Wk7 - clinical microbiology 2 Flashcards
Bacterial GI infection agents include two categories according to the mechanism by which they cause illness
Direct infection – bacterial pathogens develop in the gut after ingestion of contaminated food.
incubation time of at least 8-12h before symptoms develop
Examples: Salmonella, Campylobacter, pathogenic E.coli
Intoxication (poisoning) - bacterial pathogens grow in foods and produce toxins
Relative short incubation time (as short as few hours) because of preformed toxin in food
Examples: Bacillus cereus, Staphylococcus aureus
Clinical terminology - diarrhoea
Abnormal frequency and/or fluid stool
Usually indicates small bowel disease
Causes fluid and electrolyte loss
Severity varies widely from milk-limiting to severe/fatal - virulence of organism, degree of compromise of the host
Clinical terminology - gastroenteritis
Nausea, vomiting, diarrhoea and abdominal discomfort
Clinical terminology - dysentery
Inflammatory disorder of the large bowel
Blood and pus in faeces
Pain, fever and abdominal cramps
Clinical terminology - enterocolitis
Inflammatory process affecting small and large bowel
manifestations of GI infection within GI tract (GIT) and outwith GIT
Within GI tract:
Toxic effects e.g. cholera
Inflammation due to microbial invasion e.g. shigellosis
Outwith GIT
Systemic effect of toxins e.g. STEC
Invasive infection of GIT with wider dissemination e.g. metastatic salmonella infection
Barriers to GI infection
Mouth - lysozyme
Stomach - acid pH
Small intestine - mucous, bile, secretory IgA, lymphoid tissue (peyer’s patches), epithelial turnover, normal flora
Large intestine - epithelial turnover, normal flora
Normal GIT flora
Lower GIT has very rich microbial flora (microbiome)
Each gram of faeces contains 100,000,000,000 microbes
1kg in weight of bacteria in the gut (most are anaerobes)
99% anaerobes
Still many important facultative organsisms particularly Enterobacteriaceae e.g. E.coli, Proteus spp
Protective and metabolic function
Sources of GI infection
Many GI infections are zoonotic - symptomatic animals (e.g. Salmonella Dublin), asymptomatic shedders (e.g. reptiles and salmonella carriage, E.coli 0157 in cattle)
Human carriers important for some (Typhoid - invasive infection - becomes incorporated into gut flora - can be passed easily to others)
Environmental sources - contamination of soil and produce e.g. Listeria, E.coli 0157
Transmission of GI infection
Faecal-oral - any means by which infectious organisms from human/animal faeces can gain access to GIT of another susceptible host
3F’s:
Food - contamination - farm to fork, cross contamination - distribution chain or domestic kitchen
Fluids - water, contaminated juices etc.
Fingers - importance of washing hands - after toileting, before and after preparing or consuming food and drinks
Person-to-person transmission - infectious dose (some have high dose e.g. e.coli, some have low dose e.g. norovirus), ability to contaminate and persist in the environment
Diagnosis of GI infection
History - can get useful clues - vomiting, abdo pain, diarrhoea, travel history, food history, blood in stools
Laboratory diagnosis of GI infection
10^10 organisms of normal gut flora per gram of faeces
Looking for a needle in a haystack so need to use various methods
Enrichment broth - contains nutrients that promote growth of the pathogen
Selective media - suppress growth of background flora while allowing growth of the pathogen
Differential media - distinguishes mixed microorganisms growing in presence of specific nutrients combined with an indicator that changes colour.
Salmonella will stain black, Shigella will stain pink
Microbiology of campylobacter
Curved Gram-negative bacilli
Microaerophilic and thermophilic (42oC)
Culture on Campylobacter selective agar
C. jejuni most important species
Epidemiology of campylobacter
Commonest bacterial foodborne infection in the UK
¨ Large animal reservoir (poultry, cattle, sheep, rodents & wild birds)
¨ Infection transmitted via contaminated food (esp. poultry), milk or water
¨ Marked seasonal peaks of infection in May & September
¨ Person-to person spread rare
¨ Large point source outbreaks uncommon (doesn’t multiply in food)
¨ ~70% of raw retail fresh (not frozen) chicken is contaminated with
Campylobacter
Pathogenesis of campylobacter
Inflammation, ulceration & bleeding in small and large bowel due to bacterial
invasion
¨ Bacteraemia can occur (extremes of age, immunocompromised)
¨ Rarely causes post-infectious demyelination syndrome (Guillain-Barre),
characterised by ascending paralysis
Clinical aspects of campylobacter
Incubation 2-5 days ¨ Bloody diarrhoea ¨ Cramping abdominal pain ¨ Vomiting is not usually a feature ¨ Fever ¨ Duration 2-10 days
Treatment of campylobacter
Fluid replacement is sufficient in most cases
¨ Clarithromycin for severe/persistent disease
¨ Quinolone (e.g. ciprofloxacin) or aminoglycoside (e.g. gentamicin) for invasive
disease
Control points for campylobacter
Reduction of contamination in raw, retail poultry meat
Adequate cooking
Microbiology of salmonella
Gram-negative bacilli
¨ Member of the Enterobacteriaceae
¨ Nomenclature confusing
n Majority of human infection caused by single species Salmonella enterica
n > 2000 serotypes defined on basis of lipopolysaccharide “O” antigens of the cell wall
and flagellar protein “H” antigens (Kauffmann-White scheme)
n Commonly referred to as if they are species in their own right e.g. Salmonella enterica
serovar Dublin is written as Salmonella Dublin.
¨ Non-lactose fermenters
¨ XLD plates most commonly used in clinical labs
Epidemiology of salmonella
Found in a wide range of warm and cold blooded animals
¨ Only S. Typhi & S. Paratyphi, the causal organisms of enteric fever (typhoid &
paratyphoid, do not have an animal reservoir
¨ Acquired via contaminated food, especially pork, poultry & other meat and
milk/dairy products
¨ Waterborne infection less common
¨ Large foodborne outbreaks can occur (can multiply in foodstuffs)
¨ Secondary spread via person-to-person transmission may be a feature
¨ Seasonal peaks in summer and autumn
Pathogenesis of salmonella
Diarrhoea due to invasion of epithelial cells in the distal small intestine, and
subsequent inflammation
¨ Bacteraemia can occur (extremes of age, immunocompromised)
¨ Distant organs may become seeded to establish metastatic foci of infection e.g.
osteomyelitis, septic arthritis, meningitis etc.
Clinical aspects of salmonella
Incubation 12-72 hours ¨ Watery diarrhoea ¨ Vomiting is common ¨ Fever can occur, and is usually associated with more invasive disease ¨ Duration 2-7 days
Treatment of salmonella
Fluid replacement is sufficient in most cases
¨ Antibiotics reserved for severe infections and bacteraemia
n Beta-lactams, quinolones or aminoglycosides may be used
¨ Antibiotics and antimotility agents prolong excretion of salmonellae in the faeces
Specific control points for salmonella
The introduction of immunisation of poultry flocks lead to a dramatic reduction in
S.Enteritidis in the UK
Microbiology of shigella
Gram-negative bacilli
¨ Member of the Enterobacteriaceae
¨ 4 species
n Shigella sonnei associated with milder infections
n Shigella boydii & S.flexneri associated with more severe disease
n Shigella dysenteriae associated with most severe disease
¨ Non-lactose fermenters (useful in differential media)
¨ XLD plates most commonly used in clinical labs
Wpidemiology of shigella
Mainly associated with diarrhoeal disease in children
¨ S.dysenteriae in developing world
¨ Humans are only reservoir
¨ Large outbreaks can occur
¨ Does not persist in the environment (unlike V.cholerae)
¨ Person-to-person spread via faecal-oral route is most important
n Associated with low infectious dose
¨ Contaminated food and water less important
¨ Recent outbreaks associated with MSM
Pathogenesis of shigella
Organisms attach to and colonise mucosal epithelium of terminal ileum & colon
¨ Systemic invasion is not a feature
¨ S.dysenteriae produces a potent protein exotoxin (Shiga toxin) which not only
damages intestinal epithelium, but in some patients targets glomerular
endothelium causing renal failure as part of haemolytic-uraemic syndrome (HUS)
Clinical aspects of shigela
Dysentery ¨ Incubation 1-3 days ¨ Duration 2-7 days ¨ Initially watery diarrhoea followed by bloody diarhoea ¨ Marked, cramping abdominal pain ¨ Vomiting is uncommon ¨ Fever is usually present
Treatment of shigella
Usually self-limiting
¨ Fluid replacement is usually sufficient
¨ Some cases of S.dysenteriae infection will require treatment of renal failure
Specific control points for shigella
Only found in humans, so good standards of sanitation and personal hygiene are
key measures
Vibrio cholerae micorbiology
Comma-shaped Gram-negative bacilli
¨ Serotypes defined on basis of “O” antigens. Important serotypes: -
n Serotype O1
¨ Classical
¨ El Tor (less severe disease, more carriage, better persistence in environment)
n Serotype O139
¨ Sucrose-fermenter. Thiosulphate-bile sucrose selective/differential
medium
Epidemiology of vibrio cholerae
Cause of epidemic and pandemic cholera
¨ Endemic in parts of SE Asia, Africa, South America
¨ Can live in fresh water
¨ Only infects humans. Asymptomatic human reservoir
¨ Spreads via contaminated food or water
¨ Direct person-to-person transmission uncommon
