Week 8 Flashcards
Tetanus Microbiology
C tetani, anaerobic Gram positive bacterium, terminal spores ‘drumstick’ highly resistant. Found in the environment throughout the world. Pore-forming toxin ‘tetanolysin’ and a collagenase are needed for growth and toxin production. Only toxigenic C tetani causes tetanus
Tetanus Pathophysiology
At the site of inoculation, tetanus spores enter the body and germinate in the wound. Germination needs particular anaerobic conditions, such as dead and devitalized tissue that has low oxidation-reduction potential. After germination, they release tetanospasmin into the bloodstream. This toxin enters the presynaptic terminals in the neuromuscular endplate of motor neurons and destroys a vesicular synaptic membrane protein resulting in the inactivation of inhibitory neurotransmission that usually suppresses motor neuron and muscle activity. This paralyzes muscle fibres. Subsequently, this toxin, via retrograde axonal transport, travels to neurons in the central nervous system, where it also inhibits neurotransmitter release; this occurs approximately 2 to 14 days after inoculation. Since glycine and GABA are major inhibitory neurotransmitters, cells fail to inhibit the motor reflex response to sensory stimulation, causing a tetanic spasm. This can cause such powerful unopposed muscle activity and contraction that bone fractures and muscle tears can occur.
Tetanus Clinical features
Incubation period: Symptoms, Stiffness. Period of onset: Stiffness, spasms, autonomic dysfunction
Tetanus Neonatal prognosis
Significantly improved with ventilation. Paralysis stops the spasms which stops much of the morbidity and mortality
Tetanus Autonomic dysfunction
Difficult to differentiate from acute cardiac events in comorbid patients
Tetanus Modified Ablett Score
Grade 1 No spasm. Grade 2 Mild short-lived spasms not interfering with respiration. Grade 3 More prolonged muscle spasm interfering with respiration. Grade 4 Grade 3 but autonomic nervous system dysfunction
Tetanus Things you won’t read in the textbooks
Voice change, Spasms (can be mild in elderly patients, but beware), cardiovascular instability is early, pyrexia (can cause irreversible heat-shock), Cardiac events are common in elderly patients
Tetanus Management
Remove toxin (debride, ANTIBIOTICS, ANTITOXIN), Support (control spasms, prevent cardiovascular complications), promote recovery, vaccinate
Tetanus Antibiotic
Metronidazole for 7-10d (Penicillin potentiates GABA)
Tetanus Antitoxin treatment
IM Safe, no large improvement by intrathecal administration (but much more expensive). No difference in mechanical ventilation, autonomic dysfunction, ICU stay or hospital stay between two administration methods Human half life 28d, Equine half life 2w.
Tetanus Antitoxin prevention
Incomplete primary course: all wounds give booster, if dirty/high risk give passive immunisation. Incomplete vaccination all wounds give booster, if high risk give passive immunisation. Complete vaccination: no booster or passive immunisation required
Tetanus Supportive
Airway (tracheostomy), Spasm control (Beno, MgSO4 may help reduce requirement for muscle relaxants but not mechanical ventilation), Autonomic disturbance (use short-acting drugs as the swings are huge, Mg may reduce catecholamine response), Gastrointestinal, Hospital acquired infection
Tetanus Recovery
Important to remember QOL, critical illness in ICU for 3-4w and suffer longterm problems as other patients with prolonged ICU. Early rehab (use relatives in absence of physio) in low resource setting
Tetanus Prevention
Prevention is a much more economical option in LMIC and the cost is borne by patients in low resource settings. Vaccination is cheap (challenges: remote communities, multiple doses [5] needed, and no herd immunity). Important to keep the programs running. Unvaccinated are vulnerable (natural disasters, unintended impact, vaccine hesitancy). If you can’t vaccinate people, prevent neonatal tetanus by clean delivery/wound management
Tetanus Key messages
A toxin mediated disease with no herd immunity. Clinical course is relatively predictable at presentation. Specific therapies have limited impact on outcome and supportive management is the mainstay of treatment. Prevention is and will remain a priority.
Mpox Virology
Zoonotic orthopox, multiple animal reservoirs (primarily rodents).
