce C3a/b thus complement, coagulation, fibrinolytic, and kinin systems interact; complement (inc C3a/5a activating mast cells) neutrophil migration + monocyte migration later attracted by chemotactic agents released by macros

Answer 19

2-(1H-imidazol-4-yl)ethanamine; formed from histidine by histidine decarboxylase and found in mast cells, basophils, enterochromaffin-like cells (in gut) and histaminergic neurons increase in cellular [Ca] causes degranulation: C3a/C5ar are Gi coupled with bg subunit activating PLCbeta, inducing intracellular Ca release via IP3; SP primarily induces via receptors which are Gq coupled, again acting via PLCbeta; allergens induce cross-linking of IgE with high affinity FceRI receptor which induces phospho of adapter protein linker for activation of T cells LAT and that causes activation of PLCgamma (IP3->Ca) 4 GPCR receptors; H1 -> Gq - PLCbeta - IP3/DAG/PKC (important for inflam); H2 - Gs - cAMP up (gastric acid); H3 - Gi - cAMP down (inhib autoreceptor in CNS); H4 - Gi - cAMP down (chemotaxis/cytokine release); so get smooth muscle contraction (ileum, bronchioles, uterus), blood vessel dilation via eNOS, itching by H1 activation of pruritoceptors, H1 triple response, H2 increase HR/gastric acid secretion

Answer 20

sodium cromoglycate is mast cell stabiliser with unclear mechanism but observed to decrease Ca influx, a proposed mechanism is inhib of an inwards Cl conductance required to maintain -ve enough PM pot to sustain Ca influx raising cAMP also stops degranulation so beta2 agonists (salbutamol, formoterol) and PDE inhibitors (theophylline) in treatment of asthma helps, though main affect via bronchodilation; omalizumab stops by stopping IgE binding to FceRI h1r antags - classical antihistamines, used to treat histamine inflam; first gen like mepyramine, diphenhydramine (benadryl) permeated BBB and caused drowsiness so not suitable for systemic use, though still used topically for insect bites, and in some cold/flu remedies to aid sleeping; 2nd gen couldnt cross BBB so terfenadine, big in the 1980s but found it inhibited Kv11.1/hERG resulting in long QT interval and possibly sudden cardiac death: terfenadine is prodrug metabolised to active fexofenadine by 3A4 isoform of cytochrome P450 so enhanced risk of death if this enzymes inhibited, and this enzyme inhibited by grapefruit juice and many drugs; every new drug now screened for activity against hERG; 3rd gen are non-drowsy, lack cardiac side effects and include fexofenadine and loratadine; theyre used to treat hay fever, allergies and uticaria

Answer 21

bradykinin first identified as slow contractor of ileal smooth muscle; formed by kallikrein on kininogens (can be HMW or LMW); hageman factor (factor XII) activated by contacting -ve charged surface (collagen, BM, LPS) after leaking out of blood vessels during inflam, then converts prekallikrein to kallikrein which clips HMW kininogen to bradykinin and LMW kininogen to kallidin; bradykinin further clipped to inactivate by eg kininase 2 aka ACE B1r and B2r both Gq coupled with B1r upregulated during inflam by cytokines like IL1, B2r constitutively expressed and potently activated by bradykinin/kallidin; activating these r in vascular endothelium causes increased Ca which activates cytosolic phospholipase A2, causing prostacyclin (PGI2) production and eNOS activity; PGI2 and NO diffuse to smooth muscle, increase cAMP and cGMP respectively and mediate vasodilation (ACEi cause more bradykinin which thus causes vasodilation via this mechanism); activating Br also drives nociception (activates and sensitises) as Gq -> PKC -> phospho of ion channels involved in pain sensation kallikrein inhibited by C1-esterase inhibitor and in hereditary angioedema (HAE) mutation in C1INH causes excessive bradykinin leading to periods of severe/painful swelling; type I HAE compromises synthesis/secretion, type II allows inactive HAE to be produced; ACEi angioedema has 5x higher prevalence in african americans, possibly linked to variation in genes that control immune system; ecallantide is inhibitor of kallikrein that can treat HAE, as is recombinant C1INH, may also treat ACEi angioedema

Answer 22

named prostaglandin as first discovered in semen (from prostate gland); COX makes prostaglandins from arachidonic acid in 2 reactions, first acid cyclised and oxygenated to form endoperoxide PGG2, then hydroperoxyl reduced to form PGH2; COX1 constitutively expressed in many types of cells, COX2 also to small extent though mainly induced by inflam cell specific enzymes then produce specific prostaglandins or thromboxanes from PGH2 eg PGE2, PGI2, TXA2 (2 means 2 C=C bonds, if eicosatrienoic acid instead at first step get PGE1 etc and if eicosapentanoic acid then PGE3 etc); PGE/I2 tend to be produced locally by tissues/blood vessels, PGD2 mainly mast cells, and PGE2/TXA2 mainly by macros in chronic inflam (the specific enzymes are called eg PGD synthase)

Answer 23

Innate immunity is the first immunological, non-specific mechanism for fighting against infections, to eliminate initial cause of cell injury, remove damaged/necrotic tissue and initiate repair; has phagocytosis, cytokine secretion and complement activation; leucocytes and acute inflammatory exudate (soluble factors) recruited to site of injury and may eliminate pathogen, and in more serious cases acute phase (systemic) responses occur and consist of fever, neutrophilia (increased numbers of circulating neutrophils) and increase in acute phase proteins in plasma mast cells: key role in inflam, containing mediators of inflam eg histamine, with function to rapidly induce inflam and can degranulate within seconds of activation by a wide range of factors including allergens (IgE), danger signals (PAMPs/DAMPs) and complement components (C3a/C5a), and these cells are resident under epithelial surfaces along with macrophages where they function as sentinel cells to sense tissue damage dendritic cells bridge innate and adaptive systems, recognising pathogens at site of infection in periphery and carrying this info to the draining lymph nodes to initiate the adaptive response

Answer 24

After stimulation with proinflammatory cytokines (including IL-6), Kupffer cells produce IL-6 in the liver and present it to the hepatocytes. IL-6 is the major mediator for the hepatocytic secretion of APPs. Synthesis of APP can also be regulated indirectly by cortisol. Cortisol can enhance expression of IL-6 receptors in liver cells acute phase proteins that are produced more include CRP (opsonisation - bind dead/dying cells and bacteria to activate complement), MBL, complement, ferritin (dec fe availability), caeruloplasmin (oxidise iron to facilitate ferritin binding), serum amyloid A (recruit inflam cells, induce enzymes to degrade ecm), haptoglobin (bind haem so less iron available), fibrinogen, prothrombin, plasminogen-activator inhibitor, hepcidin (dec fe availability), a2 macroglobulin (inhib thrombin and plasmin), a1 antitrypsin (reduce inflammation) produced less: albumin, transferrin, antithrombin, C3 levels often down due to increased turnover but production actually increased

Answer 25

Left shift or blood shift is an increase in the number of immature cell types among the blood cells in a sample of blood. Many (perhaps most) clinical mentions of left shift refer to the white blood cell lineage, particularly neutrophils Less commonly, left shift may also refer to a similar phenomenon in the red blood cell lineage in severe anemia, when increased reticulocytes and immature erythrocyte-precursor cells appear In any acute inflammation, an increase in neutrophils is often seen. Infection most common but also increases may be seen after a heart attack (or other infarct), necrosis, exercise, anxiety, and other stressors.

Answer 26

Seven different mechanisms were involved in lymphopenia caused by viral infections, including cell death, elevated cytokines, chemokines and growth factors, inhibition of lymphopoiesis, lymphocyte trafficking, up-regulated expression of co-inhibitory molecules, metabolic disorders (lactic acidosis can suppress proliferation of lymphocytes) and elevated glucocorticoids. one major part is lymphocytes migrating from blood to tissue eg sequestration in lungs during viral lung infection like COVID or RSV; rapidly correct the low levels when infection resolves as they reenter blood Corticosteroids cause lymphopenia via two mechanisms: in the short term, they shift lymphocytes out of the circulating pool; over the long term, they decrease lymphopoiesis. Severe infection (bacterial or viral) can cause lymphopenia because lymphocytes move from the circulating pool into the tissues. Endotoxemia and septicemia can lead to lymphopenia, mostly as a result of the increase in corticosteroids that occurs in response to inflammation.

Answer 27

neutrophils most abundant, mobilised to sites of infection and phagocytose microorganisms and then die, being very short lived, they can also extrude DNA forming neutrophil extracellular traps NETs that trap microbes, which is seen as pus macrophages resident in CT, lining of tracts, and liver, engulf microbes and dispose of cell debris with two proposed effector subsets: M1 secrete cytokines/pro-inflammatory mediators to stimulate acute inflam response, M2/alternatively activated are associated with tissue repair and killing/expulsion of parasites, though this two subset model is probably an over-simplification, have lectins/scavenger receptors/complement receptors/TLRs with first 3 recognising bacti/fungi (eg LPS) to trigger phagocytosis, latter binds PAMPs, leading to phospho of inhibitor of NFkB to induce cytokine production

Answer 28

along with complement and phagocytes are 3rd major part of innate system, circulating in blood in partially activated state to facilitate immediate response and can move into affected tissue and proliferate; they're especially important to viral infections where they kill infected cells and maintain/increase state of inflam NKs recognise infection/cell damage through receptors signalling: loss of molecules normally expressed (missing-self), expression of molecules induced in stressed cells (induced-self) with response dependent on balance between activating and inhibitory receptors with activating receptors detecting perturbations in infected/stressed cells; inhibitory receptor signals dominate in healthy cells, major signal from MHC class I molecules present on the surface of most healthy cells and which present peptide fragments derived from cytosolic pathogens (eg viruses) to T cells, signalling the cell should be killed, thus viruses evolved means to prevent MHC class I expression and NKs see this missing-self and activate; induced self during infection/stress relies on cells expressing surface ligands for activating receptors on the NK, usually requiring signals from several different kinds of activating receptors

Answer 29

virus infected cells produce cytokines (type I IFNs) that encode an anti-viral state by inducing resistance to viral replication in surrounding cells, increasing expression of ligands recognised by NK receptors and activate NKs; local macrophages produce cytokines (CXCL8 and IL-12) that recruit and activate NKs and cause their proliferation; activated NK cells produce cytokines (IFNgamma) that activate macrophages and upregulate their killing capacity; together these steps ensure NKs induced to kill virus-infected cells and macrophages activated to phagocytose viral particles and infected cells the NKs killed kill target directly by releasing cytoplasmic granules containing perforin which forms pores in PM allowing apoptosis inducing granzymes into cell; antibody dependent cell cytotoxicity where NKs have receptors for Fc portion of antibodies and kill cells bound to the antibodies with signalling through the Fc receptor strong enough to activate the NK by itself; when NK cells outnumber DCs can kill them, if dont (ie innate response insufficient) then drive DCs to mature/migrate

Answer 30

group of protein signals made and released by host cells in response to viral infection type of cytokines IFN 1a/b produced by fibroblasts, macrophages, lymphocytes, endothelial cells and more and cause target cells to express proteins that make it hard for viruses to replicate in them; ifn 1a used for HBV/HCV and ifn 1b for MS IFNg released by CD8 and Th1 cells, blocking Th2 response and driving greater Th1 response among various mechanisms, IFNs increase p53 activity which promotes apoptosis in virus infected cells, and causes MHC class I and II expression to increase

Answer 31

primary - genetic mutations fully eliminate the function of cytotoxic T cells and NK cells secondary - external triggers like infection, malignancy, rheumatologic disease, postallogeneic hematopoietic stem cell transplantation (HSCT), drug hypersensitivity etc; commonest cause is EBV infection (or in adults, reactivation of EBV when immunosuppressed); how these triggers cause not fully clear but linked to overproduction of cytokines; secondary is still also usually in children common sx inc fever (oft high, persistent), organomegaly, lymphadenopathy, neurologic involvement (more often seen in pediatric HLH and includes seizures, meningismus, peripheral neuropathy, cranial nerve involvement, ataxia, dysarthria, lethargy, encephalopathy, and coma), pancytopenia, and coagulopathy (hemorrhage, petechiae, ecchymosis, purpura, and disseminated intravascular coagulation); edema, rashes, and gastrointestinal symptoms like diarrhea, nausea, vomiting, and abdominal pain may also be seen. acute phase proteins all up except fibrinogen down, triglycerides up, cytopenia; scoring system for likelihood, biopsy of marrow/spleen/LNs may demonstrate presentation overlaps with sepsis and must consider if sepsis not responding to mx; two may co-exist (sepsis may trigger HLH); clues pointing to HLH inc organomeg, v high ferritin, cytopenia, hypofibrinogen, thrombocytopenia without DIC; DRESS may also overlap, as can atypical infections of various kinds, and in neonates storage diseases or liver failure mx is with immunosuppression

Answer 32

complement system cascades activated by numerous mechanisms, result in opsonisation, membrane attack complex formation and generation of anaphylatoxins fibrinolytic system via Hageman factor results in generation of plasmin, a protease which degrades fibrin into chemotactic products for neutrophils and activates complement C3 kinin system via Hageman factor results in bradykinin generation to increase vascular permeability, vasodilation, smooth muscle contraction and activates complement C3 and C5 clotting system via Hageman factor via thrombin to convert fibrinogen into fibrin and fibrinopeptides, former to form a clot to limit spread of infection and latter to induce vascular permeability and neutrophil chemotaxis, thrombin also cleaves C3/C5 into C3a/C5a; Hageman factor stimulated by tissue damage

Answer 33

made of ~30 soluble and membrane associated proteins mainly made in liver and widely distributed in tissues and fluids as zymogens with many components involved in sequential proteolytic cleavage reactions to generate enzymatic products in an explosive amplification activates inflam, opsonisation of microbes and lysis of target cells, clearance of immune complexes and apoptotic cells and stimulating adaptive responses, plus chemotaxis; facilitates uptake and killing of pathogen by phagocytic cells, via complement receptors C3 is key: unusual internal thioester bond which is exposed upon cleavage in the C3b fragment and can react with hydroxyl/amino groups, with subsequent covalent linkage to pathogen opsonising it for phagocytosis and leading to generation of more C3b; C3a is an anaphylotoxin and stimulates local inflam complement receptors recognise proteolytic cleavage derivatives of C3, with CR1/3 esp important for phagocytosis of complement tagged bacteria: CR1 binds directly to C3b; C5a (through C5a receptor) delivers additional signal necessary for macrophages to begin phagocytosis and promotes neutrophil chemotaxis; CR1 also highly expressed on erythrocytes and binds C3b attached to antibody/antigen immune complexes to remove them from the blood for clearance in the liver, and individuals with low CR1 levels suffer from immune-complex disease

Answer 34

besides CXCL8, there are lipids derived from arachidonic acid, C5a, certain peptides made by degradation of bacteria, and other CXCs

Answer 35

first to act, reliant on spontaneous conform changes in C3 to expose thioester group, which in water usually leads to generation of C3H2O, allowing it to associate with factor B, which then becomes susceptible to the serine protease factor D; Bb remains associated to form C3(H2O)Bb, itself a protease (called aqueous/fluid phase C3 convertase) which cleaves C3 into C3a/C3b, role to produce enough C3b that some will attach to activating surface of pathogen (microbial surfaces are activating in general as they lack regulatory mechanism to deactivate complement), then once C3b bound can bind factor B and generate surface bound C3bBb, the alternative pathway C3 convertase which can generate more C3b bound to membranes and soluble C3a; surface bound C3b acts as an opsonin and provides +ve feedback loop instead of binding to surface C3b can remain attached to C3bBb forming C3b2Bb, the alternative C5 convertase which cleaves C5 to start the formation of the membrane-attack complex: binding of C6/7 to C5b allows C7 to insert into lipid membranes and binding of C8 to C5b67 allows insertion into membrane and subsequent polymerisation of C9 subunits to form membrane pore, effective against many gram negative bacteria and enveloped viruses

Answer 36

complement, second to act, activated by mannose binding lectin (MBL) and M,H or L -ficolin; MBL is a collectin, comprised of collagen and lectin domains and is also a soluble pattern recognition receptor that binds the close-knit arrays of mannose/fucose residues found on microbial surface of bacteria, yeast, fungi and some viruses MBL and ficolins circulate in plasma associated with 2 serine proteases: MBL-associated serine protease (MASP) 1 and 2; upon binding pathogen surface, MASP activity is initiated, cleaving C4 and then C2; C4 has internal thioester bound and C4b can attach to pathogen surface, joined by C2a to form C4bC2a, the classical C3 convertase which begins cleaving C3

Answer 37

activated if pathogen surface is recognised by antibody or c-reactive protein, which recognises bacteria, fungi, yeast and parasites; binding of antibody to surface exposes binding site for C1q present in Fc region of some antibody isotypes; C1q binds to several Fc regions and undergos conform change to activate C1r/C1s subunits; C1s cleaves C4 to expose thioester group allowing covalent attachment of C4b to pathogen surface; activated C1 associates with and cleaves c2, depositing C2a on C4b to form C4bC2a which cleaves C3 depositing C3b on the surface; membrane associated C3b generated by classical and lectin pathways can utilisie alternative pathway ampllfication loop by binding factor B; classical C3 convertase can associate with C3b to generate C4bC2aC3b, classical C5 convertase

Answer 38

early components of classical pathway facilitate clearance of soluble immune complexes by coating them with C4b/C3b so defects in C1-4 fail to clear these and have immune-complex disease activated C3 is important opsonin for bacteria phagocytosis so defects in it or its activation result in susceptibility to pyogenic (pus-forming) infections eg Staphylococcus/Streptococcus; depletion of C3 due to uncontrolled alternative pathway activation (FactorI/H deficiency) leads to similar susceptibility; complement mediated lysis is most effective defence against Neisseria so individuals with deficiencies in MAC components C5-9 suffer from recurrent Neisseria infections DAP and protectin are GPI anchored proteins so reduced GPI synthesis gives reduced expression of DAP/protectin on RBCs causing autoimmune-like conditions such as paroxysmal nocturnal haemoglobinuria due to complement mediated lysis of RBCs

Answer 39

sentinel cells (mast cells, macrophages, dendritic cells) resident in tissues help sense damage/infection by expressing pattern recognition receptors which recognise molecules associated with pathogens: pathognen associated molecular patterns (PAMPs) or cellular damage damage associated molecular patterns (DAMPs), with these cells then releasing cytokines and other inflam mediators mast cells contain granules of preformed inflam mediators (eg histamine, heparin, leukotrienes, prostaglandins); in addition to phagocytosis, macrophages produce range of cytokines (inc endogenous pyrogens which induce fever) that have local effect on vascular endothelium and systemic effects such as IL-6 and acute phase protein response; macrophages also synthesise prostaglandins and leukotrienes; inc dilation and permeability and activation of endothelium results in recruitment of acute inflam exudate IL-1beta activates vascular endothelium and lymphocytes and increases access of effector cells locally as well as systemically promoting fever and IL-6 production TNF-alpha activates endo and inc its permeability leading to inc entry of IgG, complement and cells and inc lymph drainage locally, as well as systemically promoting fever, mobilisation of metabolites and shock IL-6 inc antibody production and activates lymphocytes as well as inducing acute phase protein production and fever CXCL8 is a chemotactic factor recruiting neutrophils, basophils and T cells IL-12 activates NK cells and induces differentiation of CD4 T cells into TH1 cells

Answer 40

chronic granulomatous disease NADPH oxidase means neutrophils dont make superoxides, bacti not cleared and granulomas form neutrophils/monocytes recruited either by binding to adhesion molecules on endothelial cells and by chemo-attractants produced in response to infection; first step is rolling adhesion/weak tethering is thrombin (from blood) and histamine (from mast cells) induce P-selectin on endothelial cells, released from intracellular stores called weibel-palade bodies; E-selectin appears 1-2 hrs later, induced by IL-1 and TNFa, then the selectins bind to glycoprotein ligands (on neutrophils in low affinity interactions broken by the force of blood flow, resulting in neutrophils rolling along endothelium tight adhesion results from interaction between integrin lymphocyte function adhesion antigen 1 (LFA-1) binding to intercellular adhesion molecules ICAMs on the endothelium, with initial weak adhesions which strengthen due to conform change in LFA-1 resulting in high affinity binding state due to signalling through chemokine receptors eg CXCL8 extravasation follows with leukocytes squeezing between gaps in endothelial cells into tissues due to interactions between LFA-1 and CD31 on endothelial cell, with neutrophils secreting enzymes like elastase that degrade the basement membrane; neutrophil then follows gradient of CXCL8 (secreted by active macrophages) to site of infection, with the CXCL8 sticking to extracellular matrix to form this gradient leukocyte adhesion deficiency is rare immunodeficiency caused by defect in recruitment of neutrophils: LAD1 caused by defect in CD18, the beta chain subunit of LFA1, and it results in recurrent life threatening bacterial infection in infants monocytes also recruited but takes 24hrs

Answer 41

bloodclotting caused by local expression of TNFa prevent pathogens entering blood and spreading; however, if pathogen is widespread (severe skin burns) infection can spread with endotoxins such as LPS provoking widespread TNFa release; when pathogens enter bloodstream sepsis occurs, macrophages in liver/spleen secrete TNFa into circulation with potentially catastrophic consequences as the vasodilationtriggered by TNFa leads to septic shock, loss of BP and heart failure; the TNFa also triggers clotting in small vessels throughout body (disseminated intravascular coagulation) with failure of major organs