Pathogenesis of vibrio cholerae
Flagellae and mucinase facilitate penetration of intestinal mucous
¨ Attachment to mucosa by specific receptors
¨ Diarrhoea due to production of a potent protein exotoxin
Clinical aspects of vibrio cholerae
Severe, profuse, non-bloody, watery diarrhoea (rice
water stool)
¨ Profound fluid loss & dehydration precipitates
hypokalaemia, metabolic acidosis, hypovolaemic
shock and cardiac failure
¨ Untreated mortality 30-40%
Treatment of vibrio cholerae
Prompt oral or intravenous rehydration is lifesaving
(mortality reduced to <1%)
¨ Tetracycline antibiotics may shorten duration of
shedding
Specific control point
No animal reservoir
¨ Clean drinking water supply and proper sanitation are
key preventative measures
Other pathogenic vibrio species - associated with vibrio cholerae
Vibrio parahaemolyticus is a halophilic organism that
can cause diarrhoeal disease associated with
contaminated fish and shellfish in warm coastal
waters
Overview of e.coli
Gram-negative bacilli ¨Members of the Enterobacteriaceae n Important component of gut flora of man and animals n Some strains possess virulence factors which enable them to cause infections ¨Six different diarrhoeagenic groups of E.coli n Enteropathogenic E. coli (EPEC) n Enterotoxigenic E. coli (ETEC) n Enterohaemorrhagic E. coli (EHEC) n Enteroinvasive E.coli (EIEC) n Entero-aggregative E.coli (EAEC) n Diffuse aggregative E.coli (DAEC)
Microbiology of enteropathogenic E.coli (EPEC)
No differential media available
¨ Test selection of colonies using polyvalent antisera for common
EPEC “O” types
¨ Not routinely done
Epidemiology of EPEC
Sporadic cases & outbreaks of diarrhoea in infants & children
¨ Cause of some cases of “traveller’s” diarrhoea
Pathogenesis of EPEC
Initial adherence via pili, followed by formation of characteristic
“attatching & effacing” lesion mediated by intimin protein and Tir
(translocated intimin receptor) with disruption of intestinal microvilli
Clinical aspects of EPEC
Incubation 1-2 days
¨ Duration 1-several weeks
¨ Watery diarrhoea with abdominal pain and vomiting
¨ Often accompanied by fever
Microbiology of ETEC
No differential media available
¨ Test liquid cultures for production of toxins by immunoassays
¨ Not routinely done
Epidemiology of ETEC
The major bacterial cause of diarrhoea in infants & children in
developing world
¨ The major cause of “travellers” diarrhoea
Pathogenesis of ETEC
Diarrhoea due to action of 1 or 2 plasmid-encoded toxins
n Heat-labile (LT). Structural and functional analogue of cholera toxin
n Heat-stable (ST). Produced in addition to or instead of LT. Similar
mode of action
Clinical aspects of ETEC
Incubation 1-7 days
¨ Duration 2-6 days
¨ Watery diarrhoea with abdominal pain and vomiting
¨ No associated fever
Microbiology of EHEC
More than 100 serotypes
¨ Best known is E.coli O157:H7
¨ O157 is a non-sorbitol fermenter. Sorbitol MacConkey agar (SMAC)
Epidemiology of EHEC
Outbreaks & sporadic cases worldwide (~250 cases/year in Scotland)
¨ Large animal reservoirs (esp. cattle & sheep)
¨ Persistent in environment
¨ Consumption of contaminated food, water and dairy products & direct environmental contact
with animal faeces e.g. petting zoos
¨ Secondary person-to-person spread important (associated with low infectious dose)
pathogenesis of EHEC
Attaching and effacing lesion (similar to EPEC)
¨ Production of Shiga-like toxins. Structural and functional analogue of Shigella dysenteriae
toxin (sometimes strains called STEC [shiga-toxin producing EC] or VTEC [verotoxinproducing
EC] because toxins are toxic for cultured vero cells
Clinical aspects of EHEC
Incubation 1-7 days
¨ Duration 5-10 days
¨ Bloody diarrhoea with abdominal pain and vomiting
¨ No associated fever
¨ Haemolytic uraemic syndrome (5-10% of cases)
n Microangiopathic haemolytic anaemia
n Thrombocytopaenia
n Acute renal failure
¨ Commonest cause of acute renal failure in children in the UK
What species are the key causes of diarrhoea in children in the developing world?
EPEC and ETEC
severity may be related to underlying malnutrition
Treatment of E.coli infections
Adequate rehydration
¨Antibiotics not indicated, and in the case of EHEC
may increase risk of HUS
¨Antimotility agents also increase HUS risk
Staph aureus microbiology
Gram-positive cocci
¨ Grow well on routine media
¨ Testing for enterotoxins not routinely performed
Epidemiology and pathogenesis of staph aureus
50% of S.aureus produce enterotoxins (types A-E)
¨ Heat stable and acid-resistant protein toxins
¨ Food is contaminated by human carriers
¨ Especially cooked meats, cakes and pastries
¨ Bacteria multiply at room temperature and produce toxins
Clinical aspects of staph aureus
Incubation 30 minutes – 6 hours
¨ Duration 12 – 24 hours
¨ Profuse vomiting and abdominal cramps
¨ No fever and no diarrhoea
Treatment of staph aureus
Self-limiting disease
Control of staph aureus
Hygienic food preparation to minimise contamination
¨ Refrigerated storage
Bacillus cereus microbiology
Aerobic, spore-forming Gram-positive bacilli
¨ Not routinely tested for
Epidemiology and pathogenesis of bacillus cereus (inc. the 2 types of disease)
Spores & vegetative cells contaminate wide range of foodstuffs
¨ 2 types of disease: -
¨ Emetic disease
n Typically associated with fried rice
n Spores survive initial boiling
n If rice is bulk cooled and stored prior to frying, the spores germinate, multiply and re-sporulate
n Protein enterotoxin produced during sporulation
n Heat stable toxin survives further frying
¨ Diarrhoeal disease
n Spores in food survive cooking, germinate and organisms multiply in food
n Ingested organisms produce a heat-labile toxin in the gut with similar mode of action to cholera toxin
Clinical aspects of bacillus cereus
Emetic disease n Incubation 30 minutes - 6 hours n Duration 12 -24 hours n Profuse vomiting with abdominal cramps and watery diarrhoea n No fever ¨ Diarrhoeal n Incubation 8 -12 hours n Duration 12 -24 hours n Watery diarrhoea with cramping abdominal pain, but no vomiting n No fever
Treatment of bacillus cereus
Self-limiting disease
Microbiology of clostridium perfringens
Anaerobic, spore-forming Gram-positive bacilli
¨ Not routinely tested for
Epidemiology and pathogenesis of clostridium perfringens
Spores & vegetative cells ubiquitous in soil and animal gut
¨ Contaminated foodstuff (usually meat products)
¨ Often involves bulk-cooking of stews, meat pies
¨ Spores survive cooking, germinate and organisms multiply in cooling food
¨ Food inadequately re-heated to kill organisms
¨ Organisms ingested & sporulate in large intestine with production of enterotoxin
Clinical aspects of clostridium perfringens
Incubation 6 - 24 hours
¨ Duration 12 – 24 hours
¨ Watery diarrhoea and abdominal cramps
¨ No fever and no vomiting
Treatment of clostridium perfringens
Self-limiting disease
Control of clostridium perfringens
Rapid chilling/freezing of bulk-cooked foods
¨ Thorough re-heating before consumption
Microbiology of clostridium botulinum
Anaerobic, spore-forming Gram-positive bacilli
¨ Laboratory diagnosis based upon toxin detection
Epidemiology and pathogenesis of clostridium botulinum
Very uncommon in UK
¨ Spores & vegetative cells ubiquitous in soil and animal GIT
¨ Produces powerful heat-labile protein neurotoxin (types A, B & E cause human disease)
¨ Foodborne botulism- pre-formed toxin in food. Commonly associated with improperly processed
canned foods
¨ Infant botulism- organisms germinate in gut of babies fed honey containing spores, and toxins
are produced in gut
¨ Wound botulism- organisms implanted in wound produce toxin
¨ Absorbed toxins spread via bloodstream and enter peripheral nerves where they cause
neuromuscular blockade at the synapses
Clinical aspects of clostridium botulinum
Neuromuscular blockade results in flaccid paralysis & progressive muscle weakness
¨ Involvement of muscles of chest/diaphragm causes respiratory failure
¨ High mortality if untreated
Treatment of clostridium botulinum
Urgent intensive supportive care due to difficulties breathing and swallowing
Antitoxin
Control of clostridium botulinum
Proper manufacturing controls in canning industry
¨ Hygienic food preparation
¨ Proper cooking
¨ Refrigerated storage
Microbiology of clostridium difficile
Anaerobic, spore-forming Gram-positive bacilli
¨ Spores resistant to heat, drying, disinfection, alcohol
¨ Clinical features due to production of potent toxins (A+B)
¨ Laboratory diagnosis based two-step algorithm
Epidemiology and pathogenesis of c.diff
Spores & vegetative cells ubiquitous in environment
¨ Carriage
n 3-5% in adults in community
n May rise to 30% in hospitalised patients
n Asymptomatic carriage rates may be very high in infants
¨ Infection requires disruption of the normal “protective” gut flora
n Most commonly due to antibiotic therapy
n Can also be due to cytotoxic therapy
n Proton pump inhibitor use may be an additional risk factor
¨ Predominantly affects the elderly
¨ Major cause of healthcare associated infections
Clinical aspects of c.diff
Mild to severe with abdominal pain
¨ Severe cases may develop pseudomembranous colitis
¨ Fulminant cases may progress to colonic dilatation and perforation
¨ Severe cases may be fatal
¨ Relapses are common and may be multiple
Treatment of c.diff
Stop precipitating antibiotics
