Immunology & Infection

Infection Innate Immune System Skin, mucous membranes Compliment system – bacterial antigen binds to host antibody à chemo-attraction, opsonisation & immune complexes Phagocytes – detect opsonised bacteria & engulf to digest, move by chemotaxis Monocytes in blood (+ neutrophils + eosinophils) Macrophages in tissue Macrophages à antigen presentation à T cell activation à pyrogens à aid wound healing by factor secretion Innate Immunity - Phagocytes, NK cells, Dendritic cells, Mast cells, Cytokines, Complement & acute phase proteins (CRP) Humoral immunity – B cellsà antibody production Cellular immunity – NK cells, T cells, CD4 (T-helper) cells & CD8 (T-cytotoxic) cells Ab –from B cells (mainly IgM in early infection Complement – attracts neutrophils to pathogens, helps attach (opsonisation) and helps degranulate mast cells (à histamine à inflammation) Adaptive immune system T cells Produced in fetal bone marrow à migrate to thymus When stimulate they perform 3 functions Produce cytokines e.g. interleukins, TNF Supress immune response of other cells Kill target cells Th1 = stimulate cytotoxic T cells, Th2 = cause differentiation of B cells Support and regulate B cells to produce Ig, mediate delayed hypersensitivity and produce cytokines B cells When stimulated B-cells transform to plasma cells & produce Ig • IgM produced from 15/40 o Adult IgM Levels achieved by 1yr old • IgG at 20/40 o Adult IgG by 5 years old o IgG is only one which can cross placenta = passive immunity from mother o IgG à bacterial cell lysis by opsonisation & complement fixation Interferon gamma Activates macrophages & NK cells àIncreased expression of MHC class 1 & 2 And decreased levels of IgE production Levels increase in septic shock Can be used therapeutically to treat chronic granulomatous disease Blood test indicators Neutrophilia = bacteria Lymphocytosis = pertussis Neutropenia / Lymphopenia = severe sepsis, virus suppression and immune deficiency Antibiotics / Antivirals Inhibit cell membrane synthesis - e.g. lincomycins Inhibit protein synthesis – e.g. tetracyclines, macrolides, aminoglycosides & chloramphenicol Inhibit DNA synthesis – e.g. sulphonamides, trimethoprim, quinolones & metronidazole Inhibit cell wall synthesis – e.g. penicillins, vancomycin, cephalosporins & macrolides Penicillin Bactericidal Combine with transpeptidase à weaken cell wall (increase permeability) à cell destroyed by lysis Resistance usually due to B-lactamase (carried on plasmid) à destroys ring structure BenPen à effective on streps, meningococcus, pneumococcus & anthrax Aciclovir – inhibits DNA polymerase = acts as a chain terminator Erythromycin – inhibits ribosomes Vancomycin – inhibits cell wall synthesis Cipro – inhibits DNA gyrase Antibiotic side effects Nitrofurantoin à BIH Cefalexin à SLE like illness Trimethoprim à aseptic meningitis or diarrhoea Metronidazole à darkens urine, causes peripheral neuropathy & hypotension. With alcohol à disulfiram reaction. 80% bioavailability given PR NEONATAL INFECTIONS Increased susceptibility to infection due to: Endogenous factors Low levels of Ig Prems don’t get as much passive immunity from IgG – mostly transferred in last trimester Phagocytes are less effective Humoral activity is impaired & complement levels are low IUGR = especially vulnerable Exogenous factors Born sterile. Early antibiotic use à colonisation with resistant organisms Breeches to skin e.g. lines à predispose to infection Drugs – esp. steroids impair further Fat emulsions e.g. TPN à impair phagocytes Hyperbilirubinaemia à impaired immune function Congenital (intrauterine) 1st trimester = TORCH Investigation of suspected TORCH infections Serology for IgM, & PCR Urine, throat, nose, CSF & Faeces for CMV & Viral Culture CT for cranial calcification Ophthalmology review for chorioretinitis & Cataracts Toxoplasmosis Protozoa - from cat / undercooked meat Diagnose on PCR or serology Sx = Triad of Chorioretinitis, Hydrocephalus & Periventricular calcification 5-10% have widespread infection à hydrocephalus, epilepsy, calcification Local infection usually just affects eyes àchorioretinitis Should treat even if asymptomatic Others Coxsackie B, Varicella, HIV Varicella (at < 20/40) Cortical & cerebellar hypoplasia Rubella CMV HSV nd Microcephaly Convulsions Limb hypoplasia Rudimentary digits Approx 2/100,000 – later infection = better prognosis If 1-2/12 gest = 90% abnormalities, 4-5/12 = 20% Cataracts – 8-9/40 Cardiac (5-10/40) 2/3 have sensorineural deafness (5-7/40) Low plts Cerebral calcification IUGR 3-4/1000 live births 90% asymptomatic 10% sensorineural deafness 10-20% blind Bile duct destruction à jaundice Microcephaly, IUGR, periventricular calcification and occasionally hydrocephalus See later notes 2 trimester Treponema Pallidum (syphilis) Congenital infection if infection after 4th month Penicillin with treat mother and fetus At birth (classical) – persistent snuffles, skin eruptions & widespread metaphyseal bony lesions Many are asymptomatic Also interstitial keratitis & hepatomegaly +ve VDRL test in mother Maternal IgG will cross placenta but should be negative by 6 months Baby should be negative for IgM at birth – if +ve then need to treat Non treponemal tests = VDRL =useful for screening. False +ve in TB, malaria, measles, varicella. Decrease with treatment = check response Treponemal tests – treponemal Ab / serodia particle agglutination = used to confirm diagnosis. Can be positive in other spirochete infections (Yaws, Pinta), leptospirosis or Lyme disease. Once reactive = usually remain so Active, recent disease would cause high titres in both types of tests If VDRL = low & negative Syphylis IgM then likely that maternal infection is late latent or previous adequate treatment 3rd Trimester & Labour Viral – Varicella, Hep B, Cocksakie B, Echovirus, HIV Bacteria – GBS, Listeria, Haemophilus, Pneumococcus Protozoan - malaria Ascending infections Consider maternal features such as fever, WCC, duration of PROM, number of VE’s. Also length of labour & fetal distress e.g. E.coli, Klebsiella, Pseudomonas, Enterococcus, GBS, Grp A Step, & rarely S.Aureus PROM Increases risk of Herpes, Neisseria Gonorrhoeae, Hep B, Chlamydia Trachomatis, Candida Albicans & HIV Acquired infections (in the nursery) Bacteria – CONS, S. Aureus, GBS, Coliforms, Salmonella, Shigella, Anaerobic bacteria, pseudomonas Virus – coxsackie, rotavirus, RSV, adenovirus, echovirus Fungal – Candida albicans & parapsilosis Neonatal Sepsis Symptoms - Off feeds, handling badly, change in temp, apnoeic spells, fits Incidence - 10-25% of babies on NNU get Sepsis, ½ of Prems on NNU get Sepsis High mortality – 26% in prems with proven infection, Body wt < 1500g = highest risk Delicate surfaces & limited immune system – condition rapidly worsens Affects development – cytokines from bacteria affect brain growth Treatment - Septic screen = blood, urine, CSF, swabs + broad spectrum Abx à specifics once cultures ready Diagnosis of SEPSIS • Growth of recognised pathogen in blood culture OR • Mixed growth / skin commensals + 3 or more clinical signs (e.g. increased O2 req, apnoea, hypotension, poor sugar regulation, decreased UO) NB: CRP is only raised in 60% of cases of sepsis & is often 24-48 hours behind Early = up to Day 3 – 90% occur in 1st 24 hours 80% GBS = S. to Penicillin, 20% E.coli = S. to Gent à BenPen & Gent Late – 3-90 days – Risk increased if UAC, TPN or delayed 1st feed for >7d Gram negatives à Gentamicin S. Aureus à Fluclox Strep à Penicillin Coag –ve staph (CONS) à Fluclox / Gent / Vanc Pathogens Mostly Coag negative Staph, but GBS = 21% of significant sepsis Narrow margin for treatment – most present at 18 hours & die at 22 hours Group B Strep 1/3-1/2 of early onset neonatal infections 20% of women carry in genital tract, ½ will pass it on during birth 1-2% of colonised will develop sepsis Early Onset = septicaemia, RDS & septic shock = Approx 0.4-1 / 1000 births Late onset = meningitis (after 5-7 days) – may be from infected milk / colonisation during feeds etc Maternal Abx during labour will decrease cases of early infection Listeria Granulomata on skin Multi-organ involvement – esp. lungs & brain Green liquor If congenital often à hydrocephalus Chlamydia