DTMH Flashcards
Global burden of dengue
390 million worldwide per year
40-50% of world at risk
70% cases in Asia
Longer and more wet rainy seasons
Cases in Americas rising
Virus of dengue
RNA virus
4 serotypes
3 structural proteins (C, M, E)
7 non-structural proteins (NS)
Process of dengue replication
Binds to receptors
Clarity in mediated endocytosis
Fusion and virus assembly
Viral RNA released into cell
Translation
Viral assembly
Virus maturation
DENV release from cell
Vectors of dengue
Aèdes aegypti:
violin/lyre shaped white markings on thorax
Can bite multiple times
Aedes albopictus
Single silvery white line down thorax
Very adaptable
Clinical manifestations of dengue
incubation 5-7 days
Fever, headache, rashes, muscle pain and joint pain
Rashes of dengue
Initially maculopapular rash
Then petichael rash often at extremities ie ankles
Recovery rash: blanching
Disease phases dengue
febrile phase
Critical period
Recovery phase
Warning signs of dengue
Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation
Mucosal bleed
Lethargy or restlessness
Liver enlargement (2+cm)
Increase in Hct concurrent with drop in Plt count
Definition of acute rheumatic fever
acute multi system, inflammatory process occurring 2-3 weeks after grpA streptococcal pharyngitis
Definition of rheumatic heart disease
chronic process due to scarring of valves during ARF associated with complications such as HF and death
Properties of group A streptococcus
Streptococcus pyogènes, gram positive, beta-haemolytic cocci in chains
Clinical manifestations of streptococcus pyogenes
Superficial: pharyngitis and pyoderma/impetigo
Invasive/toxin mediated:
Skin, soft tissue, lung
Toxic shock syndrome
Necrotising fasciitis
Puerperal sepsis
Scarlet fever
Post infective disease manifestations of group A strep
Rheumatic fever
Syndenham’s chorea
RHD
Acute glomerulonephritis
Global burden of group A strep
33mill worldwide prevalence estimates from echo screening and/or from HF/stroke/arrhythmias/pregnancy related complication data
Clinical features of group A strep infection
Children aged 5-15 years
Joint pain (migratory, large joint)
Carditis (mitral first)
Chorea
Incubation: 10-14days following GAS pharyngitis
Drivers of rheumatic heart disease
Group a streptococcus is the trigger but
Kids affected - lack of immunity
Pathogenesis poorly understood
Issues with molecular mimicry - affects vaccine development
Frequency of GrpA strep infections affecting moving on to rheumatic fever - ie poverty/environments can mean some kids are exposed to over 5 different types which then drives up risk, whereas in UK may be much less
Criteria for RHD
Low risk countries
JONES 2015 in low risk
Major:
Carditis
Arthritis - poly
Chorea
Subcutaneous nodules
Erythema marginatum
Minor
Polyarthralgia
Fever 38.5+
ESR 60+/CRP 30+
Prolonged PR
Criteria for RHD
High risk countries
JONES 2015 in high risk
Major:
Carditis
Arthritis - poly or mono, polyarthralgia
Chorea
Subcutaneous nodules
Erythema marginatum
Minor
Monoarthralgia
Fever 38.0+
ESR 60+/CRP 30+
Prolonged PR
How to diagnose Rheumatic fever?
Evidence of Strep A plus
2x major criteria
1x major and 2x minor
From Jones criteria 2015
How to confirm Rheumatic fever?
- Evidence of Strep A:
a. Swab, serology, rapid test (except for chorea & indolent carditis)- Serologic tests
a. ASO & ADB - rising titre
b. Variable availability and normal ranges
- Serologic tests
Diagnosis?
- 7year old girl presents to health centre with SOB + left knee pain + abdominal pain, biventricular failure on CXR, tender gross hepatomegaly, died of cardiogenic shock
RHD
Spooning / milkmaids grip a clinical feature of…
Chorea associated with RHD
Management of rheumatic fever
Acute mx:
1. Patient/family education
2. Single dose BenPen or otherwise oral pen or erythromycin if pen allergic
3. Analgesia +/- NSAIDs
4. Diuresis, ACEi, +/- steroids
Longer term management of rheumatic heart disease
Longer term:
1. Prevent recurrence (including sub clinical)
○ Secondary prophylaxis for prevention of ARF = secondary prevention
2. Manage HF
3. Anti coagulation for AF or valve replacement
4. Assessment for intervention/surgery
Critical diagnostic test for RHD
Echocardiogram
What does secondary prevention mean in the context of RHD?
Secondary prophylaxis for prevention of ARF
What is management approach to latent RHD?
Secondary Abx prophylaxis with penicillin
Trial: GOAL, NEJM
No prophylaxis vs IM Pen 4 weekly
Pen group had 10 times less echo progression of latent disease at 2 years
What is the evidence base for anticoagulation in RHD?
INVICTUS study, RCT
NEJM
Rivaroxaban was associated with more stroke, emboli, MI, death compared to Vit K antagonist eg warfarin
(24 countries)
Where is yellow fever found? What vector?
South America and Africa
Aedes mosquito
Describe protozoa
- Taxonomic group of single-celled organisms with a nucleus (ie. Eukaryotes) that are non-photosynthetic
Define protista
Taxonomic group of single-celled eukaryotes including Protozoa, algae and slime moulds
Transmission of protozoa
Direct
* Passed directly from one infected host to another by some physical means eg faecal contamination of food or water
Via intermediate host or vector
* Very common amongst parasites
* Sometimes just mechanical transfer, but usually one or more essential life-cycle stages take place here
Definitive host: stage where the sexual stages of the life cycle take place
* May or may not be the human
Transmission of protozoa
- Direct
○ Passed directly from one infected host to another by some physical means eg faecal contamination of food or water- Via intermediate host or vector
○ Very common amongst parasites
○ Sometimes just mechanical transfer, but usually one or more essential life-cycle stages take place here
○ Definitive host: stage where the sexual stages of the life cycle take place
§ May or may not be the human
- Via intermediate host or vector
Define anthroponosis and give examples
Disease spread from humans to humans
Eg smallpox, malaria
Define zoonosis and give examples
Any disease which can be transmitted to humans from animals
- E.g. East African sleeping sickness
- These animals form reservoir hosts, which can greatly complicate control or elimination
Define trophozoite
- a general, rather ill-defined term for the feeding, growing and dividing stage of a protozoan
- Note that many organisms have specific names for life-cycle stages that could be described as trophozoites
Define cyst in parasitology
- A microscopic, resistant form shed into the environment and responsible for transmission (e.g. Entamoeba)
In the tissue, a distinct walled off cavity containing multiple organisms, often important in transmission (e.g. Trichinella, Toxoplasma). Related to general clinical usage.
Examples of protozoa that are dangerous for immunocompromised host
Toxoplasma gondii
Cryptosporidium
Acanthamoeba species
Balamuthia madrillaris
Examples of fungi dangerous to immunocompromised host
Pneumocystis jirovecii
Encephalitozoon intestinalis - microsporidiosis
Examples of gut protozoa
Giardia intestinalis
Entamoeba histolytica
Babesia microti
Newer definitions for symbiosis type relationships
- Mutualism: both benefit
- Neutralism: neither incur cost or benefit
- Commensalism: one benefits but at no cost to the other
- Parasitism: one benefits at the cost of the other
○ All pathogens now fit in here
Issues with whether something is a pathogen or not
Host immunocompetence
Symbionts
Ectopic infection
Presence of other organisms
Microbiome
Coinfections
?theory of dysbiosis
Two relevant phylums of parasitic helminths in medical parasitology
Platyhelminthes (flatworms)
Nematoda (round worms)
Two relevant classes of Phylum Platyhelminthes
Trematoda
- flukes
Cestoida
- tapeworms
Second biggest cause of human parasitic diseases
Schistosomiasis
Define metazoan and give example
Multicellular eukaryotic animal eg parasitic helminths
Characteristics of parasitic helminths
Complex metazoan
Most multicellular but some can be intracellular
Many are zoonosis -> control is more difficult
- Infection is by:
○ Ingestion of eggs/cysts on/in food (e.g vegetables, meat, fish etc)
○ Penetration of skin by infective larval stages (directly or via biting insect) - Larvae grow, moult, mature to adult and then produce offspring (eggs or larvae) which are voided from the host to infect new hosts
What does a direct helminth life cycle mean?
Parasite requires one host to complete its life cycle
What does an indirect helminth life cycle mean?
parasite requires TWO or MORE HOSTs to complete its life cycle
What is a definitive host in parasitic life cycle?
Host harbouring the sexually mature adult worm
What is an intermediate host in parasitic life cycle?
Host harbouring the larval stages
What determines worm burden that human experiences in helminths infections and what does this determine?
Level and duration of exposure ie cumulation
Worm burden determines clinical disease
Examples of diseases caused by helminth infections
Schistosomiasis - hepatosplenomegaly + peri-portal fibrosis
Hydatid cyst
Filariasis - elephantiasis
Onchocerciasis
Hookworm -anaemia
Trematode characteristics
Leaf-shaped flatworms - no body cavity, oral and ventral suckers for attachment and sucking nutrients, blind sac-like gut
‘Flukes’
Found in various tissues
All belong to sub-class Digenea ‘digenetic trematodes’
○ Means 2 or more generations in different hosts to complete the life cycle
Most important human infecting trematodes
Schistosomes (blood fluke)
• Paragonimus (lung fluke)
• Opistorchis/Clonorchis (liver fluke)
• Fasciola (liver fluke)
• Fasciolopsis (intestinal fluke)
First intermediate host for all trematode schistosome infections
Freshwater snail
Most important human trematode?
Schistosomes
- Morphologically adapted to live inside blood vessels and dioecious (separate sexes)
- Below = Schistosoma spp. = blood fluke
○ Causes Schistosomiasis
○ Affects ~250mill people worldwide
○ Eggs become lodged in tissues -> immune reaction generate granulomas and fibrosis
Common name for Cestoidea
Tapeworms
Most important human-infecting cestodes
Taenia saginata (beef tapeworm)
• Taenia solium (pork tapeworm) (larval infection=cysticercosis)
• Dihyllobothrium spp (fish tapeworm)
• Echinococcus spp (dog and fox tapeworms) (larval infection=hydatid cyst)
Characteristics of cestodes
Segmented ribbon-like (tape) flatworms
- All species of cestodes are parasitic
- Adult worms live in the small intestine of vertebrate animals (definitive host) Larval stages live in tissues of vertebrates and invertebrates (intermediate host)
What type of helminth has a full intestinal system?
Nematodes
What disease does taenia solium cause?
Cysticercosis
Most important human-infecting nematodes:
Intestinal nematodes:
• Hookworms
• Ascaris
• Trichuris
• Strongyloides
Tissue nematodes:
• Wuchereria/Brugia (Lymphatic filariasis)
Basic characteristics of falciparum
Most dangerous + most deaths
Pre-erythrocytic stage: 5.5-7 days
Incubation period of 9-14 days
Which strains of malaria can be dormant as hyponozoites?
ovale and vivax
Rare zoonosis malaria strain? Where is it found? Whats the natural host?
Knowlesi
Malaysia
Macaques natural host
Pre-erythrocytic 8-9 days
Erythrocytic: 24 hr cycle
Incubation period: 9-12 days
Fastest growth of all human infecting plasmodium
Hallmark symptom of malaria and what do changes in it correspond to?
Fever
Spikes correspond to erythrocyte cycle and syncronisation of developmental stages
What does the threshold at which symptoms develop in malaria depend on?
Endemicity, transmission intensity and age of patient
What species of malaria cause tertian fever?
Fever that recurs every third day, ie after 48hrs
Falciparum
Vivax
Ovale
What species of malaria cause quartan fever?
Fever that recurs every fourth day, ie after 72hrs
malariae
Basics of malaria pathophysiology
Erythrocytes infected with trophozoites and schizonts
Sequestration intravascularly, especially in capillaries
Rosetting (infected RBCs bind to uninfected RBCs)
Microvascular obstruction (due to RBCs becoming less deformable)
What does pfEMP1 stand for and what does it do?
P falciparum erythrocyte membrane protein 1
Mediates cytoadherence
Exported to the surface of infected RBCs
Interacts with molecules on endothelial cells including ICAM-1
Different subsets determine pathophysiology and clinical features
What codes for pfEMP1? How does change in genes affect the protein and its capability?
About 60 genes called var.
Each parasite can switch on and off specific var genes -> produces functionally different protein to evade host’s immune system
What are the principles of immunity to malaria?
- Its partial and sterile
- gradual acquisition can result in people living in endemic areas due to repeated exposure to parasites -> they lose this when they leave
- Two types of immunity in parallel: anti-parasite + anti-disease
- Age and exposure independently impact on development of immunity -> kids in moderate/high transmission settings develop immunity faster as transmission increases
What does anti-parasite and anti-disease immunity mean?
Anti-parasite: ability to control parasite density
Anti-disease: ability to tolerate higher parasite densities without fever
Intervention that has had the biggest impact on malaria control/case prevention?
Insecticide treated nets
Why has progress stalled in malaria control?
— COVID-related disruptions
— Climate change
— Humanitarian crises
— Limited funding
— Insecticide & artemisinin resistance
— Invasion of An stephensi
— Health systems challenges
Ideas for new tools to combat malaria?
Vaccines
Longer lasting insecticides (non-pyrethroid? -> growing resistance)
Vector tools to address outdoor biting
Single-dose preventive therapies (monoclonal Abs)
Diagnostic tools for latent P.vivax infection
New drugs to mitigate ACT resistance
Single-dose chemoprevention therapies
What is the R0 or basic case reproductive rate?
The defined no. of secondary cases arising from a single primary case in a fully susceptible human population
Vectorial capacity
Total no. of potentially infectious bites that arises from all the mosquitoes biting a single perfectly infectious human on a single day
What does R0=1 mean?
Stable transmission
Each new case gives rise to a single further case – Total number of cases remains the same
R0>1 means?
Cases increase until entire population is infected
R0<1 means?
Cases decline until infection disappears
What is the Ross-MacDonald equation?
R0 = ma2pn/-r(logeP)
- m = mosquito density (number of female mosquitoes per person)
- a = the frequency with which each female bites a human (vs animal)
- p = survival rate (probability of mosquito surviving a full day after being infected)
- n = length of sporogonic (extrinsic) cycle
- r = recovery rate of humans
What are the danger signs for malaria cited in the IMCI (integrated management of childhood illness) for children 2-59 months in areas of malaria transmission?
Fever or hx of fever in past 24h OR palmar pallor plus 1 or more:
- Unable to eat or drink or breastfeed
- Vomiting everything
- Multiple convulsions
- Lethargy
- Unconsciousness
- Stiff neck
- Chest indrawing or stridor
What are the danger signs in the IMAI (integrated management of adult illness) for older children and adults in areas of malaria transmission?
Fever or hx of fever in past 24h plus 1 or more:
- Very weak or unable to stand
- Convulsions
- Lethargy
- Unconsciousness
- Stiff neck
- Resp distress
- Severe abdominal pain
Definition of severe falciparum malaria
One + of below with P falciparum asexual parasitaemia in absence of alternative cause:
- Impaired conciousness
- Prostration
- Multiple convulsions
- Acidosis
- Hypoglycaemia
- Severe anaemia
- Renal impairment
- Jaundice
- Pul oedema
- Significant bleeding
- Shock
- Hyperparasitaemia
After what diagnostic tests over what period of time can you rule out a diagnosis of malaria?
At least 3 diagnostic tests over 24-48hr
What molecules do RDTS detect for malaria?
Histidine rich protein 2
Plasmodium lactate dehydrogenase (pLDH)
Both can increase through trophozoite development
Treatment for non-severe malaria?
ACT: eg artemether + lumefantrine (AL), or artesunate + amodiaquine (AS + AQ)
Reasons for recurrent malaria or patient coming back sick again?
Can result from re infection or recrudescence (eg treatment failure)
- ?drug resistance
- Suboptimal dosing
- Poor adherence or vomiting
- Substandard or fake medicines
Need to confirm recurrence with microscopy (not RDTs)
May not be possible to distinguish recrudescence from infection in individual patients -> need PCR for genotyping
Re infection very common in high risk areas
Management of treatment failure for malaria (non-severe)
Within 28 days: alternative ACT
After 28 days: consider as new infection and treat with first line ACT
Note: do not retreat with AS+MQ (artesunate + mefloquine) -> increased risk of neuropsychiatric reactions
Alternative treatment for uncomplicated falciparum malaria if ACTs are not available
- Malarone (atovaquone-proguanil), weight based, OD, 3 days
- Quinine + doxycycline, Q 8hrly + doxy daily, 7 days
- Quinine + clindamycin, Q 8hrly + clinda 8hrly, x7days
How to treat falciparum in pregnancy?
1st trimester: artemether-lumefantrine
2/3rd trimesters: treat with ACT
What is a key SE/risk of quinine treatment for malaria?
Hypoglycaemia
What malaria drugs should never be used in pregnancy?
Primaquine
Tetracyclines eg doxy
What treatment should be given to prevent relapse of vivax or ovale?
Primaquine (0.5mg/kg/day) for 7 days for children and adults
NOT if pregnant or breastfeeding
What treatment should be given to women pregnant or breast feeding if vivax or ovale? (ie to prevent relapse)
Weekly chemoprophylaxis with CQ until delivery and breastfeeding are completed
If then G6PD ok -> primaquine
What treatment should be given to G6PD negative people to prevent relapse with vivax or ovale?
Primaquine base at 0.75mg/kg bw once a week for 8 weeks (with close medical supervision)
41 yo woman presents to hospital with fever, chills, vomiting x 3d. She’s 18 weeks pregnant & lives in Uganda. She’s had malaria several times before but has no
other PMH. No concerning signs for severe malaria. PCR positive for P ovale. Treatment?
CQ - treatment dose for two days then weekly suppression whilst pregnant and breast feeding
Once stopped BF then check G6PD level and if ok -> for 7 days primaquine
How did the evidence on primaquine change in 2022?
Alternative standard dose -> shortened course regimen to 0.5mg/kg/day for 7 days rather than treating for 14 days
Was made as shorter regimen could lead to better adherence and to fewer relapses
How does primaquine work for falciparum?
Kills mature (stage V) gametocytes
What treatment is recommended to reduce risk of onward transmission of falciparum malaria in endemic low transmission areas?
Single dose of primaquine + ACT
(Not in pregnant/BF women, infants <6mths, or older infants with unknown G6PD status)
You are asked to provide pre-travel advice for a family traveling to East Africa on holiday to visit relatives for 3 weeks.
The following family members are planning to travel:
* Mother – aged 35, 15 weeks pregnant
* Son – aged 3 years, weight 17kg
* Daughter – aged 3 months, weight 5.2kg
* Grandmother – aged 65, history of depression
What will you recommend?
Mum: either mefloquine if no hx of MH issues and if grandmother is paternal, otherwise don’t go
Son: Malarone (or mefloquine)
Daughter: mefloquine
Grandmother: Malarone (or doxy)
Non-chemoprophylaxis advice for malaria
– Sleep under an insecticide treated bednet,
– Cover up between dusk and dawn
– Repellants with 30-50% DEET
Common severe malaria complications in adults
Coma/convulsions
ARDS
**AKI
Shock/hypoglycaemia
Hyperparasitaemia
Common severe malaria complications in kids
**Coma/convulsions
AKI
Shock/hypoglycaemia
**Severe anaemia
Respiratory distress secondary to acidosis
Hyperparasitaemia
WHO/UK threshold for hyperparasitaemia
WHO: >10%
UK: >2%
Blantyre coma score
Motor:
Localises painful stimulus 2
Withdraws limb from pain 1
Non-specific or absent response 0
Verbal:
Appropriate cry 2
Moan or inappropriate cry 1
None 0
Eyes:
Directed/following 1
Not directed 0
Holoendemic
Disease for which a high prevalent level of infection begins early in life and affects most of the child population, leading to a state of equilibrium such that the adult population shows evidence of the disease much less commonly than do children
Hyperendemic
Persistent, high levels of disease occurrence
Mesoendemic
An endemic disease with a moderate rate of infection. This term is often used to describe the prevalence of malaria in a local area, with 10 to 50% of children showing evidence of prior infection being considered a moderate level for that disease.
Hypoendemic
A disease that is constantly present at a low incidence or prevalence and affects a small proportion of individuals in the area. A term commonly used in malaria literature to refer to regions with low transmission.
In early years eg up to 3 years old, what is the dominant severe falciparum malaria manifestation in low vs high endemic areas?
Areas of low transmission: cerebral malaria
Areas of high transmission: severe anaemia
What three pathophysiological processes result in most of the major manifestations of severe falciparum?
Sequestration
Microvascular obstruction
Organ dysfunction
Clinical features associated with case fatality from malaria?
– Impaired consciousness (multiple factors)
– Presence of retinopathy (highly suggestive)
– Convulsions common (but can be sub-clinical)
– Increased ICP (in > 80% of children, NL in adults)
– Cerebral oedema (more common in children)
Features of retinopathy in malaria
- Retinal whitening (macular or peripheral)
- Discolouration of retinal vessels (white or orange)
Non specific:
- Retinal haemorrhages, especially with white centres
- Papilloedema
Levels of severe anaemia in malaria for children and adults
Haemoglobin < 5g/L in children, < 7g/dL in adults
Causes of severe anaemia in children and adults with malaria?
– Spleen filters both infected & damaged uninfected cells
– Intravascular haemolysis
– Bone marrow suppression
– Repeated malaria infection
Apart from the infection itself, what are some other contributors to severe anaemia with malaria?
HIV, bacterial infections, hookworm, deficiency of B12 & Vitamin A
What drives breathing issues in malaria with kids vs adults?
Kids: acidosis + pneumonia
Adults: ARDS, pul oedema, pneumonia
What is the most common pathogen associated with bacteraemia with malaria?
non-typhi Salmonella
Clinical features associated with case fatality from malaria in AQUAMAT trial?
Base deficit >8mmol/L
Coma
Uraemia (Bun?20mg/dL)
Underlying chronic illness
What are warning signs of severe malaria on peripheral smear?
High parasite density
Presence of schizonts on peripheral blood smear
Pigment in the neutrophils
What did both AQUAMAT and SEQUAMAT show?
Both showed in African and South Asian setting artesunate>quinine for severe malaria
SEQUAMAT showed even better in those with high parasite counts as brings counts down in 2 days whereas quinine takes 7
Basic management of severe malaria
- Admit
- IV/IM artesunate for a minimum of 24hrs (2.4mg/kg at 0,12,24 hrs then 24hrly, if <20kg then 3mg/kg)
- Stepdown to ACT 3 days
- Consider primaquine if vivax/ovale or low transmission area for falciparum
ALSO CONSIDER GIVING EMPIRICAL ABx eg CEFFTRIAXONE
Key side effect of artesunate?
Risk of delayed haemolysis
Rapidly kills ring-stage parasites which are then taken out of red cells by the spleen
These RBCs then return to circulation but with shortened life span -> haemolysis
Occur often 1 week after treatment: patient with s/s anaemia and dark urine (bilirubin)
Worse in patients with hyperparasitaemia and non-immune travellers
Benefit of artemether over quinine
Need smaller volumes for IM injection
In kids >5 and adults may be superior to quinine
How do you manage patients pre-referral for suspected severe malaria?
Where complete treatment of severe malaria is not possible, but injections are available, adults and children should be given:
○ A single IM dose of artesunate & referred to an appropriate facility for further care
○ If IM artesunate is not available, give IM artemether or, if that is not available, IM quinine
Where IM injection of artesunate is not available:
○ Children < 6 years should be treated with a single rectal dose (10mg/kg bw) of artesunate & referred immediately to an appropriate facility for further care
○ Rectal artesunate should not be used in older children and adults
What are some of the neurological sequelae of CM and how long do they persist for?
