Chronic Infection Flashcards
What factors determine the speed of progression of AIDS?
• The speed of progression to AIDS from diagnosis is predicted by the combination of viral load and CD4 count.
What are important. virulence factors of the HIV virus that are also used to target treatment?
Describe to pathophysiology and progression of virus
Protein capsid -p24(mainantigen detected)
- gp120: attaches to host[CD4+ T-cells]
- gp41: assists in fusion and entry of the virus into the host cell
- [Protease]cleavage ofgagandgag-[pol][proteins]during maturation of thevirion
- Reverse transcriptase: convertsviral[RNA] to dsDNA
- Integrase: helps insert the viral[genes]into the host[genome]
For fusion,CD4receptorand a coreceptor (CCR5inmacrophages, andCCR5orCXCR4inT-cells) must be present.
What are the cells affected by HIV
Cells that haveCD4receptors:T lymphocytes(e.g.,T helper cells),macrophages,monocytes,dendritic cells.
How HIV infection staged according to WHO?
WHO classifies individuals with confirmed HIV infection according to clinical features and diagnostic findings:
Primary HIV infection: acute retroviral syndrome or asymptomatic
Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic
Clinical stage 2: e.g.,
unexplained moderate weight loss (< 10%), recurrent fungal/viral/bacterial infections
Clinical stage 3: e.g., unexplained severe weight loss (> 10%), unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥ 36.7°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/mm3) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma, Pneumocystis pneumonia)
What Investigations are Done to confirm HIV and what are the indication for and HIV test?
Indications
Test all patients with clinical features of acute or chronic HIV infection
All individuals with possible past exposure, especially high-risk individuals (e.g., sex workers, men who have sex with men, IV drug users, partners of HIV-positive individuals): regular testing (e.g., annually)
One-time testing is recommended early in every pregnancy
HIV-testing requires patient consent (opt-out)
Diagnosis:
Serum HIV combined antibody + p24 antigen test to screen, then confirm with Western Blot. 50% detectable within 1 month of infection, and nearly all by 6 months.
If +ve, screen for: TB (tuberculin skin test), hepatitis A-C, syphilis,Toxoplasma, CMV.
Genotype testing to guide drug treatment.
Pregnancy test for women.
Baseline bloods: FBC, U&E, LFT, lipids, glucose.
Tests for specific presentations:
PCP: CXR shows bilateral interstitial infiltrates.
Toxoplasma: contrast-enhancing lesions on CT/MRI brain.
Cryptococcal meningitis: cryptococcal antigen in CSF and serum.
Monitoring:
3 to 6 monthly: CD4 count, HIV quantitative RNA PCR (‘viral load’), FBC.
Annual: U&E and LFTs, lipids, glucose.
CBC: possibly lymphocytopenia
Liver enzymes: if abnormal, rule out coinfection with hepatitis virus (HCV or HBV
How to HIV infection present?
Signs and symptoms
Seroconversion illness
Lymphadenopathy
Pharyngitis
Systemic: fever, malaise.
Pain: myalgia, headache.
Maculopapular rash.
Lasts 1-2 weeks.
Presentations by system
Respiratory:
Pneumocystis jirovecipneumonia (PJP or PCP). Fungal infection. Causes dry cough, sweats, SOB and desaturation on exertion, but no chest signs.
Other fungal infections:Aspergillus,Cryptococcus,Histoplasma.
TB: pulmonary TB or atypical and disseminated forms such as miliary TB and TB meningitis.
StrepandStaphpneumonia.
CMV
Neurological:
Toxoplasmaencephalitis: protozoal infection. Focal neurological signs.
Cryptococcal meningitis: fungal infection. Causes insidious, chronic meningitis, usually without stiff neck.
Primary cerebral lymphoma.
Progressive multifocal leukoencephalopathy (PML): JC virus infection.
HIV dementia: neurological decline in multiple domains, in the absence of other infection.
HIV peripheral neuropathy.
Skin:
Kaposi’s sarcoma: due to human herpesvirus 8. Purple papules on the face, mouth, back, lower limbs, or genitalia. Can also affect GI and respiratory tract.
Multi-dermatomal zoster (shingles).
Recalcitrant psoriasis.
Mouth:
Oral and oesophageal candidiasis.
Oral hairy leukoplakia: non-malignant white growths on lateral tongue due to EBV.
HSV and aphthous mouth ulcers.
GI:
Cryptosporidiosis: protozoa. Chronic diarrhoea.
CMV colitis.
HIV wasting syndrome: unexplained weight loss >10%.
Mycobacterium aviumcomplex (MAC): GI, lung, or disseminated.
Fungal:Cryptococcus,Histoplasma.
Other bacteria:Salmonella,Shigella.
Hepatitis B and C.
Cancer:
B-cell lymphoma. EBV-related.
Cervical and anal cancers. HPV-related.
Lung cancer.
Head and neck cancers.
Eye:
CMV retinitis. Mozzarella pizza sign on fundoscopy.
Infections by CD4 level
200-500: TB, candida, VZV, Kaposi’s, other pneumonias.
100-200: PCP, histoplasmosis, PML.
50-100: atypical TB, CMV retinitis/colitis, toxoplasmosis, cryptosporidiosis, cryptococcal meningitis.
<50: MAC.
How is HIV managed and Whart drugs are given in ART therapy?
Vaccines: hepatitis A and B, annual flu, pneumococcal vaccine, HPV. Avoid live vaccines if CD4 <200: VZV, MMR, BCG, oral and intranasal vaccines, yellow fever.
Combination antiretroviral therapy (cART, aka highly-active ART [HAART]):
Triple therapy: {2 x NRTI} + {NNRTI or protease inhibitor or integrase inhibitor}.
