ICL 2.24: Zoonotic Bacterial Diseases Flashcards
what’s the microbiology of bartonella?
gram (-) coccobacillus
aerobic
what’s the microbiology of ehrlichia?
gram (-) coccobacillus
what’s the microbiology of anaplasma?
gram (-) coccobacillus
which stain do you use for bartonella species?
gram stain poorly
instead do Warthin-Starry silver staining of lymph nodes/lesions
you’ll see brown to black coccobacilli against a pale yellow/amber background
in what media do you grow bartonella?
chocolate agar
hemin required
optimal growth at 34-37 C, 5% CO2
takes 14 days for colonies to grow though….
what’s the reservoir for bartonella?
animal and arthropod reservoirs
do not appear to cause disease in animal reservoir hosts, but do in other animals
how is bartonella transmitted?
different pathogenic species are transmitted by fleas, lice, or sandflies
NOT TICKS
which cells do bartonella infect?
RBCs or endothelial cells in human hosts
primary niche of bacterial colonization is believed to involve the vascular endothelium
what’s the unique effect that bartonella have on the body?
they cause vasoproliferative lesions = angiogenesis
what is the infection process of bartonella species?
- they colonize the vascular endothelium
- at five-day intervals, bacteria are released from the primary niche into the bloodstream
(bloodborne bacteria can reinfect the endothelium to start another infection cycle)
- bloodborne bacteria also bind to, invade, and replicate within RBCs
they specifically replicate in an intracellular membrane-bound compartment
- eventually, they stop replicating and persist within RBCs for several weeks
different Bartonella species reach different levels of bacteremia/RBC infection rates
how do Bartonella enter endothelial host cells?
dntry of Bartonella into endothelium is dependent on actin cytoskeleton
they bind to various extracellular matrix (ECM) components and membrane proteins
then single bacteria or small clusters are internalized in Bartonella-containing vacuoles (BCVs) but they stay right at the surface
it’s the injection of T4SS that interferes w/ internalization and allows bacterial clustering on surface
these clusters are surrounded by actin-rich protrusions of the host cell membrane and are eventually engulfed as large assemblies in invasome structures = looks like big bumps on cell surface EM
so the bacteria is finally taken up via the invasome!
how do Bartonella enter host RBCs?
- attachment mediated by T4SS or flagella
- small secreted deformation factor induces pits & trenches on RBC membrane
- dvaginations containing the bacteria pinch off into interior
- bartonella replicate in the RBC vacuole & persist there for the lifetime of RBC
this increases the likelihood for its spread through blood-feeding insects
how do Bartonella trigger vascular tumor formation?
vasoproliferative bartonellae adhere to and invade endothelial cells
they cause direct stimulation of endothelial cell proliferation and inhibition of apoptosis
they also trigger proinflammatory response that recruits macrophages and other leukocytes
at this point the bacteria produce angiogenic factor which causes the macrophages to make vascular endothelial growth factor (VEGF)
VEGF is potent stimulator of angiogenesis
“angiogenic factor” itself also directly stimulates blood vessel formation
then to top it all off, bacterial colonization/growth and macrophage activation results in hypoxic conditions which again, upregulates VEGF
all of this VEGF results in paracrine stimulation of endothelial cell proliferation
this whole combination of stuff mediates vascular tumor formation!!!! it looks like a kaposi sarcoma
what disease does bartonella henselae cause in immunocompetent vs. immunosuppressed people?
healthy people = cat scratch disease
immunocompromised people = bacillary angiomatosis (BA) or peliosis
what is the reservoir for bartonella henselae?
domestic cats! (sometimes dogs too)
50% of cats in the U.S. are infected at some point during their life span; especially kittens
cats are more likely to be infected in warm humid climates
infected animals usually are not sick
what are the 4 diseases that can be caused by bartonella henselae?
- cat scratch disease
- bacillary angiomatosis
- peliosis = vascular lesions in liver or spleen; not just on the skin like BA!
- endocarditis
what do the colonies of B. henselae look like on agar?
small white irregular colonies
all different sized circles
how is bartonella henselae transmitted?
cat to cat transmission is via flea bite
cat to human transmission is largely through direct contact/trauma = cat scratch, bite or even licking of wound
what are the symptoms of cat scratch disease?
caused by bartonella henslae
1 week after cat scratch you may see:
- papule or pustule at innoculation site
- fever
- tiredness
- headache
1-4 weeks later bacteria travel to nearby lymph nodes like armpit, groan or neck and lymph nodes will get really big and painful
in an immunocompetent person the infection is self-limiting and nodes usually shrink to normal size within weeks to months
do you develop protective immunity following cat scratch disease?
yup
antibodies produced during infection are subsequently protective
what are the possible complications associated with cat scratch disease?