Resolve within 6 mth: Hypotonia, ataxia, tremors, cortical blindness, aphasia
Persist: Motor deficits
Worsen: SAL(T) + cognitive deficits
Develop: behavioural disorders, epilepsy
What are some of the associations of placental malaria and which pregnancy is most at risk?
First pregnancy then reduction in risk -> can acquire Abs against CSA-binding iRBCs and resistance to placental malaria
IUGR
Preterm labour
LBW
SGA
Stillbirth
Pathophysiology of placental malaria
- Sequestration in intervillous space of placenta
- Cytoadherence via chondroitin sulphate A
First time mothers: lack immunity to CSA-binding parasites so highly susceptible to parasitaemia and chronic infection
SO important reservoir for infection
Why can malaria be difficult to diagnose during pregnancy?
Women living in endemic areas develop anti-malarial immunity from lifelong exposure to falciparum parasites -> controls infection
What is IPTP?
Intermittent preventitive treatment of malaria during pregnancy.
Given:
Curative dose of an effective antimalarial drug (currently sulfadoxine-pyrimethamine) to all HIV-negative pregnant women in areas of moderate to high malaria transmission without testing whether infected or not
Usually given at each antenatal visit
When should a blood transfusion be considered for severe anaemia in malaria?
– In high transmission settings, transfuse children if Hb < 5 g/dL (Hct < 15%)
– In low transmission settings, Hb < 7 g/dL (Hct < 20%)
What does HIV infection do to malaria severity?
increases malaria severity
- Higher parasite densities (in partially immune)
- Risk of severe malaria & death (in less immune)
- In pregnant women, ↑adverse effects of placental malaria
What are two relevant drug reactions in HIV if being managed for malaria?
Efavirenz increases AQ exposure & risk of toxicity
Avoid artesunate and sulfadoxine if taking co-trimoxazole
Avoid artesunate and amodiaquine if being treated with efavirenz or zidovudine
Common severe manifestations of vivax
Severe anaemia
Respiratory distress (especially in children)
Acute renal failure
How is Knowlesi defined?
Defined as for falciparum but with two differences
– Hyperparasitaemia = parasite density > 100,000/µL
– Jaundice & parasite density > 20,000/µL
Associated with high parasite densities, treat as for falciparum
WHO guidance for severe resistant malaria
Treat with artesunate and CQ together
Repeat films after course of treatment
Current threats to malaria control?
Drug resistance
Insecticide resistance (pyrethroids)
P falciparum lacking HRP2/3 (RDTs don’t pick up parasite)
Anopheles stephensi
Goals for TB vaccine
Prevent infection, progression of disease especially pulmonary, prevent reinfection and reactivation
Better TB vaccine for neonates/infants compared to BCG (aim to be safer in immunocompromised) + more sustainable to produce
Vaccine to improve TB treatment outcomes -> prevent re-infection, increase proportion of survivors to cure, shorten and simplify drug treatment regimens (ie vaccine in addition to treatment)
Risk factors for childhood TB
- Infectiousness of index case
- Age of child
- Proximity to and duration of contact with index cases
- Immune status of child
- Children of families living with HIV
- Other illnesses eg HIV, pertussis, malnutrition, post-measles etc
Three most frequent symptoms of TB in children
- Persistent unremitting cough >2-3 weeks
- Intermittent fever
- Weight loss/failure to gain weight
What is the differentiation between young and older kids in terms of TB presentation and diagnosis? (binary)
Young children <5
- High risk of LN and disseminated disease
- Clinical diagnosis more common
Kids >15 years
- Higher risk of adult type disease
- Bacteriological confirmation of TB is common
Why do young children eg <2 years old have a higher risk of LN TB and disseminated disease?
Immaturity of immune system
Less resident macrophages and existing ones more immature
Two pathways for TB infection in kids?
- 50-90% -> containment with granuloma leading to latent infection (more likely the older child is)
- Primary progressive pulmonary disease -> disseminated disease (military TB, TB meningitis)
Investigations for TB
- Immune based tests – Tuberculin Skin T est; Interferon-γ Release Assay
- Radiology – X ray, CT scan
- Sputum samples collection
- Pathogen detection tests:
i. Microbiological tests – culture
ii. Molecular / Nucleic acid amplification test – GeneXpert, Truenat - Histological tests – FNAB/FNAC
- Biomarkers – futuristic, subject of intense research
How does the TST work, what does a positive result suggest and what is it impacted by?
Delayed-type hypersensitivity reaction to PPD; heterogenous mix of mycobacterial proteins
§ Positive TST suggests M.tb infection or sensitization to M.tb Ag - results do NOT indicate or rule out TB disease
Impacted by prior BCG vaccination (false positive), NTM exposure, HIV
Is IGRA helpful to diagnose TB in kids?
§ Sub-optimally sensitive in children + in immunosuppression
Indeterminate results common in young children
Common CXR manifestations of TB in kids?
Hilar lymphadenopathy
Pulmonary effusion
Paratracheal lymphadenopathy
Miliary TB
Adult type disease if older eg dense alveolar consolidation, cavities
Types of sputum sample collection for children with suspected TB?
Spontaneous sample: older children or adolescents
§ Sputum induction (<7 years)
§ Gastric washings (<6mths)
BAL
§ Not necessary if induction can be done
Personnel need to be trained, hospital admission needed with overnight fasting
What is the value of culture for TB diagnosis in kids?
Childhood TB is paucobacillary: 95% of TB cases in children <12 years are smear negative
Culture-positive: 4.2% (<5yo), 5% (5-9 yo) and 21% (10-14yo)
Culture positivity in kids rarely exceeds 30%
How are the majority of TB cases in children diagnosed?
Clinical features +/- radiology
Extrapulmonary manifestations in children of TB
Enlarged, non-tender LNs (esp cervical)
Painful swelling of joint or bone, which has slowly arisen over time
Angular deformity of spine
Abdominal swelling - hard, painless (+/- free fluid)
What are the challenges in diagnosing TB in kids?
1) TB in children mimics other common childhood diseases
2) Childhood TB is paucibacillary in nature
3) CXR changes often non-specific; inter-reader variability
4) TST / IGRA of limited value in TB-endemic settings
CSF features of TBM
Elevated opening pressure
Cells (?mononuclear, can be some neutrophils, variable no.)
Elevated protein
Low glucose
Xpert ultra and culture ~50% (no single test can rule out TBM)
Relationship between diabetes and TB?
Diabetes is associated with active TB -> 3.6 fold higher TB risk
What is latent vs subclinical TB?
Latent
- Asymptomatic
- Sputum does not contain enough bacteria -> can’t culture it
- CXR would be negative
Subclinical
- No symptoms and don’t feel ill
- But TB prevalent and active
- Ie if given a sputum pot they can produce some and TB can be grown
- Might have some CXR changes
What is MDR TB?
Resistance to rifampicin and isoniazid
Pre-diagnostic loss to follow up (LTFU)
Screened for disease but no investigations
Pre-treatment LTFU
Diagnosed with disease but not started on treatment
Normal regimen for TB prevention?
Daily isoniazid
6-9 months
(most programmes go for 6 months)
Other options compared to standard regimen for TB prevention? 2024 update,
Weekly rifapentine and isoniazid for 3 months
- issues with regulation and rolling out
OR
Daily isoniazid plus rifampicin for 3 months
OR (conditional recommendation)
1 month regimen of daily rifapentine + isoniazid or 4 months of daily rifampicin
2024 update:
levofloxacin daily for 6 months for people exposed to multidrug- and rifampicin-resistant TB
Normal regimen for TB prevention in children<15 years?
Daily rifampicin and isoniazid for 3 months
What was the DOTs policy package? What disease was it for? What are the 5 strategies?
TB
○ Increase political will
○ Diagnosis based on quality-assured sputum testing: “passive case finding”
○ Uninterrupted standard 6 months treatment course ie uninterrupted drug supplies
○ Patient support (DOT - directly observed therapy)
○ Systematic reporting % cure
What are the possible treatment outcomes for TB?
- Treatment success: Cured + Treatment completed cases
- Failed treatment
- LTFU
- Died
- Not evaluated
Diagnostics for Malaria
- Field based
○ Microscopy
○ RDTs - Molecular methods
○ qPCR (quantitative PCR/real time PCR)
○ PCR (eg nested PCR methods)
Genome sequencing (eg field-based Nanopore sequencing)
How can falciparum parasites produce a false negative RDT result?
Parasites found to lack HRP2 and HRP3
- Method of resistance to evade diagnostics ie gene deletion
Why is vivax more widely spread geographically?
Can replicate/survive at lower temperatures
- Can be transmitted by lots more mosquito species
- More transmissible to mosquitoes and make them earlier on in infection
- ?day biting so nets less effective
Traditionally less efficient at invading Duffy negative RBCs but this is now changing
Which malaria parasite has the fastest erythrocytic cycle?
Knowlesi
What plasmodium can cause chronic, undetectable infection?
malariae
low parasitaemia
quartan fever pattern
slowest erythrocytic cycle
Where is Knowlesi restricted to and why?
SE Asia esp Malaysia
Mosquito presence
Macaques prevalence
Two species of plasmodium ovale?
Curtisi
Wallikeri
Information to obtain from diagnostics for malaria?
- Species?
- Parasite density?
- Is it original infection or relapse?
- Any drug resistant genotypes?
How can microscopy correlate with severity of clinical status of malaria?
Lots of gametocytes -> sicker patient
Parasite starts accelerating sexual reproduction for onward transmission
3 formulations of RDTs for malaria?
○ Pan-plasmodium LDH
○ P.falciparum-specific HRP2
○ P.falciparum-specific LDH
What plasmodium species gives a lot of false negatives with RDTs?
Ovale
Can you use nested PCR to quantify parasitaemia?
No
Only species detection
What type of molecular diagnostic test can you use to work out species and parasitaemia?
qPCR or rtPCR
What can whole genome sequencing tell you for malaria?
○ Species
○ Drug resistance markers
○ Multiplicity of infection (clonal/polyclonal -> ie are there multiple strains of species infecting patient)
○ Original infection/relapse
○ Origin of infection
Goals of the End TB strategy vs SDG targets
- Drop TB cases (reduce incidence 90%)
- Drop deaths from TB (reduce by 95%)
- Drop catastrophic costs due to TB
By 2035
(Goals made in 2014)
SDG targets by 2030
- reduce incidence by 80%
- reduce deaths by 90%
- reduce catastrophic costs to 0
TB is most prevalent in which group
Adult men = 55%
Evidence based TB interventions that could be scaled up straight away (3)
- Digital CXR + Computer Aided Diagnostics then sputum PCR at primary care
○ Convenience screening +/- symptoms
CAD since 2022 being recommended for first time as alternative to human interpretation - Urine-LAM (TB antigen) screening for all hospitalized HIV+ medical patients
○ New LAM tests may expand this remit - Community interventions with evidence for affordable impact
- Digital CXR-based
- Symptom + smear microscopy-based
Microscopic features of Plasmodium falciparum
- Red cells NOT enlarged
- Rings appear fine and delicate and there may be several in one cell
- Some rings can have two chromatin dots
- Presence of marginal or applique forms
- Unusual to see developing forms in peripheral blood films
- Gametocytes: crescent shape appearance
○ Do not appear in peripheral blood in first few weeks of infection
Maurer’s dots may be present
Microscopic features of Plasmodium vivax
- RBCs containing parasites usually enlarged
- Schuffer’s dots in red cells
- Mature ring form large and coarse
- Developing forms frequently present
Features of plasmodium malariae malaria
- People can be infected for long periods before symptomatic
- Incubation 18-40 days
- Quartan fever pattern
- Slowest growth => longest erythrocytic cycle
- Associated with rare kidney pathologies and fatalities
- Frequently low parasitaemias
Microscopic appearance of plasmodium malariae
- Ring forms can have a squarish appearance
- Can also be bulls eye -> ie centralised in cell
- Trophozoites can be band form or compact
- Mature schizonts -> daisy head appearance with 8-10 merozoites
- Red cells NOT enlarged (parasite likes old cells)
Chromatin dot may be on inner surface of ring
Microscopic features of Plasmodium ovale
- Red cells enlarged
- Comet forms common
- Rings large and coarse
- Schuffner’s dots
- Can have fimbriae -> jagged edge
- Mature schizonts
- Similar to those of P malariae but larger and more coarse
Which plasmodium species shows seasonal variability?
Ovale
Causes of eosinophilia
Atopic
Haematological
Rheumatological
Drugs
Infection - most commonly parasites
Differentials for transient, migratory lesions
Loa loa
Gnathostoma
Sparganum
Why should you not use ivermectin to treat loa loa and what should you use instead?
Can result in large inflammatory reaction in people who have lots of microfilariae eg encephalopathy due to body reaction in response to worms being killed
What is a dimorphic fungi?
Yeast in the beast
Mould in the cold
eg histoplasma
Treatment of causes of transient migratory lesions
Albendazole or Ivermectin (but not IVM for loa loa)
Clinical tests for fungi
Beta D glucan
Galactomannan
Serology (less helpful in immunocompromised patients eg HIV, as can’t mount a proper response)
If particular suspected cause, then specific test eg Histoplasma urinary Ag
Treatment of disseminated histoplasmosis
Amphotericin B (ambisome is liposomal form)
Treatment of localised, pulmonary histoplasmosis
Itraconazole
Examples of dimorphic fungi
Histoplasma
Blastomyces
Coccidioides
Paracoccidiodes
Sporothrix
Penicillum = Talaromyces
Containment level 3
Two common yeast species causing disease in humans
Candida eg albicans or non-albicans
Cryptococcus neoformans
What type of organism does India ink reveal thick capsule for?
Cryptococcus neoformans
What disease might a person pick up by inhaling air in a bat cave?
Histoplasmosis
Common in bat faeces
Manifestations of disseminated histoplasmosis
Reticuloendothelial involvement
Skin nodules
Mouth ulcers
Renal, bone, CNS, liver lesions
Adrenal involvement (hypo)
Uveitis, panophthalmitis
A farmer from rural Sudan presents with 6 months of worsening foot pain, non-healing ulcers and difficulty walking. USS showed a soft tissue mass behind the ankle and he had some nodular skin changes over the heal. What is most likely diagnosis and how would you treat?
Madura foot eg Eumycetoma pedis
Prolonged course of antimicrobial eg Itraconazole or Voriconazole
- Difficult as need levels and monitoring
Triad of mycetoma eg Madura foot
Tumour - growth
Tracts - body’s attempt to drain and get pus out
Grains - release of grainy liquid of fungal colonies
Most common cause of fungal Madura foot
Madurella mycetomasis
- a environmental soil mould
- hot spot in Sudan
Differentials for mycetoma ie Madura foot
Actinomycosis
Podoconiosis
TB
Non-tuberculosis mycobacterium
Bacterial osteomyelitis
Types of liver flukes
Fasciola (big)
Opisthrochis
Clonorchis
Treatment for fasciola
Triclabendazole 10mg/kg/PO
2 doses 12-24 hours apart
What are opisthrochis and clonorchis and where are they endemic? How do you get them? How do you treat them? What pathology are they associated with long term?
Liver flukes eg trematodes
Central and east Asia eg Kazakhstan, Siberia, eastern Russia
Eating raw or undercooked fish
Treat with praziquantel
Cholangiocarcinoma
How do you get fasciola hepatica or gigantica?
Eating watercress
How can you diagnose fasciola hepatica acutely vs chronically?
Acute infection
§ Eosinophilia
§ May have positive serology (6-8 weeks for Ab to develop)
§ Negative OCP (not early enough to get eggs in stool)
Chronic
§ Positive serology
§ May have eosinophilia
§ Intermittent eggs in stool
Differentials for liver abscess?
Bacterial
Amoebic (singular, big, ring-enhancing)
Echinococcosis
Differentials for umbilicated lesions in SE Asia
- Molluscum contagiosum
- Cytomegalovirus
- Cryptococcus neoforms
- Dimorphic fungi: histoplasmosis/talaromycosis
- Syphilis
- TB
- Trichoepitheliomas
- Tuberous sclerosis
28M from Northern Thailand presents with Fever + weight loss +
non-productive cough + skin lesions + abdominal discomfort.
O/E: hepatomegaly and he is covered in umbilicated lesions. A biopsy shows yeast with inner septum. What is the diagnosis and treatment?
Talaromycosis caused by Talaromyces marneffei
Management:
- Severe:
○ Induction: Ambisome 7-14 days or Amphotericin B IV (0.7mg/kg/day) at least 14 days
○ Consolidation therapy: Itraconazole PO BD for next 10 weeks
Mild/moderate:
Itraconazole
If HIV positive then secondary prophylaxis with itraconazole until CD4+ count of >100 cells for at least 6 months (suggestion)
Features of talaromycosis
Dimorphic fungus
Bamboo rats are reservoir
Associated with HIV and poverty
Infectious mould spores inhaled from soil
Skin lesions only present in around 50% of patients (usually late stage infection)
Symptoms: weight loss, prolonged fever, fatigue, diarrhoea
Signs: hepatosplenomegaly, anaemia, lymphadenopathy
CXR: chest signs common, may see diffuse reticulonodular or alveolar infiltrates
Relationship between incidence, duration of HIV and prevalence
P ~/= ID
Treatment increases -> duration of disease to rise + incidence to fall
- HIV prevalence should continue to rise or be stable for time to come
Means need to consider its role in aetiology and management of other conditions
When were ARTs first approved by US FDA?
1987, more in 1990s and 2000s
The HIV fast track targets (by 2030)
95 95 95
* First 95: 95% of PLHIV know their status
* Second 95: 95% of PLHIV on treatment
* Third 95: 95% of PLHIV on treatment achieved viral suppression
Where is HIV incidence now increasing?
Middle income countries eg
- West Africa
- South America
- Asia
Where is HIV-2 most prevalent?
West Africa and places with ties to WA
Mechanisms of transmission of HIV
Sexual
- Transmission through semen, vaginal fluid, blood, anal mucus
- Heterosexual transmission is main mode of spread globally
Parenteral
- Transmission through skin or via blood/blood products
Mother-child transmission
During pregnancy, labour or through breastfeeding
HIV prevention tools
- Treatment
○ Treatment as prevention (U=U) - HIV combination prevention
○ Behaviour change including consistent condom use
○ Biomedical interventions: eg Voluntary medical male circumcision, Pre-exposure prophylaxis (PrEP)
○ Supportive political and health care environment - Prevention of mother-to-child transmission (PMTCT)
HIV testing for access to treatment and some prevention
Equation for HIV reproductive number
R0 = c x ß x D
R0: Basic reproductive number
C: Exposure rate
–Influencing factors: Norms around multiple partnerships, sexual violence
ß: Probability of HIV transmission
–Influenced by: Ability to negotiate condom use, age at first sex, availability of PrEP
D: Duration of infectious period
–Influenced by: Access to treatment
What is a concentrated HIV epidemic?
HIV has spread rapidly in one or more defined subpopulation but is not well established in the general population.
Numerical proxy: HIV prevalence is consistently over 5% in at least one defined subpopulation but is less than 1% among pregnant women in urban areas.
What is a generalised HIV epidemic?
HIV is firmly established in the general population.
- Numerical proxy: HIV prevalence consistently exceeding 1% among pregnant women. Most generalized HIV epidemics are mixed in nature, in which certain (key) subpopulations are disproportionately affected.
What is a mixed HIV epidemic?
People are acquiring HIV infection in one or more subpopulations and in the general population. Mixed epidemics are therefore one or more concentrated epidemics within a generalized epidemic.
WHO identified populations at risk of HIV infection?
Five key populations in 2016 WHO guidelines
1. Sex workers*
2. People who inject drugs
3. Men who have sex with men (MSM)
4. People in prisons or other closed settings
5. Transgender people
Also region- or country-specific populations at elevated risk
- Migrant populations
- Occupational groups: fisherfolk, truck drivers, miners
Adolescents*
Why are adolescent girls at higher risk of HIV?
- Biological vulnerability: higher per-act risk of sexual transmission, higher STI prevalence, anatomical development
- Behavioural vulnerability, including risky sexual behaviour
- Social and structural vulnerability: gender-based violence, lack of access to services increase risk and decrease access to PrEP and other HIV prevention
Properties of HIV (virology)
- Retroviridae family
- Lentivirus
- HIV-1 and HIV-2 species
Single stranded, sense RNA
Process of HIV infection (cellular)
- Gp41 and Gp120 bind onto CD4 cell using CCR5 or CXCR4 co-receptor
- Fusion with membrane
- Expels capsid into cell cytoplasm
- Capsid makes way to nucleus via nuclear import (using microtubules)
- Then viral RNA exposed
- Reverse transcription
- Integration of proviral DNA into human genome -> stays there forever in that cell
- Transcription to make proteins eg enzymes, viral particles
- Nuclear export
- Assembly of new virus with utilisation of cell membrane -> budding
- Release of new virion
Maturation
Pathogenesis of HIV
- Local infection of mucosal tissues
○ Can’t detect virus in blood in this stage - Death of mucosal memory CD4+ T cells
- Infection established in lymphoid tissues eg LNs
- Viraemia after infection in blood
- Spread through body
- Immune response -> but is incomplete and dysfunction ie partially control viral replication
○ Abs can’t completely neutralise virus
○ Cytotoxic T lymphocytes - Due to widespread dissemination of HIV in lymphoid tissue -> clinical latency due to reservoir
○ Chronic + concentrated low-level viral production in lymphoid tissues
○ Inflammation associated with viraemia
§ Cytokine storms
§ CV disease
§ Metabolic issues - Eventually increased viral replication
- AIDs -> destruction of lymphoid tissues + depletion of CD4+ T cells
How to test for HIV? What are the respective window periods?
Two tests: 4/5th generation assays
○ Ie get two positive results
Then immunotyping
4/5th generation include:
p24Ag + Abs combined OR
separate p24 Ag and Ab components
(p24 is protein in viral caspid)
Window period 45 days for Ab/Ag assays, 90 for POCT
What does high viraemia in HIV mean for HIV species?
- Immune selection pressure –> escape mutants –> quasispecies created
- 1-10 mutations per replication cycle, with production of 1 billion virions a day
- Older infection = more diverse
- Drug selection pressure
What is virological failure in context of HIV?
- Failure of ART to reduce viral load
WHO can define as viral load >1000 copies on ideally two tests - Need to do genotypic resistance test:
Protease and integrase are standard
Can result from archive mutations -> means can re-emerge if patient re-started on treatment having been incompletely treated in the past (which may be unknown to healthcare provider)
What is pre-treatment drug resistance in context of HIV?
HIVDR detected in individuals initiating ART regardless of prior antiretroviral (ARV) drug exposure(s) (e.g. prior ART followed by default from care ie stopped taking it or lost to f/u, pre‐exposure prophylaxis (PrEP), post‐exposure prophylaxis (PEP))
Means archive mutations can re-emerge when ART is started
IE: PDR may either be transmitted at time of initial infection or acquired by prior exposure to ARV drugs
Drug resistance concepts for HIV
- Mixed population including drug-resistant minority variants
- Subtherapeutic drug levels e.g. adherence issues
- Selection pressure -> resistant variants flourish
- Usually not “fitter” than wild-type
- Take away drug (ART cessation/onward transmission)
○ wild-type takes over again - Archived resistance
- Compartmentalisation e.g. CNS
Properties of HIV-2
- Origin West Africa
- More indolent
- Slower progression
- Slower CD4 decline
- VL lower
- Intrinsic NNRTI resistance
What is the most important determinant of OI risk?
CD4 count at baseline
Two components:
1. Number of CD4 T cells
2. Differences in phenotype and function of pathogen-specific CD4 T cells
What is the definition of advanced HIV disease?