When to start: the traditional thresholds were CD4 ≤350, AIDS-related illness, or pregnancy. However, research now suggests clear benefits of starting treatment as soon as the diagnosis is made.
Treating co-infection:
Active TB: standard 4-drug regimen. Overlapping toxicities and drug interactions make TB-HIV co-treatment difficult, but if CD4 <350 (and especially <100), cART should be started as soon as practical e.g. within 1-2 months of starting TB treatment.
Latent TB: 6 months isoniazid and pyridoxine.
Hepatitis C: combination direct-acting antivirals (seeviral hepatitis), paying attention to drug interactions.
Prophylactic antibiotics:
Co-trimoxazole for PCP and toxoplasma if CD4 <200.
Azithromycin for MAC if CD4 <50
How transmission of HIV infe tion from and infected mother be prevented?
The following measures during pregnancy reduce the risk of vertical transmission to near zero:
cART, regardless of CD4.
Delivery: vaginal if virally supressed, C-section if viral load >50 copies/ml, plus intrapartum IV zidovudine infusion if viral load >1000 copies/ml.
No breastfeeding.
4 weeks ART for baby: zidovudine if maternal viral load <50, cART if >50.
What are the common drug interactions and side effects of ART?
Common side effects
GI:
Diarrhoea and vomiting.
Hepatitis, especially nevirapine.
Skin:
Mild rash.
In rare cases, hypersensitivity or SJS/TEN.
Metabolic:
Lipodystrophy: fat reduction peripherally (head and limbs) but gain centrally. Seen with protease inhibitors and NRTIs.
Diabetes and dyslipidaemia. Especially with protease inhibitors, but possible with all.
Common drug interactions
AEDs: phenytoin and carbamazepine should be avoided.
Sildenafil: use lower dose.
Lorazepam should be avoided.
How are NRTI’s and NNRT’s used and what are the side effects
Nucleoside reverse transcriptase inhibitors (NRTI)
Drugs:
Common combinations: emtricitabine/tenofovir, abacavir/lamivudine, lamivudine/zidovudine.
Others: didanosine, stavudine.
Side effects:
Osteoporosis (tenofovir).
Myocardial infarction (abacavir).
Peripheral neuropathy.
Pancreatitis (didanosine, stavudine).
Lactic acidosis.
Zidovudine: myelosuppression, myopathy.
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Drugs: nevirapine, efavirenz.
Side effects: psychosis and vivid dreams (efavirenz).
Hepatatoxicity
Rash, Steven Johnsons
Interactions: warfarin.
What are the side effects of Priotease inhibitors and integrase inhibitors?
Protease inhibitors
Drugs: indinavir, atazanavir, lopinavir, ritonavir (boosts others).
Side effects:
Gallstones and ↑BR (atazanavir).
Kidney stones (indinavir). Lipodystrophy GI upset low platelets Hyperglycemia-Inhibition of GLUT 4
Interactions:
Rifampicin
Digoxin: use lower digoxin dose.
Oral contraception: use higher contraceptive dose.
Others
Integrase inhibitors: dolutegravir, raltegravir.
Increase CK
Entry and fusion inhibitors: enfuvirtide, maraviroc (CCR5 antagonist).
What is IRIS?
Immune Reconstitution Inflammatory Syndrome. This occurs as a failing immune system recovers and starts to mount more exaggerating inflammatory responses. These can be disordered and unpredictable at first. There are two broad categories of IRIS: paradoxical and unmasking. In paradoxical reactions, the inflammatory response to a known opportunistic infection may become more pronounced. In unmasking reactions, there may be no overt evidence of opportunistic infection due to the body’s inability to mount a coordinated inflammatory response due to profound immunosuppression. As the immune system recovers new signs and symptoms may emerge that lead to the diagnosis of opportunistic infections that were there all along. IRIS can generally be managed effectively with anti-inflammatory drugs such as NSAIDs, or with steroids, but can occasionally be dangerous.
What does Cryptococcus neoformans cause and how is it identified?
Environmental encapsulated yeast:
C.neoformans var neoformas/gattii/grubii
C gattii: infection rare in ummunocompetent hosts
var neoformans is found worldwide (pigeon droppings)
var gattii: Tropical and sub-tropical (eucalyptus trees)
Usual route of acquisition - inhalation (rarely cutaneous/organ transplant) .
Risk Factors: T-cell deplete individuals (e.g. HIV,haematological disorders, iatrogenic immunosuppression), steroids, Hodgkin’s, lymphoma
Headache may not be accompanied by fever or neurology
Investigations: Cryptococcal antigen/India Ink stain of CSF/Fungal culture
Treatment: Liposomal amphotericin B & flucytosine and then fluconazole
Remember HAART needed in HIV but caution re: IRIS
What are the risk factors for reactivation of latent TB and how is it treated?
Lifetime risk of reactivating TB ~10%, highest in first 2 years after infection
Risk factors
HIV infection
Immunosuppression – cancer, chemo, steroids, anti-TNF
Diabetes, renal failure, IVDU, malnutrition, GI surgery, silicosis, smoking, age and frailty
Can be treated with 3-6 months of isoniazid +/- rifampicin
6 months of isoniazid mono therapy if need to avoid rifampicin eg-on antiretrovirals
What are the drug interaction of Rifampicin?
Oestrogens – alternative methods of contraception must be advised, preferably use of an intra-uterine device and condoms, continuing for 4 weeks after stopping the rifampicin.
Corticosteroids – normal prednisolone/dexamethasone doses must be doubled whilst on rifampicin.
Blood phenytoin levels will be significantly reduced, so regular doses will need to be titrated up using phenytoin levels.