Answer 42

antibodies work via neutralisation (blocks biological activity of target molecule), opsonisation (coat antigen and interact with receptors on phagocytes allowing more efficient recognition of antigen) and complemet activation (recruits complement to antibody-coated antigen, possibly causing direct lysis or facilitating complement opsonin activity)

Answer 43

arise in bone marrow, mature in thymus where genes encoding TCR rearrange to generate clones with different specificities TCR only recognises degraded proteins complexed with MHC, antigen processing by antigen presenting cells generating these peptides for display; 2 major classes based on function, accessory molecule expression and type of MHC presenting; MHC class I on most cells (except eg RBCs) and associates with peptides produced in cytosol, and complex recognised by class I restricted T cells expressing co-receptor CD8, maturing into cytotoxic T cells and important in targeting virus infected/tumour cells; MHC class II (using external peptide) restricted T cells express CD4 and mature into T helper cells to help B cells/cytotoxic T cells; class II primarily on professional APCs; both types also produce cytokines

Answer 44

T: in peripheral/secondary lympoid organs, where nodes/spleen designed to optimise interaction between APC and T/B lymphocytes: lymphatics drain fluid containing antigens and dendritic cells from tissues and collect via afferent vessels to pass through macrophage lined sinuses where antigens/microbes captured to stop passing into the blood; lymphocytes enter node through specialised high endothelial venules, dendritic cells from periphery having captured antigens, naive T cells then survey antigen displayed on MHC molecules of dendritic cells and those which recognise the antigen/MHC complex retained and stimulated to differentiate into effector T cells B: cells with receptors specific for antigen helped by activated T effector cells and stimulated to produce antibody; some B cells concentrate into areas around follicular dendritic cells (not to be confused with dendritic cells), guided by chemokine CXCL13; FDCs use receptors for IgB and complement to trap antigens in antigen/antibody/C3b complexes, don't process it but do hold it for long periods of time on their surface for screening by B cells with those cells that have highest affinity for antigen preferentially induced to proliferate in process called affinity maturation; localisation of APCs, B cells and T cells maximises chance of B-T cell co-operation

Answer 45

pairs of heavy/light chains held together by covalent disulphide bridges and non-covalent forces, with both chains constructed from structurally related Ig fold domains; light chains have 1 constant and 1 variable domain and present as 1 of 2 types (kappa 2/3 and lambda 1/3); heavy chains have 1 variable and either 3 (IgG, IgA, IgD) or 4 (IgE, IgM) constant domains 5 main classes of antibody (IgA/D/E/G/M) distinguished by heavy chains denoted alpha/delta/epsilon/gamma/mu with the heavy chain determining the function of the antibody hinge region gives molecule flexibility to interact with antigen, with flexibility also present at the V-C junction and likened to ball-socket joint antigen binding site: formed by interaction between light/heavy variable domains, with variation concentrated in 3 complementarity determining regions (CDRs)

Answer 46

4 distinct subclasses. The evolution of IgG subclass switches is regulated by interaction with T cells and follows a 1-way direction (IgG3 → IgG1 → IgG2 → IgG4) the response to proteic antigens is prevalently mediated by IgG1 and IgG3, while IgG2 mediates the response to polysaccharide antigens; IgG1 is the most abundant and is biggest contributor to total IgG IgG3 and IgG1 exhibit the most efficient activation of the classical complement cascade. Under conditions of high antibody titer or high antigen density, IgG2 is capable of activating complement as well, but IgG4 is generally incapable as a result of above IgG2 is most important for dealing with encapsulated bacteria and its deficiency incs risk if strep pneumoniae, Hib, and neisseria infections (matures late hence why children <2yo more vulnerable to encapsulated bacti infections) IgG def presents as recu OM, sinusitis, pneumonia

Answer 47

IgG is the only antibody class that significantly crosses the human placenta. This crossing is mediated by FcRn expressed on syncytiotrophoblast cells. There is evidence that IgG transfer depends on the following: (i) maternal levels of total IgG and specific antibodies, (ii) gestational age, (iii) placental integrity, (iv) IgG subclass, and (v) nature of antigen, being more intense for thymus-dependent ones In some situations, such as mothers with primary immunodeficiencies, exogenous IgG acquired by intravenous immunoglobulin therapy crosses the placenta in similar patterns to endogenous immunoglobulins and may also protect the offspring from infections in early life. Inversely, harmful autoantibodies may cross the placenta and cause transitory autoimmune disease in the neonate maternal antibody levels then gradually wane, generally gone by 6mo but sometimes persisting slightly beyond this

Answer 48

in a primary response, B cells with receptors for antigen internalise, process and present it to T helper cells which then activate B cells to produce antibody, usually of relatively low affinity; antibody binds and clears antigen, so only B cells with highest affinity continue to capture and present antigen to T helper cells, and thus are stimulated further to proliferate and predominate; is a fast evolution system, doing in days what would take classic evolution thousands of years, and enables immune system to keep up with rapidly mutating pathogens mature naive B cells initially produce IgM/IgD isotypes, only types produced at same time; isotype/class switching then allows change in constant region isotype; AID (activation induced cytidine deaminase) made only by stimulated naive cell, targets switch sequence in C gene to which cell will be switched; patients lacking AID only make low affinity IgM - hyper-IgM syndrome; isotype switched to determined by cytokines expressed by Th cells eg IL4 IgE, ifng IgG1

Answer 49

coating surface of antigen to enhance phagoctyosis, with receptors for Ig or complement components (C3b) able to bind antibody/complement opsonised antigen; macrophages and neutrophils express Fcg receptors which efficiently recognise Fc of IgG, particularly IgG1; receptor engagement leads to phagocyte activation and results in enhanced antigen uptake/degradation; IgM activates complement very efficiently and can be recognised by C3br; binding of antigen/antibody complexes by C3br present on RBCs delivers the complexes to the liver/spleen for removal by macrophages adcc is antibody dependent cell-mediated cytotoxicity; NK cells, neutrophils, eosinophils, and phagocytes express FcgRIII, and ligation of this receptor on NK cells triggers release of cytoplasmic granules containing lytic enzymes; ADCC cannot be triggered by free Ig, but requires complexes of antibody/antigen to provide multiple Fc regions for recognition; eosinophils mediate unique form of ADCC to defend against helminths with IgE binding to surface of worms and recognised by FceRI, a high affinity receptor for IgE; the eosinophils then release granules containing proteins that are toxic to helminths, this is esp important as parasites may be too big for phagocytes to ingest

Answer 50

Mast cells/basophils have FceRI, binding IgE very strongly, with cross-linking of these receptors when antigen binds signalling for release of inflam mediators into surrounding tissues; the degranulation occurs in seconds and is associated with synthesis/release of lipid and cytokines, prostaglandins, leukotrienes and TNFa; this response is also triggered by allergic reactions when allergens bind to IgE on mast cells; FceRI has prebound IgE for binding of the target antigens antibody responses shut down by B cells using negative feedback: antibody produced in response to antigen binds and forms immune complexes, B cells specific for the antigen can bind the complexes with FcgRIIb (to bind antibody) and BCR (to bind antigen) at same time, providing a negative signal which terminates the B cell response

Answer 51

MHC is large locus on chromosome 6 coding for MHC I/II and many other proteins involved in antigen processing/presentation; class I/II are cell surface glycoproteins whose function is to present peptides to T cells; have similar 3D structure but significant biochem diffs; class I presents intracellular pathogens, II extracellular; specific binding sites for CD4/8 co-receptors unlike antibodies/TCRs, single MHC can bind broad range of peptides composed of diff aa combos - promiscuous binding specificity MHC molecules (Human leukocyte antigens HLA) must be able to present peptides from potentially any pathogen to T cells; polygeny refers to expression of multiple independent loci encoding class I/II genes, three class I (HLA-A/B/C) and 3 class II (HLA-DP/DQ/DR) isotypes; polymorphism refers to existence of many alternative forms of same gene within human pop, with MHC genes being most polymorphic known with large numbers of alleles at each locus, sometimes in excess of 3000; loci are closely linked genetically and in 97% cases inherited as set of alleles (haplotype); allele expression is co-dominant meaning both mat and pat expressed on same cell; due to polymorphism at each locus, in outbred pops it is virtually impossible for 2 individuals to express same combo of MHC alleles, this advantageous as heterozygotes can present more peptides and activate more T cells than homozygotes

Answer 52

each MHC molecule binds different characteristic set of peptides with aa at certain positions on peptide conserved because they need to make specific contacts with pockets in the binding groove, these referred to as anchor residues and together they determine peptide-binding motif for that MHC molecule; aa at non-anchor positions are not as strictly constrained and may show considerable variability, accounting for the diverse range of peptides presented by a single MHC molecule in the absence of infection, MHC molecules are occupied by self-peptides; peptide presentation requires balance in binding stringency as low results in large no of diff peptides binding giving only a small number of any particular peptide-MHC allele combo at cell surface but high stringency gives many copies of same complex at surface but pathogens with small genome may not have a suitable peptide for presentation by host's MHC molecules; typically cell with 100,000 MHC class I of single allotype presents >1000 diff peptides; roughly 1/1000-1/10000 random peptides are able to bind a particular MHC allele; individual MHC-peptide complexes may be present at 1-5000 molecules per cell with mean of 100; T cells may be activated by a single MHC-peptide complex but may require up to a few thousand

Answer 53

present endogenous peptides to CD8 cytotoxic T cells proteins in cytosol continually degraded into peptides, primarily by proteasome, which are then moved into ER by transporter associated with antigen processing TAP; peptides of suitable length/sequence loaded onto partially folded class I molecules in complex process assisted by range of chaperone proteins; fully loaded MHC peptide complexes released from chaperones and pass through golgi, following secretory pathway to cell surface IFNg changes proteasome in cells it binds to, so it produces peptides which can bind to MHC class I; genetic non functional tap causes MHC class I deficiency giving feeble CD8 response

Answer 54

class II molecules pass through ER during biosynthesis, and binding of peptides in ER prevented by a/b chains associating with third invariant chain Ii which blocks peptide binding groove, acts as a folding chaperone and targets class II/Ii complexes into the endocytic pathway; II Ii complexes pass through golgi and sorted into endocytic pathway where Ii is partially removed leaving a small protein called CLIP in the peptide binding groove; antigens are taken into cell by endocytosis and degraded into peptides by proteases; within protein loading MIIC compartments, CLIP peptide is removed and antigen derived peptides with appropriate binding motifs are loaded into empty class II molecules; MHC class II/peptide complexes are then transported to cell surface for presentation to CD4 T cells; hep C mount CD8 response but this needs macros/DCs to present antigens on MHC I but hep C only infects hepatocytes so phagocytose, present on MHC II, cross presentation to get it onto MHC I - maybe transfer from dead cell to macro in phagocytosis, maybe from endocytic vescile to cytosol allowing usual class I presentation route

Answer 55

specificity controlled by TCR which sees fragmented antigenic peptides bound to MHC molecules; 2 main subsets distinguished by CD4/CD8 expression, effector function and MHC restriction CD8/TCR bind class I releases cytokines like IFN-g, inhibits viral replication, activates macrophages, kills virus-infected cells and tumour cells; CD4/TCR binds class II, helps naive B cells, activates macrophages, helps CD8 cells and secretes cytokines

Answer 56

selected for: successful beta chain rearrangement, positive selection, negative selection with overall aim to eliminate harmful and reject useless types with only about 1-2% of double positive (CD4+/CD8+) thymocytes surviving selection; negative selection helps prevent autoimmunity by deleting autoreactive cells while positive selection ensures peripheral T cells will be useful since cells that can not recognise self MHC cannot become activated pos: unique to T cells, newly arranged TCR tested against self-peptide/MHC complexes expressed on cortical epithelial cells in thymus, and those with moderate affinity receive a positive signal to continue maturation with lack of interaction resulting in death by neglect; expression of CD4/8 co-receptors is altered to match MHC restriction - the class to which positive selection took place - with surviving cells being CD4+ single positive if selected against class II complexes or CD8+ single positive if selected against class I complexes neg: potentially autoreactive thymocytes expressing TCRs with high affinity for MHC/self peptide are eliminated by apoptosis, and negative selection cannot eliminate T cells with receptors recognising combos not expressed in thymus, these instead dealt with by peripheral mechanisms; thus low affinity die by neglect and high affinity negatively selected, so only those with moderate selectivity survive

Answer 57

mature naive T cells have TCRs which recognise MHC/peptide complexes but require additional stim to activate with 2 signal hypothesis proposing that signal 1 is TCR engagement with MHC and co-stim molecules giving signal 2 eg CD28 interacts with B7.1(CD80) and B7.2(CD86) on the APC and CD40L on T cell interacts with CD40 on APC; both sets of molecules deliver essential signals to T cells without which they don't become activated; expression of co-stim molecules is defining feature of pAPCs; some CD8 need DC and activated CD4 for same virus (make IL2) in order to be activated

Answer 58

peripheral infection initially sensed by innate system and DCs take up antigen in infected tissue and are activated by innate receptors, increasing class II synthesis and begin expressing B7.1/2, then migrate to lymph nodes where they remain and present antigen to circulating T cells; naive T cells enter lymphoid organs from blood through high endothelial venules and continually circulate through node and back to blood making contact with thousands of APCs; if antigen recognised, T cell binds strongly and ceases migration and co-stim binding (MHC CD28 etc) induces naive T cell to proliferate/differentiate into expanded population of armed effector Th cells; activated T cells express CTLA4 which upon binding B7 inhibits the T cell proliferating; CD28 importance shown by TGN1412; upon activation, PLCgamma with Ip3 Ca calcineurin activatin NFAT (IL2 made, autocrine to promote t cell prolif), DAG activating PKC which activates NFkB naive antigen specific B cells interact with the effector Th cells: first binds antigen via Ig and internalises it (signal 1 for B cell activation), processes and presents antigen on surface with MHC, expressing same complex as that expressed by the DC and recognised by the Th; CD28/CD40L on Th binds to B7 and CD40 on B cell with cross-linking of CD40 on B cell (B cell activation signal 2) promoting proliferation, providing B cell survival signals and promoting Ig class switching; interaction between the co-stim molecules (B-T co-operation) is essential; activated B cells bind to follicular dendritic cells, specialised stromal cells that hold intact/unprocessed antigen on their surface in long-lived immune complexes, only present in B cell follicles and enable activated B cell to form germinal centres

Answer 59

naive CD4 Th0 can differentiate into distinct subsets based on nature of antigenic challenge and cytokines present during proliferation; Th1 produce cytokines that support inflam/cell mediated responses, they activate mainly macrophages, NK cells and CTLs and are important in dealing with intracellular pathogens like mycobacteria; Th2 activate immune responses that assist in elimination of parasitic infections; Th17 vs extracellular bacteria and some fungi differentiation into Th1/2 occurs early in immune response so cytokines produced by innate system (DCs, macrophages, NKs) have vital role in focusing immune response; abundance of antigen, MHC/peptide conc and TCR affinity also influence response with abundant antigen/high affinity TCR interaction stimulating Th1 and low peptide abundance or with weak affinity for TCR stimulating Th2; the early decision is crucial as Th1/2 bias is self-reinforcing; Th1 pathway corresponds to cell-mediated immunity by activating macros which increases inflam to defend against intracellular bacterial, viral and protazoan infections; Th2 pathway promotes production of pathogen specific IgE antibodies that work with basophils, mast cells and eosinophils to control parasite infections, corresponding to humoral immunity in which antibodies dominate with this response also promoting tissue repair rather than inflam; ifng/IL12: Th1, IL4: Th2, Il6: Th17 (Th17 enhances neutrophil response)

Answer 60

inflammatory response which is disproportionate or lasts too long risks injury to the host mechanisms are complex and include eg termination by immunoreceptor tyrosine-based inhibitory motifs (ITIM), inhibition by soluble antagonists, receptor endocytosis or ubiquitination, and auto-inhibition by newly synthesised intracellular inhibitory molecules interaction of IL-1α and IL-1β with the IL-1 receptor (IL-1R1) initiates a cascade of activation signalling via the upstream Toll/IL-1R (TIR) domain and the downstream MAP kinase-nuclear factor (NF)κB pathway to promote inflam; production of soluble IL-1R antagonist terminates response by competitively binding IL-1R and is up-regd by pro-inflam cytokines inc IL-1 itself; also upreg'd is decoy receptor IL-1R2 which lacks intracellular signalling domain

Answer 61

resolution of inflammation is coordinated and regulated by a large panel of mediators anti-inflammatory effects and pro-resolving effects are not totally overlapping: anti-inflammation mainly refers to an inhibitory/blocking action (e.g., stopping immune cell extravasation, which is a hallmark of acute inflammation), whereas pro-resolving actions indicate an inherent stimulation and activation of specific processes, such as apoptosis specialized lipid mediators [lipoxins (e.g., LXA4), resolvins (e.g., RvD1), protectins; peptides [e.g., annexin A1 (AnxA1), ACTH), gases (H2S, CO), adenosine, neuropeptides like ACh failure of these systems implicated in role in chronic inflammatory and autoimmune diseases like IBD, and severe asthma diminished expression of LXA4, its receptor FPR2, and 15-lipoxygenase, the major enzyme involved in LXs generation pro-resolving cascade becomes operative during resolution, whereby one pro-resolving mediator would induce another one and coordinated programs of resolution initiate shortly after the beginning of the inflammatory response; some signalling pathways are even shared, with NF-kB either pro or anti-inflam depending on how it is dimerised (miRNAs important in controlling this over time) chemokines depleted by binding to decoy receptors and by cleavage from MMPs produce by macros

Answer 62

There is switch from AA derived proinflam lipids to lipoxins; proinflam eicosanoids cause exudate neutrophils to phenotype switch and start producing lipoxins; COX2 also involved in producing anti-inflam PGD2 and others Neuts also release proteases that degrade cytokines; neutrophils also release calprotectin which is antimicrobial (chelates Mn and Zn), activates innate response, but when bound to other proteins released by neutrophils it can inhib chemotaxis and suppress cytokine production Macros switch from producing proinflam cytokines (M1) to TGF-b and IL-10 and generate lipoxins (M2); they phagocytose debris and take part in repair processes; this class switch is driven by cues in the micro environment Neutrophils undergo apoptosis after phagocytosis or after being around for 5 days or less as well as due to death factors like TNFa and Fas produced by macros; and lymphocytes apoptose due to balance of survival cytokines like IL-2 and death factors including TNFa, or die after a few days (some variants can persist as memory cells)

Answer 63

smoking has been shown to inc WCC by 14-19% which may persist in ex-smokers too (all subtypes) the level tends to fall within 2 weeks, and then not any further after that

Answer 64

acquired, not hard-wired; danger hypothesis: rather than self from non-self, immune system distinguishes dangerous from harmless; to provoke a strong adaptive response, antigen must be injected in mixture called adjuvant; these cue IS that infection is taking place by converting soluble protein into particulate material which is ingested by APCs; many contain bacterial products which stimulate macrophages through PRRs; eg complete Freunds adjuvant CFA contains ground-up mycobacteria; central tolerance occurs during lymphocyte dev and peripheral tolerance after lymphocytes leave primary organs central for T cells: acquired, not hard-wired; danger hypothesis: rather than self from non-self, immune system distinguishes dangerous from harmless; to provoke a strong adaptive response, antigen must be injected in mixture called adjuvant; these cue IS that infection is taking place by converting soluble protein into particulate material which is ingested by APCs; many contain bacterial products which stimulate macrophages through PRRs; eg complete Freunds adjuvant CFA contains ground-up mycobacteria; central tolerance occurs during lymphocyte dev and peripheral tolerance after lymphocytes leave primary organs central for B cells: ideally wouldn't need to be tolerized as need T cell help but B cells react to abundant antigens on self cells as they develop, either antigens on cells or soluble proteins in high dose; negative selection of self-reactive B cells demonstrated experimentally: mice express transgene coding for IgM against H-2Kk MHC, in Kd mice immature B cells didn't self-bind antigen and large number in spleen expressed anti-Kk Ig on PM; when mice also expressed Kk, the immature B cells were deleted, and small number expressed the mu chain encoded by the transgene, but it had been edited so no longer bound Kk

Answer 65

central tolerance not perfect: many antigens not expressed in thymus/bone marrow, others not until immune system has matured with tf AIRE switching on peripheral genes in thymus to expose T cells to their products; 4 mechanisms for peripheral tolerance: ignorance (potentially self-reactive T cells not activated eg antigens hidden from immune system in immunologically privileged sites (testis, eye, brain); split tolerance eg T cell tolerance established, dont bother with autoreactive B cells as they need T cell help and take 100-1000x more antigen to tolerise anergy is state of non-responsiveness, induced in T cells if TCR engaged by MHC with costim absent, and immature B cells may be anergised in similar but not well understood way, either in bone marrow or just after entering circulation (in this case due to large amounts of non-crosslinked antigen), cells dont die in this state; suppression where Tregs stop autorective T cells reacting; Tregs are CD25+ (IL2 r) and express Fox3p tf; natural Tregs educated in thymic selection with intermediate affinity for self-antigen in MHC and not deleted by -ve selection, with removal of Tregs resulting in autoimmunity; also inducible Tregs after contacting self antigen on MHC II they suppress proliferation of naive T cells which respond to antigens on same APC, thus specific suppressive effects that may require cell contact; non-inflam cytokines IL4/10 and TGFb may contribute to downreg, as may activating the enzyme IDO needed for T cell growth, inhib of proinflam cytokines, absorption of IL2, signalling to APC to reduce B7 expression; peripheral Treg induction not well understood with things that favour their dev suggested to include: cytokine profile, chronic low dose antigen exposure, lack of costim, antigen presentation by immature DCs (this may occur in gut associated lymphoid tissue, rich in TGFb and cells exposed to microbiome and food antigens); people without FoxP3 suffer profound system autoimmunity, IPEX syndrome: immune dysregulation, polyendocrinopathy, entropathy X-linked