¨ Oral metronidazole (mild [0 severity markers]). Oral vancomycin (severe [≥ 1 severity markers or
no improvement after 5 days metronidazole])
¨ Refractory recurrent disease may require faecal transplant
Control of c.diff
Antimicrobial stewardship
n Remember that any antibiotic therapy will disturb the normal gut flora to some extent
¨ Avoid/stop unnecessary antimicrobial treatment
n Restrictive antibiotic formularies to minimise use of “high risk” antibiotics
¨ Cephalosporins
¨ Fluoroquinolones
¨ Clindamycin
¨ Co-amoxyclav
¨ Infection Prevention & Control measures
n Source isolation
n Hand hygiene
n Use of Personal Protective Equipment (PPE)
¨ Cleaning/disinfection with hypochlorite disinfectants
Microbiology of listeria monocytogenes
Gram-positive coccobacilli
¨ Selective culture media available for culture from suspect foods
¨ Standard laboratory for blood and CSF samples
Epidemiology & pathogenesis of listeria
Widespread among animals and the environment
¨ Pregnant women, elderly and immunocompromised
¨ Overall number of cases small, but mortality high
¨ Infection associated with contaminated foods, especially unpasteurised milk and soft cheeses, pate, cooked
meats, smoked fish, and coleslaw
¨ Outbreaks occur associated with contaminated ready to eat foods and produce
¨ Can multiply at 4oC
¨ Invasive infection from GIT results in systemic spread via bloodstream
Clinical aspects of listeria
Median incubation period 3 weeks
¨ Duration of illness 1-2 weeks
¨ Initial flu-like illness, with or without diarrhoea
¨ Majority of cases present with severe systemic infection
n Septicaemia
n Meningitis
Treatment of listeria
Intravenous antibiotics (usually Ampicillin and synergistic gentamicin) is required
Control of listeria
Susceptible groups should avoid high risk foods
¨ Observe use by dates
¨ Wash raw fruit and vegetables and avoid cross contamination
Microbiology of h.pylori
Gram-negative spiral shaped bacilli
¨ Microaerophilic. Urease-positive
¨ Diagnosis by detection of faecal antigen or urea “breath test”. Serum antibody tests mainly
of use in epidemiological surveys of past or current infection.
Epidemiology and pathogenesis of h.pylori
One of the most common bacterial infections in the world
n 70% prevalence in developing world; 30-40% in developed world
¨ Thought to be faecal-oral or oral-oral
¨ Humans are the only reservoir
¨ Infection acquired in childhood and persists life long unless treated
¨ Pathogenesis is complex involving cytotoxin production, and a range of factors to promote
adhesion and colonisation
Clinical aspects of h.pylori
Infection is asymptomatic unless peptic ulceration develops
¨ Now established as cause of >90% of duodenal ulcers, and 70-80% of gastric ulcers
¨ Gastric cancer risk
Treatment of h.pylori
Combined treatment with a proton pump inhibitor and combinations of antibiotics such as
clarithromycin and metronidazole eradicates carriage and facilitates ulcer healing
GI infections in developed world vs developing world
Developed world:
Large economic burden
Mainly associated with foodborne infection
Pathogens have important animal reservoirs
Developing world:
High mortality - particularly in children <5 years old
Mainly a problem of lack of clean water and poor sanitation
Viral gastroenteritis =
Inflammation of the stomach and intestines caused by virus(es)
People at higher risk of gastroenteritis
Children under age of 5
Old age people - especially in nursing homes
Immunocompromised people
Important viruses that cause gastroenteritis
Norovirus Sappovirus Rotavirus (the above 3 = Calciviridae) Adenovirus 40 & 41 Astrovirus
What people does norovirus/sappovirus (Calciviridae) cause gastroenteritis in?
Can affect all ages and healthy individuals but often most serious in young and elderly
What people does rotavirus/adenovirus/astrovirus cause gastroenteritis in?
Affects mainly children under 2 years old, elderly and immunocompromised
Structural features of norovirus
Family: Calciviridae
Non-enveloped (so can survive longer), single stranded RNA virus
Five genotypes - only 3 affect humans (GI, GII and GIV)
Genotypes divided into at least 32 genotypes
Most common in the UK is the GII-4 strain
Transmission of norovirus
Person to person (faecal-oral, aerolised e.g. by toilet flush, fomites)
Food borne (most commonly in shellfish)
Water
Infectious dose is very small (10-100 virions)
Can affect all ages
24-48 hour incubation period
Can shed virus for up to 3 weeks after infection
Clinical features of norovirus
Can be asymptomatic (not common) Vomiting Diarrhoea Nausea Abdominal cramps Headache, muscle aches (viral symptoms) Fever (minority) Dehydration in young and elderly
Usually lasts 12-60 hours
Complications of norovirus
Significant proportion of childhood hospitalisation (cant manage fluid balance - become dehydrated)
In elderly increased post infection complications (dehydration, AKI, inc. potassium levels)
Chronic diarrhoea and virus shedding in both solid organ transplant patients and bone marrow trasnplant patients - shedding for up to 2 years
Treatment of norovirus
Symptomatic therapy - oral and or IV fluids; antispasmodics; analgesics; antipyretics
(might use immunoglobulins for immunocompromised patients
Immunity against norovirus
Although antibodies are developed to norovirus, immunity only lasts 6-14 weeks (when the virus re-circulates next year can become infected again).
Due to the incomplete understanding of immunity and the fact norovirus can’t be cultured there have been issues with creating a vaccine
Reports have shown a link between the expression of human histo-blood antigens (HBGAs) and the susceptibility to norovirus infection.
Infection control of norovirus
Isolation or cohorting
Exclude symptomatic staff until symptom free for 48 hours
Do not ove patients
Do not admit new patients
Thorough cleaning of the ward/hospital/cruise ship/bus - dilute hypochlorite or hot soapy water
hand hygiene - contaminated hands are probably the single most common vector for the spread of norovirus
Rotavirus - structural features
Family: Reoviridae Double stranded, non-enveloped RNA virus 5 predominant strains, G1-4, G9 G1 acounts for >70% infections Stable in environment and fairly resistant to hand washing
Transmission of rotavirus
Low infectious dose (10-100 virus particles)
Mainly person to person via faeco-oral or fomites (surfaces etc.)
Food and water borne spread is possible
Spread via respiratory droplets is speculated
Clinical features of rotavirus
Incubation period 1-3 days
Clinical manifestations depend on if its the 1st infection or reinfection
Symptoms: Watery diarrhoea, abdo pain, vomiting, loss of electrolytes leading to dehydration
Symptoms usually last 3-7 days
1st infection after age 3 months is usually the msot severe (after stopped being breasfed)
Hospital outbreaks in paediatric wards are common
Complications of rotavirus
Severe chronic diarrhoea Dehydration Electrolyte imbalance Metabolic acidosis Immunodeficient children may have more severe or persistent disease
Immunity against rotavirus
Antibodies against VP7 and VP4 (proteins found on the surface of rotavirus) and secretory Ig! are important
1st infection is usually seevre - 1st infection doesn’t lead to permanent immunity; Subsequent infections are less severe
Re-infection can occur at any age
By age 3, 90% of children have serum antibodies to one or more types
Younger children may suffer up to 5 re-infections by age 2 years of age
Rotavirus vaccine
In 2013 Rotarix was introduced to the childhood immunisation schedule.
Live attenuated vaccine derived from a virus isolated from a 15-month old child, attenuated by serial cell culture passage
In clinical trials Rotarix has been shown to protect against gastroenteritis due to rotavirus serotypes G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]; some efficacy agaonst uncommon rotavirus genotypes G8P[4] and G12P[6]
The vaccine is over 85% effective at protecting against severe rotavirus gastroenteritis in the first 2 years of life
Is a live vaccine - taken orally
Might still get rotavirus but will be less severe, less likely to get hositalised
Adenovirus - structural features
Family: Adnoviridae Double stranded DNA virus >50 serotypes causing range of illnesses Adenovirus 40 &41 cause gastroenteritis Symptoms: fever and watery diarrhoea Treatment: supportive No vaccine for adenovirus 40 & 41
Features of Astrovirus
Single stranded, non-enveloped RNA virus
Family: Astroviridae
Causes less severe gastroenteritis than other enteric pathogens
Infection usually as sporadic cases but can be outbreaks, usually in young children
Diagnosing these viruses (causing gastroenteritis)
All these virus are detected by polymerase chain reaction (PCR) which detects the DNA or RNA
Testing done at Virology lab, GRI
Samples: vomit or stool
All of the following cause gastroenteritis except:
- Rotavirus
- Norovirus
- Adenovirus 42 & 43
- Astrovirus
- Sappovirus
A - Andeovirus 42 &43
The most important consideration of the treatment of diarrhoea is:
- Antibiotics
- Antivirals
- Antispasmodics
- Salt and fluid replacement
- Vaccines
A - salt and fluid replacement
The following are spread via the faeco-oral route except:
- Norovirus
- Rotavirus
- Poliovirus
- Hepatitis D
- Hepatitis E
A - Hepatitis D
Many viruses replicate in the gut but most do not cause D&V e.g.