Sulphonylureas eg gliclazide. BM control in diabetics may deteriorate and adjustments need to be made
Anticoagulants – warfarin, dabigatran, abixaban, rivaroxaban. Increased INR monitoring at initiation of therapy. Manufacturers of newer anticoagulants recommend monitoring for signs of thrombosis.
Use TB drug monographs
Whatt are the signs and symptoms of TB and what different systems can be affected?
Signs and symptoms
Overview:
Primary infection is usually asymptomatic, with active disease usually representing secondary reactivation.
Onset can be insidious and non-specific.
When symptoms occur, there are often systemic features: fatigue, malaise, fever, night sweats, weight loss, anorexia, and immunosuppression.
Organ-specific TB
Pulmonary TB:
Chronic productive cough ± haemoptysis, clubbing.
Can progress to pneumonia, pleural effusion, lobar collapse, and bronchiectasis.
Accounts for 60% of TB cases in UK.
Genitourinary TB:
Frequency, dysuria, loin/back pain, haematuria.
Can progress to renal TB, salpingitis, epididymitis, and cystitis.
Tuberculosis lymhadenitis
Others:
Skeletal TB: most commonly affects spine (Pott’s disease). Can lead to vertebral collapse.
Skin TB (aka lupus vulgaris): rough nodules, often on the face or shin, which are +ve for AFB. Other TB skin manifestations include scrofula (‘cold’ cervical lymphadenopathy), erythema nodosum, and erythema multiforme.
Peritoneal TB: abdominal pain, diarrhoea, vomiting, ascites.
TB meningitis: neurological signs are usually preceded by weeks of systemic symptoms. TB can also cause tuberculomas: tubercles in the brain.
TB pericarditis: acute or constrictive pericarditis.
Miliary TB
Affects multiple organs so symptoms are varied; there are often retinal signs.
What Investigations are done to identify active and latent TB?
CXR
CXR is the first line investigation. Get it even in extrapulmonary TB.
Primary infection findings:
Distinct Ghon focus in the middle zone, or an area of patchy consolidation. Sometimes the parenchymal focus is too small to detect.
Cavitating lesion (air-filled) in the apices, especially the right.
Other signs include patchy consolidation and linear or nodular opacities.
Miliary TB findings:
Diffuse 1-10 mm shadows throughout lung fields.
Microbiology
Getting samples:
Pulmonary: 3 sputum samples (including 1 early morning), ideally spontaneous. Otherwise induce with nebulized saline (airway irritant) or do bronchoalveolar lavage. In kids, gastric lavage is preferred to BAL as it is more sensitive.
Extrapulmonary: aspirate or biopsy lymph nodes, ascites, organs, pus, urine, or CSF.
Investigations:
Microscopy, culture, and sensitivities. AFB smear and microscopy usually involves Ziehl-Neelsen staining, which is around 65% sensitive. Culture in a Lowenstein-Jensen medium typically takes 4-8 weeks and is around 80% sensitive.
Nucleic acid amplification tests (NAAT) allow diagnosis a week earlier than culture, with a similar sensitivity.
PCR for rifampicin resistance.
Histology of biopsies for caseating granuloma.
Immunological testing
Methods:
Mantoux (aka PPD): a tuberculin skin test. A delayed hypersensitivity response to tuberculin develops from 2-10 weeks after primary infection. Also +ve post BCG vaccination.
Interferon gamma release assays (IGRA): Quantiferon Gold or T-spot. Measures T cell response (IFN-γ release) to TB antigens. More specific than tuberculin skin tests.
Uses and limitations:
Both are around 80% sensitive.
Cannot distinguish between latent and active TB, so especially limited for individuals from endemic regions.
More useful for screening contacts than diagnosis. Mantoux usually first, then confirmed with IGRA, or use IGRA first in those with previous BCG.
Other investigations
HIV screening for all
Basic bloods – FBC, LFT, U&E – may show systemic and extrapulmonary disease, and are required for baseline values before starting treatment.
Imaging for suspected extrapulmonary TB: CT/MRI (CNS, abdo, bone), US (pericardial, lymph node, GU), XR (bone).
What is the role of the BCG vaccine in preventing TB
BCG vaccine:
Reduces infection risk by 25% and active TB risk by 70% (in children).
In addition to those identified through screening, give to children at risk i.e. high risk UK areas, family from high risk countries.
Also offer to those at risk through occupational exposure e.g. vets who handle TB-prone animals, prison staff, long-term foreign travellers.
What are the side effects of anti-TB medication?
Side effects of TB medication
Rifampicin: hepatitis (so stop if ↑BR), orange urine/tears, P450 inducer (inactivates warfarin and contraceptive pill), flu-like symptoms.
Isoniazid: hepatitis, agranulocytosis, P450 inhibitor. Peripheral neuropathy can result from pyridoxine depletion, so give supplements to all.
Ethambutol: optic neuritis. Colour vision goes first, so check it using Ishihara charts before starting.
Monthly visual checks
Pyrazinamide: hepatitis, arthralgia.
Reduce dose if egfr less than 30
How can active TB be treated?
Drug treatment:
Treat before confirmation by culture if clinical suspicion is high. Consider continuing treatment even if culture is negative but clinical signs are strong.
6 months treatment with RIPE:Rifampicin andIsoniazid throughout, andPyrazinamide andEthambutol for the first 2 months (4 for 2, 2 for 4).
Add further 6 months of dual therapy for meningeal TB.12 months in total
Add steroids for meningeal and pericardial disease.
Consider directly observed therapy (DOT) to increase adherence
How to treat multi drug resistance TB?
Check notion
What are the stages of syphilis?
Most cases are in men who have sex with men.
Signs and symptoms
Primary syphilis:(3-4 weeks)self limiting(heals in 2-8 weeks)
Chancre: painless hard ulcer at infection site.(mouth ,anus,vagina)
Inguinal lymphadenopathy.