Intracellular pathogen 50-60% of vaginally delivered infants of +ve mums become infects à conjunctivitis or less commonly pneumonia Treat with erythromycin Neonatal Conjunctivitis Oft no infect, if pus à swabs & scrapings (assume GC until proven otherwise) GC = Opthalmia Neonatorumà can cause corneal damage à IV pen + cleaning + eye drops Chlamydia à tetracycline eye drops & erythromycin Umbilical infection Should drop off in a few days, if not à swabs & systemic Abx Cord infection = Funisitis Stump infection = Ompahalitis Usually due to E.coli, other Gr-ve or S.Aureus Thrush White plaques in mouth (can’t be rubbed off) à oral nystatin Erythematous rash on perineum à nystatin cream Sepsis Sepsis – systemic inflammatory response to possible infection Severe sepsis – hypoperfusion leading to organ dysfunction due to sepsis Septic Shock – BP < 5th centile for age Refractory Septic Shock – low BP persists beyond 1 hr despite IVI requiring Vasopressor support Decreased arterial tone à low SBP Decreased venous tone à pooling Vascular obstruction à 3rd space losses Recognition – may Sx are non-specific e.g. poor feeding, lethargy, decreased tone Treatment Treat infection, optimise O2 levels, support circulation with vasopressors & ionotropes, treat anaemia (Hb < 8) and correct any coagulopathy In Neonates – see neonatal notes Septic Shock Due to Gr- lipopolysaccharide OR Gr+ve lipoteichoic acid Cytokine cascade è TNF, IL 0, 6 & 8, platelet activating factor & interferon gamma è Triggers compliment and coagulation cascade è Activates polymorphs & increases ACTH à increased cortisol Sx Peripheral vasodilatation Myocardial depression Hypotension Ventilation insufficiency Lactic acidosis Capillary leak from uncontrolled immune response Pyrexia Pyrexia High Temp à reduces viral replication & increased phagocytosis Causes: infection, malignancy, autoimmune, factitious, undiagnosed Fever without a focus = new fever? where Pyrexia of unknown origin = Fever > 38o for > 3/52 AND no cause despite 1/52 of hospital assessment Diagnostic approach STOP antibiotics and antipyretics Full set of bloods in 3x cultures, urine, stool, CXR, EBV serology, CMV, HIV, Mantoux 2nd line Ix include ANCA, RF, dsDNA, marrow, etc Toxic Shock Syndrome Morbidity / mortality can be up to 15% “menstrual TSS” = tampon use = staph infection “Non-menstrual TSS” = less common, can occur in anyone Due to toxin produced by bacteria (usually S.aureus / Str.Pyogenes) Main toxin is TSST-1 Presence of TSST-1 antibody is protective Multisystem acute inflammatory process - Assoc with wound infections, burns, varicella Toxins act as superantigen à non specific T cell binding à polyclonal activation of large numbers of non-specific T-lymphocytes & macrophages à excess cytokine production (esp TNFa & IL-1) à tissue damage & fluid loss to 3rd space à hypotension & shock • Fever > 38.9 • Rash – diffuse macular erythroderma • Desquamation 1-2 weeks post onset • Low BP - < 5th centile or postural drop > 15mmHg or postural sx • 3 or more organ system affected o GI – D&V o Muscular – severe myalgia/CK 2x uln (upper limit of normal) o Mucous Membranes hyperaemia o Renal – Ur or Cr 2x uln o Hepatic – transaminase or bili 2x uln o Plts low o CNS – disorientation, altered conc • Must have negative blood, throat & CSF for everything except S.aureus o (exclude measles, leptospirosis, rocky-mountain spotted fever) Probably if 5/6, definite if 6/6 Rx – Aggressive fluid management required to prevent tissue hypoxia, Abx to cover staph and strep, Clindamycin helps prevent further toxin production, debride, support Meningitis 1/500 between 1month & 10yrs, 1/4000 neonates (high mortality) Increased risk if overcrowding / exposure to cigarette smoke Access via bloods / retrograde neurone spread, direct contagious spread (sinusitis, OM, Congenital malformations or trauma) Inflammatory response (IL-1 & TNF) à decreased BBB junctions à increased permeability à WCC à CSF but also à vaculitis, oedema, CSF outflow obstruction & raised ICP Brain oedema à raised ICP & decreased cerebral blood flow à anaerobic metabolism & decreased CSF glucose) Neonate – ¼ of neonatal sepsis Grp B Strep (50-60%), E.coli (20%), S.aureus, faecalis, pneumonia, listeria Sx temperature instability, poor feeding, vomiting, lethargy, irritable, decreased responsiveness Postnatal 6-12 months is highest risk. 90% of cases occur before 5 yrs Sx – fever, nausea, vomiting, irritability, headache, neck stiffness, decreased consciousness, full fontanelle, seizures Child – Neiserria Meningitidis (= Gr-ve diplococci = meningococcus = 60-70%) S.Pneumoniae (30%) H.Influenzae, M. TB, Enterovirus, Grp B Strep Y.Adult – Meningococcus O.Adult – Strep Pneumoniae Bacterial is usually preceeded by UTRI S&S: classical signs absent under 18 months, instead fever, poor feeding, vomit, drowsy, convulsions, rash only with meningococcal disease (fever + purpura unless proved otherwise) Kernigs sign = flex hip & knee to 90o. Knee extension = hamstring extension = resistance Brudzinski’s sign = passive neck flexion in supine position à flexion of hips Neck stiffness = resistance to passive flexion Ix: Rx: LP, blood cultures, blood glucose Bacteria à raised Neut, High Pro, Low Gluc TB à High Lymph, normal / raised Pro, Low Glu Encephalitis à normal CSF IV Abx (broad spectrum until CSF results back) Chemoprophylaxis – if HiB/N.meningitidis as rifampicin TB: Follows rupture of tubercle to CSF, 75% skin test +ve, 80% have CXR signs (HiB = highest risk for resulting deafness) Aseptic meningitis = non pyogenic cellular response, usually secondary to virus e.g. enterovirus, CMV, EBV, HSV ½, HHV 6, Measles, mumps Meningococcus (Neiserria Meningitidis) Gram negative diplococci Usually affects 2-20m, peak incidence in winter Can have septicaemia without meningitis Petechial rash due to cytokines, prostaglandins & free radicals à vasculitis à DIC IgM found in CSF Prophylaxis for contacts aims to eradicate nasal carriage = cipro / rifampicin Encephalitis Can be due to: Direct invasion by neurotoxic virus e.g. HSV 1&2, Varicella, CMV, EBV, less commonly HHV6, Rubella, Mumps (80% + = enterovirus, Others = arbovirus / herpes / measles) Post infections – delayed swelling due to immune response e.g. measles / zoster Slow virus infection – e.g. HIV / SSPE Usually viral, can à demyelination S&S: Non specific febrile illness f.b. Fever, nausea, vomiting, pain in neck / back / legs / photophobia Acute onset headache (frontal / general), hyperaesthesia, irritable, lethargy Can develop focal neurology / seizures Herpes Simplex – only 10% have gingivomastitis & skin lesions, HSV infection à neonate (skin, eyes, mouth, encephalitis, disseminated) OR children (acute, sub-acute, brain stem encephalopathy, psych syndromes, aseptic/benign recurrent meningitis, myelitis) Signs can mimic temporal SOL, untreated mortality 70% Dx: nasopharyngeal swabs, faeces, urine, serum (acute + 2-3 weeks later) for PCR CSF – polymorphonuclear, normal glucose (low in mumps encephalitis) EEG & neuroimaging Rx: acyclovir + symptomatic support Measles – irritable, drowsy, seizures (2-4 days post rash), no specific Rx Sub-acute Sclerosing Panencephalitis (SSPE) – late complication of measles Varicella – benign, acute but self-limiting Reye Syndrome Acute encephalitis & fatty liver infiltration Linked to HiB, Varicella, Aspirin Sx - vomiting, URTI, seizures, lethargy, hyperventilation, coma. NB AVOID LP (high risk of coning), Rx: ↓ICP by hyperventilation, hypothermia & osmotherapy Mouth Ulcers IBD Drugs (e.g. steroids / NSAIDs) Underlying haematological disorder Infection e.g. rubella, varicella, HSV, Measles Rashes of childhood (rash appears on day …) Very Sick People Must Take Early Retirement VIRAL INFECTIONS Measles (a paramyxovirus virus) incubation = 8-14 days à prodromal illness 2-4 days Varicella Scarlet Fever Pox (small) Measles Typhus Enteric Fever (Typhoid) Rubella Day 1 2 3 4 5 6 1-7 (fever, coryza, cough, conjunctivitis), lymphadenopathy Koplik’s spots in mouth (white, punctate, ulcerated mucosal lesions marked by necrosis, neutrophilic exudate, and neovascularisation) = 2d before rash Fever peaks as prodrome finishes & rash starts à maculopapular Rash approx 4-7 days post prodrome = “florid” Rash starts