Poliovirus (and all other enteroviruses), Adenoviruses OTHER THAN types 40&41, Hepatitis A/E
50 people had been eating at a restaurant and became unwell.The illness consisted of nausea (97%), vomiting (97%), abdominal cramps (86%), chills (78%), muscle aches (67%), fever (64%), headache (61%) and diarrhoea (58%).
Median incubation period was 31.3 hours, one ill person was hospitalized and 10 sought medical care. All those that were unwell had eaten a ‘sub’ sandwich. One person seeking medical attention tested positive for E. coli O157:H7. The illness lasted approximately 48 hours with some malaise thereafter. What was the likely cause of the outbreak?
Calicivirus
Shiga toxin-producing E. coli O157:H7 (STEC)
Campylobacter
Enterotoxigenic E. coli (ETEC)
Preformed Staphylococcus aureus enterotoxin (food poisoning)
A - Calcivirus
Summary of gastroenteritis:
Norovirus causes outbreaks of D&V in all age groups
Rotavirus causes D&V in under 2s - common in winterr, vaccine available
Adeno 40 & 41 and astrovirus behave like rotavirus but are rarer
__
Features of septci arthritis
Children and adults usually present with fever (60-80%)
Single hot joint - knee(50%), hip (20%)
Polyarticular involvement in 10-20% of patients
Los of movement
Pain
Septic arthritis - key investigations
Blood cultures (using aseptic technique) Joint aspirate (Gram, mircoscopy for crystals and culture) FBC CRP Imaging
Pathogens associated with septic arthritis
Common:
MSSA or MRSA
Streptococci (S.pyogenes, Group G strep, pneumococcus (commoner in children))
Less common gram -ves: H.influenzae (commoner in children) Kingella (common in nurser) N.meningitidis (common for causing single joint infection) N.gonorrhoeae E.coli P.aeruginosa Salmonella species
Treatment for septic arthritis
At least 2 weeks IV antibiotics
Often 3 weeks IV antibiotics followed by 3 weeks oral
Monitor response by CRP and clinical
CRP is not useful for diagnosis but good for monitoring response to treatment
Arthroplasty = Resection arthroplasty = Revision arthroplasty = Arthrodesis = Arthrosis = Pseudo-arthrosis =
Arthroplasty – putting in an artificial joint.
Resection arthroplasty – taking the diseased joint out and putting in an artificial one.
Revision arthroplasty – re-operating on an artificial joint
Arthrodesis – Fusing two bones together
Arthrosis – a joint
Pseudo-arthrosis – allowing two bones to articulate against one another but without a joint e.g. Girdlestone
Expected infection rates from prosthetic joints
Hip surgery 0.3-2%
Knee surgery <4% (higher as more complex and more exposed)
Risk factors for developing septic arthritis after primary arthroplasty
RA Diabetes mellitus Poor nutritional status Obesity Concurrent UTI Steroids Malignancy
Risk factors for developing septic arthritis after revision arthroplasty
Prior joint surgery
Prolonged operating room time
Pre-op infection (teeth, skin, UTI)
2 methods of spread of septic arthritis
Local spread:
Accounts for 60-80% of PJIs
Mostly organisms from skin surface
Direct communication between skin surface and prosthesis while fascial planes heal
Usually manifests in immediate post-op period
Acute <4 weeks
Delayed/late >4 weeks (up to 50% PJIs present two or more years after surgery)
Haematogenous spreaD: Accounts for 20-40% PJIs Presents later Intact surrounding connective tissue often limits infection to bone/cement interface Can be any organism Oral organisms Pyogenic skin sepsis Genitourinary or Gastrointestinal instrumentation
Virulence (in context of septic arthritis)
Virulence (ability to infect) of the organism will dictate presentation
Low virulence organisms result in low grade indolent infections which are tenacious e.g. coagulase negative staphylococci
Highly virulent organisms result in fulminant infection or septic shock e.g. MSSA, MRSA, Group A or G Beta Haemolytic Streptococcus
Staphylococcus aureus infections do particularly badly!
Pathogenesis of septic arthritis from prosthesis
Prosthesis requires fewer bacteria to establish sepsis than does soft tissue
Avascular surface allow survival of bacteria as protects from circulating immunological defences and most antibiotics
Cement can inhibit phagocytosis and lymphocyte/complement function
Clinical presnetation of septic arthritis
Pain Effusion Warm joint Fever and systemic symptoms If has a prosthetic joint, may also have: Loosening on xray Discharging sinus Mechanical dysfunction (difficult to walk on etc.)
antibiotic prophylaxis for septic arthritis
-
What are the 3 surgical options for septic arthritis?
- DAIR to leave the infected joint in
- Take the infected joint out
- In and out
Describe DAIR - the surgical option for septic arthritis
DEbride, Antibiotics, Implant retained
If prosthesis infection is acute (<30 days since infection), then it is still mechanically functional and can be kept in but infected tissues should be debrided and the joint washed out to reduce the burden of infection then IV antibiotics started for 4-6 weeks
Discuss the option of taking the infected joint out (due to septic arthritis)
If the infection occurs over 30 days since surgery then it may no longer be functional and may need removed
Removal involves taking out the prosthesis and all the cement (can’t heal if foreign body retained)
Options:
Girdlestone procedure
One stage revision (put a new one in during the same operation are removing the infected one)
Two stage revision (delay putting in a new one until treated the existing infection for 4-6 weeks)
Each time a revision is performed (due to septic arthritis) the chances of success and cure of infection…
reduce dramatically due to anatomical distortion and infection becomes harder to suppress making amputation a possibility
Definition of septic arthritis
Septic arthritis is defined as the infection of 1 or more joints caused by pathogenic inoculation of microbes. It occurs either by direct inoculation or via haematogenous spread.
1st investigations to order for possible septic arthritis
Investigations to consider
Synovial fluid gram stain and culture
Synovial fluid white cell count
Blood culture
White cell count
Investigations to consider:
MRI
Diagnosis and management of prosthesis infections: Top tips
Do not start antibiotics pre-operatively unless the patient has a life threatening infection
Do send multiple intra-operative specimens to microbiology from at least 5 different sites
Do also send debrided tissue to a histopathologist
Realise that swabbing a post-operative wound will provide very little useful diagnostic information about what is going on with the prosthesis
Do not stop IV antibiotics immediately post-operatively (even if think isn’t an infection - as could infect new joint with no antibiotics - need to wait until no infection is confirmed)
Measure CRP regularly
What is osteomyelitis
Progressive infection of bone characterised by death of bone and the ofrmation of sequestra
How is infection in osteomyelitis spread?
Haematogenous spread
Contiguous spread - overlying infection (e.g. cellulitic ulcer), trauma (compound fracture), surgical inoculation (anaerobes can enter)
How does osetomyelitis more commonly affect?
Problems associated with osteomyelitis
Acute osteomyelitis is commoner in children than adults
Often undertreated with oral antibiotics and so may recur
Causative bacteria similar to septic arthritis but also include anaerobes
Diabetic foot infection
More complex than septic arthritis
Usually involves bone (osteomyelitis) but can also involve joints
Need to optimise diabetic control as well as treat infection so should involve a diabetologist
Vertebral discitis
Infection of a disc space and adjacent vertebral end plates
Can be very destructive with deformity, spinal instability risking cord compression, paraplegia and disability
Similar organisms to septic arthritis and osteomyelitis
Remember tuberculosis
When is sex bad for us?
Non-consensual sex Exploitative sex Sexual dysfunction Unwanted conception Infection
What is the name of the study that looks at sexual behaviour
NATSAL
Benefits of sex
contributes to health and quality of life:
Fitter
Lower rates of depressive symptoms
Better cardiovascular health
Risk factors for STIs
Age - more prevalent in younger people due to more likelihood of multiple partners
Gender - more common in younger women but older men (men more likely with gonorrhoea)
Location - more prevalent in larger cities due to population and night life (e.g. London)
Personal factors - partner choice/number, use of condoms etc.