Answer 66

direct analogous to type II hypersensitivity, eg Graves disease due to Ab to TSHr, Ab not subject to feedback inhibition and so overproduction of thyroid hormone/hyperthyroidism; in hashimotos thyroiditis, Abs block hormone production causing hypothyroidism; either may result in a goitre; in myasthenia gravis autoantibodies to ACh r block Ach at NMJ nd cause downregulation of AChr; rheumatic fever another example immune complex mediated similar to type III hypersensitivity; systemic diseases like SLE and vasculitits almost certainly from immune complex deposition, esp in kidney; in SLE, wide range of anti-cytoplasmic and anti-nuclear autoantibodies giving butterfly/wolf rash on face, and possibly significant depletion of complement; SLE more common in african/asian women and complement deficiencies impairing immune complex clearance (C1/2/4) are predisposing factors T cell mediated eg type 1 diabetes, rheumatoid arthritis, MS - analagous to type IV hypersensitivity; T cell mediated damage leads to tissue destruction without needing autoantibody (though almost all autoimmune patients have autoantibodies); mechansims: direct CTL destruction, TNF destruction, recruitment of macros, induction of apoptosis by Fas; model of MS may be transferred by T cells: immunise rat against myelin basic protein, isolate Th1 cells, these cause MS if injected into another animal

Answer 67

most associated with one or more HLA allotypes (polymorphc variants found in normal pop) eg HLA DQ6+ people 12x more likely to get MS then - people but also + common in normal people and not all people who get MS have this allotype; multiple alleles within the HLA haplotype may contribute to susceptibility genetic susceptibility important role in most with GWAS showing multiple loci associated with many common autoimmune conditions; endocrine factors play role with most occurring more often in females, ankylosing spondylitis 3-4x more freq in males; environmental factors also major role with 20-40% twin concordance rate for common diseases, and likely factor being infection; environmental factors estimted to be 50% of susceptibility to T1D, MHC another 25% and the last 25% other genes

Answer 68

suspect - first line investigations FBC w differential white cells, Ig studies (albumin to show not just losing protein) then specific Ig tests and lymphocyte subsets anxiety and psychosis often dominant in 22q11DS; quite variable penetrance despite being AD; thymic transplant can help (T cell count low, B count normal) serology not useful if cant produce antibodies, must use PCR transplant early in life often very succesful men/pneump meningitis or sepsis, other encapsulated infections rec -> ?complement def immunodef can lead to immune dysreg -> autoimmune, lymphoid malignancy: may be first manifestion of immunodef may be sec to HIV, radiotherapy, DMARDs, lymphoma, major kidney/liver problems, autoants to cytokines, CLL, SLE, hyposplenism antibody def: encapsulated bacti rec infections, not viral or intracellular bacti; oft have enduring GIT infection with eg giardia -> loss (protein losing enteropathy, nephrotic syndrome) - serum albumin will be low -> dec production (B cell disease eg NHL, drugs eg rituximab targets CD20 on B cells) so ritux causes hypogammaglobulinaemia differentials if encapsulated rec: low complement, hyposplenism measure serum Ig (inc serum protein electrophoresis), antibodies to pneumo, Hib, MMR, check B cell numbers Needs IG replacement therapy Phagocyte def: lack of neutrophils -life threatening infections with commensals; abscesses and granulomatous processes, bad periodontal disease - staph aureus, g- bacti Deficient cell mediated: intracellular pathogens: mycobact, toxoplasm, cryptospor, viruses, candida, PCP, skin sarcoma, kapsosis -> steroids, immunosup, HIV -> may have haemolytic anaemia, ITP, thyroiditis, vasculitis if suspect test for HIV, check T cell numbers and function think immunodef if lymphopenia in a child in SCID T cells + 1 other ype of cell (B cell, NK cell) is affected serious, persistent, unusual, recurrent (autoimmune, lympoma) -> consider immunodef anti-TNFa can reactivate TB so CXR first

Answer 69

consider if pt has 2 or more of these features: 4 or more ear infections in a year, 2 or more serious sinus infections in a year, 2 or more pneumonias within a year, failure to thrive, recurrent abscesses, persistent thrush or fungal skin infection, need for IV abx to clear infections, 2 or more deep/systemic infections like sepsis, family history of immunodef baseline FBC, lymphocyte markers, immunglobulins consider specific antibodies (tetanus, Hib, pneumococcus) – if strong clinical suspicion of recurrent bacterial infections Complement function (C3, C4, CH50, AP50) – e.g. recurrent invasive bacterial infections, recurrent bacterial meningitis. * Neutrophil oxidative burst – e.g. recurrent skin & soft tissue infections/abscesses, fungal infections. * HIV test interpreting antibody results: Normal immunoglobulins with protective specific antibodies means Ig def unlikely Low IgG, with normal or low IgA and/or IgM (regardless of specific antibodies) - consider Ig def unless obvious nephrotic syndrome, protein losing enteropathy etc Low IgA with normal IgG and IgM; and protective specific antibodies - Significant immunodeficiency unlikely (partial IgAD, or maturational delay) Low IgM, with normal IgG and IgA; protective specific antibodies (if tested)- May be viral infection (especially in young), rarely clinically significant, check again in 3mo note: low lymphocyte count on FBC <2.8x10*9/L in child age under 1 year should never be ignored and if thought to be reactive ensure follow up repeat is arrange to confirm it normalises, otherwise needs work up for possible SCID - need to check lymphocyte subsets and immunoglobulinsl if confirmed prophylactic co-trim + fluclox + aciclovir and nurse in positive pressure room, discuss urgently with immunology on call (GOSH)

Answer 70

usually presents at 4-6mo old as this when maternal placentral transfer runs out will see susceptibility to extracellular encapsulated organisms like strep pneum, HiB< staph aureus; thus mostly see sinus, lung, and otitis media infections; also GI (giardia, salmoella) and maybe meningitis, septis arthritis, skin infection commonest 3 are X-linked agammaglobulinaemia (bruton disease) which is x linked recessive, causing absent B cells and normal T, v low levels of all serum Ig; needs IVIg and aggressive abx; onset after a few mo common variable immunodef is weakened B cell ability to make antibodies w normal levels of B and T cells and low IgG and IgA with IgM low or normal; CVID is an umbrella diagnosis characterized by complex pathophysiology with an antibody deficiency as a common denominator T cell function might be affected; onset later in childhood even second decade, chronic/rec pneumonia, URTI, diarrhoea, lympha and splenomeg; inc'd risk of autoimmune haem, ITP, pernicious anaemia and risk of gastric carcinoma, astrocytoma and NHL; early diagnosis and treatment of infections needed, immunisation considered on an individual basis based on specific immune function, IVIg replacement is mainstay of treatment, and In those children with CVID who despite adequate Ig-RT suffer from recurrent sinopulmonary infections posing the risk of chronic lung damage, additional antimicrobial prevention with the use of co-trimoxazole, amoxicillin, or azithromycin is recommended selective IgA immunodef - most common primary immunodef, 1 in 700 ppl; normal B and T cells and circulating Ig but IgA deficient; so mild that usually doesnt need treatment but shouldnt be given IgA in any form as then sens -> anaphylaxis (so eg IgA def blood in transfusions)

Answer 71

molecular basis for XLA is a disruption in B cell development due to mutation in Bruton's tyrosine kinase (Btk). Affected individuals inherit a defect that prevents precursor B cells in the bone marrow from forming mature, circulating B-lymphocytes that would otherwise be capable of proliferating and differentiating into antibody-producing plasma cells results in dangerously low, clinically undetectable levels of all immunoglobulin isotypes in the serum rendered vulnerable to invasive infections from encapsulated bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae), have an increased incidence of enterovirus infections (e.g., poliovirus, coxsackievirus, echovirus), and chronic diarrhea (from Giardia lamblia) commonly present with a history of recurrent upper respiratory tract infections, including sinusitis and otitis media, beginning after 6 to 9 months when most of the maternal antibodies have been exhausted. However, hospitalization for bacterial pneumonia, requiring intravenous antibiotics for resolution, is usually what prompts the diagnostic work-up for immune deficiency disease Lymphoid tissues are typically hypoplastic in XLA patients. The tonsils may be difficult to visualize, and the cervical/inguinal lymph nodes may not be palpable Test results consistent with a diagnosis of XLA in a male patient with a history of recurrent bacterial infections would include finding: Serum levels of IgG, IgM, and IgA that are more than two standard deviations below age-matched controls Absence of mature B lymphocytes in the peripheral circulation (i.e., fewer than 1-2%) Little or no increase in antibody titers 3-4 weeks after protein- or polysaccharide antigen vaccines (e.g., immunizing against pneumococcal pneumonia or diphtheria-tetanus) Low or absent BTK protein or mRNA expression levels Detection of disease-causing mutations in the Btk gene mx with regular IVIg, prophylactic abx, and receive all vaccines except live ones

Answer 72

multi-organ, fibro-inflammatory condition with tumefactive lesions of unknown etiology and characteristic histopathological features pathological hallmark of this disease is dense lymphoplasmacytic infiltrate with IgG4 positive plasma cells - it is very specific and looks similar in all organs commonly involved organs are the pancreas, kidneys, orbital adnexal structures, salivary glands, and retroperitoneum Japanese Comprehensive Clinical Diagnostic (CCD) Criteria for IgG-4RD Clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs. Hematological examination shows elevated serum lgG4 concentrations (greater than 135 mg/dL). Histopathological examination Radiological images cannot differentiate between malignancy and benign disease - biopsy is required; Symptoms are commonly attributed to other conditions and other diagnoses may have been made years before diagnosis, e.g. urinary symptoms in men attributed to common prostate conditions pt often responds well to corticosteroids, sometimes eg biliary stent can be done for faster sx relief if pancreas affected; one in remission can be maintained with steroids or steroid sparing agent

Answer 73

inc'd susc to viral, fungal, protozoal and TB, usually with more severe sx than humoral immunity problems failure to thrive more common too in this, and may often be fatal in childhood SCID has failure of stem cells to diff into T and B cells; 50% x-linked, 50% AR - various genes can cause eg MHC, common gamma chain etc; usually presents in first 3mo, will have failure to trive, resp infections and opportunists like PCP, candida (may see persistent oral or nappy candida), aspergillus, cryptosporidium, and CMV (CMV pneumonia is a problem); chronic diarrhoea (giardia, crypto, candida), cutaneous candida, herpes, varicella; thymus absent (unlike eg bruton disease) and no lymphoid tissue so no splenomeg or lymphadenopathy as in CVI; lymphopenia, low Ig, abnormal T cell function test if diagnosed in a neonate needs CMV PCR testing protective isolation on diagnosis; treat w bone marrow transplant, consider amphotericin (candida) and cotrimox (PCP) proph, IVIg, no live vaccinations and blood products must be CMV negative, leucodepleted and irradiated to prevent GVHD and CMV transmission haematopoietic stem cell transplant and gene therapy are potential definitive therapies 50-80% of adults in UK carry CMV< so if a mother is breastfeeding a child with SCID, a blood test will be taken from the mother to see if she is CMV positive because the virus can be transmitted in breast milk. While waiting for the result, mothers are supported to express their milk. The result normally comes back after 24 to 48 hours. If the result is positive, it is advised to stop breastfeeding, owing to the risk of transmitting CMV to the baby, and formula milk feeds will be recommended

Answer 74

Involution is seen normally as an age related decrease in the thymic size; When the normal size thymus gland decreases in size in response to any stress (e.g., sepsis, major surgery, use of steroids or other immunosuppressants), it is known as thymic atrophy. It is usually transient and the thymus returns to normal after the stress resolves - may shrink by up to 40% hypoplastic thymus defined as less than twice the width of the third thoracic vertebra hypoplasia/aplasia most commonly associated with DiGeorge syndrome which is due to the abnormal development of the third and fourth pharyngeal pouches and is characterised by variable T-cell deficiency Immunodeficiencies with T-cell abnormalities like ataxia telangiectasia or severe combined immunodeficiency syndrome are also associated with thymic aplasia or dysplasia

Answer 75

x linked recessive condition with combined b and t cell defect giving immunodef, chronic eczema, and thrombocytopenia (so maybe petechiae) w very small platelets; IgA/E raised and IgM low; cell mediated and humoral types of susc (commonly see HiB, strep, EBV, VZV, CMV, molluscum, PCP, aspergillus, candida) as well as inc'd risk of lymphoma and autoimmune disease (haemolytic anaemia, vasculitis); they won't produce normal antibody response to pneumovax vaccine; molecular genetic testing to confirm diagnosis caused by mutations in the WAS gene, which provides instructions for production of a protein called WASp. This protein plays an essential role in relaying signals from the surface of the blood cell to the cell’s actin cytoskeleton, the network of fibers that make up the cell’s structural framework. Immune cells that lack the WASp protein have a decreased ability to respond to their environment, fight invaders, and form functional platelets aggressively treat infections, IVIg, splenectomy can inc platelet count and may need prophylactic antibodies after that; manage eczema in usual ways; bone marrow transplant should fix most problems and gene therapy being researched

Answer 76

AR inheritance, combined B and T cell defect cerebellar ataxia in first 5 years, oculocutaneous telangiectasia, rec sinopulm infections leading to bronchiectasis, mental retardation and growth failure inc'd malignancy susc inc lymphoma, leukaemia, medulloblastoma chromosomal fragility, as in bloom and fanconi syndromes low levels of IgA/E and IgG2, IgM present, AFP and CEA raised IIIg can be used, and aggressive treatment of lung infections to prevent pulm deterioration

Answer 77

DiGeorge syndrome, also called 22q11.2 deletion syndrome, results from a microdeletion in a portion of chromosome 22 that leads to a developmental defect in the third pharyngeal pouch and third branchial cleft. One of the consequences of this is incomplete development of the thymus gland. An underdeveloped thymus gland results in an inability to create functional T cells. Features of DiGeorge syndrome can be remembered with the CATCH-22 mnemonic: C – Congenital heart disease (conotruncal eg VSD) A – Abnormal faces (characteristic facial appearance inc hypertelorism) T – Thymus gland incompletely developed C – Cleft palate H – Hypoparathyroidism and resulting Hypocalcaemia 22nd chromosome affected

Answer 78

due to abnorm dev of 3rd/4th pharyngeal pouches giving spectrum of disease thymic hypoplasia (t cells <30% circulating lymphocytes), hypocalc from absent parathyroid glands (tetany in first days or weeks of life), hyperteloism, low set ears, antimongoloid slant to eyes, micrognathia, carp-shaped mouth, cleft palate truncus arteriosus and interrupted aortic arch B cell and Ig function intact foetal thymus graft, irradiated blood products (prevent GVHD) note if CXR shows no thymic shadow in neonate + kid has infection think SCID or digeorge syndrome

Answer 79

T cell abnorm resulting in chronic candida of skin, mucous membranes and nails May have FH 50% will have an autoimmune disorder humoral immunity intact treat with antifungals and manage the autoimmune condition

Answer 80

aka hyperimmune IgE syndrome AD inheritance w v high IgE levels + raised eosinophils distinguished by the clinical triad of atopic dermatitis, recurrent skin staphylococcal infections, and recurrent pulmonary infections skin manifestations usually appear very early, a few weeks after birth. They include a pruriginous eczematoid rash affecting the scalp and face, that is rapidly superinfected with Staphylococcus aureus, resulting in weeping, crusty, and follicular infectious lesions. Recurrent cold staphylococcal skin abscesses that are associated with little or no inflammation are seen in these patients. Candida infections are common; they affect the skin, mucous membranes, and nails. Recurrent pneumonia is typical, predominately due to S. aureus, and less frequently due to Streptococcus pneumoniae, and Haemophilus. It can get complicated with the development of recurrent lung abscesses, bronchiectasis, and pneumatoceles. These pneumatoceles can get colonized with Aspergillus and Pseudomonas. Other infectious manifestations such as sinusitis, bronchitis, otitis externa, gingivitis, dental abscess, septic arthritis, and osteomyelitis can be seen Patients with Job syndrome have characteristic facial features that appear in early adolescence or earlier in late childhood, for example, facial asymmetry, prominent forehead, deep-set eyes, broad nasal bridge, ncreased inter-alar distance, prognathism, and high-arched palate; Musculoskeletal abnormalities are common. They include hyperextensibility of the joints, scoliosis, and osteopenia. Bone density is decreased and is the source of multiple pathological fractures that occur in approximately 50% of patients (long bones and ribs). Scoliosis of variable severity is observed in approximately 60% of patients; Decreased resorption of the roots of the deciduous teeth may result in prolonged retention of the deciduous teeth, preventing the appearance of definitive teeth; they may have aneurysms of arteries in various places most effective treatment, for now, for this condition is the long-term, sometimes continuous, use of antibiotics; MDT mx of other complications diagnosis of Job syndrome could be difficult and arise with other diagnoses including in particular other types of primitive (chronic granulomatous disease) or acquired (HIV infection) immunodeficiency, severe atopic dermatitis, or cystic fibrosis.

Answer 81

usually present in first few months of life neut defects may be quantitative (see earlier card on neutropenia) or qualitative monocyte adhesion def is AR disorder caused by abnormal ICAM that neuts use to adhere to surfaces; may present with delayed separation of the umbilical cord, repeat soft tissue infections w/o pus, gingivitis; neutrophilia/granulocytosis is present, may be high enough to look like leukaemia if ongoing bacti infection; bone marrow transplant and proph abx chediak-higashi syndrome is AR with abnormal chemotaxis and degranulation; giant cytoplasmic inclusion bodies in neuts, mild bleeding disorder due to defective plat aggregation, and partial albinism; in second decade may progress to accelerated phase w organomegaly and bone marrow infiltration which is oft fatal

Answer 82

autosomal recessive disorder that is characterized by easy bruising, oculocutaneous albinism and recurrent pyogenic infections mutation of the lysosomal trafficking regulator (LYST) gene or Chediak-Higashi syndrome (CHS1) gene disrupts the protein synthesis and affects the storage and secretory functions of lysosomal granules of leukocytes, fibroblasts, dense bodies of platelets, azurophilic granules of neutrophils, and melanosomes of melanocytes. The defects result in enlarged vesicles and non-functional lysosomes Lymphocytes containing these large granules function poorly in the antibody-dependent, cell-mediated cytolysis. Patients also exhibit alterations in the neutrophils, leading to neutropenia, impaired chemotaxis, and delayed phagolysosomal fusion which, in turn, leads to an impaired bactericidal activity; deficiency of serotonin and adenosine phosphate-containing granules in platelets led to the impairment of platelet aggregation as well as prolonged bleeding time metallic or "silvery" appearance of the hair, depigmentation of iris, and normal or reduced acuity; recurrent infections that are often severe and typically begin in infancy. Patients are more susceptible to bacterial and fungal infections with staphylococcal, streptococcal, pneumococcal, and beta-hemolytic species being the most predominant. Skin infections and upper respiratory tract infections are some of the most common infections. Recently, periodontitis has been identified as an important indicator of immune dysfunction; bleeding symptoms are usually mild and include epistaxis, mucosal or gum bleeding, and easy bruising and don't need medical intervention; neurological sx due to the long-term progression of the disease and include stroke, coma, ataxia, tremor, motor, and sensory neuropathies, and absent deep tendon reflexes accelerated phase in 85% of ppl, can arise at any age, and is HLH with ever, hepatosplenomegaly, lymphadenopathy, neutropenia, anaemia, and sometimes thrombocytopenia; this is the commonest cause of mortality and most pts die within first 10 years of life diagnosis should be considered in individuals that exhibit signs of immunodeficiency; pigment dilution of the skin, hair, or eyes; congenital or transient neutropenia; and signs of unexplained neurologic symptoms or neurodegeneration, film or bone marrow biopsy can help by showing the large granules, and molecular genetic testing to confirm allogeneic hematopoietic stem cell transplantation, sunglasses and sunscreen, rehab early if neuro sx develop

