2.3 Enteric fever, Leptospirosis, Hepatitis A & E Flashcards
Enteric Fever
- Life threatening systemic infection
- Gram negative bacillus
- Typhoid fever – due to ________________
- Paratyphoid fever – due to ______________
- Ratio of disease caused by S. typhi : S. paratyphi about 10:1
- Worldwide, typhoid fever most prevalent in impoverished overcrowded areas with poor access to sanitation
Epidemiology of Typhoid Fever
- Typhoid and paratyphoid fevers are endemic at high incidence (>100/100 000 p.a.) in the Indian subcontinent, South-east and South-central Asia, and at medium incidence (10–100/100 000 p.a.) in the rest of Asia, Africa and Central and South America
Salmonella enterica serovar Typhi;
Salmonella enterica serovar Paratyphi A/B/C
[TRANSMISSION: Enteric fever]
Typhoid fever is an exclusively human disease transmitted via water or food contaminated with the urine/faeces of a patient/carrier (faeco-oral route):
• Common in overcrowded conditions (e.g. informal settlements, refugee camps)
• Raw food and vegetables are also important in some countries where human faeces is used as fertilisers or contaminated water is used
• 2 – 5% of previously infected individuals become chronic asymptomatic carriers, which shed viable organisms in urine/faeces for > 1 year (can infect others):
• ______________ constitute the long-term reservoir of S. typhi and S. paratyphi A and B
Chronic gallbladder carriers
[Pathogenicity / Virulence: enteric fever]
- The molecular mechanism of Salmonella pathogenicity is complex
- Pathogenic Salmonella spp. are distinguished from non-pathogenic relatives by the presence of specific pathogenicity genes: pathogenicity islands (PIs)
- The type III secretion system (T3SS) proteins encoded by________________ are associated with the pathogenicity at molecular level
- The T3SS encoded by SPI-1 contains _____________ while SPI-2 is responsible for intracellular pathogenesis and has a crucial role for ______________
- The virulence genes of Salmonella spp. encoding five different Sips (Salmonella invasion protein): Sip A, B, C, D and E induce __________________
- The bacterial invasion of several host cells and the inflammatory response (neutrophils, monocytes-macrophages, T and B lymphocytes) with high cytokine production are important elements causing the clinical manifestations
- The increase in cytokines in peripheral blood causes fever after an incubation period of ________. Initially there is low fever, that rises progressively, and by the second week it is often _______________
two Salmonella PIs (SPIs);
invasion genes;
systemic S. enterica infections;
apoptosis in macrophages;
5–21 days;
high and sustained
[Infectivity: Enteric Fever]
- Estimated inoculum size necessary for infection is _____________
- Infection occurs by ingestion, penetration through the intestinal mucosa to the ______________
- After multiplication, organisms enter bloodstream via the ___________ (causing a transient primary bacteraemia) to the liver and spleen
- Further intracellular multiplication occur before huge numbers of organisms enter the bloodstream, marking the onset of clinical illness (secondary bacteraemia)
- Metastatic infection (e.g. to ______________________) occurs during secondary bacteraemia
- Due to invasion of the Peyer’s patches, they become _________. Later, necrosis of the superficial layer leads to formation of ulcers. If an ulcer erodes into a blood vessel, ___________ results. Transmural perforation can cause peritonitis.
100,000 bacteria;
mesenteric lymph nodes;
thoracic duct;
gallbladder and Peyer’s patches;
hyperplastic;
severe haemorrhage
Salmonellae invade the intestinal epithelial cells by a complex mechanism that includes triggering ____________, formation of ___________, and phagocytosis of the bacterium into the cells. The ruffling–internalization process is controlled by a type III secretion system encoded by genes found in the __________ (containing genes inv A–H).
These genes are located on Salmonella Pathogenicity Island 1, SPI-1. Salmonella that cause enteric fever must be able to survive and replicate within the host macrophage system so that they may establish a systemic infection. The genes necessary for survival inside macrophages are constituents of a two-component response regulator termed phoP/ phoQ. Genes activated by this phoP/phoQ are known as pag genes, and are required to promote intracellular replication of.