Only the chancre site itself is infective.
Secondary syphilis:
Occurs around 6 weeks to 6 months after primary infection.
Rash: generalised and including the palms and soles.(maculopapular and non itchy)
Fever, headache, my/arthralgia.,lymphadenoapthy,splenomegaly,hepatitis,alopecia
Condylomata lata: highly-infectious wart-like lesions on genitals.
Resolves in 3-6 weeks.seld limiting
Neurosyphilis generally only occurs at this stage if immunosuppressed.
Latent phase:
Early: asymptomatic, <2 years from infection.(risk of sexual and vertical transmission).treated with single penicillin dose
Late: asymptomatic, >2 years from infection.risk of vertical transmission.Longet treatment course
Tertiary syphilis:
Gummatous syphilis: granulomas in bone and cartilage. May lead to saddle nose.
Neurosyphilis: dementia, tabes dorsalis (dorsal column loss).Argyll Robertson pupil,meningitis asymptomatic but abnormal csf altered behaviour
Ocular syphilis-painful red eye,visual disturbance, may cause blindness
Cardiovascular: vasculitis, stroke, aortitis and mycotic aneurysms.
What Investigations are done for Syphilis?
Dark field microscopy of swabs from genital lesions. PCR can be used for oral swabs.-For primary syphilis
Treponemal tests: treponemal enzyme immunoassay (EIA) IgM and IgG. Confirm +ve result with TPPA or TPHA.Determine exposure to syphilis.Remain positive life long
Non treponemal-Quantitative VDRL or rapid plasmin reagin (RPR) if treponemal tests +ve to determine stage and titre (i.e. disease activity).,response to treatment
Lumbar puncture for CSF if there are neuro signs.
How would you monitor response to treatment?
ain in weight, improving cough and sputum, sputum smear and culture ‘conversion’ (i.e. sputum becomes smear then culture negative). Patients often get paradoxically worse for 2-6 weeks before clinically improving. Radiological improvement lags behind clinical improvement.
What is DOT and when should it be offered?
He should be treated with DOT = directly observed therapy (or possibly VOT = video observed therapy) in view of his recurrent infection and social risk factors
DOT should be offered to all patients who:
do not adhere to treatment (or have not in the past)
have been treated previously for TB
have a history of homelessness, drug or alcohol misuse
are currently in prison, or have been in the past 5 years
have a major psychiatric, memory or cognitive disorder
are in denial of the TB diagnosis
have multidrug‑resistant TB
request directly observed therapy after discussion with the clinical team
are too ill to administer the treatment themselves
When is Drug induced liver injury suspected with tb meds and how should it be treated?
General principles of drug-induced liver injury (DILI)
HRZ all hepatotoxic – Z most likely
Acute hepatitis, cholestasis or granulomatous hepatitis
Often asymptomatic – or abdo pain, jaundice, fatigue, N+V, itching
If ALT > 3 x baseline (with symptoms), or > 5 x baseline (without symptoms), or if bilirubin rises – STOP all treatment
Unless patient so sick they need treatment
In which case, use a non-hepatotoxic regimen.
Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK
- sequentially reintroduce each of the anti‑TB drugs at full dose over a period of no more than 10days, starting with ethambutol and either isoniazid (with pyridoxine) or rifampicin. [new 2016]
1. 7.4.2 In people with severe or highly infectious TB who need to interrupt standard therapy because of a reaction, consider continuing treatment: - for hepatotoxicity, a combination of at least 2 anti‑TB drugs of low hepatotoxicity (such as ethambutol and streptomycin, with or without a quinolone, such as levofloxacin or moxifloxacin) and monitor with a liver specialist for further reactions
- for a cutaneous reaction, a combination of at least 2 anti‑TB drugs with a low risk of cutaneous reactions (such as ethambutol and streptomycin) and monitor with a dermatologist for further reactions. [new 2016]
How common is Syphilis and how is transmitted?
300% increase in early syphilis since 2010
Disproportionately affects MSM
2019 – 31% syphilis cases were in HIV positive MSM
Indicator disease for other STIs
Transmission Sexual Only in early syphilis 30-50% contacts infected Vaginal, oral and anal sex
Blood-Borne
Needle sharing
Blood transfusion – very rare
Accidental Innoculation
e.g. healthcare workers
Transplacental
More common in early syphilis (higher bacterial load)
Cases occurs despite maternal screening
What are the complications of congenital syphilis?
Adverse pregnancy outcomes
Miscarriage, stillbirth, prematurity
Early congenital syphilis
Hepatosplenomegaly, lymphadenopathy, desquamating rash
Severe anaemia, jaundice
Late congenital syphilis
Hutchinson’s triad – pegged teeth, keratitis, deafness
Others – saddle nose, bone and joint deformities developmental delay
Routine antenatal screening
How is Syphilis treated?
Penicillin by injection is first line treatment for all stages (other antibiotics are less reliable)
Duration of treatment - depends on the syphilis stage
Early syphilis (primary, secondary, early latent) – single dose
Late syphilis (late latent, unknown, tertiary) – 3x weekly doses
Ocular and neurosyphilis – daily for 10-14 days
Monitoring efficacy
4 fold decrease in non-treponemal test titre
Jarisch-Herxheimer reaction
Triggered by penicillin treatment ,inflammatory response triggered in response to killing the pathogen
Acute onset fever, muscle aches, flushing, rash and palpitations
Managed conservatively; steroids(used prior to penicillin) used for prevention in neurosyphilis
How is contact tracing done?
Primary-Partners in past 3 and half months
Secondary/early latent-Partners in past 2 yrs OR
3/12 before last neg test
Late -not infectious
Management Options for Syphilis Contacts
Testing and empirical treatment
Testing now and at end of window period (12 weeks)
What Investigations are done for Syphilis?