Answer 83

rare, 75% x linked and 25% AR; abnorm in NADPH oxidase subunits in neut membrane so fail to produced superoxide radicals as part of their oxidative burst first year of life present with catalse pos organism infections (catalse destroys any H2O2 the organism produces, if catalase neg then this H2O2 can be used by the neuts to make up for the defect in endogenous production cat +ve organisms inc staph, salmonella, e coli, candida, aspergillus most common presentation is severe infection of skin and lymph nodes, esp cervical w abscess formation that is oft recurrent and becomes chronic overtime; can get pneumonia w abscess and empyema formation, osteomyelitis, hepatic and perianal abscesses; chronic diarrhoea (may be misdiagnosed as crohns due to granulomatous nature, also as pt may develop an inflam colitis with diarrhoea, weight loss, failure to thrive and perianal disease), hepatosplenomeg and failure to thrive common, and granulomas can obstruct gastric antrum, ureters, and sinuses functional diagnosis of CGD is made by the demonstration of the inability of phagocytes from affected individuals to produce superoxides followed by genetic testing; nitroblue tetrazolium test uses colourless/yellow dye that normal neuts reduce to deep blue, defective dont, carrier may have intermediate transition will mount normal response to viral infections treat infections with abx and surgical drainage when needed (needs to be prompt, any febrile illness gets ciproflox, also give abx prophylaxis for any invasivae procedure inc eg OGD); proph co-trimoxazole and itraconazole haematopoietic stem cell transplant or gene therapy can be used as curative approach, latter more experimental

Answer 84

Deficiencies of early components of the classical complement pathway, including C1, C4, and C2, are associated with encapsulated bacterial infections like Streptococcus Pneumoniae and Haemophilus Influenza type b.+ inc'd incidence of CTDs like SLE (as early classical complements like C1 bind to cells undergoing apoptosis and facilitate the elimination of such cells. The body produces autoantibodies against these uncleared cells that result in autoimmune disorders) deficiency of C3 is associated with severe recurrent pyogenic infections early in life deficiencies in C5-9 result in inc'd susc to neisserial sepsis eg mening, gono deficiency of mannan-binding lectin has been linked to an increased frequency of pyogenic infections and sepsis, particularly in children and neonates, when the adaptive immune system has not been matured. Screening for the complement system includes tests for the classical complement pathway (CH50), the alternate pathway (AH50), and the mannose-binding lectin (MBL) pathway (MBL by ELISA). Low CH50 and normal AH50 suggest early classical complement component (C1, C2, and C4) deficiency. Low AH50 with normal CH50 suggests a deficiency of early alternative complement pathway factors (factor B, factor D, and properdin). Low AH50 and low CH50 suggest common terminal complement (C3, C5, C6, C7, C8, or C9) deficiency. If CH50 and AH50 are both normal and the clinician still suspects complement deficiency, MBL functional assay is indicated to screen for MBL deficiency Complement deficiency is not typically treated with complement protein supplementation due to the infeasibility of overly frequent infusions, the risk for bloodborne infections, and the risk of developing antibodies to exogenous complement proteins. This condition is managed on a case-by-case basis with antibiotics for each episode of infection as well as regular visits with their immunologist patients with complement deficiency should undergo all routine bacterial and viral vaccinations, especially meningococcal and pneumococcal vaccinations, and do not have a contraindication to live vaccines any autoimmune flares can be managed with immunosuppression

Answer 85

mastocytosis (too many), mast cell activation syndrome (right number, activate too easily); two conditions have overlapping symptoms as both result in too many mast cell mediators being released varying symptoms which can come and go but inc some of derm (hives, easy bruising, flushing, itchiness, pale or reddish complexion, burning in skin; cardiovascular (tachy, arrhythmias, syncope, lightheadedness); GI (diarrhoea, constipation, vomiting, cramping, nausea, reflux, swallowing difficulties, tight throat); coughing or wheezing; muscle and joint pain possible; inc'd risk of serious anaphylaxis; nasal congestion diagnosis of MCAS if recurrent episodes of above symptoms, elevated serum tryptase or other mast cell mediators, improvement with use of mast cell stabilisers, H1 or H2 antihistamines, antileukotrienes skin biopsy for mastocytosis

Answer 86

HIV binds to CD4 receptors on helper T-lymphocytes, monocytes, macrophages and neural cells. CD4 cells migrate to the lymphoid tissue where the virus replicates and then infects new CD4-positive cells. As the infection progresses, depletion or impaired function of CD4 cells predisposes to the development of immune dysfunction ART is new name for HAART stage 1 is acute prim infection/seroconversion illness: Occurs between one and six weeks after infection. 20-60% present with symptoms at this time; Common symptoms are a glandular fever-type illness with fever, malaise, myalgia, pharyngitis, headaches, diarrhoea, neuralgia or neuropathy, lymphadenopathy and/or a maculopapular rash. Rarely, meningoencephalitis. Acute infection may be asymptomatic; Although clinical features are similar to infectious mononucleosis, consider HIV seroconversion illness if there are unusual signs - eg, oral candidiasis, recurrent shingles, leukopenia, or CNS signs; refer for specialist assessment and to start treatment stage II: asymp, CD4/8 levels normal stage III: Nonspecific constitutional symptoms develop: fever, night sweats, diarrhoea, weight loss; may also be minor opportunistic infections - eg, oral candida, oral hairy leukoplakia, herpes zoster, recurrent herpes simplex, seborrhoeic dermatitis, tinea infections; collection of symptoms and signs is referred to as the AIDS-related complex (ARC) and is regarded as a prodrome to AIDS AIDS: person develops certain serious opportunistic infections or diseases - as a result of damage to their immune system from advanced stage 3 HIV infection; severe immunodef; life-threatening infections and unusual tumours Diagnosis is based on detecting anti-HIV antibodies in serum. Rapid testing is offered by some sexual health clinics and can produce a result in 20 minutes Acute infection may be detected by the presence of p24 antigen or HIV RNA by polymerase chain reaction (PCR) and precedes the appearance of IgM and IgG. A combination test checking for the presence of HIV antibody and p24 antigen (the so-called 'fourth-generation test') is provided by hospital and is very accurate. It takes about four weeks annual test recommended for MSM, people who inject drugs, sex workers; more freq if high risk behaviours; test right away those presenting with symptoms; sexual partners of someone diagnosed with it

Answer 87

Detection of HIV antibody: enzyme-linked immunosorbent assay (ELISA), Western blot; Assessment of viral load; detection of virus or viral antigen: HIV RNA or branched DNA (bDNA) assay FBC: anaemia, thrombocytopenia, lymphocytopenia with reduced CD4 cell count; check esr; assess for other infections (tuberculosis, hepatitis B, cytomegalovirus (CMV), toxoplasma, syphilis, varicella) and coexisting STIs; Baseline CXR and cervical smear Standard anti-HIV IgG antibody tests cannot be used before 18 months of age, as maternal antibodies may be detected. HIV DNA PCR and virus culture are the best investigations in children born to infected mothers also stage disease: CD4 count greater than or equal to 500 cells/mm3 or 29%. CD4 count equal to 200-499 cells/mm3 or 14%-28%. CD4 count less than 200 cells/mm3 or less than 14%; for staging take CD4 count and clinical category: A if asymp, acute infection; B if symp disease inc opportunists; C if AIDS indicator condition at any point (these inc broncial or oesphageal candidiasis, lymphoma, PCP, parasitic or fungal disease, CMV, rec pneumonia, wasting, herpes bronch/pneum/oesophagitis or chronic ulcers, CMV clinics to monitor CD4 count (<200 at risk of opportunisti, >500 normal) and viral load (rate of replication, measured with PCR, rising may indicate ART nonadherence, resistance, interaction with other meds)

Answer 88

ART may cause lipodystrophy syndrome which includes fat redistribution, insulin resistance and dyslipidaemia. Preferred initial therapy is usually three drugs: efavirenz plus tenofovir or abacavir, plus lamivudine or emtricitabine also: Immunise against hepatitis B, pneumococcal disease and Haemophilus influenzae type b (and possibly influenza and hepatitis A). Because of immunosuppression, HIV patients should not receive BCG vaccination, yellow fever, oral typhoid or live oral polio immunisations. Primary chemoprophylaxis is used when the CD4 lymphocyte count drops below a certain level; Secondary chemoprophylaxis is used to prevent the recurrence of an infection that has already occurred UK recommendations are to offer co-trimoxazole to all patients with a CD count below 200/mm3 or with a history of oral candidiasis, a CD4 T-cell percentage of all lymphocytes <14%, or a previous AIDS-defining illness note s/e of co-trim: treatment is often limited by severe side effects such as hepatotoxicity, rash, anaemia, thrombocytopenia, and neutropenia; it may cause a cholestatic jaundice picture and even severe hepatic necrosis

Answer 89

Cerebral toxoplasmosis is the most frequent central nervous system (CNS) infection when CD4 count is <200/mm; due to cyst reactivation; subacute symptoms include focal neurological disturbances, headache, confusion, fever and seizures; usual practice is to treat these symptoms as toxoplasmosis and consider biopsy if there is no improvement in 7-10 days. Treatment is sulfadiazine and pyrimethamine plus folinic acid PML is a progressive demyelinating condition of advanced disease caused by the John Cunningham virus (JCV) and presents with focal neurological signs, changes in personality and ataxia. The diagnosis is by MRI and JCV detection by PCR in a CSF sample. There is no specific treatment and the patient usually dies within six months unless effective ART is used HIV enceph: HIV directly infects the nervous system and most patients dying of late-stage HIV disease have histological evidence of brain damage; may be increasing motor problems affecting activities of daily living. Movements may be slow; need to differentiate from cytomegalovirus (CMV) encephalitis, which usually presents with rapidly progressive convulsion and dementia. Investigations to exclude other causes of neurocognitive impairment may need to be carried out - eg, vitamin B12, folate level, TSH, syphilis, hepatitis C, glucose and vitamin B1 as well as screening for dyslipidaemia. CSF examination may be required, especially when there are other signs of CNS infection; MRI; eliminate depression, anxiety and the effects of alcohol and drugs kaposi's sarcoma - presents as multiple ecchymotic skin nodules, macules or papules. It occurs in about 15% of patients despite the advent of ART. It often affects the face early in HIV. It is also found on mucosal surfaces, usually on the hard palate. Visceral disease commonly affects the lungs and gastrointestinal tract, causing dyspnoea, cough, haemoptysis, abdominal pain or bleeding; treatment of localised disease has been with radiotherapy, cryotherapy or intralesional vinblastine but is being superseded by pegylated liposomal doxorubicin or liposomal daunorubicin given IV NHL - develops in 3-10% of people living with HIV, with most tumours being extranodal. Around half of these are associated with Epstein-Barr virus (EBV) infection and these are more aggressive with lower survival rates. CNS sites are common, presenting with symptoms and signs of space-occupying cerebral tumours and this carries very poor prognosis with three months' survival without ART. Tumours outside the CNS can respond to standard chemotherapy regimens. Rituximab should be given concomitantly. Opportunistic infections may cause death during chemotherapy

Answer 90

HIV antibody tests can be negative for three months following exposure, and repeat testing is necessary if an initial test is negative Testing for the p24 antigen, checking directly for this specific HIV antigen in the blood. This can give a positive result earlier in the infection compared with the antibody test. PCR testing for the HIV RNA levels tests directly for the number of viral copies in the blood, giving a viral load in genomes/copies per ml Prophylactic co-trimoxazole (Septrin) is given to patients with a CD4 under 200/mm3 to protect against pneumocystis jirovecii pneumonia (PCP). PEP involves a combination of ART therapy. The current regime is Truvada (emtricitabine and tenofovir) and raltegravir for 28 days. HIV tests are done immediately and also a minimum of three months after exposure to confirm a negative status

Answer 91

Seroconversion: development of detectable antibodies against an infectious agent 3-12 weeks after infection Symptomatic in 60-80% cases – similar to glandular fever Sore throat Lymphadenopathy Fever Rash Rarely meningoencephalitis Serology: Antibodies to HIV p24 or gp41 antigens develop at 4-6 weeks. Both can be detected by ELISA, then get confirmatory Western Blot. Viral detection is not used in diagnosis: instead being used to monitor response to treatment (aim for undetectable viral load) prim CNS lymphoma: 30% cerebral lesions in HIV. Associated with EBV. Single/multiple homogeneous enhancing lesions.; also consider toxoplasmosis, cryptococcus, PML, HIV dementia HHV8 Purple papules/plaques on skin/mucosa Resp involvement can cause haemoptysis Mx: radiotherapy and resection HAART: highly active anti-retroviral therapy: at least 3 drugs Typically 2 nucleoside reverse transcriptase inhibitors (NRTI) and either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) also HIV risks of: Ophthalmology: CMV retinitis. Pizza retina. IV ganciclovir. Cryptosporidium: diarrhoea. Oral thrush Shingles Hairy leukoplakia: EBV Aspergillosis

Answer 92

Indications: trauma, infection (EBV), hypersplenism (hereditary spherocytosis, elliptocytosis), malignancy (lymphoma, leukaemia) At high risk from sepsis due to encapsulated organisms (post-splenectomy sepsis, PSS) S. pneumoniae H. influenzae N. meningitidis Prevention Lifelong PO penicillin V Immunization against HiB, meningitis A+C (meningococcus), influenza (annual), pneumococcal (every 5 years) see howell-jolly bodies

Answer 93

overwhelming post splenectomy infection - encapsulated bactis, 5% lifetime risk penV or clarithromycin for at least 2 yrs + vaccines for encap bacti, annual flu cipro + present to A&E if get a fever due to risk it may be opsi

Answer 94

80-90% of time is vertical transmission, with rest blood transfusion/products, sexual activities/abuse, ivdu; blood products screened so risk of this should be reduced vert transmission risk higher if mother has low CD4 count, if born before 34 weeks, if second birth, if born by vaginal delivery 14% risk of vert transmission, breast feeding incs risk by further 14% - thus c section and advise against breast feeding (but not this advice in 3rd world countries where death from malnut bigger risk than from AIDS)

Answer 95

prenatal acquisition has short incubation, sx dev at 4-6mo; peri/postnatall sx tend to start at 2-3yo and tend to have better prognosis may have non specific sx like failure to thrive, puo, generalised lymphad/hepatosplen, chronic dermatitis, parotid enlargement, chronic candida nappy rash, rec otitis media may have disorders in B cell function presenting as you'd expect opportunistic infections like PCP (bal and antigen staining to diagnose), myobacterium avium intracellulare, GI candida, cryptospor, cryptococ (meningitis; PCP more common than in adults, may be presenting illness if prenatal acquisition lymphocytic interstitial pneumonitis due to infiltration of lungs by lymphocytes and plasma cells; 50% of HIV kids get; bilat reticulonodular shadowing on CXR and later in disease dyspnoea, cough, wheeze, hypoxaemia, mediastinal lymphad, clubbing; LIP presentation longer survival than opportunistic infection presentation encephalopathy, failure of brain growth (microceph, dev delay, spasticity, ataxia), characteristic enhancement of frontal lobes and BG (poss calcification), cerebral atrophy, ventriclar enlargement, white matter attenuation; CNS tumours less common than in adults, as are kaposis etc get polyclonal B cell activation giving hypergammaglobulinaemia leading to autoantibodies production, may get eg coombs pos haem anaem and other autoimmune diseases

Answer 96

Children acquire HIV through: 1. Vertical Transmission – this accounts for around 90% of all infections in children 2. Infected Blood Products – this is rare in the UK 3. Sexual Exposure – including sexual abuse and assault, is extremely rare Perinatally infected infants and children have accelerated disease progression due to a higher viral set-point and an active thymus (with a larger pool of cells permissive to HIV infection). In addition, naïve T cells have an impaired functional phenotype and are unable to process pathogens effectively some of the more common signs: failure to thrive opportunistic infections, esp PCP, recurrent bacti infections (OM, sinusitis, skin infections, meningitis, pneumonia), candidiasis, chronic diarrhoea (infectious agents or directly due to HIV effect on gut) lymphoid interstitial pneumonitis (rare in adults, common in kids esp after ART started) persistent generalised lymphadenopathy dev delay may be caused by opportunistic infections or neoplasms, but is most commonly due to HIV crossing the blood-brain barrier directly. Children may present with developmental delay, spastic diplegia or regression of milestones in young children, impairment of expressive language in 2-4year olds, and behavioral abnormalities with loss of concentration and memory, cognitive impairment in older children If the child is under 18 months of age and vertical transmission is suspected HIV PCR should be performed If the child is over 18 months of age an HIV 1+ 2 antibody test should be performed All specimens must be labelled with ‘Danger of Infection’ stickers and placed in ‘Biohazard’ bags HAART is currently recommended for all children with HIV infection irrespective of the CD4 count (%) and/or viral load - therapy must be continued during any hospital admission Co-trimoxazole prophylaxis is recommended from 1 month of age if HIV PCR screening is positive at any stage or if the infant is confirmed to be diagnosed with HIV. This should only be stopped if HIV infection is subsequently excluded Immunisations should be given as per the national schedule

Answer 97

prophylaxis is recommended for all HIV-infected children aged ≥6 years who have CD4 T lymphocyte (CD4) cell counts <200 cells/mm3 or CD4 percentage <15%, for children aged 1 to <6 years with CD4 counts <500 cells/mm3 or CD4 percentage <15%, and for all HIV-infected infants aged <12 months regardless of CD4 count or percentage Infants with indeterminate HIV infection status should receive prophylaxis until they are determined to be HIV-uninfected co-trimoxazole is usual choice for prophylaxis; dapsone is an alternative (careful with both if pt has G6PD) if dev acute pneumonitis then IV co-trimoxazole, switching to oral to complete a 21 day course; moderate-severe cases should also receive short course of steroid Prominent clinical features of PCP among HIV-infected children are fever, tachypnea, dyspnea, and cough. The severity of these signs and symptoms varies from child to child. Onset can be abrupt or insidious with nonspecific symptoms such as mild cough, dyspnea, poor feeding, diarrhea, and weight loss Most children with PCP have substantial hypoxia with low arterial oxygen pressure (PaO2 typically <70 mm Hg) and an A-a gradient >30 mmHg. CD4 percentage is often <15% and CD4 counts are usually <200 cells/mm3 in children aged 6 years and older. Lactic dehydrogenase is often increased, but this is not specific for PCP. Serum albumin may be depressed. Chest radiographs most commonly reveal bilateral diffuse parenchymal infiltrates with “ground-glass” or reticulogranular appearance, but they also can be normal or have only mild parenchymal infiltrates. The earliest infiltrates are perihilar, progressing peripherally before reaching the apical portions of the lung. Rarely, lobar, cavitary, nodular, or miliary lesions; pneumothorax; or pneumomediastinum are observed definitive diagnosis requires culture, induced sputum analysis is an option but for most kids, esp younger ones, BAL is required and results may be positive for ≥72 hours after initiation of PCP treatment so treatment should not be delayed while awaiting results

Answer 98

ix - detection of anti-HIV IgG only diagnostic after 18mo as before may have acquired via placental transfer; pcr can detect HIV virus in blood, can look for p24 antigen; viral culture of white cell gold standard mx - recieve almost all vaccines except live polio, no BCG, no MMR co-trimox if CD4 count low eough; AZT (zidovudine), not in asymp kids reg f/u to monitor growth, dev, symptoms, s/e f treatment (for azt bone marrow suppression and hepatotoxicity) psychosocial support preventing mat to baby transmission: Taking antiretroviral medications to reduce viral load * Consider mode of birth If VL < 50 copies/ml safe to have a vaginal delivery If VL > 50 copies/ml caesarean section recommended; <400 needed if on HAART * Feeding newborn with formula milk from birth. * Baby antiretroviral medications for first 2-4 weeks of life. baby will be tested for HIV at – birth, – 6 weeks, – 12 weeks, – and then between 18 months and 2 years of age. To make the diagnosis in a baby, a sensitive test called a PCR (polymerase chain reaction) will be undertaken to look for actual virus in the baby’s blood. The baby test results will tend to reflect the mothers HIV illness in the tests from birth to 12 weeks, but loss of maternal antibodies will be confirmed by 18 months to 2 years of age

Answer 99

Neonatal PEP should be commenced as soon as possible after birth, and at least within 4 hours. * In the context of known maternal resistance to zidovudine with VERY LOW or LOW RISK, zidovudine monotherapy is still recommended for infant PEP. * If HIGH RISK (combination PEP indicated) and there is a history of documented maternal zidovudine and/or nevirapine resistance, seek expert advice. If advice is not immediately available, commence standard three-drug PEP (zidovudine, lamivudine and nevirapine) until guidance is provided Two weeks of zidovudine monotherapy is recommended if all the following criteria are met: * The woman has been on cART (combined AntiRetroviral Therapy) for longer than 10 weeks; AND * Two documented maternal HIV viral loads <50 HIV RNA copies/mL during pregnancy at least 4 weeks apart; AND * Maternal HIV viral load <50 HIV RNA copies/mL at or after 36 weeks Extend to 4 weeks of zidovudine monotherapy: * If the criteria above are not all fulfilled but maternal HIV viral load is <50 HIV RNA copies/mL at or after 36 weeks; * If the infant is born prematurely (<34 weeks) but most recent maternal HIV viral load is <50 HIV RNA copies/mL Use combination PEP if maternal birth HIV viral load is known to be or likely to be >50 HIV RNA copies/mL on day of birth, if uncertainty about recent maternal adherence or if viral load is not known If a woman is known to have HIV-2 infection, follow the above advice as for HIV infant PEP but if HIGH RISK (combination PEP indicated) nevirapine will not be effective. Seek expert advice. If advice is not immediately available, commence zidovudine, lamivudine and raltegravir until advice available