CD4<200 cells/mm3
OR
WHO stage 3 or 4 event
Children<5 years old with HIV
Clinical manifestations of HIV?
- Primary HIV infection
○ Acute viral illness or asymptomatic - Chronic viral infection: direct viral effects and inflammation
○ Adenopathy, haematological, skin disorders
○ Higher risk of non-HIV cancers, cardiovascular disease, osteoporosis
○ HAND, wasting syndrome, HIVAN - Opportunistic infections and cancers: impaired cellular immunity
○ Many pathogens; related to CD4 count - ART-associated effects eg IRIS, toxicity
What is IRIS?
Immune reconstitution syndrome
- High mortality in first 12 months of starting ART
- Usually 4-6 weeks after starting ART
Two forms:
○ Paradoxical IRIS
○ Unmasking IRIS
Causes of lymphadenopathy in HIV at any CD4 count
TB (TB - IRIS)
Syphilis
Lymphoma
KS/Castlemans
NTM
Causes of lymphadenopathy in HIV at CD4<100
Nocardia
Dimorphic fungi infection eg hits, emergomycosis, talaromycosis, sporotrichosis
Cryptococcus
Mucocutaneous manifestations of mild/early HIV infection
- Herpes zoster
- Papular pruritic eruption (PPE)
- Molluscum contagiosum
- Apthous ulcer
- Oropharyngeal candidiasis
- Oral hairy leukoplakia
What is PPE in HIV and how does it present?
Papular pruritic eruption
○ Eosinophilic folliculitis
○ Occurs at any CD4 count
○ ++ discomfort; can lead to scarring
○ No specific treatment:
§ Antihistamines, symptomatic
○ Easily confused with dimorphic fungal infection –> always biopsy if CD4 <100 or constitutional symptoms
Differentials for molluscum like rash in HIV?
§ Cryptococcosis
§ Histoplasmosis, talaromycosis
§ Mpox
Causes of apthous ulcers
§ Early HIV
§ Lymphoma and KS
§ Herpesviruses: HSV, CMV
§ Other infections
§ Tuberculosis
§ Syphilis
§ Deep fungal infection
§ Leishmaniasis
§ Rheumatologic diseases and IBD
Two forms of pneumocystis jiroveci and characteristics? How do you diagnose PCP?
Ascus forms (cystic)
Transmissible form
Thick cell wall containing beta-glucans
Contains cholesterol (not ergosterol, so can’t be targeted by traditional anti-fungals)
Immune stimulus
Trophic forms (trophozoite)
Replicative form (more abundant in lungs)
Wall-less -> biofilm
Contains cholesterol (not ergosterol, so can’t be targeted by traditional anti-fungals)
Immune evasive
DIAGNOSING IT”
§ Gold standard bronchoscopy: not available
§ Sputum-based tests not accurate enough
§ Most patients started on empiric therapy
qPCR:
good rule out test on induced sputum and oral wash
B-D-Glucan:
After a negative test: Rules out PCP with 95% certainty up to a pre-test probability of 50%
After a positive test:
Increases chance of PCP to ~70% for any HIV-
associated pneumonia (prevalence of PCP ~25%)
Treatment for PCP
Co-trimoxazole 21 days high dose
TMP-SMX = trimethoprim-sulfamethoxazole, used both for PCP prophylaxis and treatment
Respiratory illnesses at any CD4 count in HIV
Bacteria (especially pneumococcal disease)
TB and PTLD
Resp viruses
NTM
Respiratory illnesses in HIV with CD4 <200
PCP
KS
Lymphoma
Respiratory illnesses in HIV with CD4 <100
Cryptococcus
Dimorphic fungi
CMV
What causes oral cell leukoplakia? How can you differentiate it from candidiasis?
EBV
- No treatment
You can do tongue scrapings on candida throat/tongue, not on OCL
Differential diagnosis for mediastinal lymphadenopathy in HIV
TB
Lymphoma
Mycobacteria
Dimorphic fungi
Cryptococcus
Nocardia
Differential diagnosis for pleural effusion in HIV
- TB
- Bacterial
- KS
- Cryptococcosis
- Lymphoma (KSHV-related)
Treatment for toxoplasmosis?
Treat toxoplasmosis with co-trimoxazole
Differential diagnosis of lymphocytic meningitis in HIV
- TBM
- Cryptococcal meningitis
- Viral meningitis
- Bacterial meningitis (pneumococcus and meningococcus)
- Listeria
- Syphilis
Differential diagnosis of intracranial mass lesion in HIV
- TB
- Toxoplasmosis
- Nocardia
- Pyogenic brain abscess
- Lymphoma
- Cryptococcus
- Syphilis
Differentials for severe weight loss in HIV
- Opportunistic diseases - TB, NTM, lymphoma, deep fungal, leishmaniasis
- HIV wasting syndrome
- GI pathology
- Painful oral/oesophageal lesions
- Severe chronic diarrhoea - Other malignancy
- Depression – very common & often unrecognized
- Lack of financial resources to buy food
35 years old female
Known HIV positive, treatment defaulter, CD4 = 14 cells/µL
1 seizure
2 week history of headache
Stiff neck
Cough for 1 month
Weight loss, diarrhoea
Mild meningism
Glasgow Coma Score 14/15
Ddx?
Toxoplasmosis
CMV
PML
Cryptococcal meningitis
TBM
Bacterial meningitis
Viral meningitis
VZV
Primary CNS lymphoma
Pathogen detection tests for CNS infections in HIV
○ Stains (Gram, AFB, India Ink)
○ Bacterial, mycobacterial and fungal culture
○ Cryptococcal antigen (CrAg) test (close to 100% sensitivity and specificity)
○ Xpert Ultra MTB/Rif
○ Pneumococcal Ag tests
○ Viral and bacterial PCRs (multiplex)
○ Toxoplasma serology
Non-specific investigations for CNS infections in HIV
- Blood tests
○ Malaria film, FBC, U&E
○ Blood cultures
○ HIV test and CD4 count - LP
○ Opening pressure
○ Appearance
○ Cell count & differential
○ Protein & glucose
Only real contraindication to LP in LMICs where scanning is not possible is focal neurological deficit (excluding CN palsies) suggesting mass lesions
How is cryptococcal meningitis investigated?
CrAg tests (close to 100% sensitivity and specificity), india ink staining (ring enhancing), culture
What did the Ambition-cm trial show?
Single high-dose liposomal amphotericin based regimen for treatment of HIV-associated Cryptococcal meningitis
○ Novel single dose treatment was both safer and more effective
Now being used in Botswana, Eswatini, Malawi, Zimbabwe, Uganda
Treatment of cryptococcal meningitis
Induction treatment:
Single-dose Liposomal Amphotericin B* 10mg/kg plus
Flucytosine (5FC)100mg/kg/day (4 divided doses) & Fluconazole 1200mg/day for 2 weeks; then
Consolidation treatment:
Fluconazole 800mg/day for 8 weeks; then
Maintenance treatment:
Fluconazole 200mg/day until CD4 > 200 cells/µL and virally suppressed on ART
- Do not give steroids -> worsen outcomes
Start ART 4-6 weeks after starting anti fungal to avoid IRIS
Clinical manifestations of Amphotericin B toxicity and management?
- Renal impairment, K+/Mg2+ wasting, anaemia, thrombophlebitis
- Give 1L N. Saline + 20mEq K+, 2 Slow-K Tablets (16 mEq) twice daily, 2 Slow-Mag Tablets (143mg Mg2+)
Alternate day creatinine + electrolytes, twice weekly Hb
Should you give steroids in cryptococcal meningitis?
No - worsens outcomes
When should you start ART for cryptococcal meningitis?
Start ART at 4-6 weeks after initiating antifungal therapy to avoid immune reconstitution syndrome
How common is raised ICP in cryptococcal meningitis? How do you manage it?
Common ≈ 75 %, can occur at initial presentation, on treatment, IRIS
Communicating hydrocephalus
Headache, Visual/hearing loss, CN palsies, depressed GCS, confusion
Management is with therapeutic lumbar punctures - daily LP’s until OP <25cm H20
Who should be screened for cryptococcus? If positive how should they be managed?
Individuals with CD4<100
Ideally offer LP if available
Treat patients without evidence of CNS disease with high dose fluconazole 1200mg for 2 weeks, then standard consolidation and maintenance therapy
If LP positive then manage as cryptococcal meningitis
When should you consider TBM in a patient?
- Chronic headache + meningism
- Cryptococcal investigation negative
- CSF compatible
- Routine bacterial cultures negative
- Evidence of TB elsewhere (TB on CXR: 44% in HIV+ TBM)
Often CD4 count may be >100-200
Management of TBM
- Standard quadruple therapy (RIPE), 9-12 months duration
- Steroids: maybe but benefit in HIV-infected subset not clear - currently evidence suggesting no benefit nor in TB pericardial disease
-ART: data on timing not clear, most would delay initiation until around 9-12 months after initiation of TB treatment and give steroid cover
TB medication may help prevent TBM in HIV positive individuals. Give BCG in kids.
CD4 level likely in toxoplasmosis in HIV+ people?
CD4 <100cells/microL
Management of toxoplasmosis
Initial therapy:
- Pyrimethamine 200mg OD loading then 75mg OD plus Sulfadiazine 6-8g/daily divided QDS
Or
- Clindamycin 450mg pd QDS
Increasingly used:
Co-trimoxazole (high dose) much more widely available
Secondary prophylaxis:
- Initiate ART without delay (low risk of IRIS)
Long term co-trimoxazole prophylaxis until sustained (>6m) response to ART with CD4 count >200 cells/µl
Don’t give steroids -> can confuse therapeutic trial
Top HIV associated malignancies
Cervical cancer
Kaposi’s sarcoma
Lymphomas esp Non-hodgkin’s lymphoma
Castlemann’s disease
Clinical features of TB in individuals without HIV vs HIV infected immunosuppressed individuals
- Pulmonary TB
- Upper lobe infiltrates with cavities
- EPTB less common
- Mild immunosuppression (eg CD4 >350) is similar
VS
- Thoracic lymphadenopathy and pleural effusions more common
- Extrapulmonary disease more common with declining CD4 counts
- Disseminated disease
- Post-mortem have shown dissemination in 90%
- Lower zone nodules, non-cavitating or normal CXRs
- Very severe:
- Sepsis with bacteraemia + organ dysfunction
- ~25% admitted with sepsis have TB. Microbacteraemia in 40-50%
Key microbiological investigations for TB
Microscopy - sputum smear for AFB
Culture - gold standard
Molecular techniques
- PCR eg GeneXpert
Antigen detection eg urinary LAM (only can use in HIV)
Can do urine Xpert Ultra (high specificity but lower sensitivity) and stool Xpert Ultra
4 TB screening options for patients with HIV
- WHO 4 symptom screen (cough, fever, weight loss, night sweats)
- CRP, cut-off >5 mg/L
- Chest X-ray (+CAD)
- WHO recommended molecular diagnostic (medical inpatients)
Screen with IGRA or TSTs
Screen at every visit to a health facility
What features in adults living with HIV should prompt TB testing and what tests?
PLHIV
-Signs /symptoms of TB
-Advanced HIV
-Seriously ill
-Positive screening test
Do:
- urinary LAM
- Sputum Low complexity molecular testing eg geneXpert
What features in children living with HIV should prompt TB testing and what tests?
-Signs /symptoms of TB
-Positive screening test
Do
Respiratory sample -> Low complexity molecular testing eg geneXpert
Stool
Low complexity molecular testing eg stool Xpert ultra
What is Focused Assessment with Sonography (FASH) for HIV/TB ?
Use USS as POC to look at 6 points to look for:
- Pleural fluid
- Pericardial fluid
- Ascites
- Focal liver lesions
- Focal splenic lesions
When should ART be started in patients with HIV and TB? What is the exception?
Start ART as soon as possible within two weeks of initiating TB treatment regardless of CD4 cell count among people living with HIV
Exception: TBM (start 4-8 weeks after)
What is paradoxical TB-IRIS?
- Started TB treatment and newly go on to start ART
- Then clinical deterioration
- Usually happens within weeks of ART
Paradoxical as patients should get better and not worse
What is unmasking TB-IRIS?
- Not on TB treatment
- Newly started on ART
- After a couple of weeks -> deteriorate and new S/S + new diagnosis of HIV associated TB
Management of TB in HIV?
RI for 6 months
PE for 2 months
+ pyridoxine
Common SEs of TB treatment?
Hepatitis
Rash
Arthropathy (pyrazinamide)
Optic neuritis (ethambutol)
Peripheral neuropathy (isoniazid)
What is the issue with co-treating TB and HIV? What regimens are suggested for it?
Rifampicin - potent CYP450
Many HIV drugs metabolised by CYP450
- Atripla: efavirenz + lamivudine + tenofovir
○ But issues with resistance - Dolutegravir + Tenofovir + lamivudine + dolutegravir 50mg
○ Ie give with rifampicin but need to double dose of dolutegravir so give extra tablet top up
Management of TB IRIS?
Steroids eg PO Prednisolone
Features of TB IRIS
- 8% have paradoxical IRIS after starting ART
- Usually worsening pulmonary infiltrates / enlarging LNs
- 25% hospitalized, 2% mortality
- Prednisolone reduces severity /hospitalization / need for procedures
Risk factors:
○ Low CD4 count / high viral load
○ Extrapulmonary TB
○ Early ART (but mortality lower)
○ Prophylactic prednisolone reduces IRIS by 30%
Risk factors for TB IRIS
○ Low CD4 count / high viral load
○ Extrapulmonary TB
○ Early ART (but mortality lower)
○ Prophylactic prednisolone reduces IRIS by 30%
Parasite factors involved in malaria clinical outcome
Drug resistance
Multiplication rate
Invasion pathways
Cytoadherence
Rosetting
Antigenic polymorphism
Antigenic variation via PfEMP-1
Malaria toxin
Host factors involved in malaria clinical outcome
Immunity
Proinflammatory cytokines
Genetics eg SCT, thalassaemia, ovalocytosis, CD36, TNF-a, ICAM-1 etc
Age
Pregnancy
Geographical and social factors involved in malaria outcome
Access to treatment
Cultural and economic factors
Political stability
Transmission intensity -> seasonality, infectious bites per year, epidemics
What processes actually cause fever in malaria?
Schizont rupture
- release of parasite proteins eg immunogenicity materials triggering immune response
Malaria toxins
eg Haemozoin, Parasite DNA, GPI (Glycophosphatidylinositol)
causes pro-inflammatory cytokine release
Splenic clearance of iRBC via activation of splenic macrophages -> cytokine storm -> systemic inflammation over activation
What are the two major hypothesis for cause of CM?
- Mechanical hypothesis = vascular obstruction by parasitised erythrocytes
○ Evolutionary basis of cytoadherence to brain endothelial cells
§ To avoid clearance of parasitised erythrocytes by the spleen
§ For optimal development condition: low O2 pressure found in post-capillary venules - Immunopathology hypothesis = effector function of immune cells
○ Endothelium activation and damaging
§ Up-regulation of parasite, platelets and monocytes receptors (cell accumulation within microvessels)
§ Endothelial shrinking, induction of apoptosis
What host endothelial receptor is important for cytoadherence in falciparum malaria?
CD36
- Parasites sequester in microvessels via CD36 -> avoid clearance by the spleen
○ CD36 is a scavenger host endothelial cell receptor which is widely distributed
Over 75% of encoded PfEMP1s have a binding domain for this receptor
3 processes through which sequestration of falciparum malaria occurs
- Cytoadherence
- Rosetting
- Clumping
Impair blood flow leading to anaerobic glycolysis, acidosis and tissue damage
What cytokine levels correlate with mortality, parasitaemia and disease severity in CM?
TNF-alpha
What are the two main complications of pregnancy associated malaria?
- Preterm delivery (<37wks)
○ Associated with malaria parasitaemia and anaemia - Foetal growth restriction
○ Chronic infection and placental insufficiency
○ Lack of nutrients to foetus
○ TNF, IFN-Y, IL-1 and IL-2 production elevated
§ High TNF linked to fetal growth restriction and preterm delivery
IFN-Y related to low birth weight
What is the pathophysiological of placental malaria?
- iRBCs accumulate and aggregregate in placental intervillous spaces
- RBC use the VAR2CSA type of PfEMP-1, which binds to chondroitin sulfate A (CSA)
- The sequestration blocks the transfer of nutrients from mother to embryo
- VAR2CSA found during pregnancy that are absent in men and non-pregnant women
- Women with PAM remain afebrile - suggesting local pathology - with some aspects of acquired immunity remaining unaffected by placental parasitisation
- Elevated type 1 pro-inflammatory responses in placentas of malaria-infected mothers
- Sequestration of infected erythrocytes -> inflammatory environment -> release of C&C -> recruitment of monocytes and macrophages into intervillous space
○ TNF, IFN-Y, IL-1 and IL-2 production elevated
§ High TNF linked to fetal growth restriction and preterm delivery
IFN-Y related to low birth weight
Two unique features of placental malaria
- VAR2CSA found during pregnancy that are absent in men and non-pregnant women
- Women with PAM remain afebrile - suggesting local pathology - with some aspects of acquired immunity remaining unaffected by placental parasitisation
Pathophysiology of malarial anaemia
- Loss of infected RBCs: lysis or phagocytosis
○ Haemolytic anaemia
○ Misconception: SMA arises simply from the lysis of infected RBC. ➔ Lysis of infected RBCs is not the most significant cause of SMA
○ Minor loss, parasitaemia < 1%
- Loss of uninfected RBCs
○ Phagocytosis, phosphatidylserine and other markers involved as ‘eat me’ signal
○ ~12 uninfected RBC are lost for every iRBC during malaria infection - Suppression of BM erythropoiesis -> prevention of replacement
Why are uninfected RBCs destroyed during malarial anaemia?
Changes in plasma membrane of uninfected RBCs during malaria infection targets them for destruction: ’eat me’ signal
* Phosphatidylserine externalization
* Oxidation
* Reduced deformability
Binding of immune components to the surface of uninfected RBCs also targets cells for destruction
* Binding of malaria RSP-2 (ring surface protein 2) on the surface facilitates recognition
* Immune complexes and IgG (specific for parasite material that may stick to uninfected RBC) promotes phagocytosis
* Complement binding
Destruction of uninfected RBCs generally mediated by splenic red pulp macrophages
How is erythropoiesis suppressed during severe malarial anaemia?
- Haemozoin (a breakdown product of haemoglobin produced by the parasite) inhibits erythropoiesis
- Suppressive cytokines:
○ TNF inhibits all stages of erythropoiesis
○ IFN-Y inhibits erythroid cell growth, differentiation and survival - Hepcidin is released by the liver and blocks iron availability for incorporation into haemoglobin
- MIF (migration inhibitory factor) inhibits erythropoiesis by direct effects on erythroid precursors and bone marrow rather than modulation of TNF production
What do erythrocytes containing altered Hb display less of in malaria?
How do haemoglobinopathies confer an advantage to prevent/dampen malaria pathogenesis?
PfEMP1
- Prevention of parasite from establishing its own actin cytoskeleton within the host cell
- Impaired vesicular transport
- Distorted trafficking of PfEMP1; less in the surface
- Reduced cytoadherence
- Data limited to HbS and HbC
What is reservoir of leptospirosis?
Comes from proximal tubules of mammals
so high in animal urine eg rats
outbreaks when floods
What are the four types of epidemic curves and their principles?
Point source:
- Questions typically refer to weddings eg outbreak of vomiting after cream puffs at a wedding
- Should settle after exposure is over
- Most cases within same incubation period
Extended common-source:
- The continual exposure means continue cases
- If you stop the exposure, ie break the water pump, then the cases should stop
Propagated source:
- Transmission occurs from person to person rather than a common source
- Can have multiple waves
- Cases in one peak can be sources for cases in a subsequent peak
- May have progressively taller peaks (if incubation period and infectiousness period similar)
Intermittent source
- Multiple peaks
- Length bears no relation to incubation period -> reflects intermittent times of exposure
- eg contaminated food source
What are the 12 steps for outbreak responses?
- Prepare for field work -> identify an investigation team, mobilise appropriate resources
- Establish the existence of an outbreak/epidemic
- Verify diagnoses of cases
- Establish a working case definition
- Systematic case finding to identify additional cases
- Conduct descriptive epidemiological studies (time, place, person)
- Develop hypotheses
- Evaluate hypotheses (often with case control study)
- If required, reconsider/refine hypotheses and do additional studies to test them
- Implement control and prevention measures (as early as possible)
- Communicate findings
- Institute surveillance
Three types of case definition in outbreaks?
- Proven/confirmed
○ Usually are symptomatic
○ Are within suspected incubation period
○ Have positive test: ie serology, culture, PCR etc - Probable/suspected
○ ?live in epidemic area
○ Symptomatic - Possible
○ Milder symptoms
○ ?Not necessarily in traditional incubation period
○ ?Might have had contact with proven or probable case in preceding given amount of time
Two forms of protozoa, which one causes infection?
Cysts (can sit/lay dormant for a while)
Trophozoites (cause active infection)
Non infectious causes of bloody diarrhoea
- IBD
- Ischaemic colitis
- Radiation colitis
- Bowel cancer
- Vasculitis
Viral causes of bloody diarrhoea
VHF esp Lassa, Marburg, ebola
-CMV if CD4 low
Top bacterial causes of bloody diarrhoea
- Shigella (p to p spread)
- E coli (p to p spread)
- Campylobacter
- Salmonella
Other
- C difficle
- Yersinia enterocolitia
- Plesiomonas shigelloides
Parasitic causes of bloody diarrhoea
- Schistosomiasis
○ Intestinal -> eggs in mesenteric veins -> portal spread -> portal HTN and varices
§ Can distinguish from other liver diseases as liver function quite preserved - Amoeba (E histolytica)
- Balantidium coli
- Malaria
- Helminths
- Very heavy trichuris (but tends to be due to rectal prolapse)
Electrolyte deficiency with invasive shigellosis?
Hypokalaemia
Precautions for faecal-oral spread
PPE
Hand-washing
Sanitation
Incineration
Clean surfaces
Identify common sources for spread
Prevent iatrogenic infections
What are the drug classes for HIV treatment?
NRTI: nucleoside reverse transcriptase inhibitors
- Pretend to be nucleotides
- Drug class associated with most toxicities - ?secondary to introduction of them into cell
- Risk of mitochondrial toxicity
NNRTI: non-nucleoside reverse transcriptase inhibitors
- Bind to reverse transcriptase and cause confirmational change so doesn’t work as well
INSTI: integrase (strand transfer) inhibitors
PI: protease inhibitors
Capsid inhibitor (lenacapavir): 6 monthly subcut injection, not yet licensed, could be gamechanger
Other drugs that aren’t really used:
CD4 inhibitor: ibalizumab
- Withdrawn in Europe, only available in USA
- IV every 2 weeks
- Very expensive
CCR5 inhibitor: maraviroc
- Rarely used
Fusion inhibitor: enfuvirtide
BD subcut injections
When should rapid ART for HIV NOT be started?
- TBM: after at least 4 weeks, but start within 8 weeks of anti-TB treatment
○ Consider adjuvant steroids - After TB treatment started: within 2 weeks
- Cryptococcal meningitis
○ Increased mortality with immediate ART
○ Defer until 4-6 weeks after CM treatment start
Until 2000s what ART formula would HIV patients have?
Until 1996: NRTI
1996 - 1999: PI + NNRTI
2000+: INSTI + new (2 NRTI + 1 other)
What is the characteristic resistance mutation to Lamivudine?
M184V
What is the only effective dual drug therapy for HIV ART?
Dolutegravir (II)
Lamivudine (NRTI)
WHO guidelines for ART?