behind ears rash spreads from head to body à confluent & blotchy Improves after 3-4 days of rash Minimum exposure to rash is 10 days Infective 1-2d before and 4d after rash Complications (occur in 1/3) Bronchopneumonia & otitis media are common Encephalitis – starts with headache, drowsiness, vomiting up to 14 days after illness, 1/5000, 15% die, 25% brain damage Lymphopenia Subacute Sclerosing PanEncephalitis (SSPE) - can occur 4-10 years later – slow progressive deterioration with high levels of measles Ab in blood & measles virus in brain tissue Others - corneal ulcers, stomatitis, gastroenteritis, increased risk of appendicitis In endemic countries – malnourished children à confluent rash à darkens à desquamation à depigmentation & can à cancrum oris (gangrene of face) Rx: maintain hydration & nutrition If within 72 hours of exposure can give vaccine à long term immunity If vaccine contraindicated (or 3-6 days) à give gammaglobullin Mumps (a Paramyxovirus) 85% occur in children under 5, but more severe in older children Sub clinical infection common Spread by direct contact, saliva / droplet & urine Incubation – 14-21 days (can be up to 25 days) à Fever, malaise, myalgia, headache, parotitis & submandibular glands, ear ache & trouble swallowing Affects ALL salivary glands – parotid most obvious because largest Raised amylase (even if no pancreatitis = salivary) àswellings settle in 7-10 days. RASH is rare but is maculopapular if occurs Infective 1-2d pre and 9d post parotid swelling Complications Meningitis / encephalitis - >10% clinical, 65% subclinical (headache, photophobia & neck stiffness) CSF with increased Lymph. & raised protein. Can à sensorineural deafness Epididymo-orchitis – affects 25% of adolescents (30% bilaterally), affects fertility but does not cause sterility Rarely - Pancreatitis, thyroiditis, myocarditis, eye & joint involvement, decreased Plts, oophoritis, arthritis, transverse myelitis, cerebellar ataxia, deafness If exposed pre-vaccine then no point in vaccinating now as response too slow Rubella (Rubella virus) Usually mild, can pass unrecognised Infective 1-2d pre and 7d post rash Incubation 14-21 day Prodrome with cough / mild coryza àpink maculopapular rash (for 3 days) – Starts on face & spreads down trunk General lymphadenopathy, transient arthralgia, conjunctivitis Complications – RARE thrombocytopenia, encephalitis, arthritis, URTI High risk to fetus – see earlier in notes IgM within 2-3 weeks of infection Vaccine = > 90% protection In early 1900s were 6 rash causing Not a severe childhood illness – BUT high risk in pregnancy childhood diseases therefore vaccination programme 1st – Measles nd 2 – Scarlet Fever Erythema Infectiosum (5th disease) 3rd – Rubella Parvovirus B19, 4th – no longer recognised Droplet spread 5th – Erythema Infectiosum Mainly infectious during incubation (isolation has no effect) 6th – Roseola Infantatum 4-21d incubation NB: excludes some other classics à Erythematous maculopapuar rash starts on face = such as varicella “slapped cheek” à Trunk & limbs - lacy reticular rash to rest of body Lasts approx. 1 week, can be arthralgia of small joints If occurs during pregnancy can à severe anaemia, hydrops & death NB: not infectious once rash appears Complications include aplastic anaemia, haemolysis & arthralgia Infection of pregnant mother can à aplastic crisis in fetus Roseloa Infantatum (exanthema subitum /6th Disease) Due to HHV 6 & 7 Usually under 2 yrs. High fever but not very ill (can have febrile convulsions) Miserable child Mild pharyngitis & lymphadenopathy After 3-4 days temp drops & rash appears = small red/pink flat lesions on trunk, then limbs can persist for a few days Then rapid recovery Common cause of febrile convulsions Fever resolves before rash appears (therefore can be mistaken for antibiotic rash) Hand, Foot & Mouth Disease (Coxsackie / Entero virus) Common in young children, occurs in epidemics Vesicular regions on palms, soles & mouth (see right) Low grade fever Varicella Zoster (Chicken Pox) Common & highly infectious, mild in children Incubation 14-16 day à Low grade fever, rash (macule à papule à vesicle (spread centripetally) à crusts & scabs). Can also occur on mucous membranes à shallow ulcers à Should be no scarring as the scabs heal Maternal Zoster developing 7d before or 5d after birth = high risk of fatal neonatal zoster. Therefore give IVIg (ZIG) & observe closely. If vesicles develop à aciclovir Complications – uncommon in healthy children Encephalitis - with cerebellar ataxia 3-8 days after rash. 80% à complete recovery (CNS infection most commonly in cerebellum) Pneumonia - rare & dangerous, esp if haemorrhagic rash. More likely if immunosuppressed, or if adult (compared to child) Can get 2o staph skin infection Rx – acyclovir only if high risk Herpes Simplex DNA virus, enveloped Incubation 2-12 days HSV1 = spread by close personal contact – skin & mucous membranes above waist HSV2 = genital form, also found in neonates (maternal transfer). * Is some cross over between 2 Neonates – 3 methods of presentation (usually HSV2) 40% risk of transmission if maternal infection & NVD Neuro Sx = 1/3 with encephalopathic Sx, usually at 1014d Systemic Sx – present in first few days with shock, resp failure, severe hepatitis & coag disorders Cutaneous – inc rash & keratoconjunctivitis in 2nd week à rarely become seriously ill 70% mortality, high morbidity among survivors Rx - acyclovir Children < 10% become clinically unwell Acute Gingivomastitis – common in preschool, high fever, swelling, bleeding gums, ulceration, enlarged cervical glands, pain on eat/drink, lasts 10-14 days Keratoconjunctivitis – severe periorbital oedema, dendritic ulcers of cornea, scarring & loss on vision, Increased risk if eczema Rx: topical idoxyuridine Cold Sores – variable recurrence Meningoencephalitis – Can occur by reactivation (therefore no skin lesions). High mortality rate, frontal/temporal lobe involvement on EEG Rx: Acyclovir can ↓mental handicap Common cause of erythema multiforme (also cause by EBV, Mycoplasma, TB & Grp.A Strep + drug reactions) Eczema herpeticum Primary HSV infection – mild to severe forms Abrupt crops of vesicles appear over 7-9 days à coalesce High fever for 7 days Reactivation can occur Can à death due to fluid/electrolyte loss, dissemination to brain/organs or 2o bacterial sepsis Glandular Fever (infectious mononucleosis) Epstein Barr Virus Rare below 4yrs / over 40yrs Incubation 4-7 weeks, droplet spread (nasopharyneal secretions) Pathology Virus replicates in epithelial cells in pharynx à sore throat, then in B cells in epithelium. Infected B cells spread through reticular endothelial system (liver, spleen & LNs) à splenomegaly, hepatomegaly & lymphadenopathy. Cytokine release à fever. Immune reaction is for T cells to attack B cells à mononucleosis. Can cause autoimmune haemolytic anaemia due to cold agglutinins (resolves in 1-2 months) Symptoms - Most classical symptom triad is “fever, pharyngitis & lymphadenopathy”. • Tonsillitis with thick white exudate 90% - Can have added strep A pharyngitis • Generalised LN (90%) • Hepatomegally (10%) • Splenomegally (50%) • Jaundice occurs in up to 10% • Petchiae on palate (also with Grp A strep / lymphoma / leukaemia) • Transient upper eyelid oedema (Hoagland sign) • Maculopapular rash – 10-20% If given ampicillin often have Macular erythematous rash – DOESN’T MEAN ARE ALLERGIC. Complications – chronic fatigue, hepatitis, jaundice, anaemia, 0.1-0.5% splenic rupture, meningoencephalitis, Guillaine-Barre syndrome Ix - Blood Film (mononuclear cells), Early elevation in serum transaminases Monospot test (serology Ab based) = IgM means active infection (85% sensitive, 100% specific) False +ve due to toxoplasmosis, rubella, lymphoma, leukaemia Rx: self-limiting disease, will persist for weeks – months. Avoid contact sports for minimum of 3 weeks as risk of splenic rupture Assoc with – Burkitt’s lymphoma & nasopharyngeal carcinoma Poliomyelitis (Poliovirus) Now eradicated from developed world à Mild illness with fever, sore throat, headache & vomiting for up to 3 days à Then recovery for 1-7 days à Then pain & stiffness in neck, back & legs + Paralysis (due to anterior horn cell damage) (usually