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