First line:
Tenofovir-DF (TDF) + emtricitabine or lamivudine + dolutegravir
(TLD = Teno/Lamni/Dolu is 1 pill but not available in UK yet)
Alternative first line:
TDF + lamivudine + efavirenz 400
Don’t use efavirenz if country has resistance rates of >10%
if DTG not available then boosted PI should be used
Consider TAF instead of TDF if pre-existing bone disease or renal impairment
What are TDF or TDX and what are their biggest SEs?
What could you start instead?
Tenofovir disoproxil fumarate = old tenofovir = TDF, TDX (same drug but different salts)
- These are old tenofovir
Biggest SEs: renal impairment and reduction in bone mineral density
Can consider new tenofovir: TAF = Tenofovir-alafenamide
or another drug
If an individual is established on ART, what test should be used to monitor treatment according to WHO guidelines?
Monitor viral load
Don’t monitor CD4 count
Now in London/?UK once CD4>350 stop monitoring it
If viral load testing not available then use CD4 cell count with clinical monitoring
What threshold can be used to assess ART failure using dry blood spot specimens?
> 1000 copies/ml
Same as for plasma
What biochemical marker can dolutegravir cause a harmless rise in?
Creatinine
Not indicative of renal disease
37 year old man
Chronic HBV 04/2022 starts
tenofovir-DF + lamivudine + efavirenz FDC
10/2023: 6M viral load undetectable
04.2024: 12M viral load 2700
What would you do?
Resistance testing if available
Otherwise, according to WHO guidelines if Viral load >1000 on NNRTI then switch as pre-treatment resistance common in many countries
Switch to 2nd line after single VL >1000 reduces mortality &
transmission & is cost-effective (at $500 DALY threshold)
Key toxic drug reaction examples with ritonavir or cobicistat? (4)
§ Midazolam
§ Amiodarone
§ Rivaroxaban
§ Fluticasone
British HIV guidelines for treatment?
INSTI + 2NRTIS
- TAF + emtricitabine + bictegravir (Biktarvy)
- Abacavir/lamivudine/dolutegravir (if HLAB5701 negative, 10-year CV risk <10%)
- Dolutegravir + TAF/TDF + lamivudine or emtricitabine
OR
INSTI + 1 NRTI
- Dolutegravir + lamivudine
○ No baseline lamivudine resistance
○ Baseline VL <500,000
○ Baseline CD4>200
○ No need to include tenofovir for hep B treatment/prevention
What intervention can reduce the risk of transmission of HIV by 50%?
Male circumcision
FTC for HIV - full name?
Emtricitabine
TDF for HIV - full name?
Tenofovir disoproxil fumarate
TAF for HIV - full name?
Tenofovir-alafenamide
RAL for HIV - full name?
Raltegravir
What does post-exposure prophylaxis for HIV involve?
- Up to 72 hour after exposure
- POCT negative
- Tenofovir/emtricitabine and raltegravir OD for 28 days
- Vaccinate for hepatitis/assess risk for other STIs
- Emergency pregnancy prevention
- Follow up testing for HIV
○ Minimum 45 days after completion of PEP course
○ If 28 day PEP course is completed this is 73 days (10.5 weeks) post-exposure
What does pre-exposure prophylaxis for HIV involve?
- Truvada OD (can be on it long term) = FTC/TDF (for anyone at risk) OR Descovy (FTC/TAF) OD for men and transgender women
- Cabotegravir IM injection every 8 weeks
Population most at risk of HIV at the moment?
Cisgender adolescent and young women
Brand name for emtricitabine and tenofovir disoproxil?
Truvada
What ARTs is Descovy?
Emtricitabine/tenofovir alafenamide
What monitoring should be done for patients on ART?
VL: at 6M, 12M then yearly
CD4 every 6M until established on ART
Ideally also check
Creat & eGFR for TDF
Pregnancy test for women of child bearing potential
What monitoring should be done for patients with suspected ART failure?
Creat & eGFR for TDF
HBV surface Ag before switching drugs if not done at baseline or negative and not-vaccinated
If >50-<1000 copies/ml VL: enhanced adherence counselling and repeat VL testing at 3 months -> if above >1000 then switch, if <50 then maintain, IF still >50-<1000 copies/ml VL then maintain ART, enhanced adherence counselling and repeat VL testing at 3 months -> if still high then switch
If VL>1000copies/ml and on NNRTI based ART -> switch
(high risk of resistance)
A patient is started on ART and on yearly check VL is 750 copies/ml, what do you do?
Enhanced adherence counselling and repeat VL testing at 3 months
IF still >50-<1000 copies/ml VL then maintain ART, enhanced adherence counselling and repeat VL testing at 3 months -> if still high then switch, if <50 then maintain
How does dolutegravir cause a rise in creatinine?
Inhibits OCT2, a renal transporter
Highest in first 4 weeks
Not harmful to kidneys nor reflective of renal disease
What is Hy’s law?
Jaundice + transaminitis on ART -> associated with worse mortality
Switch the most likely culprit
○ Eg AZT to TDF
○ 3rd agent to another 3rd agent
○ Atazanavir = PI
§ Not really used anymore
§ Can cause jaundice
§ Risk of renal impairment
A patient with HIV on atazanavir has hyperbilirubinaemia on routine blood tests, would you switch their ART?
Only if jaundiced + transaminitis
Atazanavir alone causes unconjugated hyperbilirubinemia
What is the WHO screening guidance for patients with HIV for Hep B and C?
- At enrolment to care/initiation of ART
- At treatment failure/switching ART regimen
- At re-engaging following care interruption
WHO recommendations for NNRTI resistance?
Switch away from NNRTI at 1st detectable VL
- Pre-treatment resistance common in many countries
- Resistance common at virological failure
- Although many will resuppress, outweighed by risk of more resistance + consequences of treatment failure
- Switch to 2nd line after single VL >1000 reduces mortality & transmission & is cost-effective (at $500 DALY threshold)
WHO guidance for second line ART regimens?
If non-DTG regimen is failing:
- DTG in combination with optimised NRTI backbone
If DTG-based regimens are failing:
- Boosted PIs with optimised NRTI backbone
2 types of causative agents for hookworm and examples:
- Human/intestinal hookworm
○ Humans are definitive hosts
§ Ancyclostoma duodenale
§ Necator americanus - Animal hookworm
○ Humans are accidental host
○ Multiple species
○ Can invade and parasitise humans
○ Ancyclostoma ceylanicum
○ Ancyclostoma braziliense
○ Ancyclostoma caninum
Features of cutaneous larva migrans
Hookworm infection
- ‘Skin-worm-moving’
- Intensely pruritic
- Creeps along for days “serpinginous”
- Track – due to an inflammatory, allergic response to the microscopic larva
- Represents IgE-mediated response to filariform larval migration → histamine release → itchy ++
- Secondary bacteria infection can occur
- Gradually will self-resolve once larvae enter circulation and migrate to the lungs
Features of lung migration of hookworm?
- Usually asymptomatic
- Less commonly → eosinophilic pneumonitis
- IgE-mediated immune response to larvae in the lungs
- Leads to transient cough, wheezing, chest pain and haemoptysis
- Lobar infiltrate on a CXR can mimic bronchopneumonia
- “Loeffler’s syndrome”
10 key facts about strongyloidiasis
1) Widespread distribution
2) Walking barefoot on soil contaminated with human faeces
3) Mostly asymptomatic or low grade GI disturbance
4) Auto-infection cycle for decades
5) Serpiginous rash of larva currens
6) Beware small bowel obstruction (duodenal aspirate)
7) Hyper-infection syndrome, normal eosinophils
8) Cellular immuno-suppression including HTLV-1
9) Travellers and migrants are different
10) Eosinophilia, serology, microscopy and charcoal culture
What soil transmitted helminth can cause auto infection?
Strongyloides
Classes of dimorphic fungi
○ Histoplasma
○ Talaromyces = penicillium
○ Blastomyces
○ Coccidioides
○ Paracoccidioides
○ Sporothrix (rose gardening one)
What is the 3rd most common opportunistic infection with HIV in China, Vietnam and Thailand?
Talaromycosis
Management of talaromycosis
- Severe:
○ Induction: Ambisome (ie liposome amphotericin) 3-5mg/kg/day IV for 10-14 days OR Amphotericin B IV (0.7mg/kg/day) at least 14 days
○ Consolidation therapy: Itraconazole PO BD for next 10 weeks - Mild/moderate:
○ Itraconazole 200mg BD for 8-10 weeks - Maintenance therapy:
Itraconazole 200mg OD lifelong or until CD4>100 for 6 months while on ART
What pathogen causes Talaromycosis? What are some key facts and treatment for it?
Talaromyces marneffei
Thermally dimorphic geographically restricted fungi
* Rainy seasons soil exposure (inhalation of conidia)
* Bamboo rats enzootic reservoir
* 3rd commonest opportunistic infection in advanced HIV in endemic areas (SE Asia- Thailand, Vietnam and China)
* Mortality 97-100% without treatment
* Delay in diagnosis doubles mortality 24-50%
* Newer diagnostics: PCR, metagenomic next-generation sequencing
Severe: liposomal Amphotericin B or amphotericin B for 14 days
Then consolidation: itraconazole BD for 10 weeks
Mild: itraconazole BD for 8-10 weeks
Maintenance: itraconazole lifelong or until CD4>100 for 6 months on ART
Examples of NRTIs
Zidovudine (AZT), Lamivudine (3TC), Abacavir (ABC), Tenofovir disoproxil fumarate (TDF), emtricitabine (FTC)
Examples of NNRTIs
- Efavirenz (EFV)
- Rilpivirine (RPV)
- Doravirine (DOR)
Examples of INSTI
- Dolutegravir (DAG)
- Raltegravir (RAL)
- Bictegravir (BIC)
Examples of protease inhibitors
- Ritonavir (RTV)
- Lopinavir (LPV)
- Atazanavir (ATV)
- Darunavir (DRV)
What is lenacapavir? What is it used to treat?
Caspid inhibitor
Shown promise for HIV -> only given 6monthly subcut injections but not licensed yet
In a patient with HIV who has cryptococcal meningitis when should you start ART?
4-6 weeks after CM treatment has started due to increased mortality with immediate ART
In a patient with HIV who has TB meningitis when should you start ART?
After at least 4 weeks but within 8 weeks of anti-TB treatment and consider adjuvant steroids
What did the START study for HIV show?
- RCT on starting ART
- Delayed (until CD4>350 or AIDS related symptoms) vs start immediate group
Better for immediate group - faster viral suppression
- lower mortality
- lower AIDs related events
What does a dolutegravir and lamivudine combination not cover for?
Hep B = Need tenofovir
Which ART can be given IM every two months and what class does it belong to?
Cabotegravir
A 37 year old man with chronic HBV 04/2022 starts tenofovir-DF + lamivudine + dolutegravir FDC. 10/23 VL undetectable. 4/24 VL 2,700. What do you do?
WHO: enhanced adherence counselling + repeat VL at 3M
* Many people will resuppress
* Resistance emergence uncommon
07/2024 VL undetectable
Consistent with data from ADVANCE (1st line DTG vs EFV) which shows most participants resuppress on continued DTG
How do you encourage adherence in HIV treatment?
Adherence:
- Secure drug supplies
- Longer drug supplies
- Education
- Simple dosing
- Adherence tools
- Aim for longer acting medication
Attendance:
- COVID lessions
- Virtual care
- Transport support
- REACH study
What did the NADIA trial show for HIV?
- NADIA trial looked at dolutegravir or darunvair in combination with lamivudine plus either zidovudine or tenofovir for second line treatment of HIV
- Showed dolutegravir is non-inferior to darunavir but is at greater risk of resistance in second line therapy
Also tenofovir should be continued in second-line therapy rather than being switched to zidovudine
What are the four classes of protozoa?
Amoebae
Flagellates
Sporozoa
Ciliates
What are the two types of amoebae to know?
Entamoeba
Naegleria
What are the three types of flagellates to know?
Leishmania
Giardia
Trichomonas
What are the two types of sporozoa to know?
Plasmodium
Toxoplasma
What is a type of ciliate?
Balantidium
What are the three classes of helminths?
Cestodes (tapeworm)
Trematodes (flukes)
Nematodes (roundworm)
What are key types of cestodes/tapeworms?
Taenia saginata
Taenia solium
Hymenolepsis nana
Diphyllobothrium latum
Echinococcus sp
What are the key types of trematodes/flukes?
Liver flukes eg Fasciola, Clonorchis, Opisthorchis
Lung flukes
Tissue flukes
Blood flukes eg schistosomiasis
What are the two types of nematodes/roundworms?
Geohelminths
Filariae
What are types of geohelminths?
Ascaris
Trichuris
Hookworm
Strongyloides
Toxocara
Trichenella
Enterobius
What are types of filariae?
Lymphatic filariasis
Loa loa
Onchocerca
Dracunculus
What are the key features of Ascaris?
“Giant roundworm”
Crenelated eggs
Adult worms 200-350mm in size
Large bowel location
Soil to mouth
Clinical features:
- Asymptomatic
Loeffler’s
GI obstruction
Cholangitis
Peritonitis
Distinct feature: lung migration
Eosinophilia only if in lungs
Treatment: albendazole
What is Loeffler’s syndrome?
Disease in which eosinophils accumulate in the lung in response to a parasitic infection
What are the key features of Trichuris?
“Whipworm”
Bulb-ended eggs
Adult worms 50mm in size
Large bowel location
Soil to mouth
Clinical features:
Asymptomatic
GI upset
Stunting
Rectal prolapse
Distinct feature: overlap with ascaris
Often eosinophilia
Treatment: albendazole
What are the key features of Ancylostoma or Necator?
“Hookworm”
Thin-walled eggs
Adult worms 10mm in size
Small bowel location
Skin penetration
Clinical features:
Asymptomatic
CLM
Loeffler’s
GI upset
Anaemia
VERY ITCHY
Distinct feature: lung migration
Eosinophilia can be high
Treatment: albendazole or ivermectin
What are the key features of Strongyloides?
“Threadworm in USA”
Ellipsoid eggs with larva
Adult worms 1mm in size
Small bowel location
Skin penetration
Clinical features:
Asymptomatic
Larva currens
GI upset
Hyper-infection
Distinct feature: auto-infection
Eosinophils common but not in hyper infection
Treatment: Ivermectin
What are the key features of Enterobius?
Pinworm (Or called threadworm in the UK)
Eggs are flat on one side
Adult worms 1-2mm in size
Located in rectum
Transmitted faecal to mouth
Clinical features:
Asymptomatic
Pruritis
Vaginal discharge
Distinct feature: Family clusters/sellotape test
Eosinophilia: unusual
Treatment: albendazole
Basics of clinical presentation of hookworm?
Early illness:
- Larva migration in the skin -> cutaneous larva migrans
- Larva migration in the lungs -> coughing, wheeze
Late illness:
- Correlates with worm burden in the GI tract
- Adults bite on intestine and suck blood -> anaemia
Features of GI infection with hookworm
- Often asymptomatic
- Adults rarely pass spontaneously - worms hold on tight and only 1cm long
- Two adults sit and sexually reproduce in GI tract + blood suck -> can last for years
- Nausea, abdominal pain + diarrhoea
- Late infections
- Hookworm anaemia -> major concern in endemic areas
- Each adult: 0.03-0.2ml blood/day
- May contribute to growth restriction in heavily-infected children
Lifecycle of human/intestinal hookworm?
Eggs in faeces
Rhabditiform larva hatches
Development to filariform larva in environment
Filariform larva penetrates skin
Larvae can be developmentally arrested and dormant in tissues
Reactivated larvae may enter the small intestine
If they get into lung circulation -> exit -> coughed up and swallowed
Eggs in faeces
Life cycle of animal hookworm/cutaneous larva migrans? eg
Ancylostoma canium/braziliense
Uncinaria stenocephala
Skin penetration via larvae through skin
BUT animals definitive hosts
Adults in small intestine
Eggs in faeces of animal definitive host
Hatched rhabditiform larva develops in environment
Rhabditiform larva develops into infectious filariform larva
Traditional story/presentation of Ancylostoma braziliense?
Hookworm
Person lies on beach that dogs have been running on etc (ie there faeces have been in contact with beach)
Get rash wherever their faeces touched -> clinical diagnosis of cutaneous larva migrans
Treat with ivermectin or albendazole
Life cycle of ascaris?
Hands carry infective ova from soil contained with human excreta/dust/veg etc
Larvae penetrate mucosa
Enter lymphatics and venules
Migration to right heart and lungs -> into alveoli -> moult twice
Ascend resp tree -> descend oesophagus to mature in intestine
Maturation in humans 2 months
Adults live around 1 year and make 100,000 eggs a day
Eggs leave body and complete cycle -> have to complete in soil before affecting the next person
Management of ascaris?
- Kill the worms
○ Albendazole
○ Mebendazole
○ Pyrantel pamoate - Manage the complications
○ Surgery for obstruction
○ ERCP for pancreatitis - Break the cycle
○ Better sanitation
○ Hand hygiene
○ MDA
Clinical features of ascaris?
Early infection:
- Asymptomatic
Can get lung migration and Loeffler’s syndrome -> IgE mediated response to larvae in lungs -> transient wheezing, coughing, chest pain, haemoptysis
May see Charcot Leyden crystals on microscopy
Late infection:
GI worm burden related -> can be asymptomatic
Nausea/abdominal pain/diarrhoea
Malnutrition
GI complications eg bowel infection /perforation -> peritonitis
Ectopic infection -> migration up biliary tree causing pancreatitis, biliary sepsis and peritonitis
What parasite causes cutaneous larva currens?
Strongyloides
What is the clinical syndrome of strongyloides?
- Usually asymptomatic
- Larval invasion of the GI tract → Abdominal pain, intermittent diarrhoea
- Larval penetration → petechial haemorrhages and pruritis at site of entry (eg peri-anal skin)
- Larval migration → Rash → cutaneous larva currens
- Larval invasion of the lungs → cough, wheezing, chronic bronchitis
Life cycle of strongyloides
Filariform larvae in soil penetrate skin
Larvae move via venous system into lungs
Larvae swallowed and develop into adult females in GI tract -> eggs produced by asexual reproduction
Eggs hatch into rhabditiform larvae -> excreted in stool
Some rhabditiform larvae transform to filariform larvae and reinvade gut wall -> reinfection
The rhabditiform larvae outside of the body develop and mate ie adult males and females reproduce sexually and develop into filariform larvae
What is the rash caused by strongyloides? What are some features?
Cutaneous larva currens
- Intensely pruritic
- Moves linearly for hours (faster moving, shorter duration than hookworm’s cutaneous larva migrans)
- Represents IgE-mediated response to filariform larval migration
- Resolves quickly when larvae enter circulation
Features of larval infection with strongyloides in the lung?
- Usually asymptomatic
- Less commonly → eosinophilic pneumonitis
- IgE-mediated immune response to larvae in the lungs
- Transient cough, wheezing, chest pain and haemoptysis
- Lobar infiltrate on chest x-ray may mimic bronchopneumonia
Ie “Loeffler’s”
What is strongyloides hyper infection?
· Immunosuppressed individuals – T-lymphocyte depletion
○ HTLV-1, HIV
○ Malnourished
○ Iatrogenic immunosuppression (steroids, chemotherapy, transplant patients etc)
· Leads to a faster reproduction cycle
· Migration to ectopic sites
· Spread of faecal bacteria to normally sterile sites
· Can → recurrent gram negative bacteremia, CNS involvement, granulomas, abscesses…
How should you investigate strongyloides?
- Usually eosinophilia - up to 80%
○ Check over a time period as can have periods of high and of normal -> depends on movement of worm - Faecal ova, cysts and parasites – but low sensitivity – worms are difficult to detect as usually few in number. NPV 50%
- Serology (ELISA IgG) if immunocompetent
○ Can stay positive for long time -> don’t use it as indicator of cure but can use it to diagnose in chronic infection
○ Cross reactivity for other parasitic diseases eg schiso - Test to do:
○ Charcoal stool but not routine
In hyper-infection:
- Suspect the diagnosis and try to find the worms
- Gram negative rod sepsis, bacteraemia, pneumonia, meningitis
- Eosinophilia - rare
- Serology rarely helpful -> slow turnaround, poor NPV
- Look for larvae in stool and the sputum
Treatment for Strongyloides?
Ivermectin>albendazole
Screen and treat before planned immunosuppression (ie if risk factors then before chemo/radio etc)
Life cycle of trichuris?
Whipworm
Embryonated eggs are ingested
larvae hatch in small intestine
adults move to caecum
unembryonated eggs pass in faeces
eggs develop in soil -> become embryonated
Clinical presentation of whipworm?
eg trichuris
Severity = correlates with burden of worms
Light infections:
○ Abdo pains
Heavy infections (800+ worms):
○ Dysentry
○ Growth stunting
○ Associated with anaemia (0.005ml blood/worm/day, unlikely causal, likely multifactorial)
○ Rectal prolapse due to tenesmus
Lots of inflammation -> higher intraabdominal pressure -> need to open bowels a lot
Diagnosis and treatment of trichuris?
Eggs in stool OCP? Adults are visible on colonoscopy
Treat with albendazole > mebendazole
What is a feature of strongyloides hyper-infection on a blood count?
Normal eosinophil count
What is different about travellers and migrants with strongyloides infection?
Migrants more likely to have positive serology but negative symptoms
Travellers less likely to have symptoms but positive serology
What is different about travellers and migrants with strongyloides infection?
Migrants more likely to have positive serology but negative symptoms
Travellers less likely to have symptoms but positive serology
Lady goes to pit latrine in Nigeria late at night and gets sudden eye pain. Goes to hospital next day and eye is red with extensive corneal scarring. Cause?
Venom ophthalmia
Caused by spitting cobras
Management of venom ophthalmia
- Immediate irrigation with any clean bland fluid
- Pain killing eye drops: 1% adrenaline or tetracaine (LA)
- Fluorescein staining/slit-lamp examination to exclude corneal abrasion
- Topical Abx eg tetracycline/chloramphenical
- Topical cycloplegic eg atropine
+/- eye pads
Complications of cobra ophthalmia
Acute conjunctivitis
Hypopyon
Panopthalmitis
Anterior uveitis
Clinical manifestation of spitting cobra bites?
Skip lesions
Venom comes out of front of fangs
Can inject venom into lymphatics
Leads to extensive scarring, can need extensive debridement and can end up with contractures
Also can get superimposed staph infection on top or marjolin’s ulcer
Causes of growing burden of NCDs worldwide?
- Growing and ageing populations
- Success in preventing and treating communicable disease
- Success in preventing childhood disease
- Urbanisation and globalisation
- Change in RFs eg ETOH, tobacco, diet, physical activity
What is the WHO: “25x25” strategy (2012)? How was this updated?
Aim for 25% reduction in mortality by 2025
Four priority diseases
1. CVD
2. Diabetes
3. Cancer
4. Chronic respiratory diseases
Update: 5. Mental and neurological conditions
Five priority interventions:
1. Tobacco control
2. Salt reduction
3. Improved diets and physical activity
4. Reduction in hazardous alcohol intake
5. Essential drugs and technologies
Update: address air pollution
What are the 5 priorities to address NCDs in fight for UHC?
- Prevention
- Primary healthcare
- Equitable access to medicines
- Sustainable financing and investments
- Engaged and empowered communities
Strategies for CVD prevention and management in LMICS?
Acute and chronic CVD mx
Clinical based RF control, smoking cessation, BP control
Lipid and diabetes mx
Improving medical education
Healthcare financing
Policies for smoking, diet, physical activity modulation
Tackle social determinants of health
HEARTS global initiate for CVD diseases
Healthy lifestyle counselling
Evidence based protocols
Access to essential medicines
Risk based CVD management
Team based care
Systems for monitoring
How does diabetes present differently in Black Africans compared to White Europeans?