Principles of STI management
Diagnosis before treatment Screen for accompanying STIs Simple treatment regimens Follow-up after treatment Partner notification Non judgemental patient support, counselling, education
Gram stain seen with gonorrhoea
Gram negative diplococci
Test for gonorrhoea
Nuclei acid amplification test (NAAT) - using male urine or female vulvovaginal swab
Disseminated gonorrhoea
This is where there appears to be no sexual symptoms but infection gets to extremities and joints –> joint pain and swelling
Treatment of gonoorhoea
Cefriaxone - 500mg
Azithromycin - 1g - covers resistance and chance that infection is in fact chlamydia
Partner notification
Chlamydia trachomatis (including treatment)
Frequently asymptomatic
infection can lead to tubal damage/infertility:
- 16% of infected women will develop PID
- Screening in England –> no evidence that this reduces prevalence of PID
Treatment:
Doxycycline 100mg twice a day for 1 week (for 3 weeks if have LGV)
If not able to take doxycycline (e.g. if pregnant) - Azitrhomycin 1g oral stat, followed by 500mg once a day for 2 days
Lymphogranuloma venereum (LGV)
Common in MSM patients
Lymphotropic chlamydia
Severe procitis causinf constipation and rectal bleeding
Looks like Cancer or Crohns
Presents with inguinal ‘bubos’ –> swollen lymph nodes
Primary syphilis
Presents with a chancre
3 weeks after exposure
This is an ulcer where the microorganism has imbedded itself –> likely on lip or anus
Describe the natural history of syphilis
Exposure - by penetrative sex or oral sex
Primary lesion - chancre - can be anywhere but is PAINLESS –> goes unnoticed especially if it is the cervix or rectum
Secondary lesion (rash) - highly infectious at this stage, can affect anywhere. Causes a disseminated rash. Constitutional symptoms: fever, sore throat, malaise
Latent syphilis (+ve serology only) - can lie latent for years. Latent stage - asymptomatic but has positive serology
Tertiary syphilis has several manifestations:
Gumma - granulomatous, sometimes ulcerating lesions, commonly found in bones
Cardiovascular - vasculitis (aortitis), aortic incompetence, angina, aortic aneurysm
Neurological - meningovascular disease, retinal haemorrhage
Treatment of syphilis
Penicillin injection (benzathine penicillin) - very effective
Are given a local anaesthetic as is pain
(Doxycycline can be used if have a penicillin allergy)
What does HPV cause and management of HPV
HPV 6/11 cause genital warts (benign)
HPV 16/18 causes dysplasia –> cervical cancer
Management: proper sue of condoms, vaccination for HPV now available, cyrotherapy to freeze warty tissue (using liquid nitrogen), surgical removal of warts, Condyline (podophylotoxin) - burns away HPV infected tissue, Aldara (imiquimod) - 3 times a day
Features of HSV and management
HSV = Herpes simplex virus
Produces wide spectrum of clinical problems, may facilitate HIV transmission. Type 1 and 2 can both be present on mouth and genitals, no preference
HSV type 1 - genital wart
HSV type 2 - cold sores
Management - Aciclovir
Features of molluscum contagiosum
Pox virus Sexually transmitted similar to warts - on pubic area/groin Extensive/on face may indicate immunosuppression in adults Usually self-limiting - reassure
What are the 3 viral STIs we need to know about
HPV, HSV, molluscum contagiosum
Common pathogens causing septic arthritis vs causing oesteomyelitis
Septic arthritis: Staphylococcus aureus (MSSA/MRSA) Haemophilus influenza (commoner in children) Neisseria gonorrhoea (disseminated gonorrhoea)
Osteomyelitis:
Staphylococcus in 90% of acute osteomyelitis
Others: Haemophilus influenza, Salmonella
Cellulitis is characterised by
oedema, erythema and warmth
Commonest microorganisms causing cellulitis
S.aureus and strep pyogens (A,B,C,G)
How is HIV transmitted
HIV enters the body through open cuts, sores or breaks in the skin; through mucous membranes, such as those inside the anus or vagina; or through direct injection
Activites that allow HIV transmission:
Anal or vaginal intercourse (oral sex is not an efficient route of transmission)
Injecting drugs + sharing equipment
Mother-to-child transmission (before/during birth, or through breast milk)
Transmission in health care settings
Transmission via donated blood or blood clotting factors
How does HIV cause illness
HIV infects cells in the immune system such as T helper cells, macrophages and dendritic cells
HIV infection causes depletion of CD4 T helper cells by:
- Direct viral killing of cells
- Apoptosis of uninfected ‘bystander cells’
- CD8+ cytotoxic T cell killing of infected CD4+ cells
Abnormal B cell activation resulting in excess/inappropriate immunoglobulin production
Once CD4+ cells fall below a critical level (<= 200), the person is at risk of opportunistic infections and some cancers
HIV latency
Viral latency is a state of reversibly non-productive infection of individual cells.
In HIV the term latency is generally used to describe the long asymptomatic period between initial infection and advanced HIV (AIDS)
With PCR it has become clear that HIV replicated actively throughout the course of the infection even during the asymptomatic period
HIV resistance
HIV can mutate while it is multiplying in the body - thus formation of drug-resistant strains
A person can initially be infected with drug-resistant HIV or develop resistant HIV after starting HIV medicines.
Drug-resistance testing results help determine which HIV medicines to include in HIV treatment regimen.
Medical adherence is important - taking HIV medicines everyday and exactly as prescribed will reduce the risk of drug resistance
HIV diagnostic tests
HIV antibodies tested with an ELISA test, then confirmed with Western Blot.
More recently core p24 antigen tests have been used. p24 protein is present on the surface of the virus
HIV Clincial markers
CD4+ Cell Count:
Calculated from total lymphocyte count
Normal CD4 count is >500 cell/mm^3
Risk of opportunistic infection increases sharply below 200/mm^3
Aim to start therapy at counts above 350mm^3
HIV plasma RNA (VIRAL LOAD):
The level of viraemia is measured by quantative PCR of HIV-RNA, known as viral load.
‘Undetectable’ means below 40 copies/mL
Describe the clinical course of HIV
- Primary infection (Seroconversion):
Initial exposure to HIV. Incubation 2-4 weeks; Diagnosis is often msised - Acute HIV syndrome:
Wide dissemination of virus, seeding of lymphoid organs –> flu like symptoms
The clinical manifestations are typically glandular-fever like:
- Infectious mononucleosis (EBV)
- Secondary syphilis
- Drug rash - maculopapular rash
- Viral infections - CMV, Rubella, Influenza, Parovirus - Clinical latency:
Individuals are asymptomatic
Persistent generalised lymphadenopathy
HIV continues to replicate at very low levels, although it is still active - Constitutional symptoms:
Night sweats, diarrhoea, weight loss, oral hairy leukoplakia, seborrhoeic dermatitis, tinea - Opportunistic disease:
Thrush, TB, pnuemocystic jerovecii, candidiasis, toxoplasmosis
Management of HIV
HAART (Highly Active Anti-Retroviral Therapy):
‘Triple therapy’ - 2 nucleosides (NRTIs) + 1 drug from another class:
- Integrase inhibitors
- Protease inhibitors
- NNRTIs (non-nucleoside reverse transcriptase inhibitors)
The aim is to suppress the viral load to undetectable and to recover the CD4 count
Main symptoms of acute HIV infection
Systemic: fever, weight loss Central: malaise, headache, neuropathy Pharyngitis Mouth: sores, thrush Lymph nodes - lymphadenopathy Oesophagus - sores Skin: rash (maculopapular rash) Muscles: myalgia Liver and spleen: enlargement Gastric: nausea and vomiting
Challenges with ART (antiretroviral treatment -for HIV)
Good adherence is essential Psychological impact Short-term side effects Drug-drug interactions - mediated by CYP450 induction/inhibition Emerging longer term toxicities
Short term and long term toxicity associated with ART
Short term:
Rash, hypersensitivity, CNS side effects (sleep disturbance, vivd dreams, mood changes), renal, hepatic
Long term:
Body shape changes (lipoatrophy or lipodystrophy), renal (Tenofovir), hepatic, lipid, bone
Prevention of mother to child HIV transmission
Treat mother during pregnancy Reduce risk at delivery Treat baby early on (with post exposure prophylaxis) Avoid breast feeding Universal antenatal HIV screening
Antibiotics for TB
1st line drugs are Rifampicin, Isoniazid, Pyrazinamide & Ethambutol.
Pyrazinamide has little activity agasint slow growing bacilli and is thus dropped after 3 months when typically only sloe growing bacillin remain.
Once sensitivities of the TB are known, ethambutol can also be dropped.
Rifampicin and isoniazid are continued throughout the duration of therapy, typically 6 months.
Isoniazid can lead to peripheral neuropathy due to antagonism of the effects of pyridoxine (Vitamin B6). Hence, pyridoxine treatment as a prophylactic measure is added to the standard regimen.
Rifampicin is a potent inducer of hepatic cytochrome P450 enzymes that can lead to dramatic changes in the metabolism of numerous drugs that will thus require dosage adjustment.
Rifampicin, isoniazid, pyrazinamide are all potentially hepatotoxic and this can be rapid and profound requiring initial careful monitring of therapy.
Ethambutol can affect vision, so visual acuity prior to starting treatment should be recovered to allow changes to be evaluated better
What are the complications of TB?
Although classically a respiratory infection, TB can affect virtually any organ system. Extrapulmonary TB has the following fairly typical presentations:
- Nodal TB. Cervical lymph nodes are typically involved.