Mpox Clinical features
Acute febrile illness. Incubation 1-2w, invasion period 0-5d (fever, headache, fatigue, LN), 1-2 into fever -> skin eruption - a few to several thousand lesions appear and evolve simultaneously. Centrifugal vs centripetal distribution. Often quite painful. Macules -> papules -> vesicles -> pustules then scab
Mpox Clades
1 Predominantly West Africa. 2 Central Africa
Mpox Epidemiology
Initially in small jungle villages from zoonotic jumps - rural and rare disease, but as time goes on spreading into other areas. Increased over 1970-2019 associated with urbanisation, increased populations. Smallpox vaccination ended in the 1980s, and worldwide waning immunity has likely contributed to increasing susceptibility. 2018-2022 imported cases, associated with animals in quarantine
Mpox Clade 2b
May to October 2022. Sexual health clinic presentation with blistering lesions, systemic illness. 85,000 cases in non-endemic areas over 110 countries. UK epi - Clade 2b mpox - community engagement through Grndr. WHO PHEIC 2022. 25% of those infected living with HIV, 98% GBMSM aged 20-40. Prevention - immunisation, change in behaviour, infection-associated immunity
Mpox Epi study
Used condoms collected - scavengers (brothels, public spaces) - tested for Mpox DNA found 1% had evidence of Mpox, looked for cooccurrence of other STIs - great example of lateral thinking and creativity
Mpox Clade 1a
Geographically limited to DRC and other West African countries. Zoonotic, less person-person transmission. CFR 4.6%
Mpox Clade 1b
Increasing incidence in DRC, ascertainment bias, initially CFR 4% (likely over estimated as the mild cases do not present, difficult to access testing, and if diagnosed may be asked to isolate which adds to stigma, and inability to go to work and support yourself/family) Retrospective review of HSV/VZV swab negative tests in Burundi - wide distribution M=F, children>adults - likely represents spread in childhood. WHO declares PHEIC 08/2024 - spread through DRC, Burundi, Rwanda, Kenya, Uganda, -> Sweden, Thailand, India, Germany, UK, Zambia, Zimbabwe. Epi: predominantly high-contact sexual networks. CFR 0.38%
Mpox Key messages
Waning immunity to poxviruses. Global outbreak clade 2b controlled (mostly gay, bisexual and MSM). Clade 1 continues to occur with increasing geographic spread. Some sexual transmission clade 1. We don’t have much good data for clade 1 as diagnostics lacking
Mpox Transmission
Person-to-person: direct contact with infectious rash, scabs or body fluids, respiratory secretions, fomites (lower risk, but can occur), pregnancy transplacental. Also possible to contract from infected animals either by being scratched or bitten, or by preparing or eating meat, or using products from an infected animal
Mpox Incubation
1-2w, physicians are currently recommended to monitor patients up to 21d, typically prodrome first then rash 1-4d later
Mpox Key messages
Transmission data strongest in clade 2b. Sexual transmission, but also close skin contact. Transmission different in different clades (or is this about different populations?). Some sexual transmission of clade 1. Not much good data for clade 1
Mpox Diagnosis
PCR for DNA. Best diagnostic specimens are taken directly from the rash (deroof). In the absence of skin lesions, testing can be done on oropharyngeal, anal or rectal swabs
Mpox Differential diagnoses
Primary or secondary syphilis, VZV, disseminated Crypto, HSV, DGI, Molluscum, other causes genital/anal diseases and proctitis: Chancroid, LGV, Behcet’s disease, Inflammatory bowel disease
Mpox Clase 2b case series
Male 97-100%, Fever 62-72%, Rectal pain 14-25%, Lesions 95-100%, genital 46-73% and anal/perianal 31-42%
Mpox Severe Mpox
Proctitis, genital deformity/abscess, pharyngitis, lymphadenopathy, bacterial superinfection, encephalitis, pneumonia, HIV infection - higher rates of complications, higher mortality - esp in those with CD4<50
Mpox Key messages
Fever and a rash. Examine thoroughly. Site of exposure/infection may determine clinical manifestations. Lymphadenopathy. Bacterial superinfection. Severe disease and death can occur. Gap in knowledge clade 1
Mpox Tecovirimat
Antiviral stockpiled for smallpox preparedness. Interfering with VP37 protein that is found on the surface of orthopoxviruses (inc smallpox, mpox, cowpox). Trials of tecovirimat did not reach statistical significance on the primary end point in lesion resolution. But probably does have clinical benefit (vs placebo) in those treated early, and those with severe disease - more trials required
Mpox Supportive care
Assess pain (mucosal lesions may not be visible on exam). Oral lesions (mouthwash, salt water gargle, viscous lignocaine), rectal lesions (stool softeners, sitz baths, topical lignocaine, avoid opioids). Stay in contact with patients in community. NSAIDs with caution. Tecovirimat may still have a place (trials). Most recover without complication.
Mpox Vaccines
Jynneos, Imvamune, Imvanex - live, non-replicating vaccinia virus. 2 doses, 4 weeks apart. Contraindicated: Mpox symptoms, severe allergy to egg, ciprofloxacin and gent in the insipient. Safe to administer to PLWHIV and atopic dermatitis. Fractional dosing as intradermal used during the outbreak, instead of the standard subcutaneous. There is a long lag time to create the vaccine due to the extensive passaging through cell lines required, so this was the strategy used to quickly achieve cover. Efficacy is what happens in trials under supervision. Effectiveness is what happens in the real world. Initially there was no access in Africa (acting CDC Director) - “This is a classic example of constrained access for Africa for a product, in this case, vaccines. Even if we wanted to buy, there is nowhere to buy, because they are manufactured in modest numbers and then countries stockpile them in case they need them, while where it is actually needed, on the continent of Africa, we don’t have access”
Mpox Infection control
Fomite transmission in hospital room has been described. PPE recommended in hospital: gloves, gown, N95, eye protection. Dedicated footwear that can be decontaminated. Cover lesions. Avoid unnecessary movement around hospital. IPC at home: able to manage their self-care. Dedicated, well-ventilated room separate from others in the household. Cover lesions. items such as eating utensils, linens, towels, electronic devices or beds should be dedicated to the person with mpox.