Investigations
Direct-Primary Syphilis-Dark field microscopy of swabs from genital lesions. PCR can be used for oral swabs.
Treponemal tests: treponemal enzyme immunoassay (EIA) IgM and IgG. Confirm +ve result with TPPA or TPHA
Determine exposure to syphilis
Remain positive life-long
.
Non. treponema -Quantitative VDRL or rapid plasmin reagin (RPR) if treponemal tests +ve to determine stage and titre (i.e. disease activity).
Lumbar puncture for CSF if there are neuro signs.
What are the stages of Sypilis?
Primary(3-4 weeks after inoculation)
Chancre(s) (sore) at the site of infection
Usually firm, round and painless
May go unnoticed esp. if not visible (e.g. in mouth, anus or vagina)
Without treatment the chancre disappears by 2-8 weeks
Secondary(around 6 weeks) Rash (90%) Generalised, including palms and soles Classically maculopapular and non-itchy Condylomata lata – moist, warty lesions in genital area
Systemic illness Fevers, fatigue Lymphadenopathy, splenomegaly Hepatitis Alopecia
Latent Syphilis
Asymptomatic infection following untreated or unrecognised primary and secondary syphilis
Early latent
Within two years of infection
Risk of sexual and vertical transmission
25% have recurrence of secondary syphilis
Can be treated with a single dose of penicillin
Late latent
Diagnosed after more than two years of infection
Risk of vertical transmission,cannot be transmitted sexually
Requires longer treatment course
Tertiary syphilis(2-20 year but can occur any time)
Gummatous Granulomatous lesion(s) with central necrosis
Cardiovascular
Aortitis → aneursym, aortic regurgitation
3° neurosyphilis
General paresis – progressive dementia
Tabes dorsalis – neuropathy, ataxia, pupillary changes(Argyl robertsons)
Ocular syphilis (uveitis)
Painful, red eye(s)
Visual disturbance – floaters, flashing lights
May cause blindness
Neurosyphilis Asymptomatic abnormal CSF findings Meningitis Altered behaviour Stroke – secondary to vasculitis Tertiary neurosyphilis
What is the Clinical presentation of Lyme disease?
Erythema migrans
increases in size and may sometimes have a central clearing
is not usually itchy, hot or painful
usually becomes visible from 1to4weeks (but can appear from 3days to 3months) after a tick bite and lasts for several weeks
is usually at the site of a tick bite
May be associated with fever, headache, ‘flu-like symptoms
neurological symptoms (weeks to months after exposure):
facial palsy (may be bilateral) / other unexplained cranial nerve palsies
lymphocytic meningitis
mononeuritis multiplex or other unexplained radiculopathy
cardiac problems:
heart block (1st degree commonest)
Pericarditis, myocarditis
Late features of lyme
Months to > 1y after exposure Joints (US infections): inflammatory arthritis affecting 1or more joints that may be fluctuating and migratory Knee ‘always’ affected Late cutaneous (European infections): acrodermatitis chronica atrophicans Lymphocytoma (classically earlobe)
Non specific features
fever and sweats swollen glands malaise fatigue neck pain or stiffness migratory joint or muscle aches and pain cognitive impairment, such as memory problems and difficulty concentrating (sometimes described as 'brain fog') headache paraesthesia
How is Lyme disease treated?
Early disease (e.g. ECM rash) Oral doxycycline 21d (NICE) [evidence that 10d is sufficient]
Meningitis / radiculopathy / CN palsy
iv Ceftriaxone 21d
Data suggest oral doxycycline equally effective
How to define successful treatment?
~30% have some post-treatment persistent symptoms for few months
But by 12+ months not statistically different to background population rate
There is no test for ‘active infection’
Role of re-treatment?
High quality (RCT) evidence that long antibiotic courses offer no additional benefit
What causes Lyme disease?
Bacterial infections spread by arthropods, usually ectoparasites – such as ticks, lice, mites, and fleas – which feed on mammalian blood and transmit the bacteria through their saliva.
Lyme disease
Pathophysiology and epidemiology
Infection with variousBorreliaspecies (e.g.B. burgdorferi), a spirochete transmitted by theIxodestick which lives on small mammals and deer.
Tick must usually be attached for >24 hrs for infection to occur.
Found throughout northern Europe and much of the US (esp. northeast). In UK, common sites are the Highlands, Lake District, and New Forest.
Commonest in summer.
What Investigations are done for Lyme disease?
Clinical diagnosis for most: erythema migrans plus endemic area.
Serology – ELISA (IgM and IgG) then confirmatory Western blot – only needed if diagnosis unclear or there is disseminated disease.
What are the causes of Acute hepatitis?
1.Drugs(especially PCM)
2.Infection (viral infection)
Budd chiari
Autoimmune
toxins
pregnancy related
ischemia
malignancy
Wilsons
Viral •Hepatitis A •Hepatitis B •Hepatitis C •Hepatitis E •Cytomegalovirus (CMV) •Epstein-Barr Virus (EBV) •Varicella zoster virus (VZV) •Herpes simplex virus (HSV) •Adenovirus •Hepatitis D (only Hepatitis B infected patients) •Yellow fever & other travel-associated viruses
Bacteria
Leptospira
Typhoid
TB
Q fever (Coxiella)
fungal
Invasive fungal infections e.g. candidiasis
•
parasitic
Malaria
Liver flukes
Schistosomiasis
How can Hep B prevented?
Improved sanitation and hygiene 2. Education e.g. travellers of mode of transmission. 3. Hepatitis A vaccination Purified, inactivated, hepatitis A virus Who? Travellers to endemic areas Men whom have sex with men IVDU Chronic liver disease Haemophilia Occupational risk e.g. lab workers, sewage workers Following exposure to infected individual When? Ideally >2 weeks before required Booster needed after 6-12 months
What are the similarities between Hep A and E
- Both hep A & ‘classical hep E’ transmitted faeco-orally
- Both hep A & ‘classical hep E’ both travel associated and mainly resource-poor settings.