asymmetrical). If severe à bulbar paralysis & resp failure à Once fever subsides à weakness & paralysis start to improve (but can take up to 18 months – any residual after that is likely to be permanent) Vaccines Oral live polio = OPVSabin, Inactivated vaccine = IPVSalk Oral vaccine passes through bowel & is excreted à boosts immunity in family, but may cause mild episode in subject. NB: avoid oral vaccine in household contacts of immunosupressed RSV Most common cause of pneumonia in <1yrs Tachypnoea, Chest recession & hyperinflation + creps +/- wheeze NPA is 90% sensitive (immunofluorescence) Increased risk of recurrence wheeze Moluscum contagiosum DNA pox virus Usually max 5-20 lesions. Can be widespread if immunocompromised. Skin colours small papules with central umbilication Minimal surrounding erythema Can become secondarily infected (esp if trauma / stratched etc) Can also have eczema type rash with it Can persist for up to 1 year Viral warts (human papilloma virus) Common Spread by scratching / skin breaks If immunocompromised then difficult to eradicate Plantar Warts (HPV) Related to hand warts Pressure modifies growth and appearance Most regress spontaneously Hepatitis A Enterovirus faeco-oral spread (rapid in nursery) Mild in children, malaise, headache, nausea, vomiting, abdo pain Usually starting to improve when become jaundice & dark urine – may last 2 weeks Fulminant hepatitis is rare Hepatitis B Sexual contact / IVDU / Vertical transmission, 50-160 days incubation, 10% à carrier Mothers… Who develop acute Hep B in 3rd trimester have 70% risk of infant developing disease HBsAg = present for several weeks post infection Persistence = chronic infection = carriage Carriage can be proved by : • HBsAg x2 at 3months apart • OR by HBsAg AND anti-HBc (IgG antibody to core antigen) at the same time If carrier then = risk of transmission to baby therefore need vaccination HBeAg = high viral replication (90% risk of vertical transmission) Therefore if present give HBIG ** If giving HBIG and Vaccine then should be given in separate limbs (otherwise will inactivate each other!) Are all screened for surface antigen at booking. Who are chronically surface antigen +ve pass infection via placenta 40% of children with persistent Hep B will die in adult life of Hepatocelluar Ca / Chronic liver disease NO RISK of breast feeding Infants of +ve mothers Low risk à vaccinate after birth (with 24 hrs) High risk à Immunoglobulins & Hep B vaccine (within 24 hrs) Follow up vaccines at 1, 2 and 12 months of age Incubation – 50-160 days Acute Hep B is often asymptomatic (LFTs would be abnormal if done) Can be lethargy, anorexia, arthralgia, rash, papular acrodermatitis (gianotti- Crosti – see right), polyarthritis, glomerulonephritis or aplastic anaemia 25% will have jaundice Complications: Acute fulminant hepatitis, chronic hepatitis, membranous glomerulonephritis Hep E antigen = highly infective Chronic hepatitis à pruritus Hepatitis C Perinatal transmission of Hep C occurs if anti-HCV +ve If RNS +ve = 6-8% risk of transmission NO evidence that breast feeding à increased risk Adenovirus GI/resp disease based on serotype Fever, purulent conjunctivitis, erythematous rash, resp Sx Can cause bronchiolitis obliterans Herpangina Coxsackie / enterovirus Fevers, blisters to mouth, tongue, hands & feet. Resolves spontaneously Rarely severe Rabies Acute progressive encephalitis caused by RPN viruses Incubation 20-60 days post bite Once Sx begin then treatment is futile - Die within days to weeks If low risk area = Observe animal for 10 days. If animal shows signs then kill it & biopsy brain + start treatment If high risk area then treat immediately Rx: give rabies Ig as close to wound as possible then 4/52 of weekly IM gluteal BACTERIAL INFECTIONS Pertussis (bordetella) Gram –ve pleomorphic bacillus Incubation 7 day, droplet spread Toxin destroys cilia à accumulation of mucus & predisposes to secondary infection è 1-2 week coryza, URTI & unwell à cough à increasingly paroxysmal (100% of cases) è 100 day “whooping” cough – spasms followed by inspiratory whoop (60%) è Can vomit / become apnoeic / cyanosed Ix: early nasopharyngeal swab but difficult to grow – needs bordet-gengou medium, marked lymphocytosis Complications: Bronchopneumonia & bronchiectasis = responsible for most of the deaths Convulsions – due to hypoxia due to severe spasms, or due to bleed / encephalopathy (neuro complications are less than 1:150,000) Subconjuctival haemorrhages & petechiae from ↑venous pressure Otitis media, hernia, diaphragmatic rupture Rx: symptomatic, O2, suction, NG feed as req, erythromycin in catarrhal phase / for contacts Prevention: Vaccine @ 2,3,and 4 months. DTP (P = most common to react to à local reaction + febrile). Vaccine à <90% protection Minimal Ig crosses placental therefore relies on sibling immunity (no maternal cover) Scarlet Fever (group A haemolytic strep) Gram +ve cocci in chains Grp A strep causes a range of conditions - Tonsillitis, rheumatic fever, acute glomerulonephritis Scarlet fever effects due to erythrogenic toxin Incubation 2-4 days è Pharyngitis, fever, headache, malaise, thick white coating on tongue with inflamed papillae (white strawberry) è circumoral pallor (rash spares skin around mouth è fine “punctate” erythematous blanching rash (sandpaper texture) within 12 hrs è Desquamation of tongue & skin on resolution Erythema marginatum rash (pink lesions with serpigenous borders and central clearing) Complications Toxic shock syn Otitis media, pneumonia Fasciitis, myositis, osteomyelitis, Rarely - rheumatic fever, acute nephritis Rx: penicillin (or clindamycin) for 10/7 à faster recovery. Impetigo (Staph Aureus) Most common in young children (often on mouth, nose, lips) Superficial contagious pyogenic infection Signs – isolated lesions with yellow crusts, can be regional lymphadenopathy & bullae (if epidermolytic toxin). Often spread to new sites by scratching Rx – topical mupirocin (some effect), oral fluclox (7-10 days) Course – rapid resolution within few days of Abx (3-6 weeks without) Complications – only if streptococcal (scarlet fever, urticaria, erythema multiforme, post-strep glomerulonephritis Staph Scalded Skin Syndrome Exotoxins in young / immunocompromised Fever, irritable, widespread red skin à blisters within 24-48 hours Rash all over body with top layer of skin peeling à moist tender sites = Nikolsky’s sign Rx – Abx & fluid with analgesia Haemophilus Influenza B (HiB) Gram –ve Rods Peak mortality < 1yr Most commonly causes epiglottitis (Non typable HI can cause otitis media & sinusitis) Rarely can cause meningitis in children (although meningococcus & GBS more common causes) RESISTANT to penicillin SENSITIVE to ceftriaxone or cefotaxime Vaccine is bacterial capsule antigen conjugated to protein. Given at 2, 3 & 4 months + booster between 1&2 years à 95% effective Tuberculosis (mycobacterium tuberculosis / bovis) Non motile, non-spore forming Weakly +ve gram stain, Acid fast bacillus Exposure à 70-90% non-infection à 10-30% infection à 90% dormant TB = never Sx, not infectious à 10% active infection (5% within 2 yrs, 5% many years later) à Untreated 50% die within 2 years à Treated à Cure Pathophysiology Usually inhaled à lungs à 1o (Ghon) focus à regional LN where non-specific immunity controls infection & prevents dissemination (Lung + LN = 1o complex) After 4/52 either… Infection eradicated OR wall off into asymptomatic focus (latent TB = non-infectious) OR Myobacteria multiply à TB disease Spread to 2o complex or disseminated disease Transmission = airborne Increased if laryngeal TB / frequent cough or cavitating disease Children usually have poor cough and rarely cavitate = usually non infective Prognosis 1o infection at < 2yrs à serious disease within 12m with short symptomatic period 1o infection 2-10yrs à significant Sx but rarely serious disease 1o infection >10yrsà adult type disease Can à peritonitis, meningitis, pneumonia, renal, bone & joint Can spread by blood stream – splenomegaly = military TB appearance Healing of lesions takes 12-18 months à calcification Features Fever, wt loss, lethargy, poor feeding, cough, night sweats, LN, pleural effusion, enlarged liver & spleen, headaches, drowsy, vomits, erythema