Answer 100

PML (JC virus - hiv or complication of MS treatment), subacute (weeks) cognitive decline with word finding problems, naming problems, visual neglect, maybe pyramidal weakness, and new demyelination on MRI; demyelination may be across a hemisphere, less sharp than MS; maybe also if leuk/lymphoma/organ transplant; see foamy macros non specific T2 hyperintensities w/o clinical MS findings may be due to small vessel disease

Answer 101

Mode of delivery will be determined by the mother viral load: Normal vaginal delivery is recommended for women with a viral load < 50 copies / ml Caesarean sections are considered in patients with > 50 copies copies / ml and in all women with > 400 copies / ml IV zidovudine should be given during the caesarean if the viral load is unknown or there are > 10000 copies / ml Prophylaxis treatment may be given to the baby depending on the mothers viral load: Low risk babies, where mums viral load is < 50 copies per ml, should be given zidovudine for 4 weeks High risk babies, where mums viral load is > 50 copies / ml, should be given zidovudine, lamivudine and nevirapine for 4 weeks Breastfeeding is never recommended for mothers with HIV Babies to HIV positive parents are tested twice for HIV: HIV viral load test at 3 months. If this is negative, the child has not contracted HIV during birth and will not develop HIV unless they have further exposure. HIV antibody test at 24 months. This is to assess whether they have contracted HIV since their 3 month viral load, for example through breast feeding

Answer 102

most common causes of PUO in immunocompetent individuals are infective endocarditis (especially culture negative endocarditis), discitis, osteomyelitis, occult abscesses and infected implanted devices; also TB, EBV/CMV, HIV, malaria, Q fever none-infectious causes: inflam diseases inc vasculitides, SLE, sarcoidosis, gout/pseudogout, IBD solid tumours, leukaemia, lymphoma, myeloproliferative disorders, multiple myeloma drug induced, thyroiditis, hypothalamic dysfunction PE bloods: CRP, ESR, FBC + film, U&Es and LFTs, bone profile, ACE levels, TFTs, LDH, CK, ANA, rheumatoid factor, urine dip and MC&S, multiple myeloma screen, 3x blood cultures, viral swabs + consider testing for HIV, EBV, CMV, mantoux and IGRA for TB, ASOT Imaging: CXR, echo, CT TAP, consider pet CT if no localising signs (another option is white cell scan using radiolabelled white cells to localise a source -> this or PET can also be used to confirm that eg a pacemaker lead has become infected to guide source control) specific tests: USS of temporal artery, biopsy of node/organ/marrow, OGD/colonoscopy (follow IBD diagnostic path), LP

Answer 103

reptiles esp snakes very commonly carry salmonella so need to wash hands well after handling - also likely to be picked up when handling turtles, bearded dragons, and other reptiles dogs and cats may carry: campylobacter, ringworm, toxocaria (in poop -> garden), toxoplasmosis (cat poop - pregnant women and immunosuppressed should not clean litter boxes), tick-borne illnesses, cat scratch fever birds can carry cryptococcus and psittacosis and poultry can carry salmonella

Answer 104

caused by an intracellular gram-negative rod known as Bartonella henselae affects the lymph nodes draining the area of inoculation, usually from a scratch or bite of a young cat over 90% of children have self-limited lymphadenopathy accompanied by high fever. Patients with disseminated illness may have a spectrum of complications, especially in the very young, elderly, and immunocompromised hosts such as transplant or patients with HIV Cutaneous manifestations begin as an erythematous papule, vesicle, or nodule, which is known as the primary inoculation lesion. This lesion usually persists from one to three weeks but can last for months; Lymphatic system involvement presents as tender lymphadenopathy, regional, and may be solitary or multiple nodes 1 to 5 cm in diameter. There is overlying erythema. Ten percent may suppurate and require drainage Ophthalmic complications include neuroretinitis, papillitis, optic neuritis; Neurologic complications of cat scratch include ataxia, cranial nerve palsies, and a dementia-like picture in older patients. Children typically present with encephalitis or aseptic meningitis need to exclude other causes of lymphadenopathy; biopsy can confirm if needed most cases of regional lymphadenopathy resolve spontaneously in two to four month but consider antipyretics, and in serious or persistent cases azithromycin for up to 5 days

Answer 105

dd for acute febrile illness w/o localising features: bacti (infective endocarditis, occult abscess, intracellular); viral infection; fungal/protozoa infection in immunocompromised patient; non-infectious disease (lymphoma, autoimmune) fever +/- pharyngitis +/- lymphadenopathy +/- leucocytosis: EBV, CMV, HIV, toxoplasma gondii, leukaemia/lymphoma, sec syph CMV: acute self limiting fever/hep (can look like EBV but usually w/o pharyn/lymphad); prim infection in pregnancy can spread to intraut; -if born asymp most common sequalae are sensorineural hearing loss, mental retardation and cerebral palsy; Cytomegalic inclusion disease: Presents with jaundice, splenomegaly, petechiae (thrombocytopenia), intrauterine growth restriction, microcephaly, and retinitis. Complications include moderate to severe learning difficulties, neurological abnormalities, and hearing loss EBV: acute self limiting fever, pharyngitis, lymphadenopathy, splenomegaly, hepatitis; puffiness around eyes, flu like aches and headaches; up to 6 weeks after close oral contact (kissing, share toothbrush etc); persistent infection of memory B lymphocytes; oncogenic – Burkitt’s lymphoma, nasopharyngeal carcinoma, some Hodgkins lymphoma; trauma to abdo when spleen swollen can cause rupture investigating glandular fever: FBC with differential wcc, monospot test in 2nd week of infection (glandular fever) likely if monospot +ve or >10% atypical lymphs and lymphocytes >50% wcc; repeat monospot in 5-7 days if neg, if second neg consider CMV and toxoplasmosis testing if preg/immunocomp, HIV if at risk; monospot/heterophile antibodies tested for with paul bunnel (anti-sheep RBC)or monospot tests (anti-horse RBC) if suspect false pos HA test or have infective mono but negative HA for 6 weeks look for viral capsid antigens and EBV nuclear antigen IgM, later seroconversion to IgG; can look for anti-HIV antibody, antitoxoplasma antibody etc

Answer 106

measles - conjunctivitis, cough, koplik spots, purpuric rash scarlet fever (toxin from group a strep) - flu like symptoms, pharyngitis, lymphadenopathy, sandpaper rash appears a few days later starting on chest/abdo, strawberry tongue, flushed face (but no rash) rubella (prodrome of fever, conjunctivitis, and cold-like illness, then non-purpuric rash, occipital/postauric lymphad, arthralgia foetal infection - can cause first trimester miscarriage and affects 90% surviving if in first trimester, weeks 11-16 have 10-20% risk, low risk after that; iugr, Thrombocytopenic purpura (25% - 'blueberry skin'), haem anemia, jaundice, organomegaly, Meningoencephalitis (25%), Sensorineural deafness (80%), General learning disability (55%), Insulin-dependent diabetes (20%, immune-mediated but often delayed to adolescence or adulthood), 'Late-onset' disease at 3-12 months with rash, diarrhoea, pneumonitis and high mortality; microceph, cataracts, congenital glaucoma, pigmentary retinopathy, patent ductus arteriosus or peripheral pulmonary artery stenosis staph scalded skin syndrome parvovirus B19 acute resp infection, peak in spring and ages 4-10, symptom free for 5-7 days, then slapped cheek erythema then erythematous rash on limbs; transient aplastic crisis in chronic haemolytic anaemia (sickle cell anaemia, hereditary spherocytosis) children <15y infection in pregnancy can lead to foetal anaemia, hydrops and foetal loss (no congenital abnormality) HHV6 - roseola infantum: sudden high temp, coryzal symptoms, anorexia, swollen eyelids/glands for 3-5 days then pinkish maculopapular rash on chest and tummy, spreading to face/neck/arms, usually not itchy, usually disappears in 2 days lab tests for virus specific IgM to diagnose infection, IgG to determine susceptibility to infection in exposed pregnant woman

Answer 107

typical measles presents with fever, usually of 39ºC or more without antipyretics, maculopapular rash, and at least one (and usually all three) of cough, coryzal symptoms, and conjunctivitis. The prodromal phase occurs 10–12 days after contracting the infection and lasts for 2–4 days before the rash becomes apparent. Symptoms include increasing fever, malaise, cough, rhinorrhoea, and conjunctivitis. This latter symptom may help differentiate measles from other flu-like illnesses. Fever increases during the prodromal phase to around 39ºC at about the time the rash appears, and then gradually decreases. Koplik's spots may appear on the buccal mucosa at the end of the prodromal phase, a day or so before, or around the same time as the rash, and disappear over the next 2-3 days. These consist of 2–3 mm red spots with white or blue-white centres. These are pathognomonic for measles but can easily be confused with other mouth lesions. The rash is erythematous and maculopapular and may become confluent as it progresses. It appears on the face and behind the ears first (when other symptoms tend to be at their most severe), before descending down the body to the trunk and limbs, and forming on the hands and feet last, over the course of about 3–4 days. The rash fades after it has been present on an area for about 5 days, with the total duration of rash being up to 1 week Consider a different cause for the rash if the person is likely to have immunity to measles, clinical features are atypical, there is no history of contact with measles or travel to measles-endemic countries, and there are no local outbreaks If there is any suspicion of measles infection, immediately notify the local HPT. Measles is a notifiable disease. Clinical diagnosis alone is unreliable, infection must be confirmed by laboratory investigation (but notification should not await laboratory confirmation) - HPT will send an oral fluid testing kit to the affected person for IgM/IgG and/or viral RNA testing ddx: parvovirus, roseola, strep, EBV, kawasaki, zika/dengue/chikungunya, drug reaction, and rubella In children without fever, other causes of florid rash including erythema multiforme and viral or allergic urticaria should be considered rubella: rash usually starts behind the ears and on the face, and then spreads down the body (similar to measles). However, the infection is generally mild, and if fever is present it rarely occurs after the first day of the rash. There may be post-auricular and sub-occipital lymphadenopathy. Koplik's spots are not visible low threshold for admission of infants under the age of 1 years, children who are immunosuppressed and pregnant young people with suspected measles, due to the higher risk of complications in these groups - keep in negative pressure cubicle until 4 days after rash onset Children and young people with mild or moderate disease and no risk factors for severe complications (high risk - infants under the age of 1 years, children who are immunosuppressed) can be managed in the community with the usual advice on antipyretics and self-care for febrile viral illnesses - isolate at home until 4 days after rash onset supportive mx, abx if secondary infection eg pneumonia, IVIg or high dose vitamin A based on infectious diseases team advice if severe/immunosuppressed may get primary measles encephalitis during the infection: sx of fever, headache, irritability, encephalopathy (altered mental status), seizures and involuntary movements or motor deficits (hemiplegia/paraplegia), and coma; long-term neurological sequelae leads to hemi or paraplegia, intellectual disability, recurrent seizures, and deafness during resolution phase or weeks to months afterwards may dev ADEM; is immune mediated unlike PME which is due to direct viral invasion 3-20 years after infection may dev SSPE due to persistence of the virus in the brain; diffuse slowing and burst suppression on EEG with hyperintensities throughout the brain

Answer 108

acute infectious meningo-encephalitis, especially viral; demyelinating encephalitis (post-infectious e.g. measles, Mycoplasma); Hashimoto’s encephalitis (euthyroid, high titre anti-thyroid microsomal antibody, steroid-responsive); para-neoplastic encephalitis; cerebral abscess, sub-dural empyema, acute hydrocephalus; cerebral vasculitis (may have stroke-like focal neurological deficits) cerebral vein thrombosis (headache, visual blurring due to raised intracranial pressure)

Answer 109

viral meningitis / encephalitis; tuberculous meningitis; Listeria meningitis; spirochaete meningitis (Lyme, leptospirosis, neurosyphilis); fungal meningitis (Cryptococcus); partially treated pyogenic bacterial meningitis; cerebral abscess, para-meningeal infection; sarcoidosis; malignant meningitis

Answer 110

within 2 hours of abx being given CSF may be sterile for meningococcus and within 4 hours for pneumococcus and so if LP done after this time window following abx unlikely you will grow cultures; CSF PCR may remain informative for a longer period The latex agglutination test (LAT) can be useful for diagnosing partially treated bacterial meningitis (ABM) when bacterial cultures are usually negative. It's a simple, immunological test that identifies bacterial antigens in cerebrospinal fluid (CSF)

Answer 111

Enteroviruses (echo, Coxsackie) > Mumps > HSV less common: HIV, EBV, VZV, Lymphocytic chorio-meningitis virus (LCMV) – zoonosis from mice rarely: Arboviruses, Rabies HSV encephalitis: severe sporadic encephalitis – haemorrhagic necrotizing infection of the temporal lobe; fever, headache, seizures, hemiparesis, aphasia – sometimes fatal; survivors often have permanent neurological deficits including amnesia (damage to hippocampus); on suspicion of diagnosis, early treatment with high dose i.v. Aciclovir 10mg/kg 8 hourly for at least 10 days; confirmation by PCR of CSF for HSV DNA (brain biopsy if necessary) general lab tests for viral enceph: CSF PCR, throat swab and stool culture for eneteroviruses, blood serology

Answer 112

Flu-like prodrome RUQ pain Fever Jaundice (mixed) Deranged LFTs: >20x normal in acute disease, AST

Answer 113

biphasic. Abrupt headache, fever, malaise, myalgia lasting 3-4 days. Most recover at this point. Severe cases: back pain, N+V, jaundice, hepatitis, bleeding, rashes

Answer 114

eg Zika, dengue, and yellow fever Risk for transmission of all three of these viruses exists wherever competent mosquito vectors, predominantly Aedes aegypti, are found, and zika can also be sexually transmitted chikungunya is not a flavivirus but is a ddx for these ix and also mosquito borne In about 75 percent of cases there are no symptoms. When symptoms occur, illness begins abruptly after an incubation period of five to eight days. There may be high fever (up to 40°C) often accompanied by a severe headache and retro orbital (behind the eye) pain, muscle and joint pains, nausea, vomiting, abdominal pain and anorexia. High temperature can persist for five to six days. Around the third to fourth day, a maculopapular skin rash may be seen on the chest, trunk and extremities. Health professionals should be alert to the warning signs of severe disease, which include: mucosal bleeding, abdominal pain, liver enlargement, blood in vomit/stool serology and viral pcr supportive mx only, antivirals and steroids don't help usually

Answer 115

90% due to EBV, can be CMV, HHV6 Saliva, semen, blood Infects epithelial cells and B cells Classic triad Sore throat Fever Lymphadenopathy Other clinical features Splenomegaly: 50% patients. Avoid contact sports for 8 weeks! Palatal petechiae Hepatitis: ALT derangement Lymphocytosis Haemolytic anaemia: cold agglutinins (IgM) 99% develop maculopapular pruritic rash on taking amoxicillin Malignancy: Burkitt’s, nasopharyngeal carcinoma, lymphoma Diagnosis Heterophile antibody test: infected B cells produce polyclonal IgM which agglutinate RBCs Management Supportive

Answer 116

clinical diagnosis confirmed by saliva sample ->IgM mumps antibody consider if pt has parotitis - reaches full size in 2-3 days, usually other gland follows but 25% cases unilat; may be tender, have earache, problems pronouncing words; viral signs as in other flashcard + anorexia, headache; watch for epididymoorchitis, oophoritis (N&v, lower abdo pain), viral meningitis (fever, headache, vomiting, neck stiffness, tiredness peaking over 2 days and resolving in a week), mild/transient pancreatitis, temp deafness unlikely if had both doses of mmr, under 1yo, or previously had; consider if contacts consider EBV, parainfluenza, flu, adenovirus, parvovirus b19 etc; acute suppurative parotis (staph aureus, mycobaceteria), parotid duct obstruction, sarcoidosis, sjogrens, wegeners notify local health protection unit; self limiting over 1-2 wks, drink lots of fluid and use paracetamol/ibuprofen, warm/cold packs; stay off school/work for 5 days consider 1 wk follow up, seek medical advise if epidoorchitis or meningitis symptoms if contacted possible mumps: mmr vaccine if not had both doses, seek advice if get symptoms - cant give mmr if pregnant, nor if immunocompromised epididymoorchitis treat in similar way + bed rest, unlikely to impact fertility but if severe/bilat or pt worried offer semen analysis 3mo later admit if meningitis/encephalitis

Answer 117

Chickenpox sec infection NSAIDs may increase this risk whilst this commonly may manifest as a single infected lesion/small area of cellulitis, in a small number of patients invasive group A streptococcal soft tissue infections may occur resulting in necrotizing fasciitis Rare complications include pneumonia encephalitis (cerebellar involvement may be seen) disseminated haemorrhagic chickenpox arthritis, nephritis and pancreatitis may very rarely be seen

Answer 118

keep cool, trim nails calamine lotion school exclusion: NICE Clinical Knowledge Summaries state the following: Advise that the most infectious period is 1–2 days before the rash appears, but infectivity continues until all the lesions are dry and have crusted over (usually about 5 days after the onset of the rash). immunocompromised patients and newborns with peripartum exposure should receive varicella zoster immunoglobulin (VZIG). If chickenpox develops then IV aciclovir should be considered

Answer 119

When contact occurs with chickenpox or shingles, a careful history must be taken to confirm the significance of the contact and the susceptibility of the patient. Pregnant women with an uncertain or no previous history of chickenpox, or who come from tropical or subtropical countries, who have been exposed to infection should have a blood test to determine VZV immunity or non-immunity. If the pregnant woman is not immune to VZV and she has had a significant exposure, she should be offered varicella-zoster immunoglobulin (VZIG) as soon as possible. VZIG is effective when given up to 10 days after contact (in the case of continuous exposures, this is defined as 10 days from the appearance of the rash in the index case). Non-immune pregnant women who have been exposed to chickenpox should be managed as potentially infectious from 8–28 days after exposure if they receive VZIG and from 8–21 days after exposure if they do not receive VZIG. Oral aciclovir should be prescribed for pregnant women with chickenpox if they present within 24 hours of the onset of the rash and if they are 20+0 weeks of gestation or beyond. Use of aciclovir before 20+0 weeks should also be considered. Aciclovir is not licensed for use in pregnancy and the risks and benefits of its use should be discussed with the woman. Intravenous aciclovir should be given to all pregnant women with severe chickenpox. VZIG has no therapeutic benefit once chickenpox has developed and should therefore not be used in pregnant women who have developed a chickenpox rash If maternal infection occurs in the last 4 weeks of a woman’s pregnancy, there is a significant risk of varicella infection of the newborn. A planned delivery should normally be avoided for at least 7 days after the onset of the maternal rash to allow for the passive transfer of antibodies from mother to child, provided that continuing the pregnancy does not pose any additional risks to the mother or baby. Women with chickenpox should breastfeed if they wish to and are well enough to do so

Answer 120

otitis media: the most common complication pneumonia: the most common cause of death encephalitis: typically occurs 1-2 weeks following the onset of the illness) subacute sclerosing panencephalitis: very rare, may present 5-10 years following the illness febrile convulsions keratoconjunctivitis, corneal ulceration diarrhoea increased incidence of appendicitis myocarditis

Answer 121

Plasmodium falciparum, vivax, ovale, malaria transmitted by female Anopheline mosquitoes 800-1000 cases per annum in UK; about 50% are UK immigrants returning to country of origin for short visits variable presentation - usually fever + rigors +/- almost anything else except a rash; NOT necessarily cyclical fever; usually have no physical signs (occasionally splenomegaly); usually have normal neutrophil count, thrombocytopenia, mildly raised bilirubin - they WILL have haemolytic anaemia as parasite kills rbcs as it hatches from them P. falciparum can be rapidly fatal in the non-immune complications : cerebral malaria (coma, seizures), severe malaria anaemia, anuric renal failure, hypoglycaemia, pulmonary oedema, severe hepatic damage diagnosis: high index of suspicion – ask about foreign travel; blood films x3 thick film – more sensitive to detect small numbers of parasites, thin film – to identify species and quantify parasitaemia admit cases of P.falciparum to hospital seek expert advice for severe cases (e.g. P. falciparum >2% parasitaemia) monitor clearance of parasitaemia by daily blood films be aware of drug resistance in P.falciparum treatment: p falciparum: Quinine + artemisin combo therapy p vivax, ovale: Chloroquine followed by Primaquine (to eradicate persistent hypnozoites in the liver); Test for G6PD deficiency prior to Primaquine (can cause haemolysis in G6PD deficiency) prevention is best, w mosquito nets and spray; chemoproph: begin 1 week before travel (to identify adverse effects + achieve effective blood levels) continue for 4 weeks after return (1 week for Malarone) 3 main options for prophylaxis Mefloquine or Doxycycline or Malarone; meflo/chloroquine should be avoided in epilepsy, meflo in severe mental illness; avoid doxy if pregnant