A second pathogenicity island, SPI-2, activated within the phagosome, translocates bacterial effector proteins from the phagosome into the ____________, and prevents killing by evading the ____________.
active rearrangements;
membrane ruffles;
inv locus;
macrophage cytosol; NADPH oxidative burst
Organisms multiply in the small intestine over the period of 1-3 weeks, breech the intestinal wall, and spread to other organ systems and tissues. Organisms multiply in the small intestine over the period of 1-3 weeks, breech the intestinal wall, and spread to other organ systems and tissues. Infection occurs by ingestion and penetration through the intestinal mucosa.
At the ____________, invading bacteria are taken up by macrophages, and travel to _____________. After a brief period of multiplication here, the organisms enter the bloodstream via the thoracic duct (causing a transient primary bacteraemia) and are transported to the ______________.
Further intracellular multiplication occur before huge numbers of organisms enter the bloodstream, marking the onset of clinical illness (secondary bacteraemia). Metastatic infection (eg to gallbladder and Peyer’s patches) occurs during the secondary bacteraemia. Due to invasion of the Peyer’s patches, they become hyperplastic. Later, necrosis of the superficial layer leads to formation of ulcers. If an ulcer erodes into a blood vessel, severe haemorrhage results. _________________ can cause peritonitis.
submucosa;
mesenteric lymph nodes;
liver and spleen;
Transmural perforation
[Clinical Presentation of Enteric Fever]
The incubation period of typhoid fever varies between 10 to 20 days. In paratyphoid fever it ranges from 1 to 10 days. The duration of illness in untreated cases of average severity is usually 4 weeks.
1st week of illness:
- Rising, ____________ fever, relative bradycardia, bacteraemia, headache, malaise
- Diarrhoea (more common in ___________), constipation (more common in _______)
2nd week of illness:
- __________ high temperature
- Abdominal pain
- ___________ (crops 2-4mm pink papules which fade on pressure)
- patient looks toxic and apathetic
3rd week of illness:
- Continuous high fever and a _____________ state
- ileus or diarrhoea may occur
- Patient is likely to become ___________________
- Death may occur at this stage from __________________.
- Hepatosplenomegaly
- Intestinal haemorrhage or perforation
- Confusion, convulsions
Convalescence is often lengthy. Untreated, the mortality is historically described as approximately 20%, but with the use of antibiotics neither disease evolution nor death are common (<1%).
stepwise;
children;
adults;
Sustained;
Rose spots;
delirious confusional;
obtunded and hypotensive
overwhelming toxaemia, myocarditis, intestinal haemorrhage or perforation
Investigations for Enteric fever
- FBC – _________________
- LFT – mild transaminitis
- Isolation of organism is gold standard for diagnosis
- Blood culture – positive in 60-80% of cases, usually 1st to 2nd week
- Bone marrow culture – positive in 80-90% of cases
- Stool and urine cultures – positive from 2nd to 4th weeks
- Widal test – neither sensitive nor specific. Measures antibodies against _______________ of the causative organism.
In acute infection, ________ appears first, rising progressively, later falling and often disappearing within a few months. __________ appears a little later but persists for longer. However raised antibodies may have resulted from previous typhoid immunization or earlier infection(s) with Salmonellae sharing common O antigens with S. typhi or S. paratyphi.
leucopenia or leukocytosis, mild thrombocytopenia, anaemia;
flagellar (H) and somatic (O) antigens;
O antibody;
H antibody;
[Treatment for Enteric fever: first line]
- Ciprofloxacin and Other Fluoroquinolones (FQs) - treatment of choice for _______________________; superior to chloramphenicol even for fully susceptible strains. Defervescence occurs in 3–5 days; convalescent carriage and relapses are rare (<2%).
- Third-generation Cephalosporins - ______________________ have have an acceptable efficacy in the treatment of typhoid fever. They are less efficacious with a longer time to clinical response than the FQs against susceptible strains
- Azithromycin - is concentrated within cells, making it ideal for the treatment of infection by _____________. At least as efficacious as chloramphenicol and FQs, and more efficacious in populations with drug-resistant strains, and is considered the most appropriate first-line treatment in areas with ___________________.
both fully susceptible and MDR strains in areas where there is not yet established FQ resistance;
Cefotaxime, ceftriaxone and cefoperazone ;
intracellular organisms;
clinically important FQ resistance
[TREATMENT FOR ENTERIC FEVER: SECOND LINE]
- Chloramphenicol was introduced in 1948, and was very effective in the treatment of enteric fever. Disadvantages of chloramphenicol are the longer course, a _________________ than modern agents (5–15%), more secondary transmission, the rare marrow toxicity and aplastic anaemia; and global emergence of resistant strains. It is clinically inferior to fluoroquinolones. Still has a limited role in low-resource areas where resistance is not established and other agents are not available.