nodosum, conjunctivitis Suspect TB if 2 of: (likely if 3+) +ve matoux, clinical findings, contact, suggestive CXR, +ve histology on biopsy OR +ve culture alone TB Meningitis – 2/52 of progressive lethargy, anorexia, apathy, personality change, Sx of raised ICP, CN palsy and seizures. CSF is opalescent, raised Lymphocytes & protein, Low sugar Investigations Mantoux – skin test for tuberculin sensitivity. +ve reading = 6mm (if not immunised) or >15mm if is immunised FALSE Negatives – subcut injection, immunosuppression (drug induced or due to conditions inc HIV), recent bact / viral infection (inc whooping cough), recent vaccination, malnutrition, milliary TB, overwhelming TB meningitis, INF gamma stimulation (Quantiferon, TSPOT) = response to TB, independent of BCG vaccine. DOESN’T distinguish latent from active infection CXR – focal lesions / mediastinal LN Sputum (or BAL) for culture Gastric aspirate for acid fast bacilli TB Smear – replacing ZN stain TB culture – takes 2-3/12 PCR – for CSF (33-93% sensitive) Management Rifampicin, Isoniazid, Ethambutol (can cause visual problems), Pyrazinamide If Caucasian / no travel history/contacts then exclude ethambutol) For 2/12 then just isoniazid for 4/12 If TB meningitis = 12/12 of treatment Prevention – BCG recommended if: Family Hx TB Likely to travel to high risk area From immigrant country with high risk Parents request it NB: High Risk = Incidence = > 40 / 100,000 Mantoux Test (Tuberculin skin test) Cell mediated hypersensitivity reaction to tuberculoprotein Strong +ve = > 15mm Negative = never exposed to TB or false negatives if immune-deficient Will become +ve 3-5/52 post infection Tetanus (Clostridium Tetani) Gram +ve obligate anaerobe In infant usually general Sx at 0-3d Poor feeding, hunger, crying, paralysis & decreased movement Progresses to muscular spasms, opistotonus, rigid abdomen & jaw, hyperpyrexia & dysphagia Infection DOESN’T à immunity Toxin DOESN’T cross BBB, it diffuses to presynaptic nerve terminals in muscles then reaches brain by axonal transport IVIg is ineffective once toxin is attached to nerves Cepahlic tetanus can à severe dysphagia Diphtheria (Corynebacterium Diptheriae) Gram +ve pleomorphic bacteria, facultative anaerobe 3 different strains that can all cause diphtheria Infection usually in the throat Droplet spread (also soiled articles and skin) Incubation 2-5 days è Sore throat & inflamed tonsils è Grey Exudate membrane on tonsils can spread with epithelial destruction & membrane formation è Upper airway obstruction (by membranes) è Endotoxin also à myocarditis (in the 2nd week) & neuritis with paralysis (3rd to 7th week) Infectious – for up to 4 weeks Vaccine is modified exotoxin – 3 doses of vaccine à 75% protection Treatment of disease needs antitoxin & erythromycin Typhoid Samolella typhi Incubation 10-14 days Vague muscle pain, headache, fever Then after about 1/52 then D&V + cough & severe headache Rose spots may be seen Physical signs resolve in 2-4 weeks Complications inc perforation, myocarditis, hepatitis & nephritis Mycoplasma No cell wall therefore no reaction to gram stain è Therefore penicillins won’t work! è Uses macrolides / tetracycline Coryza à slow onset pneumonia with systemic upset Can precipitate asthma Can cause: Erythema multiforme Erythema nodosum Myocarditis Peripheral neuropathy Severe prolonged headache MRSA Cause of nosocomial pneumonia & toxic shock syndrome Responds to vancomycin Resistance to methicillin is due to a plasmid Quinupristin + Dalforpristin = synergistic effects – can only be given by central line Vancomycin Resistant Enterococcus Tend not to cause D&V Causes UTI / bacteraemia / wound infections / neonates / endocarditis Work by altering cell wall structure so Vanc cant work Can be found in normal ppn Rx – high dose ampicillin (a few strains are vanc dependent) Cat Scratch Disease Bartonella Henselae 3-10 days post scratch à rash à lymphadenitis Can à myelitis / encephalopathy Usually self limiting Opthalmia Neonatorum Most commonly due to Chlamydia (via genital tract) Incubation 5-14 days Can be mild discharge to copious purulent discharge + erythema + swelling Infection due to chalmydia trachomatis (serotypes D-K) Treat with 14d oral erythromycin Most important differential is gonococcal infection Can cross cornea and threaten vision. Presents in 1st week (4-7d) Orbital swelling, tension, profuse, purulent (sometimes bloody) discharge Treatment is tetracycline / erythromycin FUNGI & PARACITES Candida (aka monila) Flexure sparing Satellite regions Peeling edge Malaria Malaria = red cells invaded by plasmodium from female anopheles mosquitos Incubation is around 2/52 4 species Falciparum (Africa) – malignant tertian fever (48hrly), also causes low BMs in infants Ovale (S.Asia) ] – benign tertian fevers (48hrly) Vivax (S.Asia) ] – can recur if treatment is inadequate Malariae – quartan fever (72hrly) Congenital malaria is rare due to the placental protection (can resemble sepsis) Generic Symptoms 1st Sx usually 10d-4w post infection Intermittent high fever, splenomegaly, vomiting, rigors, flu, headache, myalgia, cough, increased Liver & spleen, low Plts, low Hb, jaundice, decreased LOC, seizures, shock + History of return from endemic area Blackwater fever Falciparum à severe haemolysis in a non-immune (usually Caucasian) patient “Immune” individuals (black Africans / Indians) have an element of tolerance Dx – Single blood film is not 100% diagnostic 3x thick & thin films, 12 hours apart Thick film first – if no paracites seen then NEGATIVE If paracites seen then à Thin film for more specific views to identfity species Can get dipsticks for malaria antigen. Also FBC, UE, LFT & glucose CHECK G6PD status – as affects treatments Rx: Prophylaxis – proguanil / Pyrimethamine (Fansidar) / choloroquine Treatment – quinine / cholorquinine Primaquinine needed for vivax / ovale to prevent relapse (NB; contraindicated in G6PD) Primaquinine also used to kill gametes in falciparum Resistance: of Falciparum is a problem in Sub-Saharan Africa Lymes disease Spirochaete (Borrelia burgdorferi) = Ixodes tick vector Incubation 3-32 days Early Sx Local – annular rash (erythema chronic migrans), fever, malaise, headache Disseminated – multiple skin lesions, haematogenous spread, LN, aseptic meningitis, CV VII palsy Late Sx – arthritis (waxes & wanes – 90% in knees) Complications – aseptic meningitis, dehydration, polyneuritis, memory impairment Ix - CSF shows increased L & N Treatment = 3rd generation cephalosporins Tinea Capitis Fungal infection of the scalp / hair shafts by Trichophyton / Microsporum Multiple coin lesions on scalp à hair loss, itching & scaling More common in boys Griseofulvin Active against dermatophytes & tinea Metabolised by liver Assoc with Steven’s Johnson Syn Rx may be required for up to 1 yr. Visceral leishmaniasis Aka Kala-azar Endemic to India & sub-Saharan Africa Spread by sand flies Common if immune suppression (especially HIV) Fever & hepatomegaly Schistosomiasis Transmitted by direct penetration of intact skin by cercariae (small snails). Itchy for 2-3 days. à tired, pyrexia & liver tenderness. Causes eosinophilia. Diagnosis by eggs in urine /stool or by serology. Treatment with praziquantel Yersinia enterocolitica Can cause asymmetrical polyarthritis, enteritis, uveitis, appendicitis, mesenteric adenitis, glomerulonephritis and septicaemia. Also mouth ulcers. Assoc with erythema nodosum. Diagnosis by serology GASTROINTESTINAL INFECTIONS Investigations C.Diff = stool toxin Viruses = electron microscopy Giardia lamblia = watery diarrhoea with NO blood, Faeco-oral spread, demonstrate by paracites or ova on stool microscopy Rotavirus Most common cause of gastroenteritis 3-15m Test by ELISA Watery diarrhoea, blood & mucus are rare Winter epidemics Breast feeding is protective Cryptosporidium Most common cause of diarrhoea from foreign holidays From swimming pool reservoir If NO history of swimming pools then consider HIV infection Dysentery Fever, loose stools with blood & mucus Commonly due to salmonella, E.coli 0157, campylobacter, shigella or entamoeba histolytica Pus cells & red cells in stool = blood + slime Campylobacter Gram –ve rods Incubation 1-5 days Undercooked poultry & non pasturised milk