Answer 122

Uncomplicated Fever (textbook: 48 hrly cyclical) Malaise Headache Severe Cerebral: coma, seizures Renal failure: blackwater fever (haemolysis) Hypoglycaemia ARDS DIC Blood smears THICK: more sensitive (larger volume of blood). Is Malaria present? THIN: allows determination of species and calculation of parasite count. haemolytic anaemia, thrombocytopenia, uraemia, hyperbilirubinaemia, abnormal LFTs, coagulopathy ADMIT! Uncomplicated: oral Artemisinin combination therapy E.g. Artemether + lumefantrine Severe or >2% RBCs parasitised: IV artesunate Supportive treatment e.g. management of seizures, pulmonary oedema, renal failure, lactic acidosis Malarone (atovaquone + proguanil) GI upset Renal impairment 1-2 days (begin before) 7 days (stop taking after) Chloroquine Headache Taken weekly Epilepsy 1 week 4 weeks Doxycycline Photosensitivity Oesophagitis Pregnancy 1-2 days 4 weeks Mefloquine (Lariam) Dizziness Neuropsychiatric disturbance Epilepsy + severe mental illness 2-3 weeks 4 weeks

Answer 123

suspect: FEVER +/- other non-specific symptoms (headache, malaise, nausea, vomiting, diarrhoea, abdominal pain) + Returning from malaria endemic country in last 8 months (sub-saharan africa, colombia, brazil, peru, venezuela, central america inc mexico, turkey through to china and everything south of that in asia, saudi + yemen, not in japan however) investigate: Thick and thin films and rapid antigen test, Blood culture, FBC, U&E, LFT, Clotting, CRP, G&S, G6PD, Glucose, Blood gas, sickle status, save serum, urine dip Consider: Urine MC&S, LP, Stool culture, Viral throat swabs, CXR if negative: Look for other causes of fever including other imported diseases – Consider repeat thick/thin film in 12hrs (3 clear films within 48hrs exclude malaria) if positive + uncomplicated: non-falciparum: Travel from SE Asia or Oceania? if no then chloroquine, d/c if tolerates; - Review on level 7 following day - Repeat FBC and parasite load - Start Primaquine if NOT G6PD deficient and >6m - If G6PD deficient or <6m d/w Paediatric ID if yes then admit and discuss with PID due to resistance pattern falciparum: admit and oral riamet – Repeat FBC and parasite load after 24hrs – Discharge if Hb stable and no increase in parasitaemia – Complete co-artem course – F/u in 2 weeks red flags: Impaired Consciousness – Prostration (unable sit or stand without assistance) – Convulsions – Metabolic acidosis (pH <7.3) – Hypoglycaemia (BSL <3) – Hb <8 – Renal impairment or haemoglobinuria – Jaundice (bili >50) – Pulmonary oedema – Abnormal spontaneous bleeding – Signs of shock – Parasitaemia >2% – Sickle cell if any of above or not tolerating orals then: ABC resus, IV artesunate (quinine if not available immediately), IV ceftriaxone (cefotaxime <3mo), contact PID and STRS All admitted patients should have at least 24hrs of: - Hourly neuro-observations - 4 hourly blood sugars (2hourly if on quinine) - 6hourly FBC, U&E, blood gas if haemolysing - Daily malaria film

Answer 124

Prophylaxis should generally be started before travel into an endemic area; 1 week before travel for chloroquine; 2–3 weeks before travel for mefloquine; and 1–2 days before travel for doxycycline or atovaquone with proguanil hydrochloride. Prophylaxis should be continued for 4 weeks after leaving the area (except for atovaquone with proguanil hydrochloride prophylaxis which should be stopped 1 week after leaving). It is important to consider that any illness that occurs within 1 year and especially within 3 months of return might be malaria, even if all recommended precautions against malaria were taken. Note malaria is a notifiable disease. Both chloroquine and mefloquine are unsuitable for malaria prophylaxis in individuals with a history of epilepsy. In these patients, doxycycline (children aged 12 years and over) or atovaquone with proguanil hydrochloride may be used Chloroquine can be given during pregnancy, but is not appropriate for most areas because its effectiveness has declined. If travelling to high risk areas or there is resistance to other drugs, mefloquine may be considered during the second or third trimester of pregnancy. Mefloquine can be used in the first trimester with caution if the benefits outweigh the risks. Doxycycline is contra-indicated during pregnancy Prophylaxis is required in breast-fed infants; although antimalarials are present in milk, the amounts are too variable to give reliable protection generally chloroquine only good for central america, eastern europe, and parts of middle east - check BNFc - due to resistance in SEA and africa

Answer 125

helminths are Macro-parasites which are large complex multicellular parasites. They have complex life cycles that may involve the development of infective forms in the soil or in insect vectors or in intermediate hosts For most of the medically important helminth infections, humans are the definitive host, i.e. the host in which the mature male and female adult worms develop, sexual reproduction occurs and female adult worms produce either eggs that are shed into the environment or microfilariae in blood that are taken up by biting insects A few helminth infections are zoonoses (Trichinella, Toxocara, Echinococcus); carnivorous animals are the definitive hosts, and humans are inadvertent intermediate host In developing countries, helminth infections are very common, especially in children and young adults. Estimated global prevalence of infection: schistosomiasis >100 million, hookworm >100 million, filaria >10 million. The mature adult worms typically have a long life span in the infected host (1-10 years) but adult worms are unable multiply within the definitive host - a single infective form that enters the human body can give rise to only one mature adult worm. Repeated exposure to the infective forms (e.g. by regularly walking barefoot in damp soil [hookworm] or by swimming in the lake [schistosomiasis]) leads to repeated infection with progressive accumulation of large numbers of adult worms. The severity of disease is generally related to the number of adult worms and the eggs that they produce. Infections with small numbers of adult worms are often asymptomatic, but infected individuals continue to shed eggs into the environment for long periods – tourist visitors to developing countries are usually exposed for only a short period of time and therefore usually acquire only a relatively small number of adult worms with mild disease. In endemic countries, infections with large numbers of adult worms typically produce chronic ill health (malnutrition, poor school performance) rather than dramatic acute illness Helminths that invade body tissues often evoke a specific immune response dominated by TH2 CD4+ T cells which secrete the cytokines IL4 (induces a polyclonal increase in IgE) and IL5 (induces sustained eosinophilia)

Answer 126

worm infection, broadly classified into tapeworms, flukes (trematodes), and roundworms (nematodes) round worms inc filariasis, ascaria, onchocerciasis, hookworm, pinworm, but not ringworm (this is a fungus) hookworm gastrointestinal symptoms caused by hookworm infection include nausea, diarrhoea, vomiting, abdominal pain, and abdominal fullness. A definitive diagnosis of hookworm infection depends on discovery of eggs in the stool or real time PCR; may see IDA, eosiniphilia; mebendazole treats pinworm aka threadworm: Intense perianal itching, typically worse during the night. Some people may be asymptomatic and only become aware of infection when small white thread-like worms (which may be slowly moving) are seen on the perianal skin or in the stools. In females, the genital area can also be involved and presentation may include pruritus vulvae. generally clinical diagnosis but adhesive tape test for eggs may be useful. Stool examination is much less reliable and is generally not recommended Treat with a single dose of an anthelmintic such as mebendazole (unless contraindicated) — the dose may need to be repeated in 2 weeks if infection persists. Children under the age of 6 months and pregnant or breastfeeding women should be treated with hygiene measures alone for 6 weeks. Consider treating all household contacts (unless contraindicated) as threadworms are highly transmissible. Advise rigorous hygiene measures for 2 weeks if treated with mebendazole, or 6 weeks if using hygiene measures alone If infection recurs this is usually due to re-infection not failure of anthelmintic therapy

Answer 127

for UK, only common helminth infection is the threadworm Enterobius. The female adult worm in the intestine lays eggs on the peri-anal skin at night (so itchiest then!), and the eggs become infectious within 6 hours and can survive for up to 2 weeks – peri-anal itching results in scratching and transmission of infectious eggs from person-to-person, mainly among children and other members of the same household. Treatment is a single oral dose of Mebendazole for everyone in the household – re-infection is common and re-treatment is often necessary

Answer 128

helminth blood fluke, definitive host - human, intermediate host - freshwater snail, transmitted via water S.mansoni Africa intestine chronic colitis, hepatic fibrosis & portal hypertension S.haematobium Africa bladder chronic cystitis, ureteric obstruction, carcinoma, hydronephrosis S.japonicum China intestine chronic colitis, hepatic fibrosis & portal hypertension diagnosis: cysts in stool or urine; rectal or bladder biopsy; serology treatment: oral Praziquantel prevention: basic sanitation, snail reduction

Answer 129

hookworm - Ancylostoma duodenale Necator americanus, asia and americas, iron def anaemia, maybe GI distress, but usually asymp; albendazole toxocara canis (dog poo eggs -> human mouth) - fever, hepatomegaly, choroiditis; thiabendazole filariasis - Wuchereria bancrofti (elephantiasis) and other kinds cause lymphatic obstruction; loa loa in horse fly causes subcut swelling and eyeworm; Onchocerca volvulus in black fly causes dermatitis, conjunctivitis, blindness; ivermectin treats all kinds Taenia saginata (beef tapeworm): asymp, praziquantel Taenia solium (cysticercosis): if eat larvae in pig meat then asymp, praziquantel; if eggs ingested by human then brain cyst → epilepsy; calcified cysts in muscle (rarely) praziquantel + (always) anticonvulsant echinococcus - eggs in dog faeces -> human gives hydatid cyst in liver, lung; if ruptures, anaphylaxis

Answer 130

extracellular protozoon Entameoba histolytica, definitive host - human, cysts shed in stools persistent infection of large intestine, may invade through mucosa i) amoebic dysentery – loose bloody stools +/- fever; mobile amoebae phagocytose erythrocytes ii) amoebic liver abscess – fever, RUQ pain, raised ALP, abscess on ultrasound diagnosis : “hot” stool microscopy; rectal biopsy; serology treatment : oral Metronidazole followed by oral Diloxanide or Paromomycin

Answer 131

intracellular protozoan, transmitted from dogs by sandfly bite persistent infection, outcome depends on protozoon strain and host cell-mediated immunity i) visceral (L.donovani – Sudan, India, Bangladesh, Nepal, Brazil) hepato-splenomegaly, anaemia, neutropenia, polyclonal increase IgG ii) cutaneous (L.major and L.infantum – Middle East; L.mexicana – Central America) chronic indurated plaque or ulcer iii) mucosal (L.braziliensis – Latin America) chronic oral/nasal ulceration diagnosis : biopsy with PCR to identify species, especially for L.braziliensis treatment : visceral & mucosal – i.v.Stibogluconate or Amphotericin cutaneous – topical Paromomycin or oral Fluconazole

Answer 132

a viral haem fever, mosquito transmitted, most commonly mild flu like illness: abrupt fever, headache, muscle and joint aches oft severe (bone break fever), pain behind eyes, n&v, lymphadenopathy, generalised macuopapular rash spont petechiae, bleeding gums, epistaxis are warning signs for progression to severe form (very rare); antibody screen diagnoses; supportive measures inc eg fluids if needed other vhfs inc eg ebola, lassa, yellow fever, zika, west nile, japanese enceph, generally have fever, flu like symptoms; maybe oedema, hypotension, jaundice, bleeding in mucous membranes; if severe coagulopathy giving hepatiis, myocarditis, GI bleeding (haematemsis, blood in stool) enceph, aki w hypotension, multiorgan failure; suspect in febrile returning travellers with evidence of bleeding, hypovol, inc'd vasc perm, or organ failure FBCs show leucopenia, thrombocytopenia, elevated transaminases, PT and INR up, DIC (d dimer up, fibrinogen low); virus specific IgM assay; isolation and supportive measures

Answer 133

Giardia lamblia is a type of microscopic parasite. It lives in the small intestines of mammals. These mammals may be pets, farmyard animals or humans. It releases cysts in the stools of infected mammals. These cysts then contaminate food or water and are eaten to infect a new host. This is called faecal-oral transmission. Infection may not cause any symptoms or it may cause chronic diarrhoea. Diagnosis is made by stool microscopy. Treatment is with metronidazole. Giardiasis: non-bloody. Recent travel to Spain. Can get malabsorption and lactose intolerance following infection. Metronidazole.

Answer 134

chagas: Trypanosoma cruzi. Protozoa. Travel to CENTRAL/SOUTH AMERICA. Acute phase is mainly asymptomatic except nodule (Chagoma) from kissing bug (triatomine) bite. Late phase infects muscle: myocarditis->dilated cardiomyopathy, Mega-oesophagus and mega-colon. leishmaniasis: type of trypanosome. Travel to South/Central America, Africa, India. Sandfly. (1) Cutaneous: skin lesion (often single ulcer). (2) Mucocutaneous: mucosal involvement. (3) Visceral: massive splenomegaly, hepatomegaly, grey skin with many raised nodules (kala-azar) sleeping sickness: Trypanosoma brucei. Protozoa. Human African Trypanosomiasis. Travel to Africa. Tsetse fly. EARLY: Fever, nodule at infection site, lymphadenopathy. LATE: CNS involvement: reduced GCS, meningoencephalitis.

Answer 135

toxoplasmosis: sulfadiazine and pyrimethamine, plus folinic acid kaposis: treatment of localised disease has been with radiotherapy, cryotherapy or intralesional vinblastine but is being superseded by pegylated liposomal doxorubicin or liposomal daunorubicin given IV (visceral may give haemptysis or abdo pain/bleeding)

Answer 136

serology too long for acute phase of herpes - NAAT test bechets, UC, EBV etc for non sti genital ulcers, common in women painful lymph nodes, large frothy ulcer -> chancroid (tropical) lymph venereum -> rectal ulcerations/proctitis, usually msm ulcer swab -> HSV, syph, chlam NAAT GC/CT screen: urine naat for both, throat and rectal swab for both can't culture syphillis, serology may be helpful here: IgG, IgM

Answer 137

number of factors that increase the risk of developing bacterial vaginosis: Multiple sexual partners (although it is not sexually transmitted) Excessive vaginal cleaning (douching, use of cleaning products and vaginal washes) Recent antibiotics Smoking Copper coil fishy, watery, grey or white discharge; speculum exam; Vaginal pH can be tested using a swab and pH paper. The normal vaginal pH is 3.5 – 4.5. BV occurs with a pH above 4.5. A standard charcoal vaginal swab can be taken for microscopy. This can be a high vaginal swab taken during a speculum examination or a self-taken low vaginal swab. Bacterial vaginosis gives “clue cells” on microscopy. Clue cells are epithelial cells from the cervix that have bacteria stuck inside them, usually Gardnerella vaginalis. when prescribe metronidazole advise pt to avoid also drinking alcohol (disulfiram like reaction eg flushing headache n&v) trichomonas may also be fishy, usually frothy/green discharge if present, maybe strawberry cervix BV partner doesnt need to be treated, trichomonas they do unlike above 2, pH <4.5 in candida; single dose of clotrimazole cream/pessary or oral fluc taken at night; these can damage condoms so need other contraception for 5 days after use

Answer 138

majority of cases of chlamydia in women are asymptomatic. Consider chlamydia in women that are sexually active and present with: Abnormal vaginal discharge Pelvic pain Abnormal vaginal bleeding (intermenstrual or postcoital) Painful sex (dyspareunia) Painful urination (dysuria) Consider chlamydia in men that are sexually active and present with: Urethral discharge or discomfort Painful urination (dysuria) Epididymo-orchitis Reactive arthritis Pelvic or abdominal tenderness Cervical motion tenderness (cervical excitation) Inflamed cervix (cervicitis) Purulent discharge NAAT tests diagnose; doxycycline 100mg twice a day for 7 days; if preg then azithryo/erythro; sexual partners should be treated

Answer 139

occurs in three stages: The primary stage involves a painless ulcer (primary lesion). This typically occurs on the penis in men, vaginal wall in women or rectum after anal sex. The secondary stage involves lymphadenitis. This is swelling, inflammation and pain in the lymph nodes infected with the bacteria. The inguinal or femoral lymph nodes may be affected. The tertiary stage involves inflammation of the rectum (proctitis) and anus. Proctocolitis leads to anal pain, change in bowel habit, tenesmus and discharge. Tenesmus is a feeling of needing to empty the bowels, even after completing a bowel motion. Doxycycline 100mg twice daily for 21 days

Answer 140

more likely to be symptomatic Female genital infections can present with: Odourless purulent discharge, possibly green or yellow Dysuria Pelvic pain Male genital infections can present with: Odourless purulent discharge, possibly green or yellow Dysuria Testicular pain or swelling (epididymo-orchitis) Rectal infection may cause anal or rectal discomfort and discharge, but is often asymptomatic. Pharyngeal infection may cause a sore throat, but is often asymptomatic. Prostatitis causes perineal pain, urinary symptoms and prostate tenderness on examination NAAT test to establish initial diagnosis Rectal and pharyngeal swab are recommended in all men who have sex with men (MSM), and in those with risk factors (e.g. anal and oral sex) or symptoms of infection in these areas. A standard charcoal endocervical swab should be taken for microscopy, culture and antibiotic sensitivities before initiating antibiotics single IM dose ceftriaxone, partners are treated, test of cure needed remember gonococcal conjunctivitis in a neonate. Gonococcal infection is contracted from the mother during birth. Neonatal conjunctivitis is called ophthalmia neonatorum. This is a medical emergency and is associated with sepsis, perforation of the eye and blindness. disseminated gonoccocal infection: non-specific skin lesions Polyarthralgia (joint aches and pains) Migratory polyarthritis (arthritis that moves between joints) Tenosynovitis Systemic symptoms such as fever and fatigue

Answer 141

Pelvic or lower abdominal pain Abnormal vaginal discharge Abnormal bleeding (intermenstrual or postcoital) Pain during sex (dyspareunia) Fever Dysuria Examination findings may reveal: Pelvic tenderness Cervical motion tenderness (cervical excitation) Inflamed cervix (cervicitis) Purulent discharge NAAT swabs for gonorrhoea and chlamydia NAAT swabs for Mycoplasma genitalium if available HIV test Syphilis test A high vaginal swab can be used to look for bacterial vaginosis, candidiasis and trichomoniasis. A microscope can be used to look for pus cells on swabs from the vagina or endocervix. The absence of pus cells is useful for excluding PID A pregnancy test should be performed on sexually active women presenting with lower abdominal pain to exclude an ectopic pregnancy

Answer 142

Primary genital herpes contracted before 28 weeks gestation is treated with aciclovir during the initial infection. This is followed by regular prophylactic aciclovir starting from 36 weeks gestation onwards to reduce the risk of genital lesions during labour and delivery Primary genital herpes contracted after 28 weeks gestation is treated with aciclovir during the initial infection followed immediately by regular prophylactic aciclovir. Caesarean section is recommended Recurrent genital herpes in pregnancy, where the woman is known to have genital herpes before the pregnancy, carries a low risk of neonatal infection (0-3%), even if the lesions are present during delivery. Regular prophylactic aciclovir is considered from 36 weeks gestation

Answer 143

Antibody testing for antibodies to the T. pallidum bacteria can be used as a screening test for syphilis. Patients with suspected syphilis or positive antibodies should be referred to a specialist GUM centre for further testing. Samples from sites of infection can be tested to confirm the presence of T. pallidum with: Dark field microscopy Polymerase chain reaction (PCR) The rapid plasma reagin (RPR) and venereal disease research laboratory (VDRL) tests are two non-specific but sensitive tests used to assess for active syphilis infection. These tests assess the quantity of antibodies being produced by the body to an infection with syphilis. A higher number indicates a greater chance of active disease single deep intramuscular dose of benzathine benzylpenicillin (penicillin) is the standard treatment for syphilis.

Answer 144

chlamydia asymptomatic in approximately 70% of females and 50% of males. Typical clinical features of chlamydia in males include: Urethral discharge (usually clear) Dysuria Proctitis Epididmyo-orchitis is a complication of chlamydial infection, and patients may present with scrotal pain. Typical clinical features of chlamydia in females include: Vaginal discharge Proctitis Post-coital bleeding (may indicate cervicitis) Intermenstrual bleeding Cervicitis on vaginal examination Chlamydial infection can lead to pelvic inflammatory disease (PID), and patients may present with pelvic pain with signs of systemic infection NAAT test using first pass urine from penis, or else urethral/vaginal/throat swab swab may remain positive for up to 5 weeks following treatment for chlamydia first-line management for chlamydia is: Doxycycline 100mg orally twice daily for 7 days (contraindicated in pregnancy) OR Azithromycin 1g oral, followed by 500mg daily for 2 days Lymphogranuloma venereum (LGV) is caused by a serotype of Chlamydia trachomatis. It is most commonly tested for in men who have sex with men (MSM) presenting with anal discharge and pain, or anyone presenting with rectal chlamydia. LGV requires a longer course of antibiotics (21 days), and there are higher rates of HIV and hepatitis C co-infection.