- Osteomyelitis. TB has a predilection for bones of the vertebral column. This cam also then extend to form a spinal/paraspinal abscess with cord compression or extension into the sheath of the psoas muscle, resulting in a psoas muscle.
- CNS TB. Tb can spread into the brain and CSF giving two main types of infection: a) TB meningitis, a slowly progressive condition with altered conscious level and progressive lower cranial nerve palsies. B) cerebral TB. Foci of infection can behave like a space-occupying lesion, with seizures, nervous system signs etc.
- Other organ systems that can be affected: renal tract including testes/ovaries, larynx, skin, eye, liver
Which patient groups are most likely to present with pulmonary TB?
older patients - who grew up in 1940s and 1950s when TB was much more common. The microbe can remian dormant within an infected individual and can become active again in the face of dwindling immunity that occurs with age as well as alcohol ingestion.
Those who grew up or visited areas of the world where TB is much mroe common. Would need to have stayed there for prolonged periods
Investigations for suspected TB
Sputum - examined for TB bacilli by special stains, typically the Ziehl-Nielsen stain.
in patients who are not expectorating, sputum can be induced by inhalation of hypotonic saline.
CT scan of the chest - can help differentiate between active TB and presence of bronchial neoplasm
If diagnosis is still in doubt, a bronchoscopy can be performed. This will detect any airway neoplasm and also provide additional material for culture (biopsy)
Pleural biopsy can also be helpful if patient has pleural effusion with TB
What are the barriers to HIV testing?
Patient barriers:
May not think there are at risk
Worried regarding confienitality, stigma, immigratin issues
Emplyment issues, may fear they will lose their job especially if health care worker
Criminalisation isssues
Insurance
Doctor barriers:
May not think of testing or be aware of clinical indications for testing
May assume patient is not at risk
Fear of embarrassing/offedning patient especially if taking sexual history
Lack of time
Perceived lack of counselling skills
Logistic issues to get result back to patient
What pre-test discussion is required prior to a HIV test?
Why testing is indicated i.e. due to clinical presentation or symptoms
Benefits to testing i.e. if positive the success of HIV therapy, if negative the ability to concentrate on other investigations/diagnoses
How/when the result will be available
Although best to ask sexual history in view of other STIs and transmission assessment, shouldn’t be barrier to HIV testing
Insurance companies do not require to be informed of a negative test
What is PCR
Polymerase chain reaction is a moleculear biology technique which amplifies a specific DNA sequence generating mutiple copies. It is very sensitive and specific technique for diagnosing viruses, overtaking viral cuture, serology and IH
What is P.Jiroveci (PCP)
and treatment
- Opportunistic infection
- Caused by P jirovecii, a fungus causing infection in immuno-compromised individuals
- Fungus with cyst, merozoite and trophozoite morphology. Extracellular pathogen causing interstitial plasma cell pneumonia with “foamy” exudates in the alveoli.
- Causes progressive and disproportionate SOB, fever, dry cough with failure to respond to usual antibiotic regimes.
- Usually few signs on examination or CXR, although classically causes perihilar interstitial shadowing in moderate disease. Can cause white out in severe disease.
- Diagnosed via induced sputum (50-90%), BAL (90-95%), biopsy (>95%). PCR of sample performed.
- Complications include respiratory failure, pneumothorax,
First line treatment is cotrimoxazole 120mg/kg TDS and steroid therapy
How do you define an opportunistic infection?
Organisms which do not usually cause infection but do so when host defences are compromised.
Includes viral, bacterial, fungal, protozoal and lemith infections i.e. CMV, candida, PCP, toxoplasms
What virology tests are used to diagnose HIV?
HIV antibody test is the traditional method for diagnosis. Most patietns will develop antibodies within 6-8 weeks with almost 100% at 3 months, hence the 3 month window period for HIV testing. An ELISA test is performed first and then confirmed with Western Blot. ALISA is enzyme linked immunosorbant assay which uses an antigen-antibody reaction to generate a signal and result. Western blot uses gel electrophoresis to demonstrate specific HIV proteins
More recently HIV p24 antigen testing has been used with a confirmatory antibody test. This detects p24 protein which is present on the surface of the virus. This can be positive as early as 3 week
What is an HIV viral load?
An HIV viral load is a measure of HIV RNA in the plasma. It is high in acute infection or late untreated disease with figures often >1,000,000. Viral loads at this level are accompanied by symptomatic disease in most cases. The test is also used to monitor response to antiretrovirals and should be low or “undetectable” if there is a good response. “Undetectable” differs with different assays and is often described as <40.
What is a CD4 count and the normal range?
CD4 count is a measure of the number of T helper cells expressing CD4 on their cell surface. CD4 is a glycoprotein expressed on the surface of T helper cells, as well as monocytes, macrophages and dendritic cells. It is involved in T cell activation and interacts with MHC II molecules on antigen presenting cells being involved in both cell mediated and humeral immunity. The normal range is 500-1000.
How does HIV affect the immune system?
HIV gains entry to T helper cells by binding mainly to CD4 expressed of the surface of the cell as well as other glycoproteins (i.e. gp120) and co-receptors (i.e. CXCR4/CCR5). T helper cells are depleted as HIV progresses, impairing B cell activation and antibody production as well as cytotoxic T cell immunity. At a CD4 count of <350 individuals begin to become symptomatic and this is therefore the threshold to initiate antiretroviral therapy. Below 200 there is an increased risk of opportunistic infections especially PCP. As the CD4 count drops below 100 the risk of serious infections increases and includes mycoplasma infections and CMV disease
PCP is an AIDS defining illnesses; list other illnesses that fall into this category
Viral - CMV; Herpes simplex; PML caused by JC virus Bacterial - Mycoplasma infections- TB, MAC, Kansaii - Salmonellosis - Recurrent bacteria infections including pneumonia Fungal - Candidiasis - Coccidioidomycosis - Cryptococcosis - Histoplasmosis - PCP Parasitic - Cryptosporidium - Isosporiasis - Toxoplasmosis Malignancies - Kaposi’s sarcoma caused by HHV8 (human herpes virus 8) - Cervical cancer - Lymphoma Other - Dementia/HIV encephalopathy - Lymphoid interstitial pneumonia - Pulmonary lymphoid hyperplasia - Wasting syndrome
Explain the legal implications with regard to HIV disclosure and partner notification
Firstly anyone at risk including current and past partners and children need to be informed of their risk of HIV and offered testing. This is usually done with the help of a sexual health adviser and can be initiated by the index patient or anonymously by the sexual health adviser. There is a legal obligation for this to be done.
The transmission of HIV is significantly reduced by the use of condoms however there is still a theoretical risk, which is obviously increased if there is a condom break. HIV positive individuals are legally obliged to inform their sexual partners of their diagnosis prior to any sexual activity, regardless of whether a condom is used. Failure to do this can result in prosecution especially in Scotland where there has been prosecutions for putting individuals at risk without actual transmission.
It is also vital that all HIV positive patients be made aware post exposure prophylaxis availability for their partners in the event of a condom break. This is required to be imitated within 72 hours of the episode and involves taking HAART triple therapy (2 NRTI and 1 PI) for 1 month.
What are the most common organisms associated with typical and atypical pneumonia?
By far the most common bacterium to cause pneumonia is Streptococcus pneumonia. This often presents with signs of sepsis and chest symptoms consisting of; cough purulent sputum, pleuritic chest pain and dyspnoea. Other organisms associated with a more typical presentation include; Haemophilus influenza and Moraxella cattharalis (more common if underling chest disease e.g. COPD), Staphylococcus aureus (severe necrotising pneumonia) and Group A streptococcus.
The “atypical” organisms include Legionella pneumophila, Mycoplasma pneumonia, Chlamydia species (pneumonia and psitticai) and Coxiella burnetti (Q fever). The atypical organisms should be thought of in patients with an atypical presentation and pointers to their diagnosis should be sought when taking a history
Viral causes of pneumonia should also be considered. The most common viral cause is Influenza. Therefore in the presence of an influenza epidemic it is important that studies are carried out to investigate this as a cause.
Epidemiology of pneumonia
5 – 11 per 1000 population
Highest in very young and elderly
22 – 42% patients admitted to hospital
Mortality of 8 – 14% (30% in ITU)
Most common pathogen in any pneumoniae case =
streptococcus pneumoniae
What are the typical causes of pneumonia?
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catharralis
What are the atypical causes of pneumonia?
Mycoplasma pneumoniae
Legionella pneumoniae
Chlamydophila pneumonia
Chlamdophila psittaci
Risk factors for streptococcus pneumoniae?
Alchol (immunodeficient) Smoking (destroys innate immunity) Influenza viral infection Airway disease Immunosupression, particularly HIV
Presentation of S.pnuemoniae
Abrupt onset:
Cough, fever, pleuritic chest pain
Classic signs of consolidation:
Dull percussion, coarse crepitations, increased vocal resonance
Treatment of S.pneumoniae?
Penicillin (amoxicillin)
If allergic: Macrolides (clarithromycin), tetracyclines (doxycicline)
Who does haemophilus influenzae most often affect (causing pneumonia)?