Diarrhoea lasts 5-7 days + abdo pain Can have vomiting C-diff Typically after course of clindamycin Treat with oral vanc or oral metronidazole Intestinal parasites Giardia Flagellate protozoa (paracite) Due to ingestion of cysts from food / water (faeco-oral infection route) Found in non chlorinated water – e.g. lakes / rivers Causes travellers’ diarrhoea Increased risk if young / malnourished Can be asymptomatic carrier or severe diarrhoea (including chronic diarrhoea – NOT bloody) Causes partial villous atrophy of small intestine à steatorrhoea Malabsorption à abdominal discomfort, flatulence etc. Important DD in toddlers diarrhoea Ix: cysts in stool 1 stool sample will find 50%, 3 will find 90% Best test is surface antigens by ELISA Rx: metronidazole Enterobius (threadworm) Mobile thread like worms, easily seen on separating buttocks Perianal and vulval pruritus – worst at night Ix – sticky-tape to lab for microscopy Difficult to eradicate, only Rx if symptomatic (mebendazole / piperazine) – need to treat entire family Ascaris Lumbricoides (roundworm) Ingest eggs à portal circulation to lungs à hatch à up bronchi à gut. Can cause pneumonitis & eosinophilia when in lungs Gut Sx are rare – pain, obstruction, appendicitis, malabsorption Rx: piperazine (treats adult phase) / Mebendazole Ankylostoma (hookworm) Major cause of iron deficiency in hot, humid climate. Rx with bephenium hydroxynaphoate Toxocaran canis/catis Can have migratory larvae phase in children in close contact with animal excrement à Eosinophilia, hepatomegaly & bronchospasm. Can à retinal granulomata or epilepsy Taenia (tapeworm) Inhabit intestines From poorly cooked pork & beef Can à calcification in tissues Rx niclosamide Trichiniasis (roundworm) From undercooked pork / game Periorbital oedema, prodromal D&V, myalgia, fever, eosinophilia, myocarditis, pneumonitis, elephantiasis NON PROVEN INFECTIONS Kawasaki (aka Mucocutaneous Lymph Node Syndrome) 2/100,000, 2/3 of cases are < 5yrs More common in Far East / Japanese Acute, self-limiting autoimmune necrotising vasculitis affecting medium & small vessels Features Fever (100%) – often > 40 degrees and no response to Abx but will respond to antipyretics Misery (100%) – likely due to aseptic meningitis Oral (90%) – strawberry tongue, fissured lips, erythema of oropharynx Conjunctivitis (85%) – bilateral, non-purulent Rash (80%) – polymorphous over hands, trunk & perineum Lymphadenopathy (70%) – with nodes > 1.5cm Extremities (70%) – oedema à desquamation Cardiac – myositis à arrhythmia & CCF, pericarditis & coronary artery aneurysms after 2-3 weeks (Echo at 6/62) à can cause sudden death Ix – WCC > 15 Normocytic, normochromic anaemia High plts (> 500, peaks in 3rd week) Raised ESR/CRP Low albumin, low Na, low plasma lipids Sterile pyuria & raised WCC in CSF Diagnosis Fever for > 5 days AND 4 of the 5 following criteria • Bilateral non-suppurative conjunctivitis • Mucous membranes - 1 or more of: pharyngeal injection, dry fissured lips, injected lips, and "strawberry" tongue • Extremities (1 or more) peripheral erythema, peripheral oedema, periungual desquamation, and generalized desquamation • Polymorphous rash, primarily truncal • Cervical lymphadenopathy >1.5 cm in diameter Prognosis worse in younger children (esp. with cardiac manifestations) Mx – IVIg 2g/kg x 1 dose Aspirin 80-100mg/kg/day (4 divided doses) (reduces risk from 20% to <5%). After fever settled for 48 hrs then aspirin 3-5mg/kg/day & continue until echo at 4-6 weeks (long term reduces risk of thrombosis) HIV (type 1/2) Single stranded enveloped RNA virus à reverse transcription à ds DNA à integrates to host cells HIV 1 is more prevalent Particularly targets CD4 lymphocytes & glial cells in CNS Ways to acquire: Women acquire by 33% heterosexual sex, 25% needle sharing, 36% no known risk factors Most children acquired HIV by vertical transmission. 30% risk of transmission if untreated, then further 15% risk if breast fed (high maternal viral load, low maternal CD4, vaginal delivery and prolonged rupture of membranes) 1-2% risk if fully treated Presentation General symptoms / presentations when “well” FTT Generalised LN HS megaly Parotid gland enlargement Persistent oral / nappy candidiasis Recurrent OM Chronic dermatitis Chronic diarrhoea Steadily decreasing CD4 count (assoc with…) Disseminated CMV / Mycobacterial infections CMV retinitis Persistent HSV ulceration Multidermatomal zoster Cryptococcal meningitis Chronic cryptosporidiosis Pneumocystis pneumonia HIV encephalopathy, neoplasms, FTT, lymphocytic interstitial pneumonitis Aids defining illnesses - recurrent invasive bacterial infections, pneumocystis / CMV / candida oesophagitis, encephalopathy, malignancy, wasting syndrome Diagnosis < 18months – require proof of virus as will have persisting maternal antibodies. HIV Ab (IgG) crosses placenta, therefore need to demonstrate proviral DNA HIV unlikely if 2x –ve PCR (at 0 & 3/12) Or 2x –ve Ab test < 12/12 old Or 1x –ve Ab test after 18/12 > 18months antibodies are diagnostic Pneumocystis Jivoveci (carinii) Pneumonia Obligate extracellular parasite with attributes of fungi & protozoa Most humans are sero +ve by 4yrs old 40% of HIV & 10% of ALL will get PCP without prophylaxis Present as respiratory distress with O2 requirement (Difficulty with oxygenation not ventilation) and interstitial pneumonitis on CXR Infection almost always affects the lungs à CXR shows alveolitis (looks like CLD) Diagnose by Broncho-alveolar lavage or Brushings Rx with Septrin & Steroids CMV Can cause pneumonitis in immunocompromised individuals but also CMV retinitis à visual loss Molluscum Usually self-limiting in normal individuals, but can be florid if immunocompromised Prognosis – If untreated then 20% will à rapid severe infection & death 40-50% of those infected at birth will survive to 10yrs AIDS (acquired immunodeficiency syndrome) = low CD4 count Prevention ARVs in from 28/40 to reduce viral load to undetectable Deliver by C-section unless viral load undetectable Wash baby prior to IM Vit. K AZT (zidovudine) NO breast feeding Thymidine analogue DONT GIVE BCG VACCINE Inhibits reverse transcriptase Start baby on Neutropenia is a relative contraindication Term baby, low risk à oral zidovudine SE include low Plts, low N & nausea (AZT) 4mg/kg b.d. Rapid resistance develops therefore no use High risk à Triple therapy, commence for long term therapy cotrimoxazole after 4 weeks Good for preventing vertical transmission TTOs: 4/52 AZT from hospital pharmacy HIV-PCR on day 1 (NOT cord blood as may be contaminated) = EDTA bottle looking for proviral DNA. (Infants of +ve mothers will have passively acquired IgG to HIV therefore test for proviral DNA NOT Ig) Need blood from mum for same (to ensure proviral DNA is detectable by PCR) and viral load NB: all infants will have maternal antibodies to HIV at birth therefore no use looking. Will clear by 18 months Follow up OPA at 6/52 6/52 proviral DNA & serology 3/12 ---------ll------------ (if –ve then 98-99% chance not infected) 18/12 serology (by when maternal Ab will be completely gone & therefore test is fully accurate negative) High Risk if... Mum <4/52 antiretroviral prior to delivery Viral load persistently >400 copies/ml despite rx Triple ART only if... Mother found to be infected post-delivery but before 72hrs old HIV +ve having refused ART HIV +ve & <4/52 ART Poorly controlled (viral load >400) Regime is: Zidovudine 4mg/kg bd Lamivudine 2ng/kg bd Nevirapine 2mg/kg od for 1/52 then 4mg/kg of for further 1/52 then stop (can start at 4mg/kg if mother already on it) If prem: only safe drug is AZT (can be used IV if NBM) Pneumocystis prophylaxis - not necessary if mother fully treated If risk then start cotrimoxazole after ARVs stop, 3x weekly (MWF) until HIV confirmed negative Vaccines - all can be given EXCEPT BCG. BCG can be given once 3x -ve PCR (ie usually 3/12) REPORTABLE DISEASES All food poisoning – e.g. campylobacter, E.coli 0157 All meningitis & encephalitis Malaria Dysentery TB Anthrax Diphtheria Pertussis Tetanus Scarlet Fever Measles Mumps Rubella IMMUNOLOGY IgM = recent infection IgG = immunity At birth children are protected by maternal IgG which has crossed placenta Levels naturally fall Lowest = 6 months before