- Black Africans have lower BMI (eg 27) and lower age (51.5) + less co-existing hypertension and more hyperglycaemia
HbA1c 9% vs 7.1% (in white Europeans)
WHO essential medicines for diabetes
Insulin
- Insulin injection
- Intermediate acting insulin
- Long-acting insulin analogues
Oral hypoglycaemic
- Metformin
- Empagliflozin
- Gliclazide
Types of insulin
Analogue
- Rapid or long acting
Soluble
- Regular
- Short
- SC or IV
Isophane
- NPH insulin (Neutral protamine Hagedorn)
- Intermediate acting
Lente insulin
- Zinc suspension
Intermediate - long mode of action
Theories behind diabetes prevalence in LMICS?
Thrifty phenotype diagnosis
Also lots of high sugar food/processed etc in LMICs eg South Africa
Types of insulin over time they act and examples?
Rapid acting:
- Insulin lispro
- Aspart
- Glulisine
Short acting:
- Regular insulin
Intermediate acting:
- NPH insulin (Neutral protamine Hagedorn)
Long acting:
- Insulin glargine
- Insulin detemir
Interaction between DTG and metformin?
Dolutegravir can increase conc of metformin by 200 times
What did the INTE-AFRICA Trial show?
Blood Pressure: The integrated care model showed a significant increase in the proportion of patients achieving target blood pressure levels compared to standard care.
Glycemic Control: There was a notable improvement in HbA1c levels among diabetic patients in the integrated care group.
Quality of Life: Patients reported higher quality of life scores in the integrated care model.
Adherence: Higher adherence rates were observed in the integrated care group, indicating better management and follow-up.
Hospitalization: There was a reduction in hospitalization rates for chronic disease-related complications.
What are the obstacles to effectively managing and preventing HTN?
Low awareness and access to screening
Unaffordable drugs, lack of willingness/motivation to engage with services, social norms
Lack of retention due to lack of clinicians, poor understanding of conditions, fear of side effects/long term effects and competing priorities
Low screening and inaccurate measurements
Poor use of guidelines/understanding of diagnosis and management amongst healthcare staff
Risk factors for stroke in LMICs
- Untreated HTN
- Infection
○ HIV (southern and central Africa), stroke mimics/CNS infections - SCD
Stroke mimics in LMICs in HIV positive patients?
SOL
- Tuberculoma
- Cryptococcoma
- Primary CNS lymphoma
HIV associated Ois
- Toxoplasmosis
- PML
Meningitis complications
- Acute bacterial meningitis
- TB meningitis
Relationship between infection and stroke?
Infection:
- Risk of stroke, 1-3 days higher risk but can persist for 90 days
- Pre-existing risk increased in infections
Remodelling:
- Especially in HIV
- Inflammatory process or latent infection causing vasculopathies eg Moyamoya or RSCV
Vasculitis:
- Eg TB/VZV/Syphilis
- Vasotropism -> attacking of blood vessels and wall inflammation
- Endarteritis obliterans
- Post-infective inflammatory vasculitis
Hypercoagulability
- Eg COVID
Cardioembolic
- RHD
- Chagas
Stroke mimics in LMICs in HIV negative patients?
- Hypoglycaemia
- Migraine
- Todd’s paresis
- Non-HIV associated CNS malignancies
- Autoimmune/inflammatory CNS lesions
How to manage strokes in LMICs?
- Investigations:
○ brain imaging, electrocardiogram, echocardiogram, blood test (FBC, U&Es, LFTs, CRP, HIV, VDRL), Lumbar puncture if indicated - Medications
○ low-cost medication available for management of complications
○ Aspirin
○ Insulin/anti-diabetics
○ Antihypertensives
○ Common oral agents : thiazide, amlodipine, nifedipine, atenolol, enalapril
○ Common IV agents: hydralazine, labetalol
○ Antibiotics/antivirals
○ Variable availability: thrombolytic agents (+/- access to confirmatory imaging) - Rehabilitation
○ Physios usually available but few staff may not meet patient needs
○ Other rehab specialties + equipment may not be available
○ Limited resource for long term / intensive rehab
○ Limited capacity for providing professional care and home f/u
Definition of a seizure?
A seizure is a sudden burst of electrical activity in the brain that can affect how a person behaves, moves, or senses things for a short time.
Definition of epilepsy and types?
A chronic neurological disorder characterized by a predisposition to recurrent, unprovoked seizures.
Key features of epilepsy include:
· Recurrent seizures: A person is diagnosed with epilepsy after having two or more unprovoked seizures that occur at least 24 hours apart.
· Unprovoked: Seizures are not triggered by immediate, dentifiable causes such as fever, alcohol withdrawal, or acute brain injury.
Varied seizure types: Seizures can vary in type and severity. They may involve convulsions (tonic-clonic seizures), brief periods of altered awareness (absence seizures) or focal neurological symptoms (focal seizures).
Definition of status epilepticus?
A neurological emergency characterized by prolonged or repeated seizures without the person regaining consciousness between episodes. It is defined by either of the following criteria:
1. Continuous seizure activity lasting 5 minutes or longer without interruption.
2. Two or more discrete seizures between which there is incomplete recovery of consciousness.
Status epilepticus can be divided into two main types:
1. Convulsive Status Epilepticus (CSE): The more common and severe form, where there are continuous tonic-clonic seizures, which can lead to brain injury if untreated.
2. Non-Convulsive Status Epilepticus (NCSE): Characterized by altered mental status and seizure activity without the obvious physical convulsions.
Key drug management of status
Diazepam
Phenobarbital
Phenytoin
Relationship between HIV and epilepsy?
· Potential interactions between antiretroviral therapy for HIV and antiepileptic drugs
· Greatest concern relates to the P450 system enzyme induction effects of several older-generation antiepileptic drugs (e.g. phenobarbital, carbamazepine, phenytoin), which might lower the effective dose of non-nucleotide reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), metabolized by the P450 system.
· Consequences include treatment resistance for HIV-infected patients; alternative treatment for seizures needs to be used in epilepsy patients with HIV
What is the lifecycle of a mosquito?
- Adult female mosquito mates soon after emergence from pupa and stores spermathecae (the sperm from male mosquitoes) to fertilise batches of eggs.
- After the female mosquito blood feeds, egg development starts
- Female searches for appropriate quality of water for egg laying
- Different species of mosquito make different choices as where to lay their eggs
- Larvae may hatch soon after eggs are laid or after some time depending on conditions
- 4th instar metamorphoses into pupa
- Pupa swims and breathes are but do not feed
- Pupa metamorphoses into adult mosquito which emerges at the water surface, stretches its wings and flies away
- Both sexes of adult obtain energy from sugary plant juices
Only the adult female feeds on blood to get proteins to feed her young
What are the two subfamilies mosquitoes are divided into?
- Anophelinae
- Culicinae
- Toxorhynchitinae (don’t like humans)
What diseases do not come out of Latin America?
Never
- Japanese
- Loa Loa
- Lassa, Ebola
- HAT
- Schistosoma haematobium
Very rarely
- Onchocerciasis
- Schistosoma mansoni
Why can you get Schistosomiasis mansoni but not Schistosomiasis haematobium or japonicum in Latin America?
Parts of Latin America have Biomphalaria snail for mansoni but no snail for haematobium (bulinus)
Some diseases that are quite specific to Latin America?
- Trypanosoma cruzi
○ esp in HIV -> causes neurological disease that looks like toxoplasmosis - Endemic mycoses
○ Histoplasmosis esp in HIV
○ Coccidioidomycosis
○ Paracoccidioidomycosis - Leishmaniasis
○ Generally cutaneous, wet ulcers, non-healing wet ulcers
Other
- Carrion’s disease (Oroya fever) -> Bartonella
- Bolivian haemorrhagic fever
- Oropouche
Sanctuary sites for Ebola?
Testes and Eye
Men can transmit in semen months after being sick, whilst being asymptomatic -> can prompt new outbreak
You work up a patient for TB but then they tell you they are from Arizona. What should you be considering?
Valley fever eg Coccidioidomycosis
A 37-year-old Panamanian male presented to hospital in Panama City with an illness of four months duration, characterised initially by weight loss and subsequently by progressive dysphagia, odynophagia, and new oral lesions. At presentation he was unable to swallow fluids and was severely fatigued. There was no history of fever, and his past medical history was unremarkable. A coffee farmer by trade, he lived in the highlands in the west of the country on the family plantation. Aside from the journey to Panama City for treatment, there was no history of travel. On examination, he was cachectic, pale and had non-tender hepatosplenomegaly without lymphadenopathy. An oral examination revealed erythematous ulcerative lesions on his hard and soft palate, oral candidiasis, and poor dentition. Physiological observations were within the normal range, except for a mild tachycardia of 105 bpm. Initial blood tests showed a pancytopenia, with a haemoglobin of 118g/L, white cell count of 1.5x109/L, neutrophil count of 0.5x109/L, and platelets of 88x109/L. Urea and electrolytes, liver function tests and lactate dehydrogenase were all within the normal range. A chest radiograph revealed a large right-sided shadow in the para-mediastinal area. What are your differentials?
Histoplasmosis
Leishmaniasis
Actinomycosis
TB
Lymphoma
Paracoccidioidomycosis
A 37-year-old Panamanian male presented to hospital in Panama City with an illness of four months duration, characterised initially by weight loss and subsequently by progressive dysphagia, odynophagia, and new oral lesions. At presentation he was unable to swallow fluids and was severely fatigued. There was no history of fever, and his past medical history was unremarkable. A coffee farmer by trade, he lived in the highlands in the west of the country on the family plantation. Aside from the journey to Panama City for treatment, there was no history of travel. On examination, he was cachectic, pale and had non-tender hepatosplenomegaly without lymphadenopathy. An oral examination revealed erythematous ulcerative lesions on his hard and soft palate, oral candidiasis, and poor dentition. Physiological observations were within the normal range, except for a mild tachycardia of 105 bpm. Initial blood tests showed a pancytopenia, with a haemoglobin of 118g/L, white cell count of 1.5x109/L, neutrophil count of 0.5x109/L, and platelets of 88x109/L. Urea and electrolytes, liver function tests and lactate dehydrogenase were all within the normal range. A chest radiograph revealed a large right-sided shadow in the para-mediastinal area. Grocott staining showed budding yeast-like forms. What is the likely diagnosis?
Paracoccidioidomycosis
Where is paracoccidioidomycosis found and how does it present?
Mexico in north to northern regions of Argentina -> think poor male farm workers
Typically asymptomatic pulmonary infection with lymphatic spread -> subsequent immune control leads to granuloma formation -> clearance
In children/young adults -> can get disseminated disease via reticuloendothelial dissemination
80/90% who get disease in adulthood -> reactivation of latent foci months-years after initial infection
Looks like TB!
How does chronic paracoccidioidomycosis present?
Pulmonary infiltrates (77%) and upper respiratory mucosal lesions (>50%).
In the upper respiratory tract, the mouth is most commonly affected, with lesions typically appearing as painful ulcers with ragged borders and areas of haemorrhage.
Involvement of the skin, lymph nodes, CNS and adrenal glands are also well-described but any organ system can be involved and occult disease is common. Disease is multifocal in 75% of cases.
Most sensitive test for paracoccidioidomycoses?
Histopathological tissue examination with Grocott or periodic acid-Schiff stains is highly sensitive (>95%), but more invasive. The size and multiple-budding appearance of the Paracoccidioides yeasts is distinguishing from other endemic mycoses, with ‘ships wheel’ or ‘Mickey Mouse’ structures considered pathognomonic.
Culture => can take a month and is affected by site and burden of infection
Serology -> risk of cross-activity with other endemic mycosis, sensitivity of around 80%
Treatment of paracoccidioidomycosis?
Mild/moderate: Itraconazole
Severe/CNS: Amphotericin B induction therapy then itraconazole
What is Coccidioidomycosis also known as? How does it present?
Valley fever -> lots in Latin America but can be in Arizona or surrounding states
Symptoms:
- Fatigue
- Fever + night sweats
- Weight loss
- Cough, CP, dyspnoea
- Haemoptysis
- Headache
- Arthralgia
- Looks like TB
Clinical
- Erythema nodosum (25% of pulmonary)
- Erythema multiforme
Can also have dissemianted form with extensive cutaneous involvement and multisystem involvement
CXR
- Pulmonary infiltrates
- Hilar adenopathy
Pleural effusions -> can mimic TB
Clinical presentation and vectors of Oropouche virus?
Symptoms:
- Incubation 3-10 days
- High fever + headache + myalgia/arthralgia + rash ~25%
- Severe: neurological eg meningoencephalitis, haemorrhagic eg gingival bleeding, epistaxis, petechiae
- ?Biphasic -> ~60% have relapse type picture and get sick again
- Low case fatality rate
Ddx:
- Arboviruses eg dengue, Chik, Zika
Vectors: Culicoides paraensis = biting midges + Culex quinquefasciatus, Coquillettidia venezuelensis, and Aedes serratus mosquitoes
What is Culicoides paraensis? What is it a vector for?
Oropouche virus
Key facts including epi, host, virus and management of Bolivian haemorrhagic fever?
Virus: Machupo virus
Animal: Calomys callosus eg large vesper mouse
Epi:
- Range of reservoir and human movement
Treatment: ribavirin
What are the two key types of filovirus? Where are they endemic?
Ebola -> west, tropical rainforest
Marburg -> drier forest or savannah in East
What are the pathophysiological hallmarks of ebola/marburg infection?
What is the clinical presentation?
Microvascular instability with capillary leak + impaired haemostasis +/- DIC
Fever/headache/asthenia/hepatosplenomegaly but no lymphadenopathy/possible early maculopapular rash/N&V&D/bleeding eg from gums, conjunctival haemorrhage, rectum
Likely reservoir for filoviruses?
Fruit bats
Human infection likely occurs due to exposure to infected bat excreta or saliva
Miners/forest workers/spelunkers at high risk, esp for Marburg -> have they been into a cave or mine?
Possible intermediate hosts for filoviruses?
Nonhuman primates esp gorillas and chimps and other wild animals
-> humans come into contact with their blood and bodily fluids
Esp through hunting or butchering
What causes Tungiasis and how does it present? How do you manage it?
Female sandflies -> Tunga penetrans -> burrows into epidermis of humans, often in feet to lay eggs
Pale nodule with dark centre that develops into brown/black with crust, slow growing nodules on feet (periungal regions/interdigital), systemically otherwise well. Due to contact with contaminated soil.
Ix:
Look for parasite and eggs in tissue samples and histopathological specimens
Clinical diagnosis
Mx:
- Check they have received tetanus injection/booster
- Remove flea with sterile needle, disinfect
Biggest factor contributing to reduction in Malaria from 2000s onwards?
ITN = insecticide treated nets
Key challenges to the control/prevention of Malaria?
Need to target outdoor stage, ie most interventions currently aimed at within the home which is unrealistic
- Financing
- Drug resistance
- Vector resistance
○ Biochemical
○ Behaviour - Diagnostic resistance
- Organisational
- Climate change
Key vectors of malaria in Africa?
Anopheles
- gambiae
- funestus
- arabiensis
Malaria vector control methods related to life cycle stage?
Egg Stage:
Larval Source Management (LSM)
Larval Stage:
Larval Source Management (LSM)
Pupal Stage:
Larval Source Management (LSM)
Adult Stage:
Insecticide-Treated Nets (ITNs)
Indoor Residual Spraying (IRS)
Space Spraying
Personal Protection Measures
Feeding Stage:
Personal Protection Measures
Genetic Control:
Genetic approaches (e.g., genetically modified mosquitoes)
What are the key threats to vector control in Malaria?
- Insecticide resistance
- Invasive vectors eg Anopheles stephensi
- Climate change
- Diminished access, use and durability of insecticide treated nets (ITNs
- Funding
- Outdoor transmission (residual transmission)
- Increase in vectors biting outdoors -> reducing efficiency of indoor vector control tools like ITNs and IRS
- Natural disasters, conflict situations and demographic changes
Impact of climate change on malaria vector control?
· Warmer temperatures can alter vector survival, abundance and increase the geographical spread of malaria vectors
· Extensive rainfalls and floods can create more breeding sites extending malaria transmission seasons. · Changes in weather can alter mosquito composition, resulting in higher densities of more efficient vectors. · Weather changes can affect human behaviour facilitating habits that expose them to vectors e.g sleeping outside in hot weather · Temperature changes accelerate changes in vector behaviour, enabling them to escape traditional vector control interventions
· Temperature and humidity changes can affect the efficacy of some vector control products
Why is Anopheles stephensi a problem and what are strategies to address it?
- Historically Asian vector eg India, Iran, Pakistan and Arabian penninsula
- Efficient vector of urban malaria (plasmodium falciparum and vivax)
- Breeds in domestic and other artificial water containers, man made pits etc -> urban settings -> current management not build to handle this
- Can resist high temperatures so can sustain transmission in dry seasons
- Vector difficult to target with standard vector control
What can be done?
* Increased vector surveillance
* Increase collaboration between different sectors
* Bye laws on water storage especially in urban settings
* Increase vector control strategies that can target the vector e.g larviciding
* On-going coordination meetings led by WHO
New vector control methods being considered/trialled for malaria vector control?
- Bait stations (attractive targeted sugar
baits) - Spatial repellents
- Systemic insecticides and endectocides
- Genetic manipulation, including gene
drive and self-limiting systems - Topical repellents
- Insecticide treated clothing
- Housing modification
- Lethal house lures (EaveTubes)
What are the two classes of Next generation ITNs and IRS products?
- Dual ITNs (Pyrethroids + new Insecticide)
- New IRS eg Pirimiphos-methyl, Clothianidin, eg Broflaniline WP ( Vectron T500, under evaluation)
Definition of chemo prevention wrt Malaria?
Administration of a full therapeutic courses of antimalarial treatment to a population at risk, whether infected or not, at defined time points separated by periods without drug exposure people living in endemic areas
Definition of chemoprophylaxis wrt Malaria?
Administration of an anti-malarial drug to an at risk population in such a way as to achieve protective blood levels over the whole of the period of risk sub-therapeutic doses primarily used by non-immune travelers to malaria endemic areas
What are the WHO 5 recommendations for Malaria chemoprevention in endemic areas?
- Intermittent preventive treatment of malaria in pregnancy (IPTp)
- give from 13 weeks gestation onwards, at least 3 doses during pregnancy, give at antenatal visits, allow 1 month between treatment times - Perennial malaria chemoprevention (PMC), previously known as intermittent preventive treatment in infants (IPTi)
- From 10 weeks of age onwards up to 24 months
- Sulfadoxine-Pyrimethamine normally used, with ACT now being considered - Seasonal malaria chemoprevention (SMC) previously known as intermittent preventive treatment in children (IPTc)
- Door to door/community based intervention
- Use Sulfadoxine-Pyrimethamine and Artesunate Combination Therapy (SPAQ) - Intermittent preventive treatment in school aged children (IPTsc)
- Post-discharge malaria chemoprevention (PDMC)
What does SPAQ stand for in the context of malaria chemoprevention?
Sulfadoxine-Pyrimethamine and Artesunate Combination Therapy
What are the two vaccines approved by WHO for malaria?
- RTS,S/ASO1E (Mosquirix ®): Oct 2021
- R21 /Matrix M : Sep 2023
Target of malaria vaccines?
Circumsporozoite protein
Two Malaria trials and findings
RTS,S/ASO1E (Mosquirix ®)
- 3 primary vaccinations were given prior to the season followed by an annual booster dose until children reached 5 years of age
- Compared with and to seasonal chemoprevention
- RCT showed non-inferior to seasonal chemoprevention alone, even higher efficacy when combined
- Reduction in incidence, hospital admissions and deaths
R21 /Matrix M
- RCT
- Reduction in time to first episode and all episodes, seasonal > standard by ~5%
- Efficacy held at all and seasonal sites at 24 months
With respect to Chemoprevention of malaria, what do IPTp and SMC stand for?
Intermittent preventative treatment in pregnancy
Seasonal malaria chemoprevention
Mosquito genuses that transmit Lymphatic filariasis?
Anopheles
Culex
Aedes
Mansonia
Mosquito genus for Japanese encephalitis?
Culex (tritaeniorhynchus)
Mosquito genus for West Nile?
Culex (pipiens)
Mosquito genus for Yellow fever?
Aedes, Haemagogus, Sabethes
What does Aedes transmit?
Dengue
Zika
Chikungunya
Lymphatic filariasis
Yellow fever
What is the mosquito life cycle?
- Adult female mosquito mates soon after emergence from pupa and stores spermathecae (the sperm from male mosquitoes) to fertilise batches of eggs
- After the female mosquito blood feeds, egg development starts
- Female searches for appropriate quality of water for egg laying
- Different species of mosquito make different choices as where to lay their eggs
- Larvae may hatch soon after eggs are laid or after some time depending on conditions
- Larvae swim, feed, breathe air and develop through 4 larval stages called instarts
- 4th instar metamorphoses into pupa
- Pupa swims and breathes are but do not feed
- Pupa metamorphoses into adult mosquito which emerges at the water surface, stretches its wings and flies away
- Both sexes of adult obtain energy from sugary plant juices
-Only the adult female feeds on blood to get proteins to feed her young
Terms used to describe whether mosquito enters house or not to feed?
Endophagic
Exophagic
Terms used to describe whether mosquito like to digest inside or outside?
Endophilic or exophilic
Aedes aegypti properties in terms of
- entering house or not to feed
- digesting inside or outside
- who it likes to bite
anthropophilic, exophagic and exophilic
Anopheles gambiensae
anthropophagic, endophagic, endophilic
bites late at night after people are asleep
Definition of a random sample
Each individual/each household etc has equal probability of being included
Can use random cluster sample if large population and homogenous distribution of disease
Definition of prevalence
- Number of cases of disease in a defined population at a given point in time
- Is affected by duration
o Ie if you increase duration of illness then it can drive up prevalence because you capture more people with the illness at that time of disease, but incidence is unaffected
Definition of incidence
- The number of new cases of disease in a defined population ‘those at risk’ over a specified period of time
o Population at risk should not only be those people but how much time they spend at risk
Definition of incidence risk
- Number of new cases that arise in population and divides them by the number of people who started off at risk
- Counts all people at start, then at end of period of observation tells you how many people got ill during that period
o Irrespective of whether they were all at risk at that period of time
o Easier to calculate than incidence rate, as you just count how many people you start with and how many have developed outcome disease at the end
o But becomes inaccurate if you lose people to follow up as you can’t verify them so your numerator lacks accuracy
Defined as: number of new cases in specified period/population of those disease free at start of period of observation
If they are not within the numerator then they can’t be within your denominator
Definition of incidence rate
Number of new cases that arise in population in specified period/sum of length of time during which each person in the population is at risk
- Denominator: person-time at risk
- So take every individuals person time at risk over given period of time and add them all together
- If you lose people to follow up, the numerator will still lack accuracy
If a disease only gives you partial immunity eg Covid, then you can be part of the numerator again when you become at risk again
Advantages and disadvantages of case reports?