Older people
People with underlying lung disease (e.g. COPD)
Presentation of H.influenzae
Abrupt onset:
Cough, fever, pleuritic chest pain
Dull percussion
Coarse crepitations
Increased vocal resonance
Treatment of h.influenzae and probel with resistance
Amoxicillin is given
Haemophilus organisms produce beta-lactamase - which breaks down beta-lactam antibiotics
If concerned about resistance - would use amoxicillin with a beta-lactamase inhibitor e.g.:
Co-amoxiclav
Tends to remain sensitive to:
Macrolides (clarithromycin)
Tetracyclines (doxycicline)
Features of mycoplasma pneumoniae
Atypical pneumonia
Smallest free living bacterium
Lack of cell wall
Very difficult to grow
High rates of it seen in autumn and winter
Spreads person to person
Presentation of m.pnuemoniae
Atypical presentation
Flu-like illness:
Headache, tired, achy, high temp, may have cough
When listen to chest hear signs of consolidation and confirmed on chest xray
Can have affects beyond the lungs:
Haemolysis (cold agglutinins), Guillain-Barre, Erythema multiforme, cardiac, arthritis
Diagnosing m.pneumoniae
Cannot culture due to lack of cell wall
Serology - to look for antibodies against it
PCR (sputum/throat swab) - can detect DNA of the organism
Treatment of m.pneumoniae
No cell wall so not beta lactams
Macrolides (clarithromycin)
Tetracyclines (doxycicline)
Quinolones (ciprofloxacin)
Legionella pneumophilia - how someone is infected
Find in water, soil
Humans inhale aerosol of these sources - into lungs and infects macrophages –> cause pneumonia
Presentation of legionella pneumophila
Flu like - headache, myalgia, malaise…
Diagnosis of l.pneumophila
Culture - not normally done but can be
Serology - looking for antibodies rising against legionella
Urinary antigen test - most common test done - dipstick urine to look for antigen specific to legionella
Treatment of L.pneumophila
Macrolides (clarithromycin)
Tetracyclines (doxycicline)
Quinolones (ciprofloxacin)
Clinical assessment of pneumonia
CURB65 score Confusion Urea >7 Resp rate >= 30 BP - diastolic<60 or systolic <90 65 - age over 65 years This defines severity - if have 2 or more = severe pneumonia
Regardless of CURB score is severe pneumonia if multilobar consolidation seen on a CXR and/or hypoxia on room air
Also have severe pneumonia if have signs of sepsis:
Systolic BP <100
Altered mental state
Resp rate >22 breaths/min
Investigations for pneumonia
Blood tests:
FBC, U&Es, ABGs/oxygen stats
Microbiology:
Blood cultures, sputum cultures, throat swab, urine legionella sample
Investigations:
CXR, ECG
Influenza season =
October to March
Viruses causing common cold
Rhinovirus (main cause) - 3 types A,B,C Coronavirus Parainfluenza virus Human metapneumovirus Adenovirus RSV Influenza
1-3 incubation period Persists N 1 week (up to 2 weeks) Can cause otitis media & sinutsitis Sore scratchy throat Nasal obstruction
Rhinovirus
Most common cause of the common cold Picornaviridae family ssRNA 3 species RV-A, RV-B, RV-C Non-enveloped
Coronavirus
Another common cause of the common cold
ssRNA
Largest RNA genome
Enveloped
Features of pharyngitis
Sore throat and pharyngeal inflammation
Viral infections 25% to 45% of all cases
Nasal symptoms = viral
Without nasal symptoms = bacterial
Many different viral pathogens including: Adenovirus Rhinovirus Influenza Parainfluenza
82% occurrence in infectious mononucleosis - Epstein Barr Virus (EBV), Saliva spread
HIV seroconversion
Herpes Simplex Virus
What is croup?
Croup is commonly encountered childhood infectious syndrome - distinctive cough; mostly mild but responsible for significant emergency visits (rapid onset, difficult breathing)
Treatment is supportive
Most caused by parainfluenza viruses 1-4
Features of bronchiolitis
Lower respiratroy tract infection of young children
Leading cause of hospitalisation in infants
Wheezing, tachycardia
7-10 days duration
Persistent cough for up to 3 weeks
RSV is the most common cause worldwide
Most children are infected by 2 years of age - reinfections are common but less severe
RSV is a major nosocomial hazard to at risk patients - cohorting, PPE, handwashing
RSV is also a significant burden in: immunocompromised, adults with chronic lung disease, elderly
RSV treatment and prevention
Ribivirin (oral, IV, aeorlised) has been used but benefit unclear
Ribivirin has numerous disadvantages/side effects.
Ribivirin is a broad spectrum anti-viral.
A prophylactic monoclonal antibody is available (Palivizumab/Synagis) - given IM monthly, expensive
Symptoms of influenza virus
Central - headache Nasopharynx - runny or stuffy nose, sore throat, aches Systemic - fever Respiratory - coughing Muscular - (extreme) tiredness Joints - aches Gastric - vomiting
Incubation peroid 1-2 days
Systemic symptoms persist for 3-5 days
Complications of influenza virs
Common complciations:
Acute ottitis media (children), sinusitis, pneumonia, exacerbation, dehydration (infants)
Uncommon complications: encephalopathy, Reye syndrome (children), myositis, myocarditis, febrile seizures
What subtypes of influenza cause infection in humans
A, B and C
C causes a more mild infection
Influenza treatment
M2 inhibitors - Amantadine, Rimantadine (these only work in Influenza A)
Neuramindase inhibitors - Oseltamivir, Zanamivir (these both licensed in UK -can also be used for prophylaxis) - these are the 2 that are mainly used, Peramivir, Laninamivir
RNA polymerase inhibitors - Favipiravir, Baloxavir
Type B influenza
Only found in humans - 2 lineages:
Victoria lineage
Yamagata lineage
Type A influenza
Found in humans, swine, bats and horses
Divided by type of protein found on surface:
Haemagglutinin & Neuraminidase
Influenza vaccination
Live and inactivated influenza vaccines are available
Offered to risk groups, HCW and children
Manufactured annually – based on expert opinion/surveillance
Inactivated
Trivalent vaccine:
- Two influenza A types and 1 influenza B type
Adjuvanted trivalent vaccine:
- >65 year age group (priority group 75 year and above)
- Two influenza A types and 1 influenza B type
Quadrivalent vaccine:
- Two influenza A types and 2 influenza B types
But will reduce severity, hospitalisations and death
Live attenuated intranasal influenza vaccine
Offered to children
Two influenza A types and 2 influenza B types
Manufactured annually – based on expert opinion/surveillance
83% effective at preventing influenza in children
What is an influenza pandemic?
Few, if any, people have immunity to the new virus that comes around every years
This allows the new virus to spread widely, easily and to cause more serious illness
Mycobacterium tuberculosis
These are obligate aerobes and intracellular pathogens, usually infecting
mononuclear phagocytes.
• Form very slow growing colonies, can take several weeks to grow.
• Due to a high lipid content in their cell walls, they stain weakly on a gram stain
and therefore needs a special stain - Ziehl Neelsen stain (acid-fast stain) to
identify the bacteria.
Rx factors for mycobacteria tb
Close contact (relative) with TB
• Immunocompromised e.g. HIV
• Drug/Alcohol abuse
• Homelessness
pathophysiology/genesis of tb
Mycobacterium tuberculosis:
Ariborne infection spread via respiratory droplets
Alveolar macrohages ingest bacteria
Macrophages present antigen to T lymphocytes –> cellular immune response –> granuloma formation.
Granuloma involves necrosis, epitheloid macrophages and multi-nucleated giant cells
Primary TB
• Initial lesion usually solitary (1-2cm in diameter) - named as the Ghon complex.
• The primary infection has 2 components:
• Initial inflammatory reaction
• Secondary inflammation in surrounding lymph nodes
• Within 3-8 weeks of infection, the initial lesion becomes a tubercle (granulomatous inflammation).
• The tubercle undergoes caseous necrosis (cheese like appearance) - this is known as a Ghon focus.
When combined with associated lymph nodes, it is termed as Ghon complex.
Secondary TB
Reactivation of primary infection or reinfection.
• Any form on immunocompromised may allow reactivation.
• Tubercle follicles develop and lesions enlarge by formation of new tubercles. Infection spreads by
lymphatics and a delayed hypersensitivity reaction occurs.
• In secondary TB, the lesions are often bilateral usually cavitating.
Miliary TB
Aggressive form of TB that occurs throughout the whole lung.
Made up of lots of small dots (tubercles)
• Granuloma erodes into blood (bloodborne dissemination) or
lymph vessels and the bacilli spread around the lungs
• Predominantly in those with immunocompromise (HIV)
Extrapulmonary TB
TB can spread through to many different organs once in the blood. Predominantly in those with
immunocompromise (HIV)
• CNS spread is quite common - necrotic destruction of the brain.
• Renal TB - renal parenchyma replaces with caseous necrosis.
Mantoux reaction with TB
M.tuberculosis is injected just under the skin to create a local immune response.
• There is a nodule appearance which will have lots of granulomas.