- Both weeks not days
- Both often asymptomatic (especially children)
- Both cause similar clinical picture – prodrome and acute hepatitis
- Both small risk of acute liver failure/death esp in people with pre-existing liver disease
- Both usually fully resolve within 2-3 months
- Both result in raised serum amino-transferases
- Both usually diagnosed by serological testing
- Both managed by supportive care
- Both notifiable infections
What are the differences between Hep A and E?
- ‘Sporadic’ hep E can also be transmitted via undercooked meat, contact with animals, & blood transfusion
- ‘Sporadic hep E’ can be acquired in resource-rich countries, including UK
- Hep A can cause outbreaks in UK
- Hep E often slightly longer (40 vs 28 days)
- Hep E – increased mortality pregnancy, risk of chronic infection in immunosuppressed, extrahepatic manifestations more common
- Vaccine only widely available for hep A.
- Can prevent secondary cases of hep A (vaccine/HNIG) but not hep E
What Investigation can be used identify acute, chronic,past and vaccinated Hep B
Check Notion
How can Hep B be managed?
Clinical management:
Most patients supportive care
Anti-Hepatitis B drugs only usually given in patients with severe acute hepatitis (HBV drugs to be discussed in chronic infections) – e.g. INR >1.5, protracted course (persistent symptoms/marked jaundice >4 weeks), signs acute liver failure
Screen for other blood-borne viruses (HIV, Hepatitis C)
Screen for hepatitis D co-infection
2. Prevention of secondary cases:
Again notifiable infection Inform Public Health England ASAP
Contact tracing
Give close/sexual contacts Hepatitis B vaccination +/- HBIG (Hepatitis B Immunoglobulin) to prevent infection
3. Follow up
Most adults will spontaneously clear hepatitis B infection. However, should be followed up to demonstrate clearance of infection (loss of hepatitis B surface antigen and hepatitis B surface antibody seroconversion)
Education re modes of transmission
E.g. safer sexual practices, needle exchange programmes
2. Increased testing
E.g. blood products, antenatal screening,screening of at-risk groups
3. Hepatitis B immunoglobulin (HBIG)
Pooled blood product with high levels of anti-HBs passive immunity
Can be given after high risk exposure to susceptible individuals to prevent HBV infection.
E.g. Neonates born to highly infectious mothers, unvaccinated individuals who have definite exposure (e.g. needlestick/sexual) to HBV positive source, HBV vaccine non-responders who receive possible exposure.
4. Hepatitis B vaccination
Recombinant hepatitis B surface antigen
Safe and highly effective
Can be given both pre-exposure and post-exposure to prevent infection.
Who needs to be vaccinated against Hep B?
Who should be vaccinated against hepatitis B?
1. All neonates
- part of routine childhood immunisation schedule since 2017
2. Anyone at increased risk of exposure to HBV – e.g:
Close or household contacts of someone with HBV infection
Travellers to intermediate or high prevalence areas
Individuals who change sexual partners frequently
PWID (people who inject drugs)
People receiving regular blood products e.g. haemophilia
People with renal failure who may require haemodialysis
People in residential accommodation for those with learning difficulties
Inmates of custodial institutions
Occupational risk – e.g. healthcare workers, laboratory workers, etc
3. Anyone at high risk of complications of disease e.g.
Patients with HIV
Patients with chronic liver disease
4. Post-exposure vaccination – following a known/possible exposure to HBV e.g.
Following needlestick injury
Following sexual contact
Neonates of HBV positive women
How should they be vaccinated?
Usually at least 3 doses of vaccine required
Different vaccination schedules available e.g.:
Neonates – 8, 12, 16 weeks of age
0, 1, 6 months (health care workers)
0, 1, 2, 12 months ‘rapid course’
What are signs and symptoms of acute viral hepatitis?
Signs and symptoms
Acute hepatitis (HAV, HBV, HEV):
Prodrome/pre-icteric phase: fever, malaise, anorexia, nausea, arthralgia.
Icteric phase: jaundice, pale poo and dark pee, itch, RUQ pain, hepato±splenomegaly, lymphadenopathy. Less likely to occur if <30 years old.
Usually self-resolves in 2-6 weeks.
HBV:
Acute symptoms are similar to HAV but with more extrahepatic features e.g. arthralgia, urticaria.
Adults are more often symptomatic during an acute infection than kids, who are usually asymptomatic.
But babies (90%) and kids (30%) are more likely than adults (5%) to become chronically infected.
HCV:
Acute infection is usually asymptomatic or mild.
80% become chronically infected.
What is the Pathogenesis, clinical course and 5 stages of Hep B infection?
Notion
What medical treatment can be given for hep B?
2 main goals of therapy:
Improve survival and quality of life by preventing disease progression, and therefore development of cirrhosis/HCC.
Reduce transmission of HBV
2 main types:
Nucleotide analogues:
Usually Entecavir or Tenofovir
(occasionally lamivudine, adefovir, telbivudine)
Inhibit viral DNA polymerase
Monotherapy
Oral tablets, usually taken long-term
2. Pegylated IFN-a
Induces long-term immunological control
Finite duration to treatment
Injected
Only rarely used
What are the Indications for treatment?
1.All patients with cirrhosis
All patients co-infected with HIV
Patients with a family history of HCC or cirrhosis
Patients with hepatitis e.g.