- Ampicillin is inferior to chloramphenicol.
- Amoxicillin is at least as effective as chloramphenicol in respect of ________________________.
- Co-trimoxazole is also as effective as chloramphenicol.
- None of these drugs should now be regarded as first-line therapy for typhoid and paratyphoid fever.
higher relapse rate;
fever clearance time and relapse rate (4–8%)
[Enteric Fever: Control and Prevention]
Management of Chronic Carriers
- Treat with __________: Prolonged courses of amoxicillin or co-trimoxazole may be effective, but the failure rate is high if there is chronic gallbladder disease. _____________________ have been much more effective, with cure rates of 78% and 83%, respectively.
- Emphasize good personal and food hygiene
- Avoid work as food handler if chronic carrier
Immunization
- Vaccination - for travelers to areas with moderate to high risk of exposure to S. typhi
- Vaccine protective (but not fully protective) against S. typhi
1) Oral live attenuated S. typhi (note: live vaccine)
2) IM polysaccharide vaccine
prolonged antibiotic course;
Ciprofloxacin (750 mg twice daily) and norfloxacin (400 mg twice daily)
If you think it’s typhoid… - Blood & stool cultures - Empirical \_\_\_\_\_\_\_\_\_ • Await antibiotic susceptibility • If susceptible, \_\_\_\_\_\_\_\_\_\_\_\_ • If FQ resistant, \_\_\_\_\_\_\_\_\_ - Rehydration and supportive care - Isolate patient and contact precautions - Public health – notifiable disease in Singapore
ceftriaxone;
ciprofloxacin;
azithromycin
[Leptospirosis]
- Zoonotic disease caused by spirochetes of the genus Leptospira
- Many animal reservoirs - ________ are the most important worldwide
- Transmission by direct contact with animals, or indirect contact with ___________________
Epidemiological patterns worldwide:
- Tropical wet areas: Many serovars, many reservoir species. Zoonosis by occupation and ______________ (esp. rainy season & floods).
- Urban environment: _________-borne, Zoonosis when urban infrastructure disrupted (war, natural disasters); slums.
- Temperate climates: Few serovars. Zoonosis by contact with ___________
rodents;
water / soil contaminated by animal urine;
Many;
environmental contamination;
Rodent;
farm animals
Leptospirosis
- “Leptospira” derives from the Greek leptos (thin) and Latin spira (coiled).
- The cells have pointed ends, one or both of which is usually bent into a ____________.
- Because of their small diameter, leptospires are best visualized by ______________________
- 16 genomospecies; >200 antigenically distinct serovars
- Reclassified into 21 species depending on DNA-relatedness (with 7 pathogenic species)
Distinct clinical syndromes associated with specific serovars; eg. severe disease often associated with serovars from the _____________________. This is disputed by some authors. Severity of disease is probably affected by interaction between many factors: agent, genomic changes that may alter its virulence, inoculum dose, host factors & timing of medical intervention
characteristic hook;
darkfield microscopy;
icterohaemorrhagiae serogroup
[PATHOGENESIS: Leptospires]
Leptospires first penetrate _________________ (e.g. conjunctiva or oral cavity) or abraded skin, then enter the bloodstream and carried rapidly to all parts of the body (haematogenous dissemination):
• Incubation period: 5 – 14 days
• Testing of blood using Leptospira PCR is likely to be positive during the ________________- before antibody formation and clearance of organisms from the blood
• Causes ________________ (endothelial damage and increased capillary fragility) leading to internal organ haemorrhage (________________+ ___________)
• Prolonged excretion of Leptospires in urine following primary infection (lasts up to several weeks)
intact mucous membranes;
1st week of fever;
systemic vasculitis;
hepatocellular damage + tubulointerstitial
nephritis;