Treatment of TB + side effects of the drugs
RIPE:
• Rifampicin (has interactions - CYP450 inducer)
• Isoniazid
• Pyrazinamide (stop after 2 months)
• Ethambutol (stop after 2 months)
• Long duration - 6 months
• Combination of drugs to reduce the rise of resistance
Two months of isoniazid, rifampicin, ethambutol
and pyrazinamide, followed by four months of
isoniazid and rifampicin
Pyrazinamide has little activity against very slow growing bacilli and is thus dropped after 2 months when typically only very slow growing bacilli remain.
Once sensitivities of TB are known, ethambutol can also be dropped.
Isoniazid can lead to peripheral neuropathy due to antagonism of the effects of pyridoxine (Vitamin B6). Hence, pyridoxine treatment as a prophylactic measure is added to the standard regimen.
RIP are all potentially hepatotoxic and this can be rapid and profound requiring initial careful monitoring of therapy.
Ethambutol can affect vision, so visual acuity prior to starting Tx should also be recorded to allow changes later to be evaluated better.
Rifampicin - Orange-red urine
Isoniazide - Neuropathy, SLE (give prophylactic pyridoxine)
Pyrazinamide - Gout
Ethambutol - Optic neuritis
RIP are metabolised in the liver so monitor LFTs (CYP450)
Features of a history that suggests pulmonary TB
Chronic presentation and weight loss with night sweats.
Alcohol excess is also a risk factor for TB
What patients groups are most likely to present with pulmonary TB?
An elderly patient - likley to have acquired the infection as a child in 1940s and 1950s when TB was much more common than it is now. Only about 10% of those who become infected go on to show clinical disease. However, the microbe can remain dormant within an infected individual and become active again in the face of dwindling immunity that occurs with age as well as alcohol ingestion.
The other main group of patients are those who grew up or visit areas in the world where TB is much more common than here, esp in developing world.
A key point is the strong association between pulmonary TB and infection with HIV. Need to test for HIV in all those infected with TB.
Investigations of suspected TB
Sputum culture - for presence of TB bacilli by special stains, typically the Ziehl-Nielsen stain. Organisms that retain this stain are said to alcohol and acid-fast bacilli (AFBs) and are highly likely to be mycobacteria.
The sputum will also be cultured for TB, which can take up to 6 weeks to grow. In patients who are not expectorating, sputum can be induced by inhalation of hypotonic saline.
Ct scanning of chest - can help differentiate between active TB and the presence of a bronchial neoplasm. It also provides a baseline of the extent of TB and is helpful in evaluating how successful chemotherapy has been.
If diagnosis is still in doubt, a bronchoscopy can be performed. This will detect any intra-airway neoplasm and also provides additional material for culture.
the pleural effusion should be tapped and the pleural fluid examined for TB. Pleural biopsy can also be helpful (Abrahams needle) as it may show typical necrotising granulomas in TB. However has potential complications e.g. pneumothorax
What are the complications of TB?
Extrapulmonary TB has the following fairly typical presentations:
- Nodal TB. Cervical lymph nondes are typically involved
- Osteomyelitis. TB has a predilection for bones of the vertebral column. This can also extend to form a spinal/paraspinal abscess with cord compression or extension into the sheath of the psoas muscle
- CNS TB. TB can spread into the brain and CSF giving 2 main types of infection a) TB meningitis, a slowly progressive condition with altered conscious level and progressive lower CN palsies. b) cerberal TB. Foci of infection can behave like a SOL, with seizures, nervous system, nervous system signs etc.
- Other organ systems are affected: renal tract including testes/ovaries, larynx, skin, eye, liver.
Differentiate between SIRS, Sepsis, Severe sepsis, Septic shock
SIRS -temp <36 or >38, HR >90bpm, RR >20, WCC <4,>12
Sepsis - SIRS in response to infection
Severe sepsis - Sepsis with organ dysfunction, hypoperfusion or hypotension
Septic shock - Sepsis with refractory hypotension
How is HIV transmitted and what factors would make a patient ‘high risk’?
HIV is transmitted through body fluids and/or tissues. Is transmitted through unprotected sexual intercourse, IV drug abuse, blood transfusion, needlestick injury, tattoo/piercing, anyone diagnosed with an STI
With unprotect sexual intercourse the risks are increased by:
High viral load, trauma (including sexual assault), co-existing STIs, ulcerative conditions i.e. herpes simplex/syphilitic chancre
What barriers is there to HIV testing?
Patient barriers:
May not think they are at risk
Worried regarding confidentiality, stigma, immigration issues
Employment issues, may fear they will lose their job especially if health care worker
Criminalisation issues
Insurance
Doctor barriers:
May not think of testing or be aware of clinical indications for testing
May assume patient is not at risk
Fear of embarrassing/offending patient especially if taking a sexual history
Lack of time
Perceived lack of counselling skills
Logistic issues to get result back to patient
What pre-test discussion is required prior to a HIV test?
Main points to cover form the BHIVA testing guidelines are:
Why testing is indictaed i.e. due to clinical presentation or symptoms
Benefits to testing i.e. if positive the success of HIV therapy, if negative the ability to concentrate on other investigations/diagnoses
How/when the result will be available
Although best to ask sexual history in view of other STIs and transmission assessment, shouldn’t be barrier to HIV testing.
Insurance companies do not require to be informed of a negative test
What is PCR?
Polymerase chain reaction - a molecular biology technique which amplifies a specific DNA sequence generating multiple copies. It is a very sensitive and specific technique for diagnosing viruses, overtaking viral culture and IHC.
What is P.Jiroveci (PCP)?
Opportunistic infection
Caused by P jirovecii, a fungus causing infection in immuno-compromised individuals.
Fungus with cyst, merozoite and trophozoite morphology. Extracellular pathogen causing interstitial plasma pneumonia with ‘foamy’ exudates in the alveoli.
Causes progressive and disproportionate SOB, fever, dry cough with failure to response to usual antibiotic regimes.
Usually few sign on examination or CXR, although classically causes perihilar interstitial shadowing in moderate disease
Diagnosed via induced sputum, BAL, biopsy. PCR of sample performed.
Complications include respiratory failure, pneumothorax.
First line treatment is cotrimoxazole 120mg/kg TDS and steroid therapy
How do you define an opportunistic infection?
Organisms which do not usually cause infection but do so when host defences are compromised. Includes viral, bacterial, fungal, protozoal and helmith infections i.e. CMV, Candida, PCP, Toxoplasma
What virology tests are used to diagnose HIV?
HIV antibody test is the traditional method for diagnosis. Most patients will develop antibodies within 6-8 weeks with almost 100% at 3 months, hence the 3 month window period for HIV testing.
An ELISA test is performed first and then confirmed with Western Blot. ELISA is enzyme linked immunosorbant assay which uses an antigen-antibody reaction to generate a signal and result. Western blot uses gel electrophoresis to demonstrate specific HIV proteins.
More recently HIV p24 antigen has been used with a confirmatory antibody test. This detects p24 protein which is present on the surface of the virus. This can be positive as early as 3 week
What is an HIV viral load?
A HIV viral load is a measure of HIV RNA in the plasma. It is high in acute infection or late untreated disease with figures often >1mil.
Viral loads at this level are accompanied by symptomatic disease in most cases. The test is also used to monitor response to antiretrovirals and should be low or ‘undetectable’ if there is good response. ‘Undetectable’ differs with different assays and is often described as <40
Describe the clinical stages/natural history of HIV infection
Primary infection - initial exposure to the virus, incubation period 2-4 weeks.
Acute HIV syndrome - CD4 count becomes very low and viral load increases. Flu-like symptoms, infective mononucleosis, maculopapular rash.
Clinical latency - immune system has partly dealt with the virus, however it is still present in the body at low levels, and still replicating. Patient’s are usually asymptomatic, with persistent generalised lymphadenopathy.
Constitutional disease - diarrhoea, weight loss, oral hairy leukoplakia, thrush.
Opportunistic disease - pneumocystitis jerovecii, TB, toxoplasmosis, candiadises
Tx of HIV infection
HAART (highly active antiretroviral treatment). Triple therapy - cART.
Aims to suppress viral load to undetectable (<40), allowing for CD4 recovery to improve immune system. It is triple therapy (2 nucleosides and 1 from another drug class):
- Non-nucleoside reverse transcriptase inhibitors and Nucleoside Reverse Transcriptase inhibitors –> prevents RNA reverse transcription (no DNA production)
- Integrase inhibitors –> These block the entry of viral DNA into nucleus of CD4 cells
- Protease inhibitors –> These block protease from allowing virus to pass out of cells as new HIV virus
Challenges with ART (when Tx HIV)
Good adherence (>95%) essential
Psychological impact
Short term side-effects
Drug-drug interactions (Mediated by CYP450, Reduces or increases drug levels. PPIs, Statins, Antipsychotics - OTc)
Emerging longer term toxicities (Body shape changes - lipoatrophy or lipodystrophy; Renal; Hepatic; Lipid; Bone)
Short term toxicity:
Rash
Hypersensitivity (Abacavir and Nevirapine)
CNS side effect (Efavirenz) - sleep disturbance, vivid dreams, mood changes
GI side effects
Renal Hepatic