Answer 145

gonorrhoea: ypical clinical features of gonorrhoea in males include: Mucopurulent urethral discharge Dysuria Typical clinical features of gonorrhoea in females include: Mucupurulent discharge Dysuria Rectal gonococcal infection can cause proctitis leading to rectal pain, bleeding and discharge. Oropharyngeal gonococcal infection can cause pharyngitis. Ophthalmic gonococcal infection can cause conjunctivitis. NAAT test from sites as for chlamydia and should also send swab for culture to get sensitivities first-line management for gonorrhoea is: Ceftriaxone 1g intramuscular injection as a single dose (often mixed with lidocaine to reduce injection site pain) OR Ciprofloxacin 500mg orally as a single dose (only used when antimicrobial sensitivities are known before treatment) test of cure 14 days after rx via NAAT syphilis Acquired syphilis can be broken down into: Primary: development of an indurated painless ulcer (chancre) on the genitals Secondary: widespread non-pruritic maculopapular rash (if involving the soles and palms, is almost pathognomonic for syphilis) Latent: asymptomatic infection (confirmed by positive diagnostic serology) acquired within the last two years Late latent: asymptomatic infection (confirmed by positive diagnostic serology) acquired more than two years prior Tertiary (occurs >2 years following infection): gummatous (formation of granulomatous inflammatory lesions), cardiovascular (aortitis) or late neurological involvement. In patients with lesions, syphilis can be diagnosed using a syphilis PCR swab of the lesion. Where available, dark ground microscopy can show the motile spirochete. The mainstay of diagnosis of syphilis is by using serology but art not science and immunological medical conditions (e.g. SLE and HIV) and pregnancy can affect the interpretation of syphilis serology. Rapid Plasma Reagin (RPR) Venereal Disease Research Laboratory (VDRL) RPR and VDRL are often used to monitor disease activity following treatment Treatment of syphilis is with benzathine benzylpenicillin (IM). The exact treatment regime will vary depending on the stage of syphilis A Jarisch-Herxheimer (JH) reaction can occur following the initial treatment of syphilis in some patients. This phenomenon causes a sepsis-like picture due to the release of toxins from treponemal bacterium breakdown

Answer 146

HSV double-stranded DNA viruses Symptoms of infection include blisters which progress to painful ulcers around the anogenital area. This can be accompanied by dysuria, discharge and inguinal lymphadenopathy. In the initial infection, systemic symptoms (e.g. pyrexia and myalgia) may occur. Symptoms from initial infection tend to be more severe than those of recurrent Diagnosed using PCR from swabs of lesions. When taking the swab, the lesion should be burst and a swab taken from the base of the ulcer. If no lesions are present, testing for HSV can not be performed. HSV testing can be undertaken by serology in some places managed with aciclovir (an antiviral). Symptomatic episodes can be treated with aciclovir 400mg orally TDS for five days. Treatment should be commenced within five days of symptom onset. Saltwater baths, topical petroleum jelly, oral analgesia and topical lidocaine gel can be used for pain control. Genital warts Human papillomavirus (HPV) 6 and 11 (in most cases) - double-stranded DNA viruses incubation period from exposure to infection can be up to 8 months Anogenital warts can vary in size, number, colour and texture but mostly appear as textured, soft growths. The anus, cervix and urethral meatus can all be affected. Anogenital warts can be keratinised (hard surface) or non-keratinised (soft surface). Clinical diagnosis Treatment of the visible wart may not clear the virus from the body. Therefore, warts may reoccur following treatment Warts treated with cryotherapy, excision, topical meds trichomoniasis flagellated protozoan symptomatic in up to 50% of cases. Typical clinical features in females include: Vaginal discharge (thin, frothy yellow coloured) Strawberry cervix on speculum examination Vulval pruritus Vulvovaginitis Dysuria Dyspareunia Typical clinical features in males include: Urethral discharge Urethral irritation/itching Dysuria Balanitis does not form a part of a routine asymptomatic sexual health screen in the UK. In some centres, diagnosis can be made at the time of assessment by detecting motile trichomonads on wet mount microscopy. Point-of-care testing (using a posterior vaginal fornix swab) is becoming increasingly popular Alternatively, a NAAT can be performed on vulvovaginal swabs or first-pass urine samples in men metronidazole 400-500mg twice daily for 5-7 days (first line) or 2g oral as a single dose (alternative)

Answer 147

rubella - IUGR, organomeg, jaundice, thrombocytopen, chorioretinitis, cataracts, PDA, encephalitis, deafness, celery stick metaphysis, purpura CMV - iugr, organomeg, jaundice, chorioretinitis, microceph, encephalitis, cerebral calcification, deafness, purpura, pneumonitis; IgM raised to CMV and CMV in urine toxoplasmosis - iugr, organomeg, jaundice, chorioretinitis, enceph, cerebral calcif, deafness

Answer 148

Congenital cytomegalovirus is caused by the transmission of cytomegalovirus (CMV) in the prenatal period from the mother to the baby. Features include low birth weight, microcephaly, seizures, a petechial rash and hepatosplenomegaly with jaundice. Most infants will survive with supportive care but will go on to have complications such as hearing loss, vision impairment and learning disability. Some infants will not have features of generalised infection at birth but will later have hearing loss and learning disabilities. CMV infections in adults are often asymptomatic until iugr noticed Herpes simplex may cause congenital infection if the mother develops herpes (either primary infection or reactivation) during pregnancy. The features include a vesicular rash, very low birth weight, microcephaly, microphthalmia and preterm birth. If a pregnant woman becomes infected with parvovirus B19, consequences to the foetus include hydrops fetalis and sometimes miscarriage or stillbirth. Hydrops fetalis is caused by severe anaemia, in this case, due to a combination of haemolytic anaemia and the virus affecting red blood cell precursors in the infant, and presents with oedema. The oedema is due to high output heart failure. Management is with blood transfusions. Whilst thrombocytopenia may be present in 40%, leading to a petechial rash, severe anaemia and oedema are the presiding features. Hepatomegaly may also be seen, due to its association with haemolytic anaemia, but this is not common. Microcephaly and seizures would not be seen. Congenital rubella syndrome can develop in infants whose mother contracted rubella during pregnancy, usually within the first trimester. Low birth weight, microcephaly and seizures may be present. There may also be a purpuric rash, similar to the rash in infants with congenital CMV. However, the classic triad of symptoms of congenital rubella syndrome is sensorineural deafness, eye abnormalities (e.g. retinopathy and cataracts) and congenital heart disease (especially pulmonary artery stenosis and patent ductus arteriosus). Congenital varicella syndrome can develop if a non-immune mother was infected with varicella-zoster in the first or second trimester. Whilst it may also present with microcephaly and seizures, the defining features are hypertrophic scars (rather than a petechial rash), limb defects (such as hypoplasia) and ocular defects (such as cataracts and microphthalmia).

Answer 149

ascending genital tract infection -> hit membrane first; haematogenous spread -> hit villi first in the villus, plasma cells red flag for CMV, can look for CMV inclusions meanwhile parvovirus has fetal nucleated rbcs in the villus and parvovirus inclusions (a bit like onion rings) toxoplasma - lymphoctyes rather than plasma cells, inclusions in cytoplasm rather than nucleus as for above two malaria give dark dots on rbcs

Answer 150

Women who are between 16-32 weeks pregnant are offered the pertussis vaccine to provide maternal antibodies to the foetus when it is delivered

Answer 151

GBS - beta haemolytic (complete); penicillin or clindamycin for proph listeria - g+ rod, from soft cheese/pate/raw eggs, rare before 20wks, asymp or mild fever/back pain/sore throat/headache; fever may cause premature labour, risk of stillbirth/miscarriage or neonatal sepsis (30% survivors long term effects); meningitis in elderly/immuncomp too - cover with amoxi (enceph along menin); suspect if fever and aches preceded by diarrhoea, mild flu like illness if preg listeria will cause inflam of placenta with g+ gram staining, GBS affects membranes/umbilicus more transplacental infections: CMV, parvo, HSV, rubella, syph, TB, q fever, lyme disease, toxoplasma, plasmodium group a strep (pyogenes) can do pueperal sepsis esp if eg outbreak on ward; others eg e coli, staph aureus chorioamnionitis - cytokines trigger prostaglandin levels (myomet contractions) and matrix metalloprots (PROM); oft eg e coli, GBS; umb cord inflam can be neuts around blood vessels if eg GBS etc in chorioam, or external with white plaques and high wbc count if candida this then risk of periventricular leukomalacia, myelin degen, then cerebral palsy

Answer 152

To reduce the risk of the baby contracting hepatitis B, at birth (within 24 hours) neonates with hepatitis B positive mothers should be given both: Hepatitis B vaccine Hepatitis B immunoglobulin infusion Infants are given an additional hepatitis B vaccine at 1 and 12 months of age. They will also receive the hepatitis B vaccine as part of the normal 6 in 1 vaccine given to all infants aged 8, 12 and 16 weeks. They are tested for the HBsAg at 1 year to see if they have contracted hepatitis B. it is safe for hepatitis B positive mother to breastfeed provided their babies are properly vaccinated

Answer 153

At birth BCG if risk factors 2 months '6-1 vaccine' (diphtheria, tetanus, whooping cough, polio, Hib and hepatitis B) Oral rotavirus vaccine Men B 3 months* '6-1 vaccine' (diphtheria, tetanus, whooping cough, polio, Hib and hepatitis B) Oral rotavirus vaccine PCV 4 months '6-1 vaccine' (diphtheria, tetanus, whooping cough, polio, Hib and hepatitis B) Men B 12-13 months Hib/Men C MMR PCV Men B 3-4 years '4-in-1 pre-school booster' (diphtheria, tetanus, whooping cough and polio) MMR 12-13 years HPV vaccination 13-18 years (normally age 14) '3-in-1 teenage booster' (tetanus, diphtheria and polio) Men ACWY 2-15 years - until finished year 11 Flu vaccine (annual) All women who are at least 28 weeks pregnant get RSV immunisation as of 2024, to protect their infant If children have uncertain or incomplete vaccination history there is an PHE algorithm that you follow * unless there is a documented or reliable verbal vaccine history, individuals should be assumed to be unimmunised and a full course of immunisations planned * individuals coming to UK part way through their immunisation schedule should be transferred onto the UK schedule and immunised as appropriate for age * if the primary course has been started but not completed, resume the course – no need to repeat doses or restart course note PCV13 and PPSV23 are both pneumococcal vaccines that protect against different types of pneumococcal bacteria The 13-valent pneumococcal conjugate vaccine can be given to people of any age The 23-valent pneumococcal polysaccharide vaccine, also known as Pneumovax 23, is recommended for adults 65 and older who haven't previously received a pneumococcal vaccine, or for people 2 and older who are at high risk for pneumococcal disease due to underlying medical conditions - splenic dysfunction including pt with coeliac or sickle cell that could lead to spleen problems, chronic disease of heart kidney liver lung, diabetes needing insulin, cochlear implant, immunosuppressed Children diagnosed or first presenting with an at-risk condition (excluding those severely immunocompromised) who have completed their routine immunisation schedule should receive a single dose of PPV23, at least 8 weeks after the last dose of PCV13 or PCV15. Children diagnosed or first presenting with an at-risk condition (excluding those severely immunocompromised) who are previously unimmunised or partially immunised should receive a single dose of PCV13 or PCV15, followed by a single dose of PPV23 at least 8 weeks later Severely immunocompromised children should be given a single dose of PCV13 or PCV15, regardless of immunisation status. This should be followed by a single dose of PPV23, at least 8 weeks after the last dose of PCV13 or PCV15

Answer 154

Children in the UK receive two doses of the Measles, Mumps and Rubella (MMR) vaccine before entry to primary school. This currently occurs at 12-15 months and 3-4 years as part of the routine immunisation schedule Contraindications to MMR severe immunosuppression allergy to neomycin children who have received another live vaccine by injection within 4 weeks pregnancy should be avoided for at least 1 month following vaccination immunoglobulin therapy within the past 3 months (there may be no immune response to the measles vaccine if antibodies are present) Adverse effects malaise, fever and rash may occur after the first dose of MMR. This typically occurs after 5-10 days and lasts around 2-3 days For catch up: 3 months between doses to maximise the response rate. A period of 1 month is considered adequate if the child is greater than 10 years of age. In an urgent situation (e.g. an outbreak at the child's school) then a shorter period of 1 month can be used in younger children

Answer 155

don't give to immunosup ppl! BCG measles, mumps, rubella (MMR) influenza (intranasal) oral rotavirus oral polio yellow fever oral typhoid

Answer 156

first: all studied and safe for use in humans, in fact all are things children encounter in the environment and in food in larger amounts than what is in the vaccines aluminium salts: adjuvant to increase the immune response, meaning fewer total injections needed; amount in vaccines is similar to amount in 33 ounces of breastmilk formaldehyde: to inactivate viruses and bacterial toxins during manufacture, tiny amount might be left in the injection; body naturally makes formaldehyde and it is in blood at higher concentration than in vaccine, and body breaks it down and removes it antibiotics: like neomycin, to prevent bacti contamination; in such small amounts that rarely, if ever, cause allergic reaction egg protein: some vaccines made in eggs (yellow fever, influenza) so egg protein in them and can cause allergic reaction; MMR is not as made in chick embryo cells in culture, not in egg, so doesn't cause allergic reaction even if have egg allergy gelatin: sometimes in as a stabiliser, can cause reaction only if have gelatin allergy antifreeze: aka ethylene glycol, not in vaccines; polyethylene glycol is in some flu vaccines to inactivate the virus, but is safe chemical in toothpaste among other things mercury: not in vaccines, a preservative that contained mercury used to be in vaccines but not since 2002; sometimes used in manufacturing process and tiny amount can get in but not enough to cause any effect, additionally is a different form (methyl rather than ethyl) or mercury from the toxic kind; finally no link whatsoever to ASD, ASD rates have actually increased since mercury removed fetal tissue: not in any, some viruses are grown in human cell culture for vaccines, the cell lines from these come from fetuses from the 1960s and are stable lines so no new fetuses, and is not grown in fetuses themselves

Answer 157

faeco-oral inc water contaminated with sewage, shellfish from that water africa indian subcont esp usually onset within 35 days return fever, dry cough, headache, malaise, relative bradycardia, epistaxis; second week high swinging fever, constipation, organomegaly, abdo pain, 24mm macule rose spots on abdo and lower chest, raised transaminases, abdo distension and inc'd bowel sounds; then into pea soup diarrhoea; by third week weight loss, weak pulse, and with little warning infected peyers patches can perforate or haemorrhage; neuropsych complications and can affect most parts of body + overwhelming toxaemia; improvement in 4th week if not dead paratyphoid similar but more mild, may not progress to diarrhoea evening exacerbation and morning relief points to typhoid stool and blood cultures, antibiotics

Answer 158

Enteric fever (typhoid) is caused by Salmonella Typhi and Salmonella Paratyphi. The disease is widespread in middle and low income countries. Enteric fever is acquired through ingestion of contaminated food or water. Untreated typhoid is a serious disease with up to 10% mortality Constipation or diarrhoea, ever >38C and often constant, relative bradycardia (as kids have high HR may be like 80bpm), rose spots on abdo, may be septic, have meningism, hepatitis, intestinal perf, mark these as high risk and include the travel history. * Blood Culture (send 3 separate blood cultures) (Most likely to be positive in 1 st week of illness, sensitivity approx. 50%) * Stool Culture (Become positive after 1 st week of illness, less sensitive than b l o o d cultures) * Urine culture (please discuss with the lab when sending, to ensure it is processed correctly). Please note there are no useful serological tests. But the following should be taken: * FBC (low or high WCC) * CRP * LFTs (often moderately raised ALT) also ix for other causes of fever in returning traveller eg malaria If systemically well, await culture results before starting antibiotics. Azithromycin is the drug of choice for treatment of typhoid. PO azithromycin 10-15mg/kg (Max 500mg) once daily If unwell A-E sepsis mx including IV meropenem (after PID/micro discussion) switched based on sensitivities to eg cef fever may take 5-7 days to respond. This does not necessarily represent treatment failure Positive stool culture with other (non-typhoid) salmonella serotypes usually represents a self-limiting illness, not requiring antibiotic treatment. In the case of immunosuppression, infants or salmonella bacteraemia, seek advice from immunology, microbiology or a paediatric infectious diseases specialist

Answer 159

In a young patient presenting with a single acutely swollen joint always think of gonococcus septic arthritis until proven otherwise. Gonorrhoea infection is common and delaying treatment puts the joint in danger. In your exams it might say the gram stain revealed a “gram-negative diplococcus”. The patient may have urinary or genital symptoms to trick you into thinking of reactive arthritis but remember that it is important to exclude gonococcal septic arthritis first staph aureus most common cause of sep arth though, others eg GAS, Haem inf, e coli Aspirate the joint prior to antibiotics and send the sample for gram staining, crystal microscopy, culture and antibiotic sensitivities Empirical IV antibiotics should be given until the sensitivities are known. Antibiotics are usually continued for 3 – 6 weeks in total. Choice of antibiotic depends on the local guidelines. Example regimes are: Flucloxacillin plus rifampicin is often first line Vancomycin plus rifampicin for penicillin allergy, MRSA or prosthetic joint Typically, reactive arthritis is caused by a sexually transmitted infection (STI), such as chlamydia, or an infection of the bowel may also develop reactive arthritis if you, or someone close to you, has recently had glandular fever or slapped cheek syndrome nsaids, maybe steroids if severe, and clear triggering infection

Answer 160

Mycobacterium ulcerans - necrotizing ulceration following water contact Mycobacterium leprae - leprosy; transmission from nasal discharge of untreated lepromatous patients; spectrum of disease, depending upon efficacy of host cell-mediated immunity; paucibacillary = tuberculoid if cell-mediated immunity strong; multibacillary = lepromatous if cell-mediated immunity weak, humoral strong; treatment (lepromatous) : Rifampicin + Dapsone + Clofazimine for 6-24 months

Answer 161

if suspect active TB: CXR and Consider arranging three respiratory samples, particularly if chest X-ray appearances suggest TB infection. Ideally, specimens should be spontaneously-produced, deep cough sputum samples, with preferably one early morning sample, for microscopy for acid-fast bacilli, Mycobacteria culture, and specialist molecular tests/drug sensitivity testing if extrapulm features also consider: Joint or spinal plain X-rays; abdominal, renal tract, or lymph node ultrasound scans; early morning 0urine samples for dipstick testing, microscopy (looking for sterile pyruria) and Mycobacteria culture; echocardiogram (pericardial disease) ; CT scans of the chest, central nervous system, or bones/joints.

Answer 162

CSF needs micro, culture, cytology CT or MRI should be performed treat if clinically suspicious even if rapid testing negative. do not wait for microbiological or molecular diagnostic confirmation Suspect TBM if there is a CSF leucocytosis (predominantly lymphocytes), the CSF protein is raised, and the CSF:plasma glucose is <50%. if lesion visible on imaging (eg tuberculoma) then biopsy should be attempted if possible or try biopsy of other potential sites eg lungs, lymph nodes RIPE or 2mo then RI for further 10 adjunctive dex or pred should be given to all regardless of severity all should be tested for HIV rifampicin: Inhibits DNA-dependent RNA polymerase Hepatotoxicity Red or orange body fluids CYP450 inducer Cutaneous flushing isoniazid: Inhibits synthesis of mycolic acids Hepatotoxicity Inhibits CYP450 Drug-induced systemic lupus erythematosus Vitamin B6 deficiency peripheral neuropathy sideroblastic anemia co-administer with pyridoxine (B6) Pyrazinamide: Unknown but may work through host phagolysosomes Hepatotoxicity Hyperuricemia Arthralgias Ethambutol: Inhibits arabinosyltransferase and disrupts cell wall carbohydrate polymerization Optic neuropathy (red-green colour blindness)

Answer 163

mycoplasma pneumoniae: prolonged and gradual onset flu-like symptoms classically precede a dry cough bilateral consolidation on x-ray cold agglutins (IgM): may cause an haemolytic anaemia erythema multiforme, erythema nodosum meningoencephalitis, Guillain-Barre syndrome and other immune-mediated neurological diseases deranged LFTs, peri/myocarditis, serology to diagnose; macrolides legionella: also flu like, dry cough, deranged LFTs, treated with macrolide but lymphopenia, hyponat, bradycard, urinary antigens diagnose psittacosis from cleaning bird cage/pet birds; Flu-like symptoms (90%): fever, headache and myalgia; organomeg, fails to respond to penicils Respiratory symptoms (82%): dyspnoea, dry cough and chest pain serology confirms (usually part of atypc pneumonia screen) coxiella: prodrome: fever, malaise causes pyrexia of unknown origin transaminitis atypical pneumonia endocarditis, manage with doxy as for psittacosis CURB65 =2 oral or iv amoxi + clarithro, doxy and clarithro if atypc; 3+ iv co-amox and clarith, specialist if atypc metro to cover for anaerobes if aspiration CXR 4-6 weeks later to check recovery, rule out any cancers etc

Answer 164

early phase is due to bacteraemia and lasts around a week may be mild or subclinical fever flu-like symptoms subconjunctival suffusion (redness)/haemorrhage bilat calf ache second immune phase may lead to more severe disease (Weil's disease) acute kidney injury (seen in 50% of patients) hepatitis: jaundice, hepatomegaly aseptic meningitis serology, PCR, culture (takes a long time) Mx: doxycycline (mild), IV benzylpenicillin or ceftriaxone (severe) question will mention sewage workers, farmers, vets, rowers, swimming in rivers