Adv: rapid sharing of new info about rare occurrences and useful in hypothesis generation
Dis: one experience, ?coincidental, lack of comparison group
Advantages and disadvantages of cross sectional surveys?
o A representative sample of a population is studied to quantify a disease, an exposure or both
o ‘Snapshot’ of population at a single point in time
o Exposure and disease assessed simultaneously
§ Eg surveys
§ Trends over time can be examined using repeated cross-sectional surveys eg polling before elections
Adv: quick and relatively easy, can measure prevalence, can measure prevalence of RF, can measure demand for service (for health service planning), hypothesis generation
Dis: prevalence subject to singular point in time, can’t measure incidence, can’t determine causality
Advantages and disadvantages of case control studies?
o People with disease (case) and people without the disease (control) are compared by looking at past exposure of each group to potential causes
§ Retrospective
o Adv: Can be useful for investigating causation, particularly if disease is rare or long ‘incubation’ period after exposure (when cohort studies impractical), quick and inexpensive, can examine multiple exposures
o Dis: selection bias (ensuring case population is representative of larger control population apart from outcome is hard), impractical if exposure is rare, not always certain that exposure preceded disease, cannot measure disease incidence
OR: yes/no for cases compared to yes/no for controls for given exposure
Advantages and disadvantages of cohort studies?
o Study people with a risk factor to see if they develop particular diseases
o Can do descriptive or analytic cohort studies
o Recruit people free from disease, classify participants at baseline as exposed or unexposed, follow both to determine outcome, compare incidence of outcome between exposed and unexposed
o Usually prospective
o Adv: can measure incidence, useful for prognosis and causation, useful for rare exposures, can examine multiple outcomes, can show exposure comes from disease, can measure exposure and outcome data directly so more accurate and less risk of bias
o Dis: expensive & time consuming, impractical/efficient if outcome is rare, vulnerable to losses to follow up
o Retrospective cohort
§ Construct cohort based on past records
§ Efficient if accurate outcome data
§ Problematic if poor data on outcome
Nested case-control
At end of cohort study when outcomes have occurred, you can select cases (participants who developed outcome of interest during follow-up) and controls (participants who did not develop outcome during follow-up)
Advantages and disadvantages of RCTs?
o Pre-specify an outcome
o Investigator allocates exposure
o Randomisation: enables two groups to be balanced for factors/characterisations which could influence the outcome, so you isolate the effect of only the intervention you want (treatment or prevention)
o Adv: strongest evidence of effect of intervention, can examine more than one outcome, prospective, eradicates effect of bias
o Dis: expensive, time consuming, if not properly planned then can be too small or too short, not always practical (ie if no. of patients needed is prohibitively high, if randomisation is unethical), trials do not necessarily reflect what happens when intervention is delivered routinely ie in real life
Infections that can give you a hepatitis
Hepatitis ABCE
Leptospirosis
Arboviruses: Yellow fever virus (AST>ALT)
VHF: Lassa fever
Herpes viruses: CMV, EBV
Malaria
Key facts Hepatitis A
Faecal oral transmission, incubation 4-8 weeks
- Children esp <6 ~70% asymptomatic, but spreaders, >6 70% jaundiced
- Adults: jaundice, fulminant hepatitis +/- liver necrosis, risk of failure if pre-existing liver disease
- If symptoms then can be symptomatic for months
- Spontaneous resolution over 1-2 weeks
- No chronic HAV
Diagnosis: serology IgM/IgG
Vaccine
○ Effective in 95% cases, immunity for 20 years
Can’t give to kids <6 months -> need anti-hepA immunoglobulin
Key facts Hep C
Transmission: blood borne, bodily fluids
Incubation: 2 weeks - 6 months
Who:
- (IVDUs/haemophiliacs issue/needles/tattoos/dialysis)
- 15-25% spontaneous clear
- 75-85% chronic infection
S/S:
- <30% symptomatic
- Liver failure 1/2%
Diagnosis: hep C total Ab +/- Hep C RNA
- Ab can persist for whole life
- If immunocompromised or high risk (ie might not mount full immune response or slow one) then just do hep C RNA directly
- Some Ag tests available
Mx: DAAs upon diagnosis (based on detectable HCV RNA)
Vaccine: none, reinfection common esp in high risk groups
Two types of outbreaks for Hepatitis E?
- Sporadic acute jaundice
○ Genotypes 3/4
○ Consumption of undercooked or raw pork/game meat and shellfish
○ High income countries - Acute jaundice in Africa and Asia
○ Genotypes 1/2
○ Faecal contamination of drinking water
○ Humanitarian crises
In low income countries most people will be exposed to what hepatitis virus?
Hepatitis A, so most people will have Abs
How should you treat a baby if pregnant mum is Hep B positive?
- Treat child with tenofovir or TAF from week 30 to week 4 post-partum
- HBV vaccine and HBIG on first day of life
HBIG not really available outside high income countries
Hepatitis B core Ag (HbcAg) generally means
Acute infection, if persists >6 months then = chronic infection
Life cycle of Entamoeba histolytica
Ingest cyst
Swallow cysts
Pass through stomach as resistance to acid
Exist/hatch in small intestine
Release of trophozoite
Multiplication
Cysts form
Hatching in stool -> infect others
What index can help predict cirrhosis in HbsAg +ve?
AST to Platelet Ratio Index
Which demographic does E.histolytica liver disease most affect?
Adult males
no sex differences in Amoebic dysentry
Diagnostic methods for Entamoeba histolytica?
· Wet-film microscopy (but note cannot distinguish between E. histolytica and E. dispar)
○ Concentrated, fixed and stained faecal samples
· Serology - Relatively cheap. Usually strongly positive in ALA, can persist
· Tissue biopsies - likely histolytica if seen in tissue
· Antigen detection – Not all distinguish Eh/Ed. Reliable?
· Nucleic acid methods – Real-time PCR, LAMP, metagenome
· Diagnosis of ALA – Imaging, symptoms
Treatment for E.histolytica
- Invasive amoebiasis is almost exclusively treated with metronidazole or other 5-nitroimidazole drugs (equally but no more effective)
- Should be followed by a luminal amoebicide– choice depends on what is licensed locally
- Paromomycin is most effective for luminal E. histolytica
Where do Giardia cysts colonise?
Small intestine
Where do Entamoeba cysts colonise?
Large intestine
Possible pathophysiological mechanisms of Giardia?
- Malabsorption of glucose, water, Na+
- Diffuse microvillus shortening
- Loss of epithelial barrier function -> increased intestinal permeability
- Apoptosis of enterocytes
How do you diagnose Giardia?
- Wet film microscopy of faecal samples
○ Cysts easy to recognise, so specificity is high but sensitivity low - Direct fluorescence Ab staining of cysts
- Ag detection (ELISA/card; slightly less sensitive than DFA)
- Conventional, multiplex & real time PCR
How is Giardia transmitted? What permits its transmission/issues with it?
- Food, water, person to person
- Infectious dose is very small ~10 cysts
- Cysts are resistant to chlorine and other disinfectants
- Efficacy of conventional wastewater treatment processes at removing cysts is limiting
- Cysts remain viable for weeks in cold water
- Animal reservoirs of some genotypes
Treatment of Giardia
Metronidazole (1, avoid in first trimester) / Tinidazole (seems to be slightly better) / Nitazoxanide
Paromomycin appears to be effective and is regarded as safe in pregnancy
Treatment failures with nitroimidazoles are not uncommon. Drug resistance is a growing problem.
What three species of trichomonads affect humans?
- Trichomonas vaginalis
- Trichomonas tenax
- Pentatrichomonas hominis
How to diagnose trichomonas vaginalis?
- Still largely by wet-film examination
- Culture will detect 10-30% more but takes longer
- Rapid antigen detection kits provide the speed of wet film & better sensitivity than culture
- PCR and other nucleic acid amplification tests (NATS) probably the most sensitive but not yet in routine use
How is trichomonas vaginalis transmitted? Why is it an issue?
Sexually transmitted
Linked to low birthweight and also higher risk of HIV acquisition and transmission
Clinical manifestations of trichomonas vaginalis?
Most common signs and symptoms in women:*
- Purulent vaginal discharge
- Vaginal and vulvar erythema
- Urethra commonly infected causing dysuria
In men:
- Urethral discharge and/or dysuria
- Spontaneous loss of infection seems to be quite frequent
The overwhelming majority of infections are asymptomatic (98.5% in men, 73.3% in women)
Treatment of trichomonas vaginalis?
- Single 2g dose of metronidazole (MTZ)
- Tinidazole -> sig more effective but 10x more expensive (also avoid in pregnancy)
- The most recent CDC STI treatment guidelines now recommend metronidazole 500mg PO BD (women); single 2g dose (men)
Metronidazole resistance is a rare but real problem
Key features of Dientamoeba fragilis?
- Amoeboid appearance but is related to trichomonads
- Pathogenicity is controversial and certainly variable
- Reported symptoms are non-specific (e.g. diarrhoea, abdominal pain)
- The trophozoite will not be found by light microscopy unless specimens are rapidly fixed and stained
- If use PCR, infection rate is high in the general population
Treatment:
- Metronidazole (not particularly effective)
- Clioquinol - more effective in reliving symptoms
- Tetracycline - also used
- Secnidazole - may be the best
What is the only ciliate to infect humans and relevant features?
Balantioides coli
- Both cyst and trophozoite are much larger (> 50 μm) than other gut protozoa
- Very common in pigs, but rare in humans
- A large bowel parasite
- Frequently asymptomatic but can occasionally invade like E. histolytica and cause colitis, dysentery and death
- Metronidazole seems to be effective but few recent reports available
- Cysts and nucleus are huge
Definition of XDR TB?
Resistance to
- Isoniazid (INH) and Rifampicin (RIF), the two most powerful first-line TB drugs (this is what defines multidrug-resistant TB, or MDR-TB).
- Fluoroquinolones, a class of antibiotics that are key second-line drugs.
- At least one of the injectable second-line drugs, such as amikacin, kanamycin, or capreomycin.
Definition of pre-XDR TB?
- Rif resistance +/- isoniazid resistance + resistance to fluoroquinolone (mof/levofloxacin)
Definition of MDR TB?
- Combo of isoniazid and rifampicin resistance
- Unusual to have Rif resistance without isoniazid resistance
What is DOT for TB?
Key Goals of DOT:
Ensure Adherence
Prevent Drug Resistance
Monitor Side Effects:
Support Patients
Types of DOT:
In-person DOT: Patients visit a clinic or a healthcare worker comes to the patient’s home to observe them taking the medication.
Electronic DOT (eDOT): Patients record themselves taking their medication via video, which is reviewed by healthcare workers remotely. This method is increasingly being used where in-person observation is not feasible.
What are “BPaL” and “BPaLM” for TB?
Used for MDR and XDR, treat for 6 months (prior regimens used 9-18 months)
Only for adults, no CNS/disseminted/
MDR you can use BPaLM:
bedaquiline (B), pretomanid (Pa), and linezolid (L) + moxifloxacin (M)
BPaL:
bedaquiline (B), pretomanid (Pa), and linezolid (L)
SEs linezolid
Drop FBC
Eye toxicity
Peripheral neuropathy
SEs bedaquiline
Prolong QTc -> risk of sudden death
Hepatitis
N&V&Arthralgia
SEs pretomanid
Very expensive
Who can you use a urinary LAM in?
Only use if suspecting TB in HIV
Only approved for patients with low CD4 count
Only looks for active disease, ie not passive
Who do you blanket give TB preventative therapy to and what do you rule out in them?
Rule out active disease
Give preventative treatment to children under 5 and HIV positive individuals/high risk
If person has latent TB and has had contact with MDR person?
Empirical 6 months levofloxacin
Ddx for slow growing small facial lesion that has ulcerated in tropical setting. Itchy but not painful with no lymphadenopathy and systemically well.
Cutaneous leishmaniasis - localised painless ulcer with raised edges
Sporotrichosis -> Sporothrix schienckii
Cutaneous TB
Balamuthia mandrillaris (amoeba)
Francisella tularensis (Tularaemia) -> northern hemisphere only
Cutaneous anthrax - but will appear dark
Why is Amastigotes also called the Leishmanial stage?
Its the form leishmania takes in the vertebral host
otherwise = protist cell that does not have visible external flagella or cilia
What causes granulomatous amoebic encephalitis?
Balamuthia mandrillaris
What causes Sporotrichosis?
Sporothrix schenckii - dimorphic fungi
Found in soil/on plants
Enters skin through direct inoculation eg thorny plants/animal scratch
Papule -> tender ulcer
Lesions can spread along draining lymphatic vessels
?farmer/gardener
Hyperendemic in parts of Andes -> children, facial lesions
Key facts about cutaneous leishmaniasis?
Protozoa = genus Leishmania
Anthroponotic or zoonotic (reservoir small animals)
Transmission: sandflies
- Lutzomyia (New World)
- Phlebotomus (Old World)
Incubation period: weeks to months
Clinical: depends, most common is localised
Old world (Africa/Asia/Europe): >50% heal spontaneously
New world (Latin America): <20% heal sponteanously
Treatment:
OW/NW (but not L.Viannia-complex): intralesional pentavalent antimonial eg sodium stibogluconate SSG, paramomycin cream +/- cryotherapy or thermotherapy
Systemic tx: Pentavalent Antimonials (e.g., Sodium Stibogluconate or Meglumine Antimoniate) injections 20-28days OR Miltefosine OR Azoles
2nd LINE: Amphotericin B OR ambisome
L.guyanensis: pentamidine
Options for diagnosis of cutaneous leishmaniasis?
- Skin scrapping and Giemsa staining -> amastigotes
- Culture on FNA/biopsy samples
- Montenegro or Leishmania skin test -> test for delayed immune response
Causes of ptosis?
Oculomotor damage -> innervates the levator palpebrae superioris
- Lesions can result in complete ptosis
Sympathetic damage eg Horner’s -> partial ptosis via superior tarsal muscle
Causes and features of bacterial meningitis?
Streptococcus pneumonia
Neisseria meningitides
Streptococcus suis (Asia)
Rapid onset, high fever, meningism, CN involvement less common
CSF: cloudy, high leucocyte count, polymorphs, low glucose
Causes and features of TBM?
Mycobacterium TB
Hx of several days of illness, slightly less abrupt, CN involvement common
CSF: clear, high CSF protein and low glucose
Causes and features of Cryptococcal meningitis?
Cryptococcus neoformans
Hx: subacute onset, severe headache, CN involvement
CSF: normal in at least 25% of cases
What is the relevance in Hep B of
- HbsAg
- HbcAg
- HbCAb
- HBV IgM anti-Hbc
- Hepatitis surface Ag (HbsAg) to have hep B, >6 months = chronic
- Hepatitis B core Ag (HbcAg) generally means acute infection
- Isolated hep B total core Ab (HbCAb) can mean prior infection
- Core IgM Ab = acute infection
Key Hepatitis B facts
Transmission: body fluids, blood etc
Incubation: 1-6 months
Who:
* Acquiring as child -> MUCH higher risk of CHRONIC infection, worse if vertical transmission
○ <1 year: usually asymptomatic
○ >1 year: symptomatic infections
* 30% symptomatic, 95% adult cases will resolve, 1% liver failure
· 5-10% of adults get chronic infection
· Only need a small amount of exposure to blood with high viral load
Diagnosis:
- Hepatitis surface Ag (HbsAg) to have hep B, >6 months = chronic
- Hepatitis B core Ag (HbcAg) generally means acute infection
- Serology for HBV Core IgM
Vaccine:
Recombinant HbsAg - 3 doses - 95% effective in healthy people
Key facts Hepatitis E
Transmission: Faecal-oral, domestic pigs/deers
Incubation: 4-8 weeks, often preceded by prodrome and diarrhoeal illness
Who:
- Sporadic acute jaundice
○ Genotypes 3/4
○ Consumption of undercooked or raw pork/game meat and shellfish
○ High income countries
- Outbreaks of acute jaundice in Africa and Asia
○ Genotypes 1/2
○ Faecal contamination of drinking water
○ Humanitarian crises - Mortality in pregnant women can be up to ~20%
S/S: - Mild or symptomatic
- Typically resolves spontaneously over 1-2 weeks
- Liver failure rare except in pregnancy (acute liver failure in 20%), chronicity recognised in immunocompromised
Diagnosis:
- Serology (IgM/IgG) and molecular testing (HEV RNA)
Vaccine:
Licensed in China, global trials ongoing in women of child bearing age
Options for treatment of acute Hepatitis B infection?
- RCTs have not demonstrated efficacy but are safe
- Lamivudine/entecavir/tenofovir if 2 of
○ Hepatic encephalopathy
○ Bilirubin >10mg/dL (171micromol/L)
○ INR>1.6
What does HBV/HCV co-infection put you at risk of?
- 7.4% globally
- Much more likely to develop chronic HBV 30%
- HIV/HBV coinfection indication for treatment with ART against HBV (tenofovir/emtricitabine or lamivudine backbone)
- Without treatment -> progression to cirrhosis can be rapid
- Treatment does not totally stop disease progression
How does chronic HBV infection lead to HCC?
- Acute inflammation -> carcinogenic properties of virus directly -> HCC
○ Uncontrolled hep B can cause liver cancer due to integration into host genome - Acute inflammation -> Fibrosis -> cirrhosis 20% (30% decompensated) -> HCC 1-4% annually
What are the problems with treating chronic HBV? What approach should be taken?
Nucleot(s)ide reverse transcriptase inhibitors (NRTI) suppress viraemia eg TDF
But CANNOT get rid of DNA in nucleus of hepatocytes due to cccDNA forming minichromosome that remains despite therapy
Means virus can reactivate later in life eg if immunosuppressed
- Treat
○ Functional cure -> does not rule out risk - Minimise superimposed risks
○ No etoh
○ Lower infection risk
○ Control metabolic syndrome
○ Behaviour -> eg avoid groundnuts, cooking equipment with led etc
What does elimination of a disease mean?
- Reduction to zero of the incidence of a disease in a defined geographical area
- Continued interventions required to present re-introduction
Eg Polio in the Americas
What does eradication of a disease mean?
- Reduction to zero of the incidence of a disease in a defined geographical area
- Continued interventions required to present re-introduction
Eg Polio in the Americas
What are some requirements for elimination or eradication of a disease?
- An effective intervention is available to interrupt transmission
- Surveillance: Practical diagnostic tools of sufficient sensitivity and specificity to detect levels of infection that can lead to transmission are widely available
- No animal reservoir
- The disease must be widely recognised to be of public health importance
- Elimination must be perceived as a worthy goal by all levels of society
- A technically feasible intervention must have been field-tested and found effective
- Political commitment must be obtained at the highest levels (WHA resolution)
- Advocacy plan must have been prepared
What did the London declaration on NTDs 2012?
Resolved to sustain, expand and extend programmes that ensure the necessary supply of drugs and other interventions to help eradicate Guinea worm disease, and help eliminate by 2020 lymphatic filariasis, leprosy, human African trypanosomiasis and blinding trachoma
NTDs targeted for global eradication by WHO roadmap of 2012?
- Yaws
- Guinea worm
NTDs targeted for global elimination by WHO roadmap of 2012?
- Onchocerciasis in South America
- Human African trypanosomiasis due to T.b.gambiense
- Schistosomiasis
– in China, Eastern Mediterranean, Caribbean, Indonesia, Mekong basin
– In the Americas and Western Pacific Region - Chagas disease through blood transfusion (2015); intra-domiciliary
- Rabies in SE Asia and Western Pacific
NTDs targeted for elimination as a global health problem by WHO roadmap of 2012?
- Blinding Trachoma
- Leprosy
- Visceral leishmaniasis in the Indian sub-continent
- Lymphatic filariasis
What are the challenges with tests to certify elimination and for subsequent surveillance?
- Large numbers of people, vectors or intermediate hosts may need to be sampled
○ Tests should be high throughput
○ Pooling can save time and money
○ Tests do not necessarily need to be at the point of care - Sensitivity should be high
- False positives must be kept to a minimum
- Tests must be highly specific
Intervention for lymphatic filariasis to eliminate as NTD?
○ Annual or twice yearly MDA with single dose ivermectin and albendazole, plus DEC in regions where there is no onchocerciasis
– reduces microfilaraemia but does not kill adult worms
Proposed new leprosy targets for 2030?
- Zero Grade 2 disability (G2D) among paediatric leprosy patients
- Reduction of new leprosy cases with G2D to less than one case per million population
- Confirmed absence of children with leprosy for 5 consecutive years
- Zero countries with legislation allowing discrimination on basis of leprosy
Key differences between Human African Trypanosomiasis causes?
T. brucei gambiense
- Insidious onset (“sleeping sickness”)
- No confirmed animal reservoir
- POC screening test available (lateral flow HAT Sero-K-SeT)
T. brucei rhodesiense
- Acute onset - febrile illness
- Zoonosis
- Blood film usually positive
Treatment for T. gambiense?
– Until 2019
* Stage 1: Pentamidine IM
* Stage 2: Nifurtimox + eflornithine IV
– Now
* Fexinidazole is an effective oral treatment for stage 2 T. gambiense
Treatment for T.b. rhodesiense?
○ Stage 1: Suramin IV (stage 1)
○ Stage 2: Melarsoprol IV + prednisone (stage 2)
Proposed overall goal by 2030 for NTD SDG?
- 90% reduction in the number of people requiring interventions against NTDs
- 100% of population at risk protected from out of pocket health payments due to NTDs
- 100 countries have eliminated at least 1 NTD
- 2 NTDs have been eradicated
- DALYs lost to NTDs reduced by 75%
How is trachoma transmitted?
- Flies
- Fomites
- Fingers
Within Family or among close Friends
5Fs
Treatment of trachoma? old vs new
- Initially tetracycline ointment BD for 6 weeks
- Trial by Prof Bailey RCT, single-blinded in 2 Gambian villages showed single dose PO Azithromycin (20mg/kg) showed better adherence and treatments were equivalent
Reinfection was common
Now also
- Surgery
- Facial cleanliness + hygiene
WHO recommendations for azithromycin for trachoma?
Baseline survey:
- 5 years MDA where TF ≥30% in 1-9 year-olds
- 3 years MDA where TF 10-29.9%
- 1 round of MDA where TF 5-9.9%
Impact surveys:
- 1-5 years after SAFE interventions began
Surveillance surveys:
At least two years after an impact survey has shown the TF prevalence to be <5% in 1-9 year olds
What is Trachoma caused by?
Chlamydia trachomatis
- Bacterium
- Intracellular organism (biphasic developmental cycle)
Infects mucosal epithelial cells of genital tract and conjunctiva
Diagnostic tests for Yaws?
- Serological
○ TPPA (treponema pallidum partial agglutination test)
§ Stays positive for life
○ RPR/VDRL
§ Titres fall following treatment
§ Less specific - eg low level false positives from malaria - Molecular
PCR can differentiate sub-species
Basic facts and epi of Yaws?
Treponema pallidum pertenue
Found in warm/humid environment
○ West Africa
○ South America
○ Pacific
○ South-East Asia
Children = main reservoir of siease
Transmission
○ Skin to skin contact
○ ?Flies
Stages of Yaws
Primary:
§ Painless ulcer or nodule (>1cm, raised, solid) in trop world known as papillomas
§ More papillomas in West Africa as proportion of cases
§ These particular lesions heal within a few weeks
Secondary
Then spread of bacteria -> general illness, disseminated
§ Destructive lesions of skin/soft tissue
§ Face, nasal mucosa, bones of lower limbs
§ No neuro involvement/no CVS disease
Tertiary
§ Asymptomatic between stages
§ Can become latent at any stage
§ No clinical signs of disease
§ Latent cases -> important source of reinfection and onward transmission
§ Ratio latent : clinical between 6-10:1
What two countries have ?eliminated Yaws?
India and Equador
What rapid tests exist for diagnosing Yaws?
Dual Path Platform (DPP) Syphilis Screen and Confirm Test:
- Detects treponemal and non-treponemal Abs
- Can differentiate between an active infection (non-treponemal antibodies present) and a past infection (treponemal antibodies alone)
Treponemal-Specific Rapid Diagnostic Tests: treponemal Abs only so can’t distinguish between active and past infection
What did the YAWS3 trial do/show?
YAWS3 trial
One round of MDA, followed by targeted treatment of active cases and their contacts VS Three rounds of MDA at six-month intervals before transitioning to targeted treatment.