own immune system becomes fully functional ALL children below the age of 3 ½ have an element of immune deficiency Suspect in all cases of: FTT 2+ deep seated infections FH of primary immunodeficiency SPUR Serious – an infection you don’t expect to be serious e.g. NOT meningococcus Persistent Unusual – e.g. cepacia, aspergillus Recurrent If 2 episodes of meningitis à ? complement deficiency If repeated opportunistic infections e.g. PCP à ? T cell deficiency If liver abscess à ? neutrophil defect / iatrogenic e.g. line in situ If staphylococcus abscess = likely normal child with PVL staph If < 6m If 6m-5y If 5y+ = likely T-cell immune deficiency = likely Ab / phagocytic disorder = likely Ab / compliment disorder Immune Deficiency Immunology Tests Immunoglobulin levels If suspect B cell defect from history then check levels, FB vaccine Ab levels Total Ig level should be >100mg/dl Antibodies to polysaccharide vaccines Useful to quantitatively assess B cell function ( & Ig levels) In children OVER 2yrs Polysaccharide vaccines (pneumococcal vaccine) has low immunogenicity so normal titles = working B cells If low give booster & reassess in few weeks for response Antibodies to protein vaccines (diphtheria / tetanus) = useful under 2 years old If low give booster & reassess in few weeks for response PHA (phytohaemagglutin) Stimulus to T-cell proliferation = assesses T cell function Useful AFTER immunophenotyping has been performed Compares patient T-cell response to control sample Immunophenotyping (subsets) Allows estimation of T cell numbers using MABs to look for different surface antigens (the counted by fluorescent scanner) PNP enzyme activity Used in SCID children if concerns about other underlying syndromes or genetic mutations (for future pregnancy advice). SCID + Neuro abnormalities / dev delay = suggests PNP (Purine Nucleoside Phosphorylase) deficient = AR defect For patients on replacement IG therapy ½ life = 3-4 weeks – therefore check trough levels at 3-4 weeks & re-dose as required IV admin = 3-4 weekly SC = more concentrated infusion given weekly = less volume = more constant IG levels Check LFTs & Hep C status checked regularly (risk from Ig) Leucocyte adhesion deficiency LAD-1 or LAD-2 Both rare AR LAD-1 = 1 in 10 million = presents in infancy Recurrent bacterial / fungal infections (esp skin) with necrotic ulcers Increased WCC with infections – If neutrophilia then poor pus formation Commonly history of delayed cord separation f.b. stump infection Common organisms = Staph Aureus & E.coli. Diagnosis by flow cytometry showing absence of CD18 Diagnosis of type1 = flow cytometry of surface CD11b in stimulated & unstimulated Neuts Diagnosis of type 2 = lack of sialyl-Lewis X on neutrophils Rx = antibiotics and antifungals + BMT = cure Low total Ig + recurrent bacterial infections • X-linked agammaglobulinaemia (XLA) o Manifests at 6-9 months (after maternal IgGs clear) o Absent tonsillar tissue & LN o Neutropenia • Common variable immune deficiency (CVID) o AR o Manifests later than XLA • X-linked Hyper IgM syndrome o Boys o Presents with infections in 1st/2nd year of life o Absent tonsillar tissue & LN o Neutropenia Chediak-Higashi syndrome AR Increased suceptibilty to infection due to defective degranulation of neuts Mild bleeding diathesis – prolonged bleeding time + normal platelet counts. Impaired aggregation Partial occulocutaneous albinism (patches of silvery / hypopigmented skin / hair) Progressive peripheral neuropathy Tendancy to develop a life threatening lymphoma-like syndrome Gr +ve and Gr-ve and fungal infections “Accelerated phase” = life threatening = pancytopenia, high fever, lymphohistiocytic infiltration of Liver, Spleen & LNs. Diagnosis = large inclusions in nucleated red cells (seen on “Wright stained” blood & accentuated on peroxidase stain Rx: high dose ascorbic acid / BMT (only cure for accelerated phase). Panhypogammaglobulinaemia Recurrent sino-pulmonary infections, otitis media, bronchiectasis or giardiasis ALL Ig levels less than 2s.d. below the mean Includes SCID/Bruntons etc If < 2 yrs = early onset = usually X linked If later onset = more variable presentation & inheritance pattern is less certain Can be complicated by FTT, gastro disorders & autoimmune disorders Rx: gamma globulin replacement T Cell defects HIV SCID (Severe Combined ImmunoDeficiency) AR or X linked inheritance <6m old Multiple / Severe infections Rash FTT + chronic diarrhoea– usually from 1st year of life +ve FH Severe thrush – bleeds if scraped Lymphocytes < 2.8 x 109/l, y-Chain SCID XL 50% of all SCID y-chain of IL-2 receptors Low % of T & NK cells, high B cells Other mechanisms for SCID – signal transduction defects (JAK-3), reticular dysgenesis or leucocyte metabolism defects (Adenoside deaminase (ADA) deficiency) Investigations: Lymphocyte subsets to assess type of SCID (T-, B-, NK+), PHA stimulation (will be reduced) and IG levels Rx: Isolate children + bacterial & fungal prophylaxis + replacement Ig Find and aggressively treat any infection IVIg during episodes of sepsis Blood products must be irradiated (reduce GvHD) Optimise nutrition Marrow transplant = curative HyperIgM (CD40 ligand deficiency) X linked - Boys present in 1st / 2nd year of life with recurrent infections Abnormal CD40 ligand expression à impaired antibody formation B cells produce IgM but unable to make IgG / IgA & à neutropenia IgA & IgG levels low IgM = normal / high but to polyclonal IgM Assoc with neutropenia Can have tonsillar hypertrophy Di-George syndrome AD, high spontaneous mutation rate CATCH 22 Cardiac Abnormality (especially tetralogy of Fallot) Abnormal facies - hypertelorism, micrognathia, short philtrum with fish-mouth appearance, antimongoloid slant, and telecanthus with short palpebral fissures Thymic aplasia à low T cells à multiple infections Cleft palate Hypocalcemia – 2o to raised PTH 22 – 22q11.2 deletion à AD inheritance, 90% spontaneous mutation CXR - Double line sign in midline CXR = meeting of pleura where thymus should be THEREFORE ALL need immune evaluation Wiskott Aldrich Syndrome X linked Recessive Boys present with triad of • Thrombocytopenia with small plt volumes (petechiae, bleeding) • Severe atopic eczema • And Recurrent infections (Impaired cell mediated immunity + impaired antibody production) T cell defects àrecurrent viral and bacterial infections (otitis media, pneumonia, herpes etc esp to capsulated organisms) combined immunodeficiency Can have bloody diarrhoea in infancy Increased risk of autoimmune conditions & malignancy Death secondary to bleeds / infections / malignancy Ix: • Raised IgA & IgE, low IgM, normal IgG • Small platelets • WASP expression (Wiskott-Aldrich syndrome protein) Rx – bone marrow transplant / IVIg + Splenectomy + Abx If not BMT then death before 3 yrs Ataxia Telangectasia ATM gene - AR 11q - usually sporadic Abnormal DNA repair mechanism à hypersensitive to radiation Higher incidence of malignancy (esp lymphoma + adenocarcinoma) IgA deficiency (70%) and T cell abnormalities (60%) Reduced T-cell numbers & function + impaired antibody production Chronic sinopulmonary infections Ataxia ONCE walking Progressive ataxia – wheelchair in 2nd decade Occulomotor apraxia Developmental delay Occulocutaneous telangectasia by age 3 Muscle weakness with drooling Ix: Raised AFP & CEA Reduced IgA Low levels of IgE, IgG2 & IgG4 Lymphocyte subsets are useful to quantify T-cell numbers, which may be low. Common Variable Immune Deficiency AR/AD/XL. *** can affect girls Combined T&B cell deficiency with low IgG, A & possibly low IgM. Recurrent pyogenic infection esp URTI / LRTI, persistent diarrhoea (giardia). Increased autoimmune disorders & high malignancy risk. Hyper IgE Syndrome (Job syndrome) AD, partial penetrance Eczematoid dermatitis Recurrent staph infections – skin, lungs, joints Recurrent pneumonia à Pneumatoceles à further infection & pneumothorax risk High IgE & IgD, Normal IgA, G & M Poor functional antibody responses Eosinophilia Pruritic dermatitis from early infancy with poor response to steroids B-cell defects Selective IgA deficiency Most common immune deficiency Mostly sporadic (can be AR/AD/Multifactorial) IgA is normally produced by plasma cells near mucosa Present in