Answer 165

Leptospirosis is a worldwide zoonosis caused by pathogenic spirochetes of the genus Leptospira main reservoir for spirochetes is rodents, but they can also be carried by other mammals such as horses, dogs, cattle, sheep, goats, and pigs; They can then contaminate the environment, particularly water resources, by excreting the microorganisms in their urine throughout their lives - the organisms then survive in the water or soil for months; Humans become infected when their mucous membranes or damaged skin comes into contact with contaminated water, contaminated soil, or infected animal tissues During the incubation period of 2-26 days (average 10 days), Leptospira multiplies in the blood and tissues. They then bind to the capillary endothelium, causing vasculitis, which is the primary cause of multisystem involvement classical form of Weil’s disease is characterized by jaundice, renal involvement, and haemorrhage but some clinical presentations affecting the central nervous and gastrointestinal system, muscle, heart, eye, and skin may often be overlooked initial symptoms may include an abrupt onset of fever, myalgia, and headache; conjunctival suffusion often occurs; jaundice, jaundice accompanied by renal failure (Weil’s disease), liver and renal dysfunction, oliguria, hepatomegaly, lymphadenopathy, and meningitis + more rarely hypotension, splenomegaly, skin rash, myocarditis, and shock culture is unreliable and takes a long time, so serum IgM antibody titres should be measured in both acute and convalescent serum samples (may cross react in other spirochaete infections); PCR and microscopy of urine + MAT test also helpful for diagnosis acute viral illnesses, Hantavirus infection, malaria, dengue, chikungunya, scrub typhus, rickettsial diseases, typhoid fever, and ehrlichiosis should be considered in the differential diagnosis most cases mild and self-limiting, dozy or azithro can be given; ceftriaxone in hospitalised patients; may need supportive measures like fluids

Answer 166

Alpha haemolysis: strep pneumoniae, viridans Beta haemolysis Group A: pyogenes Group B: agalactiae Group D: enterococci nec fas: Essentially a rapidly worsening cellulitis with pain out of keeping with physical features; Emergency surgical debridement Empirical Abx: tazocin+clindamycin. GAS: penicillin+clindamycin gas gangrene: Acute onset excrutiating pain+shock: fever, tachycardia, hypotension, foul smelling discharge, skin discolouration, necrosis, crepitus, local oedema, black blisters/bullae Emergency surgical debridement Empirical Abx: tazocin+clindamycin. C. perf: penicillin+clindamycin

Answer 167

Early features: erythema migricans rash (80% cases), headache, lethargy, fever, arthralgia Late features: cardio (heart block, myocarditis), neurological (facial nerve palsy, meningitis) Suspect if the question mentions North America, camping, hiking Clinical diagnosis if rash present! Otherwise serology: ELISA to detect antibodies Doxycycline/amoxicillin if early Ceftriaxone if late disease

Answer 168

Botulism C. botulinum Botulinum toxin: neurotoxin irreversibly blocking ACh release Contaminated food (e.g. tinned), IVDU Clinical features Progressive descending flaccid paralysis, ataxia, diplopia Usually fully concious, no sensory disturbance Management ITU involvement Anti-toxin Tetanus C. tetani Tetanus exotoxin: inhibits GABA release Clinical features: ROAST Rigidity Opisthotonus (hyperextension) Autonomic dysfunction Spasms Trismus (lockjaw) Management Wound debridement ITU involvement e.g. ventilation IM human tetanus immunoglobulin Metronidazole Tetanus vaccine: >10 years since vaccine, or unknown/incomplete status

Answer 169

After first dose of antibiotics against Spirochete (syph, lepto, lyme) infection Fever, rash, tachycardia (but no wheeze/hypotension: cf anaphylaxis) Probably release of endotoxins from spirochete death Within a few hours of treatment Just need antipyretics

Answer 170

Advice Condition(s) No exclusion Conjunctivitis Fifth disease (slapped cheek) Roseola Infectious mononucleosis Head lice Threadworms Hand, foot and mouth 24 hours after commencing antibiotics Scarlet fever 2 days after commencing antibiotics (or 21 days from onset of symptoms if no antibiotics ) Whooping cough 4 days from onset of rash Measles 5 days from onset of rash Rubella All lesions crusted over Chickenpox*(usually 5 days after rash starts) 5 days from onset of swollen glands Mumps Until symptoms have settled for 48 hours Diarrhoea & vomiting Until lesions are crusted and healed, or 48 hours after commencing antibiotic treatment Impetigo Until treated Scabies Until recovered Influenza

Answer 171

A peripherally inserted central catheter (PICC) is a catheter (either single or double lumen) which is inserted via a vein in the upper arm and advanced until the tip is located in the superior vena cava ensure the SecurAcath securing device is in place at all times; it is waterproof, but try not to get it too wet when showering (eg bag or sleeve over it) routine care and maintenance of a PICC involves weekly flushing and dressing. However, if the PICC is used for the administration of drugs or fluids, the PICC has to be flushed immediately post completion of the infusion; flush with 10ml normal saline to remove: Grasp the PICC and gently pull the catheter straight out parallel to the vein, using hand over hand technique. Once the whole PICC has been removed, apply sterile gauze to the insertion site, and apply pressure for at least 2 minutes the tip of the PICC does not routinely need to be sent to microbiology – only in the event that there has been a suspicion or a diagnosis of infection

Answer 172

caused by species in the Brucella genus, remains endemic in the South Asian regions mainly affects cattle, sheep, horses, camels, buffaloes, and dogs, which can be transmitted to humans through ingestion of unpasteurized milk and raw meat or in contact with the secretions of the infected animals non-specific presentation with fever, anorexia, abdominal pain, weight loss, night sweats, chills, and joint pain; pattern of fever in Brucellosis may have frequent remissions lasting for >1 year, with acute and subacute forms too; AKI, neurological sx inc psychosis and seizures; Hepatomegaly, splenomegaly, and lymphadenopathy can be seen Laboratory diagnosis of brucellosis relies on 3 approaches: 1) culture of Brucella bacteria from blood, bone marrow, tissue samples, or cerebrospinal fluid and other body fluids; 2) a compatible clinical picture, such as arthralgia, fever, sweating, chills, headache, and malaise, which is supported by the detection of specific antibodies at significant titers; 3) nucleic acid amplification or serological detection methods antibiotic treatment should be administered for 6 weeks or longer to reduce the risk of relapse - various regimes exist, speak to micro/PID

Answer 173

Vibrio cholerae is a highly motile Gram-negative bacterium which is endemic in approximately 50 countries with most burden in developing countries Mild cases may be indistinguishable from other causes of diarrhoeal illness, while profound infection causes rapid loss of fluid and electrolytes in ‘rice water’ stool (containing large amounts of sodium, potassium and bicarbonate) at rates of 10–20 ml/kg/h; Severe hypovolaemia may occur within hours of symptom onset, resulting in hypovolaemic shock, hypokalaemia, lactic acidosis (owing to bicarbonate loss), acute renal failure and hypoglycaemic coma. The mortality of untreated cholera is 50–70% commonly diagnosed and treated presumptively on the basis of clinical features. It can be confirmed by isolation of V. cholerae from stool cultures performed on specific media (TCBS or TTGA agar), with rapid diagnostic tests also available fluid resus is mainstay of treatment antimicrobial therapy does not have an immediate effect on disease progression (as the toxin is already bound to intestinal cells) but decrease the duration of the disease by diminishing further production of the toxin and reducing pathogen excretion (so transmission) - doxy or azithro generally

Answer 174

Giardiasis: non-bloody. Recent travel to Spain. Can get malabsorption and lactose intolerance following infection. Metronidazole. E. coli Commonest cause of traveller’s diarrhoea; 3-4 days incubation (can be 1-10) 0157: shiga-toxin-producing. Contact with livestock. Kids>adults. think bloody diarrhoea, HUS, TTP. Campylobacter: flu-like prodrome, diarrhoea may be bloody. Can cause GBS, reactive arthritis. 2-5 days incubation though up to 10 poss Amoebiasis (Entamoebia histolytica): bloody diarrhoea, incubation 2-4 weeks up to months. Stool microscopy: warmed or within 15 min. Liver abscesses with anchovy sauce. Metronidazole. Enteric fever: typhoid/paratyphoid: Salmonella (para)typhi. (Relative) bradycardia, abdominal pain+distension, CONSTIPATION, rose spots. Shigella: bloody diarrhoea. MSM. antibiotic-induced colitis and diarrhoea: pseudomembranous colitis Exotoxins: TcdB: disrupts tight junctions Due to CLINDAMYCIN, cephalosporins, co-amoxiclav Ix Raised WCC! C diff toxin (CDT) in stool Mx First line: oral metronidazole Second line/severe infection: ORAL vancomycin OCP test: the name of the test for ova, cysts, and parasites ie stool sample test done if suspect there are parasities like giardia, cryptospor, amoebiasis, schistosomiasis, certain worms

Answer 175

Shiga toxin-producing Escherichia coli (STEC) infection. There is no effective antibiotic treatment available for STEC infection, and advise not to give antibiotic treatment Specialist advice is needed regarding monitoring for the complication of haemolytic uraemic syndrome. Specialist advice is also needed regarding stool testing for microbiological clearance in children at increased risk of transmission of infection — two consecutive negative stool samples are usually needed taken at least 24 hours apart, once the child is symptom-free for at least 48 hours, before the child can return to school With giardiasis. Drug treatment with metronidazole may be recommended following specialist advice. Advise the person that they should not go swimming for 2 weeks after the last episode of diarrhoea. With dysenteric shigellosis. Antibiotic treatment is not usually needed for children with mild symptoms of shigellosis, but if symptoms are severe (high fever, bloody and/or high-output diarrhoea) or the child is immunocompromised, seek specialist advice on the need for antibiotic treatment. Specialist advice is needed regarding exclusion of cases from childcare settings With dysenteric amoebiasis. Drug treatment is usually recommended for all confirmed cases after specialist advice. With campylobacteriosis. Antibiotic treatment is not usually needed for children with mild symptoms, as infection is usually self-limiting. If symptoms are severe (high fever, bloody and/or high-output diarrhoea), the child is immunocompromised, or symptoms are worsening, seek specialist advice regarding the need for antibiotic treatment ith cryptosporidiosis. There is no specific treatment licensed in the UK. Advise the person that they should not go swimming for 2 weeks after the last episode of diarrhoea. Seek specialist advice if the child is severely immunocompromised, owing to the risk of serious and life-threatening complications

Answer 176

Most infectious diarrhoea is a self-limiting illness, caused by viruses (rather than bacteria or parasites), with nearly half of episodes lasting less than 1 day Food poisoning may be primarily caused by enterotoxins produced by the microorganism (rather than the microorganism itself), and diarrhoea and vomiting usually have a rapid onset and last for less than 24 hours - c perfringens (inadequate storage and insufficient reheating of contaminated meat dishes or cooked meats or meat products), bacillus cereus (caused by contaminated cooked foods subjected to inadequate post-cooking temperature control that has allowed bacterial growth (such as reheated rice, pasta, meat or vegetable dishes), staph aureus rotavirus: most common cause of viral gastroenteritis in children, normally winter/spring, symptoms include watery diarrhoea and vomiting with or without fever and abdominal pain. Vomiting usually settles within 1–3 days, and diarrhoea within 5–7 days, but can persist for 2 weeks norovirus: commonest cause of gastroenteritis in England and Wales, with an increased prevalence during colder months. Infection can occur in people of all ages because immunity is not long lasting, unlike rotavirus which tends to just be kids. Symptoms begin 24–48 hours after infection and last for 12–60 hours. Sudden-onset nausea is followed by projectile vomiting and watery diarrhoea. There may be associated fever, headache, abdominal pain, and myalgia. Most people make a full recovery within 1–2 days; usually person to person but also by consumption of contaminated food (such as oysters) or water, or contact with contaminated surfaces (such as toilets, soft furnishings, or floors), and outbreaks are common in semi-closed environments such as schools, hospitals, care homes, and cruise ships adenovirus: often resp but can do gastro esp in kids campylobacter: infection may be asymptomatic in 25–50% of people or cause diarrhoea (which may be bloody), nausea, vomiting, abdominal cramps, and fever. Most cases are self-limiting within 2–3 days and usually resolve within 1 week. It is usually associated with the consumption of contaminated food and drink, such as undercooked meat (especially poultry), unpasteurised milk, or untreated water, but the source of infection is often not found e coli: Infection with E. coli O157:H7 may be asymptomatic, or cause diarrhoea (which may be bloody), fever, abdominal cramps, and vomiting. Illness is usually self-limiting and resolves within 10 days. contaminated food, exposure to animals (esp ruminants) Salmonellosis (excluding Salmonella typhi and Salmonella paratyphi causing enteric fever) The majority of cases are sporadic, but outbreaks may occur in the general population and in institutions. Ingestion of contaminated food is the most common source Typical features are watery and sometimes bloody diarrhoea, abdominal pain, headache, nausea, vomiting, and fever. The illness usually lasts for 4–7 days, and people usually recover spontaneously Shigellosis: Shigellosis is most commonly transmitted person-to-person by the faecal-oral route, particularly in households, nurseries, and schools. More rarely, it can be transmitted through contaminated food, or sexually transmitted (particularly in men who have sex with men). Typically, 1–3 days after infection, there is diarrhoea (may have blood and mucus), fever, and abdominal cramps, with or without nausea and vomiting, headache, and malaise. Shigellosis usually resolves in 5–7 days Yersinia enterocolitica: Common symptoms are watery diarrhoea (which is often bloody), fever, and abdominal pain. In older children and adults, right-sided abdominal pain and fever may occur. Symptoms typically develop 4–7 days after exposure and may last 2 days to 6 weeks. Y. enterocolitica is transmitted by direct contact with infected animals and person-to-person (faecal-oral route), and through contaminated food Cryptosporidium is one of the most common protozoal causes of gastroenteritis in the UK, and about 20% of cases are associated with recent foreign travel. It typically causes profuse watery diarrhoea associated with abdominal cramps or pain, nausea, vomiting, fever, and loss of appetite. Symptoms usually last for 1–2 weeks, and recurrence of symptoms is reported in around one-third of cases. Entamoeba histolytica (amoebiasis) Transmission occurs through the ingestion of contaminated food or water. Symptoms are often mild diarrhoea and abdominal pain, but severe disease (amoebic dysentery) can occur, causing fever, severe abdominal pain, and blood and mucus in the faeces Giardiasis can be transmitted by person-to-person spread by the faecal-oral route; by contact with the faeces of infected animals; by consumption of contaminated food or drink; waterborne including swimming in contaminated water; or by sexual transmission, particularly among men who have sex with men. Many cases are associated with recent foreign travel, particularly from South Asia, and it is the most commonly identified pathogen in returning travellers with prolonged diarrhoea. Symptoms include diarrhoea, malaise, abdominal pain, loss of appetite, flatulence, bloating, and rarely nausea. Malabsorption, weight loss, and faltering growth may occur in children.

Answer 177

Children, especially those aged less than two years, may have Clostridioides Difficile in their gut without any symptoms risk factors: * Children who have received antibiotics * Had surgery on their digestive system * Had a long stay in hospital * Immune Deficiency If child (over 2 years old) has diarrhoea during or following antibiotic therapy: STOP if possible ANTIBIOTICS, PROTEIN PUMP INHIBITORS (PPI’s), OPIOIDS, STEROIDS, LAXATIVES. (Consult microbiology if antibiotics still required to treat original infection; consider alternatives to PPI’s Send faeces for c diff Re-test after 72 hrs if CDI still suspected and first negative If positive start Treatment with VANCOMYCIN PO for 10 DAYS per BNFc dose, if diarrhoea continues discuss with micro Indicators of severe disease * Profuse diarrhoea with systemic findings (fever >38.5°C, rigors, or severe abdominal pain, tenderness, or distention) * Hypotension or shock * Ileus or toxic megacolon * Elevated white blood cell (WBC) count (>15x109/L) * Elevated age-adjusted serum creatinine level Life-threatening infection: * symptoms and signs include hypotension, * partial or complete ileus, * toxic megacolon or * CT evidence of severe disease Discuss above cases with micro, either high dose oral vanc with IV metro, or fidaxomicin If treatment recurring may need fidaxomicin or stool transplant with specialist guidance

Answer 178

Fever, which may be as high as 103°F (39.4°C) to 105°F (40.5°C) Body aches, which may be severe Headache Sore throat Cough that gets worse Tiredness Runny or stuffy nose Nausea Vomiting Diarrhoea flu season usually October to March Drink adequate fluids to avoid dehydration. To take paracetamol or ibuprofen for symptomatic relief. To rest in bed if they feel fatigued. To stay off work or school if they feel unable to attend — for most people, about 1 week will be adequate. That fever and associated systemic symptoms of uncomplicated influenza usually resolve after about 1 week, although some symptoms (such as cough and fatigue) may persist for up to 2 weeks Children with risk factors should be treated with antivirals if admitted to hospital with confirmed or presumed influenza infection (during periods that influenza is known to be circulating locally). Only treat children without risk factors who are admitted to PHDU / PICU with confirmed or presumed influenza infection. They get oseltamivir choice of antiviral agent in severely immunocompromised patients depends on the predominant circulating strain H3N2 versus H1N1 (higher risk of oseltamivir resistance with H1N1); if PCR is negative then stop the antiviral risk factors: Under 6 months old from expected delivery date Asthma on regular inhaled steroids Cystic fibrosis, Primary ciliary dyskinesia or bronchiectasis Chronic lung disease on home oxygen or long-term ventilation Congenital Heart Disease apart from minor ASD / VSD / PS Significant Immune deficiency (any cause including HIV (CD4 <200 if >5yo or <500 if <5yo) and long term oral steroids including 3mo after rx stop, on chemo/RT or had in last 6mo, on immunsupp) Asplenic or have coeliac/sickle cell Neuromuscular disease e.g. SMA, Duchenne etc Significant neurodevelopmental delay Other chronic disease where clinician feels decompensation may result generally at risk group but not immunocomp gets oseltamivir PO, likewise if immunocomp and circulating strain oseltamivir sensitive (if it's not then zanamivir inh) if unwell or otherwise complicated oseltamivir can be given NG and zanamivir IV but Po/inh are preferred route still Zanamivir not licensed <5yo so speak to PID and use on their advice For immunocompromised children with H1N1 being treated with oseltamivir, a follow up respiratory specimen should be collected 48-72 hours after commencing treatment to check that the virus remains sensitive to the drug. Test for antiviral resistance in patients who do not respond after 5 days of treatment. Only children with risk factors should receive prophylaxis following exposure to a person in the same household with confirmed influenza or influenza-like illness when influenza is circulating in the community. If indicated, prophylaxis should only be used if started within 48 hours of the last contact. Choice is oseltamivir unless immunocomp + >5yo + H1N1 circulating then do zanamivir

Answer 179

acute respiratory infection caused by the Gram negative coccobacillus bacteria Bordetella pertussis. The organism is transmitted via respiratory droplets from an infected person. After an incubation period of between 7-10 days, the initial catarrhal stage develops into an irritating cough which becomes paroxysmal within 1-2 weeks. The paroxysmal coughing fits are associated with an inspiratory ‘whoop’ or post-tussive vomiting. The coughing fits may last for up to 2-3 months. Young infants may present with apnoeic episodes without the typical ‘whoop' suspect if there is acute cough for 14 days or more without an apparent cause plus one or more of the following: * Paroxysms of coughing * Post-tussive vomiting * Inspiratory whoop OR * Undiagnosed apnoeic attacks in young infants (especially if mother was not vaccinated during pregnancy) OR * Someone with signs and symptoms consistent with pertussis that has been in contact with a confirmed case of pertussis in the previous 21 days. OR * Someone who is known to be part of any on-going outbreak investigation in a specific group of people (i.e. Children attending same school/nursery) does pt need admission? - < 6 months of age and acutely unwell -Has significant breathing difficulties (i.e. apnoea episodes, severe paroxysms, or cyanosis) -Has significant complication (i.e. pneumonia, seizures) if no admission needed then: Investigate and start treatment (if within 21 days of symptom onset and high suspicion of pertussis) Notify UKHSA Exclude from nursery or school until at least 48 hours of appropriate antibiotic therapy or 21 days from symptom onset if not treated with antibiotics -Safety netting: If child gets worse with significant breathing difficulties or has significant complications, to seek medical advice. if admission needed: Notify UKHSA If >21 days ix but no mx or isolation needed If <21 days ix, start mx, and isolate until at least 48 hours of appropriate antibiotic therapy OR 21 days from symptom onset without antibiotic treatment If presents in community advise GP to manage in community per UKHSA guidelines if no criteria to admit All children who have been treated for pertussis should be offered pertussis vaccination at the appropriate age. Ix based on sx length if <21 days then: x2 Pernasal or nasopharyngeal swabs (latter sent not in transport medium) for pertussis culture and PCR Patient clinically unwell needing ICU care: * Send X2 pernasal swabs /bronchoalveolar lavage/nasopharyngeal aspirate for pertussis PCR * Full blood count (looking for lymphocytosis) if >14 days then oral fluid testing (for detecting antipertussis toxin IgG) if 2 to 16 years or in older children serum for serology If symptoms had been present between 14-21 days, you could investigate using either pertussis culture/PCR or serological tests (oral fluid testing in the right age group or serum) Immunisation within last year can confound serological tests Mx PO clari for 7 days first line, second line PO azithromycin for 3 days If macrolides not tolerated then POC co-trimox for 7 days prophylaxis given if significant exposure within last 21 days during other patient's infectious period and either <2mo (+ born <33weeks or mum not vaccinated against pertussis) or >2mo and not received full vaccine course; prophylaxis choice is same as mx course

Infectious diseases/immunology Flashcards

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