Patients with moderate fibrosis & ALT >ULN & HBV DNA >2,000
Patients with ALT >2xULN & HBV DNA >20,000
Patients age >30 who are e-Ag positive, high HBV DNA, persistently normal ALT
2.Pregnancy - all pregnant women with high HBV DNA levels (>200,000 IU/ml) start treatment at week 24–28 gestation and continue until 12 weeks after delivery
HBV positive health care workers performing exposure prone procedures with serum HBV DNA >200 IU/ml
How does Hep D present and how is it diagnosed and treated?
Infection only possible in patients with hepatitis B virus
Requires hepatitis B virus for virus assembly and release
Co-infection = infection at the same time as HBV infection
Super- infection = infection after HBV infection
- Clinical
Acute infection:
suspect if fulminant acute HBV (incr risk)
Suspect if acute hepatitis in HBV patient
Chronic HBV & HDV co-infection:
more rapid progression to cirrhosis
and HCC - Diagnosis
Anti-HDV antibodies (screening)
HDV RNA – current infection - Treatment
Usually by treating HBV
What are the different serotypes of Hep C?
Epidemiology:
Worldwide approx. 80 million people have chronic hepatitis C virus (HCV) infection (WHO)
Estimated 700 000 of them die untreated every year
Prevalence varies by country
Transmission:
Mainly parenteral
PWID - Shared needles/ injecting paraphernalia (England 23% PWID have current HCV infection)
Blood products (before 1991)
Needlestick injuries (3% risk)
Tattoos/acupuncture etc
Also sexual and vertical transmission (but lower risk than HBV).
There are at least six different strains (genotypes) of HCV (and more than 50 subtypes):
Genotypes 1, 2, and 3 - most common in the northern hemisphere
Genotype 4 - Middle East
Genotype 5 - Southern Africa
Genotype 6 - South Asia.
Most infections acquired in England are genotype1 (50.1%) andgenotype 3 (38.4 %) (PHE 2018)
Why are genotypes important?
No cross-protection between genotypes
People can be co-infected by more than one genotype.
Reinfection with another genotype.
Treatment
Some treatments are genotype specific
Different response to treatments
How is Hep C different from Hep B?
Very similar to HBV:
Acute infection chronic infection cirrhosis HCC
Again can cause extrahepatic manifestations
BUT important differences to HBV:
1. Acute infection:
Often asymptomatic (only 20% symptomatic)
Less spontaneous clearance than HBV - 55-85% progress to chronic infection (vs 5% HBV)
2. Chronic infection:
Slow development to cirrhosis (20-30% over 20-30 years)
3. NO reactivation:
Cure is possible - can NOT reactivate following immunosuppression
4. Multiple genotypes:
Reinfections possible and common
5. No vaccine
How can HepC be diagnosed?
Hepatitis C antibody
Shows whether someone has ever had hepatitis C.
Cannot differentiate current vs past hepatitis C infection
Used as a screening test.
May have false negatives in immunocompromised patients (esp. HIV) or be negative in acute HCV infections
Hepatitis C RNA - PCR
Detects actual viral RNA differentiates current from past infections.
Used in immunocompromised patients
Hepatitis C genotyping
Sample type:
Usually blood
Alternative sample types e.g. DBS (Dried Blood Spot samples) may be used for screening high risk individuals in places where venepuncture may be difficult e.g. prisons/in the community.
How can Hep C be treated?
DAAs = Direct Acting Antivirals
Drugs that target specific non-structural proteins of HCV disrupt viral replication and infection
Massive revolution in treatment options in the last decade
Highly effective (>95% cure)
Well-tolerated
Oral
Finite duration of treatment – 8-12 weeks
Expensive
Choice of which to use: HCV genotype Some specific genotypes Some pan-genotypic Drug interactions Treatment history Presence of cirrhosis Cost National/local guidelines
Endpoints of treatment:
Test HCV RNA at end of treatment
Management of chronic infection
treatment depends on the viral genotype - this should be tested prior to treatment
the management of hepatitis C has advanced rapidly in recent years resulting in clearance rates of around 95%. Interferon based treatments are no longer recommended
the aim of treatment is sustained virological response (SVR), defined as undetectable serum HCV RNA six months after the end of therapy
currently a combination of protease inhibitors (e.g. daclatasvir + sofosbuvir or sofosbuvir + simeprevir) with or without ribavirin are used
Complications of treatment
ribavirin - side-effects: haemolytic anaemia, cough. Women should not become pregnant within 6 months of stopping ribavirin as it is teratogenic
interferon alpha - side-effects: flu-like symptoms, depression, fatigue, leukopenia, thrombocytopenia
What can be done to achieve WHO’s target to eliminate Hep B,C by 2030
Ways in which it may be achieved:
Increased screening and testing
In 2017, of 71 million persons living with HCV infection globally, only est. 19% (13.1 million) knew their diagnosis
Reduced stigma
Increased awareness and education regarding modes of transmission
General public health
e.g. needle exchanges, safer sexual practices, provision of sterile medical equipment etc.
Screening of blood products.
Increased HBV vaccination
Obstetric services prevention of mother-to-child transmission
Improved access to HBV and HCV treatment e.g. hepatitis C cost of treatment:
DAAs very expensive BUT some generic versions of these medicines now available
When does Hep E cause Chronic Infection?
HEV usually causes acute hepatitis
Chronic hepatitis ONLY in immunosuppressed patients and ONLY genotypes 3/4 (i.e. not travel associated cases)
Things to remember:
1. Consider as a cause of chronic hepatitis in immunocompromised patients. 2. If a patient with acute hepatitis E is immunocompromised, they should be followed up to ensure clearance. 3. Occasionally treatment may be required (Ribavirin). 4. Hepatitis E serology may be falsely negative in immunocompromised patients – diagnosis needs HEV RNA PCR
How can pneumocystis pneumonia be identified from a bedside test and what other investigations are done?What would they show
Relatively good oxygenation at rest, but marked SOBOE raises possibility of pneumocystis pneumonia (PCP). Pulmonary embolism can also present like this.