sweat, tears, urine, gut, lung NOT cross placenta (only IgG does) 2 subtypes (1 & 2) Selective deficiency of IgA (normal others) è Recurrent LRTI & URTI + GI tract infections & Low serum IgA Also assoc with allergy / GI / neuro disease / auto immune conditions and increased malignancy risk X linked agammaglobulinaemia (aka Bruntons disease) FH of affected boys New mutations are common B cells fail to develop from precursors à no Ig made Very low / absent IgG/M/A & E Present at 6/12 when maternal antibody levels decrease Recurrent OM / Pneumonia, sinusitis at <1yr old with encapsulated organisms. Recent diarrhoea (giardia / campylobacter), chronic pulmonary disease & paucity of LN Rx – Ig infusions & avoid live vaccines Neutrophil defects Severe congenital neutropenia (inc Kostmann syndrome). ? AD. Recurrent mouth ulcers & pyogenic infections (sinopulmonary + abscesses) Chronic granulomatous disease 1 in 1 million m:f = 4:1 80% XLR, rest AR Can be maternal Sx of SLE Failure of superoxide production means neutrophils & monocytes can phagocytose catalase +ve orgs (s.aureus, Aspergillus) BUT NOT kill them. Variable course Recurrent deep seated infections (lymphadenitis / abscesses / osteomyelitis) AND non infective granulomas affecting Gut / GU tract (can cause obstruction (pyloric stenosis) or urinary retention Also get fungal infections Large Liver & Spleen Present as unusual infections by 2yrs old FTT, IBD, GI/urine obstruction 2o to granulomas Abscesses, bacterial & fungal infections Clinical features of CF but normal sweat test Diagnosis • on NBT test • or flow cytrometry for neurtrophil respiratory burst activity • or biopsy of granulomas Prenatal diagnosis available for siblings Mx – aggressive antibiotics + prophylactic septrin / itraconazole Steroids can help with granulomas Marrow transplant for cure Shwachman-Diamond syndrome AR Neutropenia, pancreatic insufficiency, anaemia, recurrent bacterial infections Sx of malabsorption & short stature Cyclical Neutropenia Falling Neuts in 3-4 weekly cycles Gingivomastitis at regular intervals is common (with fall in neuts) Diagnosis = twice weekly neuts for 8 weeks Treatment if indicated is GCSF Immune reactions Type 1 – IgE mediated à immediate response e.g. hay fever / anaphylaxis Type 2 – antibody mediated destruction of cells / tissues e.g. autoimmune haemolysis, Rh disease, serum sickness, Type 3 – circulating immune complexes deposit around blood vessel e.g. glomerulonephritis, vasculitis, arthus reaction Type 4 – sensitized T cells à delayed hypersensitivity e.g. contact dermatitis, graft V host disease Allergy Atopy = hereditary predisposition to produce IgE against common environmental allergens in type 1 hypersentivity reaction. Mast cells in epithelial tissue of resp & GI tract & skin Store histamine, tryptase, heparin, chymase & cytokines Which when released à Sm muscle contraction, vasodilatation, increased vascular permeability & mucus hypersecretion Eosinophils Contain granules with damage epithelial cells, aid mast cell degeneration, increase airway responsiveness and block muscarinic receptors à raised Ach à airway hypersecretion Capillary leak à urticaria, angioaedema & low BP Mucosal oedema à asthma, rhinitis & laryngeal oedema Sm muscle contraction à asthma & abdo pain Late phase response occurs 6-9 hrs later Testing options: Challenge (& observe response) is the best test Skin Prick – need available reagents, not 100% sensitive or specific Specific IgE is cheap but doesn’t indicate severity of reaction AND takes 3/52 after 1st exposure to become +ve IgE response = reacts within minutes (maximum 1 hour) Consistent response to exposure Exposure occurs on contact areas e.g. mouth, hands, etc Avoidance reduces symptoms Total high IgE doesn’r = allergy as can make IgE without allergen e.g. in eczema No specific evidence for cut off levels in IgE tests Specific IgE if high indicates risk of allergy but doesn’t suggest likely severity -ve IgE to a substance usually excludes allergy The only “just in case” testing of IgE which is suggested is siblings of severe nut allergies Each food substance contains a number of proteins to which people can react. Specific IgE to peanut measures a combination of those protein responses Some allergic phenotypes exist which help predict patterns e.g. cross reactions Allergy is usually dose dependent, but can be modified by certain drugs such as aspirin (reduces threshold), stress, exercise etc Allergic Rhinitis Sneeze, running, itching, cough etc. Precipitated by pollen, dust, fur etc. à large pale turbinates with nasal polyps & raised eosinophils, raised IgE & +ve allergen tests Rx – avoid triggers, oral & nasal antihistamine & steroids Urticaria Cutaneous vascular reaction Sudden, transient, itchy, erythematous wheals Usually last 20mins to 3 hrs (can be upto 48 hours) Due to extravasation of plasma into dermis (angioedema = subcut à deep swelling) Usually IgE mediated (drugs, food, insects) but can be non IgE (infection / physical) Types Foods Infectious – strep, EBV, Hep ABC, enterovirus, adenovirus Stings / bites Drugs / foods Physical – cold, heat, pressure, sunlight, vibration Papular – fleas, mites, usually toddlers. Resolves in 6-12 months 2o to underlying disease e.g. connective tissue disorders, autoimmune, thyroid, celiac Idiopathic Milk – 90% outgrow by 2-4 yrs Egg – 75% outgrown by 2-4 yrs Peanut – 20% outgrow by 5 yrs Cross reactions Peanut – soybean, green beans, peas Wheat – rye Cow’s milk – soya & goats milk Kiwi – avocado, banana, raw potato, chestnut, latex Pollen – hazelnut, green apples, peaches, almond Management Avoid / educate / medic alert Epipen Salbutamol / steroid ANAPHYLAXIS O2 Salbutamol Fluid 20mls/kg Adrenalin Chlorpenamine Hydrocortisone +/- ITU care Aim to measure serum tryptase at less than 6 hours to confirm anaphylaxis NB: ace inhibitors can cause angioedema Leukotrienes Produced from arachidonic acids Levels increase in ARDS Acts as a bronchoconstrictor Also à capillary leak / activates lymphocytes & responsible for allergic sensitisation “Slow reacting substance of anaphylaxis” consists of a number of leukotrienes Drug allergies / adverse drug reactions Allergy = immune reaction Type 1 (IgE mediated) = immediate response à mast cell degranulation Type 2 (IgG mediated) = complement activation à cell destruction Type 3 (immune complex) = e.g. SLE Type 4 (T cell mediated) = e.g. erythema multiforme Adverse drug reaction = everything else Idiosyncratic – diarrhoea with antibiotics Co-morbid condition – asthma + beta blocker Metabolic / genetic – choloroquine + G6PD Toxic – overdose Infection – EBV + amoxicillin Interactions – metronidazole + alcohol In some cases native molecule causes no reaction, but as drug is metabolised reaction occurs to metabolite = means skin prick testing may be negative Nature and speed on reaction depends on route of administration e.g. IV / PO / Neb etc Raised tryptase levels differentiates anaphylaxsis from anaphylactoid +ve tryptase is supportive, negative does not exclude Aim for a level within 6 hours, thena further level 24 hours later Delayed reactions (> 2 hours) e.g. Stevens Johnson E.g. toxic epidermal necrolysis E.g. contact dermatitis Usually clinical diagnosis ALWAYS Document as well as possible With full history, ALL meds etc Allergy tests if done Challenge test can be used to exclude allergy if patient likely to need drug and no alternatives Morbiliform rash 5-10d post drug = NOT allergy e.g. if EBV / HIV Systemic Non allergic hypersensitivity e.g. DRESS 2-6 weeks post exposure Mortality 10-25% Rash, fever, lymphadenopathy, joint / skin / organ involvement Penicillin anaphylaxis Avoid all penicillins AND 1st & 2nd generation cephalosporins Skin test for 3rd-5th generation OR graded oral challenge under supervision NSAIDs and Asthma Delayed type 1 hypersensitivity due to leukotriene pathway Can be delayed upto 6-8 hours 10-30% of asthmatics are NSAID sensitive Desensitisation To induce tolerance to allergen Only used for type 1 reactions If benefits outweight risks e.g. CF patient needing Abx Increased dose every 15 minutes over 4-5 hours Tollerance is lost after a few days therefore problem if poor adherence / will need repeat desensitisation if further course is needed