○ Three rounds of mass azithromycin administration for yaws eradication
○ Multiple rounds of treatment enable opportunity to address treatment reservoir in addition to acute cases
A single round of MDA significantly reduced the prevalence of yaws, it was insufficient to eliminate transmission in the long term. Reintroductions of yaws occurred due to untreated latent cases or people who missed the MDA. In contrast, the strategy of three rounds of MDA was more effective in maintaining lower prevalence and reducing the risk of re-emergence.
Additionally, the trial highlighted the need to monitor for potential macrolide resistance, as azithromycin-resistant strains of Treponema pertenue had been detected in some cases
Big issues with Yaws eradication?
Poor data on epi + serological same amongst different species of treponema
Limited funding
MDA with azithromycin creating resistance (de-novo mutations)
Potential for animal reservoirs -> similar infections in non-human primates
Strategy for Yaws eradication?
– Mapping to identify current foci
– Mass treatment with
azithromycin (likely with multiple rounds)
– Surveys to identify cases & contacts
– Mop-up Treatment
– Integrate with other skin NTDs
What are the types of endemic trepanematosis?
T.pallidum ssp pallidum -> Syphilis
T.pallidum ssp pertenue -> Yaws
T.pallidum ssp endemicum -> Bejel
T.carateum -> Pinta
Key facts about Pinta?
- T.carateum
- Found in warm, humid environments
○ Restricted to Latin America - Active cases in young adults are main reservoir of infection
Transmission: skin to skin contact
Key facts about Bejel?
- “Endemic syphilis”
- T.p.endemicum
○ Found in dry environements eg
§ The gulf
§ The sahel - Children = main reservoir
Transmission via
○ Skin to skin contact
○ Indirect contact via utensils
Successes and obstacles of guinea worm eradication?
What could help with success?
- Easily identifiable disease
- Relatively simple and vulnerable life-cycle
- Cheap, easy interventions
- Community focused interventions
- Vertical health programme
- Political and economic support
Obstacles to success?
- Insecurity (political etc)
- Population movement
- Donor fatigue
- Community fatigue
- Atypical transmission (dogs get infected by paratenic host)
- Pseudo-presentation
What is Dracunculiasis medinensis?
Guinea worm
60cm large nematode
What is a paratenic host?
An organism that harbors a parasite but is not necessary for the parasite’s development to its adult or infective stage. In other words, the parasite can survive and remain infective within the paratenic host, but it does not undergo any further development there. The host simply acts as a temporary “carrier” or “reservoir” for the parasite until it reaches its definitive host, where it will complete its life cycle.
Life cycle of guinea worm rule of 14?
- Lives for 10-14 months as worm in human host
- 14 days as larvae in water
- 14 days developing as larvae in vector until it can infect a human again
What are some skin NTDs?
- Yaws
- Leprosy (Hansen’s disease)
- Onchocerciasis
- Lymphatic filariasis (lymphoedema and hydrocele)
- Buruli ulcer
- Cutaneous leishmaniasis
- Mycetoma, chromoblastomycosis, and other deep mycoses
( including sporotrichosis) - Post-kala-azar dermal leishmaniasis
- Scabies
- Tungiasis
What causes buruli ulcer and who does it occur in? How is it transmitted?
Mycobacterium ulcerans
WHO
- Poor inhabitants, remote rural areas, limited access to healthcare services
- All ages and socioeconomic groups
- Africa ~50% aged <15 years
- Australia: adults mostly affected
TRANSMISSION
- Trauma -> introduction of mycobacterium to skin
- Occurs in people living close to lakes, rivers, marshy areas, mining, deforestation or flooding
- Inoculation into skin by
○ Aquatic insects
○ Mosquitoes
What drives pathology in M.ulcerans?
Buruli ulcer toxin called mycolactone
Variants driven by chemical modification of side chain of toxin:
○ A/B: African strains
○ C: Australia
○ D: Asia
Pathogenesis driven by toxin?
○ Low concs of toxin cause suppression of dendritic cells, macrophages, T-cell function abrogating cytokine and chemokine secretion in response to mitogens
Downregulation of inflammatory mediators, lipid metabolism
Early lesions:
- Clumps extracellular mycobacteria
- Subcutaneous fat necrosis
Sparse inflammatory infiltrate
Late lesions:
- Areas of acute and chronic inflammation including:
* few mycobacteria
granulomatous inflammation
Clinical manifestation of buruli ulcer?
Incubation: 32-264 days (mean 4.5 months)
No constitutional symptoms associated
Lesions appear on all parts of body but predominantly on the limbs (up to 85%)
Bones involvement (6-25% of lesions in Benin)
Active disease:
- Non-ulcerative (papule, nodule, plaque, oedema)
- Ulcerative forms and osteomyelitis
- Painless, NO LN involvement (usually)
- firm, immobile
If not treated:
Ulceration -> necrosis -> sloughing
- indurated/undermined edges, painless
Ddx for buruli ulcer?
- Abscess—————————Painful
- Lipoma———————– Mobile
- Ganglion————————-Close to joints
- Tuberculous lymphadenitis—-Constitutional symptoms
- Onchocerciasis nodule———-Painless, long history
- Subcutaneous infections such as fungal infection
- Tropical phagedenic ulcers
- Arterial and venous insufficiency
- Diabetic ulcers
- Sickle cell ulcer
- Cutaneous leishmaniasis
- Extensive ulcerative yaws
- Haemophilus ducreyi ulcers
Non Buruli ulcers are often painful
How to take sample to test for buruli ulcer? How to test sample?
- Swab
○ Get under the undermined edge of ulcerative lesions - FNA
○ For non-ulcerative lesions eg nodules/papules/oedema/some ulcerative lesions - Biopsy in case of surgery
GOLD standard: PCR (sensitivity 98%)
Other:
- Culture (sens 49%)
- Histopathology (sens 82%)
- Microscopy for AFB (sens 42%)
Current treatment for Buruli ulcer? Abx SEs?
Rifampicin 10mg/kg + Clarithromycin 15mg/kg DAILY for 8 WEEKs
In Australia: sometimes use Rif + Moxifloxacin *but no RCT
ALSO:
- Enhance wound healing: nutrition, wound care, skin grafting
- Disability prevention
- Rehabilitation
§ <2% patients
§ Skin rash (Rifampicin)
§ Anorexia/nausea/abdo pain/jaundice/renal failure (Rif)
§ Nausea/altered taste/jaundice/hepatitis (Clari)
§ Tendonitis, rash (Moxifloxacin)
A patient is treated for Buruli ulcer with 8 weeks of Rifampicin and Clari. After 2.5 weeks of treatment they return to the health centre with multiple nodules surrounding the original wound. What is your diagnosis? What causes this? How would you manage it?
Paradoxical reaction
- Multiple nodular lesions 2 weeks after start of Abx
- Inflammatory reaction that, prior to antibiotic treatment, is suppressed by mycolactone, the M. ulcerans toxin.
- As the organisms are killed by antibiotics, mycolactone production ceases and its suppressive effect is lost causing a rebound of inflammation
- Associated with high bacterial load
Can consider steroids but should heal on its own
Cover lesions with vaseline gauze + control lymphoedema with short stretch bandages +/- grafting
Complications of buruli ulcer (eg untreated or late presented)
- Contractures
- Cancer
- Amputation
- Eye complications
- Severe mental distress and reduced QOL
- Burden on caregivers
- Stigmatising
Diagnosis for buruli ulcer is mainly via?
PCR
What is podoconiosis? What causes it?
Steadily progressive foot and leg swelling (lymphoedema), often confused with lymphatic filariasis
Caused by triad of:
- Exposure to irritant soil
- Genetic susceptibility (link to SNPs in HLA Class II locus (particularly HLA DQA1) in Wellcome funded study)
- Foot vulnerability (lack of shoe-wearing and foot hygiene) + long term exposure
Rare in children, more common at higher altitudes and with Smectite in soil, farming communities + barefoot
How do you diagnose podoconiosis? How does it present clinically?
- Clinical
○ Hx, physical O/E, Ag and Ab tests to rule out lymphatic filariasis - Early signs
○ Itching, burning, splaying of forefeet, reversible plantar oedema, hyperkeratosis - Later signs
○ Persistent oedema, inter-digital maceration, nodules, ‘mossy’ changes, ‘waterbag’ or ‘fibrotic’ swelling
Ddx of lymphoedema in tropical settings
Podoconiosis
Lymphatic filariasis
Onchocerciasis
Leprosy
Protein-energy malnutrition in children
How can you tell the difference between lymphatic filariasis and podoconiosis?
- Sea level: Podo>1500m, LF<1000m
- Diagnosis: LF field ICT blood test, Podo clinical
- First symptom site: LF not food, Podo toes/foot
- LN attacks: LF precede swelling of limb, Podo follow swelling of limb
- Chief site of swelling: LF above/below knee, Podo below knee
- Prevention: LF mosquito nets/MDA, Podo: footwear/coverings/foot washing
- Treatment: LF 2 drugs (albendazole/DEC) + foot hygiene, Podo: foot hygiene, bandages, socks etc
Complications of Podoconiosis?
- Bacterial co-infection (high rates of drug-resistance organisms found, mix gram neg + gram positive Bac)
- Acute episodes (ADLA) characterized by malaise, fever, chills, diffuse inflammation and swelling of the limb, lymphangitis, adenitis and skin peeling
○ Require analgesia (e.g. paracetamol), fluids and antibiotic such as penicillin - Ulcer not responding to care -> refer to a surgeon for biopsy (?SCC/BCC)
- Deep fungal infection. Additional swelling, on which small black dots may be visible -> refer to surgeon
- Psychosocial and MH burden
Principles of podoconiosis treatment
Hygiene
- BD, room-temp washing of limbs
Skin care
- Wash + dry + rub ointment/emollients, if breakages then washing + antibac/fungal creams, cover with sterile gauze for fly protection
Bandaging
- To reduce swelling, from toes to knee, V design, 5cm above upper limit of swelling (give people 2, one to wash and one to use)
Elevation and exercise
- Raise affected limb at night, ankle circles
Footwear
- Clean socks + feet, clean between toes, avoid tight shoes + low heel
Treatment of acute attacks
- Rest& elevate affected limb
- Coldwater immersion/cold soaked towels
- Anti-histamines + analgesia
- Encourage fluids
- Abx if no improvement in 24hrs
- Refer if pregnant, rigors, high fever, vomiting, confusion
- ?Associated diseases
DON’T: exercise, warm/heat on skin, open/cut blister or skin, bandage, rub herbs etc, use scarification
What is Noma? What causes it, where is it found and what are some associated factors?
Rapidly acting orofacial gangrene
Affects kids aged 2-5 years old
14,000 cases yearly but now focused in South America, Africa and parts of Asia
Opportunistic infectioninte
Range of organisms found but not consistently (Fusobacterium necrophorum, Prevotella intermedia, Klebsiella, Streptococcus, Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola)
Risk factors = No care access + socio-demographics + comorbidities
- Aged 2-5 years
- Chronic malnutrition
- Comorbidities
- Lack of access to quality healthcare including childhood vaccinations
- Not being breastfed
- Poor oral hygiene practices
- Low socioeconomic status of the family
High no. of previous pregnancies in mother
Stages of Noma disease
0: Simple gingivitis
- Bleeding when touched or during brushing
- Red or purplish red gum
- Swelling gum
1: Acute necrotising gingivitis (indefinite duration)
- Spontaneous bleeding
- Painful ulceration of gum
- Ulceration with 1+ interdental papillae
- Fetid breath or halitosis
- Excessive salivation
2: Oedema (1-2 weeks)
- Rapid extension of gingival ulceration and mucosal tissue
- Fetid breath or halitosis
- Facial swelling or oedema
- Painful cheek
- High fever
- Excessive salivation
- Mouth soreness
- Difficulty eating
- Anorexia
- Lymphadenopathy
3: Gangrene (Progresses in 1-2 weeks)
- Excessive destruction of intraoral soft and hard tissue
- Lesion with well demarcated perimeter surrounding blackened necrotic centre
- Separation of slough -> leaves hole in face often around cheeks or lips
- Difficulty eating
- Perforation of cheek + exposition of teeth/denuded bones
- Progressive drying of facial gangrene, anorexia, apathy
4: Scarring
- Trismus (depending on lesion location)
- Sequestration of teeth and exposure of bones
5: Sequelae
- Disfiguring
- Trismus
- Teeth loss/displacement/dental anarchy
- Feeding + speech difficulties
- Fusion of maxilla and mandible bones
- Nasal regurgitation
Ddx for Noma?
> Tooth abscess
Cellulitis
Animal bites
Burn injuries
Syphilitic yaws
Buruli ulcer
Leprosy
Oral cancer
Chemical burns
Noma: will be quick destruction of facial tissue in a child with comorbidities, with well defined perimeter
Treatment of Noma?
Abx
-> typical antibiotic regimen often includes:
Metronidazole (for anaerobes)
Penicillin or Amoxicillin (for aerobic bacteria)
Gent if gram neg
Wound debridement
Nutritional support
Reconstructive surgery
Physiotherapy
Psycho-social support
WHO guidelines (condensed) for HBV treatment?
Cirrhosis -> treat with tenofovir or entecavir, if a child then with entecavir
No cirrhosis?
Basically persistently abnormal ALT + high VL -> treat
If VL <20,000 then defer and monitor
If ALT not that abnormal and/or lower VL -> defer and monitor
Should get regular screening for HCC/treatment response/toxicity (renal esp)
Why do HBV/HCV DNA/RNA levels become less helpful/not a good predictor of disease with hepatitis D co-infection?
HDV suppresses both HBV and HCV replication (DNA/RNA levels do not predict outcome)
Key facts hepatitis D?
- Single stranded RNA
- Can only infect with HBV (takes 3 proteins for viral envelope)
- Transmission: blood/body fluids (MTCT is rare)
- Epidemiology: 5% of HBsAg carriers (high seroprevalence in Middle East, Central Asia and South America and high-risk groups: IVDU, MSM, SW (a/w HCV, HIV) - up to 80%)
- Incubation: up to 3/12
- Course: usually found in screening of acute hepatitis or progressive chronic liver disease
- Co-infection: acute self-limiting; chronicity rare
- Superinfection: 5% acute liver failure; 80-100% chronicity; rapid progression (up to 80% cirrhosis in <10 years)
- HDV suppresses both HBV and HCV replication (DNA/RNA levels do not predict outcome)
- Diagnosis: serology (IgM/IgG) or molecular testing (RNA); guidelines for testing inconsistent (EASL: low HBV DNA and high ALT)
Treatment: IFN𝛼 <30% SVR at 6/12
Treatment for chronic Hep C according to WHO?
DAAs usually 8-12 weeks, for all serotypes so genotypic testing not required eg
Sofosbuvir/Velpatasvir
Glecaprevir/Pibrentasvir
Good SVR (sustained virologic response) >95%: measured as virus is no longer detectable in the blood 12 weeks after completing therapy
If uncompensated cirrhosis may need longer course
Stages of HIV infection and their respective relevant tests?
- Eclipse phase
○ Infection of mucosal tissue - Viral stage I (viral RNA)
○ Viraemic
○ Test still negative - Early Ag
○ P24 Ag - HIV-specific Ab response
○ ELISA
○ Western blots
○ Partial control of viraemia but not complete
○ Chronic infection
○ Early chronic infection stage
What is the window period for HIV testing? How does this relate to tests used for HIV?
Time between infection and test at which 99% of infections should be identified
4th/5th Gen: 45 days (4th gen median 18 days, IQR 13 - 24)
POCT/self-tests: 90 days
If you are querying resistance in a HIV case where VL is undetectable what can you do?
Send pro viral DNA
What does reversion to wild type mean in the context of HIV infection?
- Drug resistance mutations in HIV usually come at a cost to the virus, making it less “fit” in the absence of the drug. These resistant strains may replicate more slowly or less effectively compared to the wild-type virus.
- When the selective pressure from the antiretroviral drugs is removed (for example, if the patient discontinues treatment), the wild-type virus can outcompete the drug-resistant strain because it is generally more fit.
- As a result, the virus reverts to its original, drug-sensitive form.
Importance of Reversion to Wild Type:
* Clinical Implications: Reversion to wild type can be beneficial in terms of restoring sensitivity to the original drug, meaning that the same ART regimen may become effective again if resistance had previously developed.
* However, even though reversion occurs, archived resistance mutations can still persist in the viral reservoir and may re-emerge if the same drug is used again.
WHO clinical staging of HIV?
Primary HIV (CD4 ~ 350 - 500 cells/mm3)
- Asymptomatic, acute retroviral syndrome
Clinical stage 1 (CD4 ~ 350 - 500 cells/mm3)
Asymptomatic
Persistent generalised lymphadenopathy
Clinical stage 2 (CD4 ~ 350 - 500 cells/mm3)
Lots but Herpes zoster
Angular cheilitis
Recurrent oral ulceration
Papular pruritic eruptions (eosinophilic folliculitis)
Weight loss but less than 10% BW
Clinical stage 3 (CD4 ~ 200 – 350 cells/mm3)
Severe WL >10% BW
Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis
Severe bacterial infections (pneumonia etc)
Ulcerative stomatitis
Clinical stage 4 (CD4 <200 cells/mm3)
HIV wasting syndrome
Pneumocystis pneumonia
Oesophageal candidiasis
Extrapulmonary tuberculosis
Kaposi’s sarcoma
CNS toxoplasmosis
Extrapulmonary cryptococcosis
Disseminated non-TB mycobacterial infection
Chronic cryptosporidiosis
Chronic isosporiasis
Disseminated mycosis (dimorphic fungal)
Ddx for mediastinal lymphadenopathy?
- TB
- Lymphoma
- Dimorphic fungal
- Cryptococcosis
- Nocardia
- NTM
When should you screen for cryptococcal disease? What to treat with if positive?
WHO now provisionally recommend screening all individuals with a CD4 count < 200 cells/µL
Treat patients without evidence of CNS disease with high dose fluconazole 1200mg for 2 weeks, followed by standard consolidation and maintenance therapy
Most common nerve (and palsy) affected by raised ICP? How does it present?
6th nerve palsy
Inward deviation of the eye (esotropia):
The affected eye turns inward toward the nose because the lateral rectus muscle is weakened or paralyzed, while the opposing medial rectus (which pulls the eye inward) is unopposed.
Diplopia (double vision):
Patients often experience horizontal double vision, particularly when looking toward the side of the affected eye. This occurs because the two eyes are misaligned.
Limited outward movement:
There is a marked reduction or inability to move the affected eye outward (abduction). For example, if the left 6th nerve is palsied, the left eye won’t move fully to the left.
Head turning:
To compensate for the double vision, patients may turn their head toward the side of the affected nerve (the side of the weakened lateral rectus muscle). This helps align the eyes and reduce double vision.
Presentation of cryptococcal meningitis
Difficult to differentiate between other causes. Headache/meningism/fever/focal neurology/abnormal mental status.
Common causes in adults and children of meningitis in HIV high prevalent settings
Adults: strep pneumoniae
Kids: Hemophilus influenzae, Strep pneumoniae, GNRs eg E coli/Klebsiella
Textbook CSF findings TB infection:
Appearance: Clear/cloudy
Opening pressure: raised
WCC: raised (normally <500), lymphocytes
Protein: greatly raised
Glucose: low
Serum to glucose ratio: v low
Textbook CSF findings viral infection:
Appearance: Clear
Opening pressure: normal/mildly raised
WCC: raised (normally <1000), lymphocytes
Protein: mildly raised, 0.5-1
Glucose: normal or slightly low
Serum to glucose ratio: normal or slightly low
Textbook CSF findings bacterial infection:
Appearance: turbid/cloudy/purulent
Opening pressure: raised
WCC: raised, neutrophils
Protein: raised, >1
Glucose: low
Serum to glucose ratio: very low
What is the commonest cause of dysphagia/odonophagia with oesophageal lesions in HIV?
CANDIDA
Treat but a lack of response should prompt endoscopy to investigate for:
* Cytomegalovirus
* Major aphthous ulceration
* Deep fungal infections
* Malignancy
Examples of coccidian parasites that can cause infection in HIV?
Cryptosporidium parvuum
* Zoonosis, contaminated water
* Most common cause of chronic diarrhoea
* No other treatment than ART
Cystisospora belli
- Widespread in environment
- Can cause refractory disease
- Treat with cotrimoxazole (or ciprofloxacin)
34 yo woman
Chronic diarrhoea, dehydration, profound weight loss
Newly diagnosed HIV, CD4 10
HIV wasting syndrome
* loss >10 % body weight
* diarrhoea >1 month
Ddx?
- Cryptosporidium
- Isosporiasis
- Mycobacterium tuberculosis
- Non-tuberculous mycobacteria – MAC
- Cytomegalovirus
- Microsporidiosis
- Deep fungal infection eg cryptococcus, histoplasma
- Lymphoma
How does chronic diarrhoea in HIV present for small vs large bowel and what are relevant pathogens?
Small:
- Bloating + abdominal pain
- Watery and large volume
* Cryptosporidium
* Isospora
* NTM
* HIV enteropathy
* Microsporidiosis
- Ix: Endoscopy and biopsy
Large:
- Small volume, blood/mucus/WBCs
- Tenesmus
- CMV, TB, Amoebiasis, Schisto
When are patients at highest risk of severe bacterial infections with HIV? What are some common bugs?
First 3 months of ART and if not on ART. Salmonella (typhoidal and non-typhoidal), Pneumococcus, E Coli.
When would you treat with steroids for TB related conditions?
TBM -> if HIV negative / if SOL
TBM -> consider if HIV positive
Inflammatory pericarditis
Severe and neurological TB IRIS
How do you differentiate between Toxoplasmosis and brain abscess on CT?
You can’t. Would need micro. Toxo treat with co-trimox.
What virus could be found in CSF in a HIV patient with CNS lymphoma?
EBV
A HIV patient has a solitary lesion on neuroimaging and has not responded well to co-trimoxazole. What should be considered as another differential? How would you confirm this?
Consider CNS lymphoma
Brain biopsy for definitive diagnosis
Treat with chemo/radio/ART
Key facts about progressive multifocal leukoencephalopathy
· Caused by JC virus, insidious onset, occurs at CD4 counts <100 cells/µL
· Progressive focal neurology (mainly motor)
· Normal CSF (JC virus PCR usually positive), MRI is diagnostic
No known effective treatment, give ART
Histoplasmosis
- Presentation?
- Ix
- Treatment
- Progressive disseminated infection
- Fever, fatigue, weight loss, and hepatosplenomegaly
- Cough, chest pain, and dyspnea in ~ 50% of patients
- CNS, GI, and cutaneous manifestations in a smaller
- percentage of patients
If CD4 counts >300 cells/mm3, histoplasmosis is often limited to the respiratory tract with cough, pleuritic chest pain, and fever
Ix:
- Microscopy - characteristic 2 to 4 µm in diameter budding yeast
- Culture (lysis-centrifugation technique) blood, bone marrow, respiratory secretions
- PCR
Antigen detection (blood or urine) by EIA of LFA
Mild: itraconazole
Severe/CNS: induce with ambisome then itraconazole maintenance (can be lifelong eg for AIDS pts)
CMV in HIV patients
- Presentation
- Diagnosis
- Treatment
Disseminated or localized end-organ disease in individuals who have very advanced HIV disease (CD4 <50 cells/µL) – Retinitis, colitis, pneumonitis, encephalitis
Diagnose with PCR
Treat with valganciclovir
Most common malignancies in cancer?
- Cervical cancer
- Kaposi’s sarcoma
○ Mortality at 8 months after KS -> poor outcomes - Lymphomas (NHL)
- Castleman’s disease (Lymphoproliferative disorder, unicentric vs multicentric)
Impact of CD4 deletion on TB pathophysiology in HIV?