Mpox Key messages
Nosocomial transmission can occur (protect staff and other patients), fomites are important, community based care for those at home
Mpox Conclusions
Increasing incidence mpox linked to waning of immunity. Transmission - don’t forget fomites. We think clade 1 is like clade 2 but data is sparse. Vaccine available and effective. Supportive care. Good infection prevention and control practice. Endemic versus non endemic settings inequitable access to vaccine, drugs and diagnostics.
Zika Virology
ssRNA flavivirus. 2 strains - African and Asian 95% amino acid similarity. Asian strain responsible for known outbreaks. African strain has higher transmissibility and pathogenicity
Zika 2007 Yap Island
5000 of 6500 population infected. Highly competent vector, no population immunity. Possible underreporting in other countries due to similarities with other infections
Zika 2013 Pacific Islands
Unusual increase in Guillain Barre, first confirmed case of perinatal infection - 2 mothers developed symptoms just before delivery, babies tested positive just after birth - one was asymptomatic, the other had an isolated rash.
Zika 2015-2016 Americas
03/2015 Brazil notifies WHO of rash illness, cases soared, lots of epidemiological alerts of numbers of cases. 07/2015 reported patients with neurological symptoms, 10/2015 increase in microcephaly and increasing evidence of link to congenital abnormalities 01/2016 PHEIC. Cases dropped off in 2017, and still minimal cases since 2018
Zika Transmission
Vector: Aedes aegypti, day biting, well adapted to urban environments, multiple meals from multiple hosts - established in many countries. Mosquito borne transmission major driver in outbreaks. Aedes albopictus is secondary vector - more widespread global distribution including in Europe, extends into more northern latitudes than A aegypti - has not supported large scale ZKV outbreaks yet. Both can spread to newer areas. Other transmission (cannot sustain outbreaks): sexual, blood, transplacental. Has been found in breast milk, no reports of transmission. Case report in NEJM - transmission through tears and sweat
Zika Clinical features
Incubation 3-12d, 80% asymptomatic. Rash (macular, non-distinct in ~93%) and fever most common - arthralgia, arthritis, myalgia, conjunctivitis headache, back pain, mild, self-limiting
Zika Congenital Zika
Severe microcephaly is key marker, but can get congenital without microcephaly. Multi organ phenotype. Pointed occiput, redundant scalp skin, contractures, cerebral calcifications, less frequently raised hemidiaphragm. Eye problems also very common: focal retinal mottling and macular scarring, cataracts, glaucoma, optic nerve atrophy. Deafness. Seizures, tremors, hypertonia, hyperreflexia, irritability. Neurodevelopmental abnormalities may appear later in life and not be obvious at birth eg visual loss, developmental delay, seizures may develop months later. 11x more likely to die in the three years of life - <12m sepsis, hydrocephalus, microcephaly. >12m nervous system, cerebral palsy, diseases of circulatory system. Emerging evidence indicates adverse neuro effects in infants following postnatal infection. Asian strain linked to CZS, but the lack of data on African strain - possibly more severe in Africa and loss of pregnancy. No surveillance to know. Animal models suggest African strain is more pathogenic, caused embryonic death rather than live births.
Zika Congenital Zika risk
Highest risk of birth defects is infection in T1, but can occur throughout pregnancy. Asymptomatic infection can still have devastating congenital impact
Zika Dengue vs Zika in pregnancy
Dengue more severe disease in pregnancy, increased risk of death, increased risk of fetal loss, but no congenital signal. Zika no increase in maternal complications, but does result in congenital disease
Zika Neurological complications
Primary CMV and Campylobacter are still more likely to cause GBS, but Zika dose have increased rate 6d post Zika infection 24 cases per 100,000 infected with Zika virus. CNS involvement very rare (myelitis, encephalitis, optic neuritis)
Zika PCR
Short viraemic 3-5d after onset of sx. Pregnant women longer viraemic period - the longer the viraemia, the higher the likelihood of congenital. Urine excellent sample, says positive for at least 3 weeks. In principle test blood 1w, urine 3w. Can also be performed on semen, CSF, amniotic fluid, placental and umbilical cord tissue. The longest reported ‘serial interval’ between symptom onset in a man and symptom onset in his female sexual partner is 44 days
Zika Serology
IgM positive first week after symptom onset, can persist for weeks, can get false positives (non-specific reactivity, cross-reactivity), ask for repeat to see if develop IgG. IgG also appears early, may persist for years possibly life long. Cross reactivity with other flaviviruses - if previous flavivirus infection/vaccination subsequent exposure to related flavivirus cans a rapid and brisk rise in IgG against multiple flaviviruses (including Dengue) - may not develop IgM in patients with previous dengue