A bedside manoeuvre that may give more info would be to measure his SpO2 while exerting himself, e.g. walking around the department while wearing a pulse oximeter (and accompanied by a member of staff!). If he quickly desaturates, that is also suggestive of PCP.
Investigations: HIV test, chest Xray, ECG, arterial blood gas, Ddimers,
ABG - Type I respiratory failure (hypoxia, normal/low CO2 reflecting hyperventilation in face of hypoxia, no metabolic disturbance or compensation in evidence).
CXR – bilateral perihilar interstitial infiltrates, no dense consolidation. This is typical for PCP.
How does PCP present and how is it managed?
Notes on Pneumocystis jiroveci (PCP/PJP)
Environmental fungus
CD4 <200
Clinical features: dry cough, fevers, malaise, weight loss, exertional dyspnoea/ de-saturation
Hypoxia beyond chest examination findings
CXR: diffuse interstitial infiltrates with bat wing distribution ( 25% normal in early disease)
Ix: BAL for PJP oocysts
Tx: high dose co-trimoxazole +/- steroids
Remember HAART in 2/52 if HIV positive, and secondary prophylaxis
How is Toxoplasmosis diagnosed and managed?
Toxoplasmosis – noteson diagnosis and treatment
For a definitive diagnosis a brain biopsy is needed
This is a high risk procedure
Treat for 2 weeks Sulphadiazine and pyrimethamine
Trial of treatment for Toxoplasmosis and repeat imaging in 2 weeks.
If the lesions decrease in size you can continue toxoplasmosis treatment
If they increase or fail to decrease they may require a brain biopsy to look for lymphoma
What causes toxoplasmosis and how does it present?
Toxoplasmosis is causes by Toxoplasma gondii
Protozoan parasite
Cats are the definitive host
Humans can acquire infection by:
eating undercooked meat of animals harboring tissue cysts.
consuming food or water contaminated with cat faeces or by contaminated environmental samples (such as faecally-contaminated soil or changing the litter box of a pet cat).
blood transfusion or organ transplantation
transplacentally from mother to fetus
How does it present?
In immunocompetent patients toxoplasmosis may present as a ‘glandular fever-like’ illness, with myalgia and lymphadenopathy, or may not be noticed at all.
It can then lie dormant and reactivate if the patient becomes immunosuppressed.
In the UK about 40% of people have been infected but this is higher in other European countries e.g. France (90%).
If acquired in pregnancy, toxoplasma can cause congenital infection leading to miscarriage, still birth or severe disability in the child.
In immunocompromised patients toxoplasma can reactivate and most commonly causes CNS infection with space occupying lesions.
These may be multiple and are often concentrated around the basal ganglia.
Their rim enhances with IV contrast.
They can be difficult to distinguish from primary CNS lymphomas.
Tuberculomas can appear similar but there are usually symptoms such as fever, weight loss and night sweats and evidence of TB elsewhere.
Toxoplasmosis can also affect the eye causing a chorioretinitis. This is usually seen in immunocompromised patients but may occur in the immunocompetent.
How does Kaposi Sarcoma present?
Cancer of the skin
Associated with human herpes virus 8 (HHV8)
Previously a very rare cancer seen in older men of Mediterranean or eastern European descent.
Increased exponentially with the AIDs pandemic
Typically purple-brown raised lesions on lower limbs or head and neck but may occur anywhere
Visceral lesions can involve bronchial walls, causing haemoptysis/dyspnoea,
GI tract causing haematemesis, dysphagia, bowel obstruction and melaena
If there are skin lesions only, these may regress as HIV is controlled with antiretroviral medication
Chemotherpay is needed in visceral or more extensive skin disease.
How is candiasis treated?
Treated with oral fluconazole for 7-14 days
What are the common causes of diarrhoea in HIV?
There are numerous causes for diarrhoea in HIV positive patients, including C.difficile, campylobater, shigella and salmonella, all of which could cause diarrhoea in anyone, regardless of HIV status.
Cryptosporidiosis can occur in the immunocompetent but is usually self limiting.
Persistent cryptosporidium infection is an AIDs defining illness.
Major causes of HIV related diarrhoea:notion
How is Cryptococcus spread?
Cryptosporidium is a protozoan parasite
Infection is caused by drinking water contaminated with oocysts
Oocysts are not killed by chlorine so outbreaks may occur in swimming pools
Immunocompetent people usually clear the infection without treatment
In patients with HIV it may persist
First line treatment is antiretroviral therapy
What are the HIV indicator illnesses?
Universal testing: TOP/ GUM/ ante-natal/ drug dependency/ TB/ hepatitis/ lymphoma services
Consider in all medical admissions if prevalence >2/1000 or in all adults registering with GP
Anyone presenting with indicator diseases/ AIDs defining condition
See list BHIVA: UK national guidelines for HIV testing 2008. AIDS defining conditions:
TB, PCP Cerebral Toxoplasmosis, Cryptococcal meningits, PML Karposi Sarcoma Persistent cryptosporidiosis NHL(non Hodgkins lymphoma) Cervical cancer CMV retinitis
What are the potential complications of Hep C?
Potential complications of chronic hepatitis C
rheumatological problems: arthralgia, arthritis
eye problems: Sjogren’s syndrome
cirrhosis (5-20% of those with chronic disease)
hepatocellular cancer
cryoglobulinaemia: typically type II (mixed monoclonal and polyclonal)
porphyria cutanea tarda (PCT): it is increasingly recognised that PCT may develop in patients with hepatitis C, especially if there are other factors such as alcohol abuse
membranoproliferative glomerulonephritis