○ Less CD4+
○ Alteration in macrophage activation (less IFN-Y production and in turn, granuloma formation)
○ Alteration to neutrophils, less epithelioid cells, less Langhans cells
○ Less effective granuloma formation
○ Altered adaptive cell populations + altered phenotypes of cells
Advanced: increased necrosis + increased neutrophils + increase Mtb => granulomas poorly organised or absent
Strategies for HIV and TB interventions for control
2000: DOTs
Mid 2000s: HIV control
2005ish: HIV/TB Collaboration activities
2010ish: 3 ‘I’s (intensive case finding/IPT/infection control)
2012: HIV/TB policy updates eg early ART, WHO endorsed Xpert
2014ish: End TB strategy, UNAIDS 90-90-90, WHO test can treat
2020: UNAIDs 95-95-95
When might you trial antibiotics as a mode of TB diagnosis?
LMICs
- Bacterial LRTI is important differential for pulmonary TB
- Assumption that LRTI improves with short course of Abx
○ PTB will not improve with antibiotics
○ Widely used intervention (especially low resource settings)
○ Recommended in several TB diagnosis guidelines
○ Little consensus on which Abx/duration
Sensitivity ~70%, Specificity ~77%
Should you give 4 month treatment regimen with Rifapentine to TB patients living with HIV?
Rifapentine based 4 month regimens are in WHO guidelines for CD4 counts >100
(only 8% of trial participants PLHIV)
What is the difference between rifampicin and rifapentine?
Rifampicin: Shorter half-life, used daily, preferred for active TB treatment.
Rifapentine: Longer half-life, used weekly or biweekly in latent TB treatment or intermittent regimens, with fewer dosing requirements.
Both can cause orange discolouration of body liquids. Both inhibit RNA polymerase.
Which rifamycin class Abx has less interactions with ARTs so might be used more safely for TB in people living with HIV?
Rifabutin
- Less potent CYP450 inhibitor
- Can cause Uveitis
Who can you consider TPT = TB preventative therapy in? What are some issues with it? What are the preferred therapies?
- People living with HIV (PLHIV), due to their significantly higher risk of developing TB.
- Close contacts of active TB cases, especially children under 5 and immunocompromised individuals.
- Immunocompromised individuals, such as those on immunosuppressive drugs, or organ transplant recipients.
- People with silicosis, as this condition increases TB risk.
- Children under 5 years old, who are at high risk after exposure to TB.
- Healthcare workers and other high-risk populations, such as prisoners or people in homeless shelters.
Issues: resistance/poor adherence/pill burden/availabiltiy
Examples:
1st: Isoniazid/Rifapentine weekly 3 months OR Isoniazid/Rifampicin daily for 3 months
2nd: Monotherapy eg Isoniazid daily for 6-9 months
Generalised life cycle of coccidia?
Oocyst ingested
Asexual reproduction leads to schizogony repeated
OR
Sexual reproduction leads to gamete formation
Release of oocyte
Resistent oocytes (ie with outer coat) are shed in faeces
Oocyte maturation (sporulation, sporogony) normally outside the body
What do mature (sporulated) coccidian oocysts contain?
Sporocyst
Sporozoites
Residual body
Life cycle of cryptosporidium?
- Oocyst Stage (Infective Stage): The Cryptosporidium parasite starts as a resistant oocyst (a spore-like form) in contaminated food, water, or surfaces. These oocysts are ingested by a host, such as a human or animal.
- Excystation in the Intestine: Once inside the host’s stomach or small intestine, the oocyst releases infectious forms called sporozoites. This process is called excystation.
- Invasion of Intestinal Cells: The sporozoites attach to and invade the epithelial cells of the intestinal lining. Inside these cells, they undergo asexual reproduction, forming meronts.
- Asexual and Sexual Reproduction: Type I meronts release merozoites which invade new cells for further asexual reproduction, type II meronts release merozoites which undergo sexual reproduction to form microgamonts (male gametes) and macrogamonts (female gametes). These gametes fuse to form a zygote.
Formation of New Oocysts: The zygote develops into a new oocyst, if its thin-walled it can stay inside the host -> autoinfection. If thick walled it exists host, shed in faeces.
Clinical presentation of cryptosporidium?
- Wide ranging s/s: asymptomatic (common) -> life threatening
- Watery diarrhoea is most frequent symptom
○ + dehydration, WL, abdo pain, fever, N&V - Immunocompetent lasts 1-2 weeks
○ Immunity to reinfection is incomplete -> risk of multiple episodes - Chronic and more severe in immunocompromised -> infection spreads from intestine to hepatobiliary and pancreatic ducts -> cholangiohepatitis, cholecystitis, choledochitis or pancreatitis
- Risk of respiratory cryptosporidiosis?
○ Known in immunocompromised
○ New data suggesting in immunocompetent children in Malawi via cryptosporidial diarrhoea and unexplained cough, transfer via aerosolised droplets or contact with fomites contaminated by coughing
Long term morbidity (up to 10 years)
Symptoms can persist following infection eg weight loss, blood in stool, chronic diarrhoea - IBS like symptoms
Is cryptosporidiosis in infants in less-developed countries a significant cause of
malnutrition, growth impairment and cognitive deficit? Is cryptosporidiosis associated with anything else?
Cryptosporidiosis interacts in a complex way with malnutrition and the intestinal microbiome to cause long-term harm to young children in less-developed countries
- A change in intestinal cell kinetics, leading to fewer mature enterocytes and impaired nutrient uptake, may
be one significant reason (Wallbank et al. 2024)
Other associations with bowel cancer -> higher rates of infection in BC compared to controls
How do you diagnose Cryptosporidiosis?
- Light microscopy of faecal specimens - staining with Ziehl–Neelsen, Auramine or Safranin (last not quite so good)
- MUST measure (5-5.5 µm) and check bright red (Z-N)
- Direct FAT and immunochromatographic RDTs available and widely used
- But note: the mean sensitivities of the three best kits tested, by species, was C. parvum 73.5%; C. hominis 80.8%, other species 27.7% (Agnamey et al. 2011)
- The sensitivity and specificity of 3 antigen detection kits, Auramine and Immunofluoresence were good and all were better than modified Ziehl–Neelsen (Chalmers et al. 2011a)
- PCR for diagnosis and genotyping
PCR based methods appear to have the highest sensitivity and specificity - for a comparison of four commercial and four in-house protocols (including performance with some of the less-common species) see Costa et al (2021)
Size of cryptosporidium?
5micrometers, cherry red
How to differentiate cryptosporidium and cyclospora?
Cryptosporidium: 5micrometers, cherry red
Cyclospora: 5-8micrometre ie bigger, can be red, acid-fast behaviour
Criteria for identifying cyclospora?
Criteria for identifying oocysts:
– Usually round
– Small, normally about 8μm diameter
– Dark, refractile wall, thicker than most other gut protozoan
cysts
– “Broken glass” contents
In which new group is PCP incidence rising? How does pathophysiology compare to HIV patients?
solid transplant recipients and autoimmune inflammatory diseases
These patients tend to have a sudden acute onset and worse survival outcomes than HIV+
patients -> ie HIV patients have higher fungal loads but poor immune system so less mortality, whereas organ transplant patients etc have lower fungal loads but better immune system so mount more fatal responses
What is the pathophysiology of PCP?
Organism adheres to Type 1 pneumocytes lining alveoli
Seems to be immune component involved
Black on green lung on microscopy slide - what is organism and stain?
Pneumocystic cysts -> Grocott Silver stain
How do you treat PCP?
- Co-trimoxazole
○ High incidence of SEs in HIV+ patients
○ Mutations in sulphonamide target enzyme might reduce effectiveness (conflicting evidence) - Other
○ Pentamidine
○ Dapsone-trimethoprim
○ Clindamycin-primaquine
○ Atovaquone
How do you diagnose PCP?
- Need to distinguish between colonisation and actual PCP
- BAL (best sample)
○ Invasive but more sensitive than induced sputum
○ Staining (silver; direct FAT more sensitivie)
○ PCR better than microscopy
○ Metagenomic sequencing - Quantitative PCR using oral wash samples
- Some DNA has been detectable in plasma of AIDs/PCP patients but no method really used
- Detection of (1,3)-beta-D-Glucan: less invasive
○ Sensitivity high but not as good as PCR, especially when used alone
○ Specificity: same polysaccharide present in cell walls of other fungi/serum of patients who have had certain procedures etc
Performs worse if lower fungal load
What is the Epi of PCP?
- Host-specific ie human parasite
- Airborne transmission
- Transplacental transmission - rabbits, maybe humans
- Very widespread in air -> ie most kids colonised before school
- Probable later attacks of PCP in immunocompromised are NEW infections not reactivation
How do you diagnose microsporidiosis?
- Staining and light microscopy (speciation difficult or impossible)
- Electron microscopy (define species)
- Nucleic acid amplification methods (increasingly important)
- In situ hybridisation
What pathogens cause leprosy? What are some facts about them that make the diagnosis difficult?
Mycobacterium leprae and Mycobacterium lepromatosis
- Intracellular organism
- Not possible to culture
- Long incubation period
Transmission of leprosy, who does it effect?
- Unclear
- ?similar to TB, ie aerosol spraying into nasopharyngeal tract, coughing etc
○ Bacilli found in nasal droplets of highly infected people and thought to enter body through upper resp tract - Affinity for cooler sites of body -> peripheral nerves and skin
- More rarely: eyes, mucous membranes, testes, bones and viscera
- Disease:
○ Long incubation period, 3-5 years, may vary from 6 months to 20 years
○ Progress of disease depends on immunological status of person - Animal reservoirs:
○ Armadillo?
○ Some monkeys/squirrels - Has been found in soil and can survive in it - ? Environmental pathogens
Presenting complaints of leprosy? What type of skin lesions exist?
- Numbness /loss of function in hands and feet
- Deformities in hands and feet
- Painless ulcers or burns (but might smell)
- Nasal stuffiness
- Weakness in eyelids
- Reaction presentation: fever, joint pains, inflammed skin
- Skin lesions - 95% patients
Skin lesions:
○ Tuberculous end lesions are asymmetrical and well defined but there is some anaesthesia ie loss of sensation
○ Lepromatous lesions more symmetrical, widespread, at worst -> nodules and infiltration
Skin signs and nerve signs in leprosy?
Skin lesions:
○ Tuberculous end lesions are asymmetrical and well defined but there is some anaesthesia ie loss of sensation
○ Lepromatous lesions more symmetrical, widespread, at worst -> nodules and infiltration
- Enlarged nerves
- Dryness in hands and feet
- Loss of sensation in hands and feet
- Painless ulcers and wounds
- Weakness in motor function in hands and feet (progression to motor nerves being affected)
- Deformities in hands and feet
Investigations to diagnose leprosy?
- Slit skin smear for AFB
○ Suspected lesions and sites commonly affected eg forehead, eyebrows, ear lobes) are sampled - No useful serological or skin test
- Skin and nerve biopsy -> granumolas?
Bacteriological index
- ZN staining of smears made from skin slits
- Read on logarithmic scale 0-6
- Useful in lepromatous cases and unusual skin lesions
- Can start treatment where clear-cut skin and/or nerve lesions are present before skin slit smears results available
- Negative skin-slit smears do not exclude diagnosis
WHO cardinal signs of leprosy?
Definite loss of sensation in a skin lesions consistent with leprosy
Thickening or one or more peripheral nerves
Skin smear or biopsy positive for AFB
If these then start Tx
WHO classification of leprosy?
- Paucibacillary = 5 lesions or less
- Multibacillary = 6 lesions or more
If skin smear positive -> patient automatically classified as MB regardless of no, of patches
What is the treatment of leprosy? How is it changing? What are the side effects?
PB
- 6 months treatment
- 2 drugs:
○ Rifampicin once a month
○ Dapsone daily
MB
- 12 months treatment
- 3 drugs:
○ Rifampicin once a month
○ Dapsone daily
○ Clofazimine daily
NOW WHO recommends to give ALL patients the 3 drug packet but 6 months vs 12 months according to two groups. Enables just a single packet to be given. Patients don’t like it as Clofazimine causes hyperpigmentation so if they have PB then why are they taking drug?
SIDE EFFECTS
Dapsone:
- Anaemia
- Hypersensitivity syndrome (fatal in 10%)
Clofazimine
- Hyperpigmentation
- Ichthyosis (dry scaly skin)
Rifampicin
- Orange urine/tears: 1-2 days only
Safe in: pregnancy, breast feeding, HIV
Management of household contacts of leprosy?
- Increased risk of developing leprosy -> need prolonged contact with person and they probably need high BI
- WHO recommend chemoprophylaxis with single dose of rifampicin to contacts
○ Household
○ Household and neighbours
○ Communities - Screened for evidence of clinical leprosy and TB
Now new drugs being considered for contacts eg adding clarithromycin and treating for a couple of months.
- Brazilian ministry of health recommends all household contacts be given two doses of BCG
Types of adverse reactions + their features
Type 1 reactions
Features:
Can occur at any point in journey
Skin and nerve acute inflammation
Typically effects pre-existing skin lesions
Presents as large skin lesions/Scaling/Oedema/Annular lesions
Associated with facial and peripheral oedema
Nerve inflammation may lead to permanent loss of nerve function
ENL
Multisystem disorder -> can occur anytime and can be recurrent or chronic
Can present with any systemic inflammatory symptoms eg fever/malaise/oedema/any -itis type
Effective treatment: Thalidomide (but issues with access/restriction/banning etc) so patients often given other drugs eg prednisolone, Clofazimine, Azathioprine
Silent neuropathy
Lucio’s phenomenon -> Widespread ulcerative lesions in patients with high bacillary load who likely are not on treatment or who have been under-treated. Start MDT immediately
Consider steroids or other anti-inflammatories
Wound care/Abx if secondary infections
Corticosteroid adverse effects:
- Lipodystrophy
- Infections particularly strongyloidiasis
- Hypertension
- DM
- Peptic ulceration
- Mood disturbance
- Osteoporosis
- Cataracts
How are nerves effected in leprosy?
- Type 1 reactions -> Nerve inflammation may lead to permanent loss of nerve function
- Nerve enlargement -> Increased risk of entrapment + compression
- Vascular effect
- Direct effect of mycobacterium on nerve tissue
A patients with painful necrotising skin lesions to leprosy clinic. Skin biopsy shows vasculitis with thrombosis (blood clotting) and extensive bacillary infiltration. What has happened? How would you treat?
Lucio’s phenomenon
Start MDT immediately
Consider steroids or other anti-inflammatories
Wound care/Abx if secondary infections
Primary and secondary impairments of leprosy
Hand/feet:
Primary
Loss of sensation, sweat
Muscle weakness
Secondary
Claw fingers/toes/wrist/foot drop ->
Contracture
Ulceration
Loss of digits
Eyes:
Primary
Lagophthalmos
Corneal anaesthesia
Secondary
Exposure keratitis
Corneal ulcer
Blindness
Interventions to reduce disability in leprosy?
- Early case detection
Helps also pick up paediatric cases and G2D. Allow for reliable burden estimation, district prioritisation and identifying populations at risk. - Self-care practice
Skin care, wound care, exercise, footwear, health education + peer support groups - Footwear
- Psychosocial support (PSS)
- Reconstructive Surgery
need nerve assessments to find patients at risk ie muscle strength, sensation and sweating
correct wrist/foot drop, decompress nerves, collapse nose, eye surgery
Spectrum of disease in leprosy and relevant pathophysiology?
Only 5% infected with leprosy bacilli will develop the disease
Indeterminate: detectable but no clinical manifestations
Tuberculoid: strong immunity, few bacteria
Lepromatous: weak immunity, many bacteria
- Generalised -> nerves, skin + other tissue
- Macrophages ingest but don’t digest the bacilli due to lack of cell mediated immunity (CMI) -> convenient host
- Multiplication of bacilli and transport by macrophages to other parts of body
Upgrading towards tuberculoid end = not necessarily a good thing as over activity of T cells -> inflammation -> tissue damage
Clinical spectrum of skin lesions in leprosy and features? Name of classification?
TT Tuberculoid leprosy: well defined (asymmetrical, definite anaesthesia)
BT Borderline Tuberculoid: ill-defined satellites (asymmetrical, definite anaesthesia)
BB Borderline borderline: circinate (asymmetrical, definite anaesthesia)
BL Borderline lepromatous: hypoesthetic patches (symmetrical + variable lesion anaesthesia)
LL Lepromatous: Nodules and infiltration (symmetrical + variable lesion anaesthesia)
RIDLEY JOPLING CLASSIFICATION is the 5 things
Now use WHO criteria instead
Eye issues in leprosy?
○ Lagophthalmos
○ Decreased corneal sensation
○ Acute/chronic iritis
○ Cataract
Nerves to examine in leprosy?
Supraorbital
Great auricular
Cervical
Radial
Median
Ulnar
Radial cutaneous
Common peroneal
Posterior tibial
WHO disability grading for leprosy components?
Eyes/Hands/Feet
Grade 0,1,2
Grade 2 disability suggests visible functional disabilities in the person and he will not only be economically affected by these but also more at risk of stigmatisation
Basic framework for diagnosing leprosy?
History
Full examination of skin, nerves, deformities, ulcers, wounds
ST (sensory testing)
VMT (voluntary muscle testing)
Disability grading including eyes
Skin slit smears/biopsy
Two medically relevant families of snakes and basic features?
- Viperidae
○ Vipers (eg western Russell’s viper, pit viper), adders, pit-vipers, moccasins, rattlesnakes
○ Relatively short thick body, short tail, distinctive dorsal pattern, slow-moving ambush predators but strike like lightening - Elapidae
○ Cobras, king cobras, kraits, mambas, coral snakes, all Oceanian/Australian venomous snakes and sea-snakes
○ Relatively long thin body, long tail, uniformly coloured (except corals), fast, some spread good
Four main families of snake venom toxins?
○ Phospholipases A2
○ Metalloproteases
○ Serine proteases
○ Three-finger toxins (neuro, cyto toxins)
Factors influencing EPI of snakebites
- Depends on interaction with snakes and their readiness to strike
- Meteorology: heats, rains, flooding
- Cycles of diurnal and seasonal activity:
○ Snake: nocturnal hunting + mating season
○ Human: occupational (agriculture, pastoralism), building projects, travel - Sleeping on the ground
○ Nocturnal krait bites in South Asia - Intentional snake handling
○ Restaurants/leather
○ Performance
○ Religion/Science
What are dry bites for snakes?
- Cause puncture marks on skin indicating penetration by teeth or fangs
- BUT results in no evidence of local or systemic envenoming over next 24hr (no venom injected)
- Incidence varies with snake species:
○ Saw-scaled vipers (Echis): <10% bites are dry
○ Australian brown snakes (Pseudonaja): >80% of bites are dry
Mechanism unknown (?mechanical disadvantageous defensive strike, ?snake-controlled metering)
What are two examples of drugs based on reptile venom toxins? What reptiles?
ACE-I: jacaraca snake in Brazil
GLP-1: Toxin from North American Gila monster
What are the effects of envenoming per system and associated snake families?
LOCAL
Cytotoxicity (some cobras and most vipers)
- Local swelling
- Bruising
- Necrosis
- Risk of bacterial infection
Systemic
Haemotoxicity (vipers and oceanic/australian elapids)
- Coagulopathy
- Bleeding
- Extravasation
Neurotoxicity (elapids, a few vipers)
- Descending flaccid paralysis
CVS toxicity (vipers)
- Arrhythmias
- Myocardial damage
- Capillary leak
- Hypovolaemia
- Shock
Myo-toxicity
- Generalised rhabdomyolysis
- Hyperkalaemia
Nephro-toxicity
- AKI
- Pigment nephropathy
- Microangiopathic haemolysis
- Thrombotic microangiopathy
How can CVS toxicity result from snake bites?
- Hypovolaemia from extravasation into bitten limb
- Generalised increase in capillary permeability
- Direct myocardial toxicity
Causes of symptoms in snakebites?
Anxiety -> hyperventilation, conversion disorders
Pre-hospital treatment
Pre-existing medical conditions and regular medical conditions
Secondary bacterial wound infections eg tetanus, necrotising faciitis, septicaemia
Secondary hypoxic damage resulting from delayed resuscitation of venom - induced shock or respiratory failure
Then finally envenoming
Test for consumption coagulopathy as a result of snake venom?
WHOLE BLOOD CLOTTING TEST
- Bedside test for 20mins for coagulopathy
- Few ml of venous blood in new, clean, dry (soda) glass vessel
- Leave undisturbed for 20mins at ambient temp
- Tip once
- Positive -> non-clotting, incoagulable blood if blood remains liquid like water
- Negative -> clotting, coagulable blood if blood clots
- Repeat with normal control if result inconsistent with clinical status
What does pressure pad immobilisation aim to do in snakebites?
Aim to compress veins and lymphatics in immediate vicinity of bite -> draining depot of injecting venom
First aid and treatment of snakebite? Indications for antivenom?
FIRST AID
1. Remove from danger and reassure
2. Immobilise whole body, especially bitten limb (need to prevent muscle contraction)
3. Remove anything tight eg bracelets, anklets etc from limb
4. Apply pressure-pad-immobilisation immediately
5. Prevent shock, airway obstruction and resp failure in transmit, oxygen (?atropine + neostigmine for cobra bite paralysis)
6. Discourage traditional treatment
7. Get to hospital
Treatment
1. ABCDE + oxygen intubation
- Admit all proven or suspected snakebite cases for min of 24hr observation to cover late evolution of symptoms of envenoming
- Assess for signs of local and systemic envenoming (including bedside test for coagulopathy) ?ANTIVENOM (SAME DOSE for kids and adults)
- Try to diagnose species of snake
- Analgesia - paracetamol/acetaminophen
- Tetanus toxoid booster to all cases (all bites are penetrating injuries and injection provides reassurance)
- Watch for secondary bacterial wound infections (potentially fatal tetanus, nec fasc, septicaemia)
- Consider IVF/intubation + ventilation/RRT
ANTIVENOM indications:
- Shock
- Spontaneous systemic bleeding +/- incoagulable blood
- Neurotoxicity (ptosis or more)
- Black urine (haemoglobin or myoglobin)
- Rapidly progressive local swelling (especially bites on digits)
What are the different types of antivenom?
Monovalent: cover one species
Polyvalent: cover multiple medically important species in the region eg Indian Polyvalent ASVs cover for big 4
How do you dose antivenom in children as compared to adults?
SAME INITIAL DOSE
Surgical mx of snake bites?
- Drain abscesses
- Aspirate large tense blisters using fine needles
- Debride/amputate necrotic tissue early (beware of nec fasc) and apply skin grafts
- AVOID fasciotomy (s/s of raised compartmental pressure not accurate in snake bite
- Encourage early rehab
Treatment of scorpion stings? What a trick to prevent being bitten by them?
Treatment of local pain:
Infiltration/digital block with 1% lignocaine or something similar
Treatment of systemic envenoming:
Rare severe cases: may require ICU/CV/resp monitoring for minimum 24hr (ECG/echo)
Antivenom for:
- Any systemic symptoms/signs not explained by pain/anxiety alone, especially in small children
- Administration: slow IV injection/infusion
Use UV light to show them
Symptoms of fish stings?
Local:
- Intense pain, tissue necrosis, secondary marine/aquatic bacterial infections (Staph, Strep, Vibrio vulnificus, Mycobacterium marinum, Aeromonas hydrophila)
Systemic:
- N&V, fever, hypotension, bradycardia, other cardiac arrhythmias, reps distress, pulmonary oedema, delirium, convulsions, autonomic stimulation, paralysis
- Rare cardiac arrest - reef stonefish Synanceia verrucosa is most dangerous
Key examples of stinging fish?
- Stone fish (Synanceia)
- Scorpionfish (Scorpaenidae)
- Lionfish
- Catfish
- Toadfish
- River ray
- Sting ray (Potamotrygon)
- Dogfish