- Parinaud’s oculoglandular syndrome
2. encephalitis/meningitis/myelitis
what is Parinaud’s oculoglandular syndrome?
possible complication of cat scratch disease which is caused by bartonella henslae
it’s a combination of conjunctivitis and local lymphadenopathy (big bulging lymph nodes) that usually happens when the scratch is near the head
can see necrosis, vasculitis, granulomatous inflammation and cococcobacilli will be present in lesions
there’s also proliferation/dilation of blood vessels
even with all these symptoms though there’s no pain and no discharge…
in fact, it usually resolves within 2-4 months with no sequelae
you just have to make sure it doesn’t progress to encephalitis/meningitis
describe encephalitis/meningitis associated with cat scratch disease
onset is sudden
fever, convulsion is often first presenting sign
children between 7-12 at risk
recovery is rapid (within 2-14 days), sequelae are rare
what is bacillary angiomatosis?
disease state of bartonella henslae exhibited by immunosuppressed patients
lesions are usually seen in skin, but may also manifest in bone, GI tract, reproductive tract, lymph node, and CNS
*bacteremic!! BA lesions form in several organ systems & mucosa
BA is more often caused by B. quintana and B. bacilliformis
what are the symptoms of bacillary angiomatosis?
- reddish vascular nodules, multiple lesions, tenderness
lesions are undistinguishable from that of Kaposi’s sarcoma
- fever, chills, malaise, headache, anorexia
- characterized by proliferation of vascular endothelial cells and neutrophils/bacteria scattered throughout lesion
how do you treat bacillary angiomatosis?
erythromycin
2-4 weeks or longer if needed
what is the host and vector of bartonella quintana?
only human hosts
lice vectors
no known animal vectors!
how is bartonella quintana transmitted?
body lice
B. quintana multiplies in the lice intestine and is transmitted to humans by feces through altered skin –> lice feed alot which provokes scratching and allows the lice feces filled with bacteria to enter!
poor personal hygiene conditions
most current cases are seen in homeless and/or chronic alcoholism
what do bartonella quintana infections cause in immunocompetent patients?
- trench fever
- endocarditis
- chronic bacteremia
what do bartonella quintana infections cause in immunocompromised patients?
bacillary angiomatosis
it’s actually associates more with bone/subcutaneous than BA caused by B. henselae
what are the symptoms of trench fever?
caused by bartonella quintana
sudden onset of severe headache, pain in the shin bones, elevated temperature
may also see fatigue, restlessness, dizziness, macular truncal rash, NVD, splenomegaly
between days 3-7, the temperature would suddenly drop to normal
then you’d see recurrence of ~5 day cycle, with each attack being less severe
trench fever often results in prolonged disability but no fatalities reported
“quintana” = occuring every 5 days!
what disease does bartonella baciliformis cause?
Carrion’s disease = Oroya fever + verruga peruana
what is Carrion’s disease?
caused by bartonella baciliformis
a biphasic disease that is endemic in the valleys of the South American Andes
consists of both the Oroya fever = phase 1 and verruga peruana = phase 2
how is Carrion’s disease transmitted?
caused by bartonella baciliformis
transmitted by the sandfly (Phlebotomus verracarum)
no known animal reservoir
what are the two phases of Carrion’s disease? what happens during them?
PHASE 1 = Oroya fever (acute)
highly fatal febrile anemia
fever, headache, pain in the shins, splenomegaly
caused by massive invasion and lysis of RBCs from a hemolysin that B. bacilliformis produces (other bartonella species don’t produce it)
PHASE 2 = Verruga peruana (chronic)
if you survive oroya fever, the disease will progress to chronic secondary phase of verruga peruana
the bacteria colonize the vascular endothelium and cause vasoproliferative eruptions of the skin = verruga
these lesions are identical to BA lesions caused by B. henselae and B. quintana but they’re limited to the skin
they develop within 1-2 months & persist months to years
it correlates with development of humoral response
how do you treat B. henselae infections?
Cat scratch disease = antibiotic treatment not recommended
bacillary angiomatosis = erythromycin or tetracycline; 2-3 months
how do you treat B. quintana infections?
doxycycline for 4 weeks plus gentamicin for 2 weeks
how do you treat B. bacilliforimis infections?
erythromycin, doxycycline, ciprofloxicin; 1-2 week
how do you diagnose bartonella infections?
diagnosis is hard and you often have to use symptoms, history and geography
so like evidence of cat scratch/bite (CSD, BA), trip to South America (Carrion’s disease), poor living conditions (trench fever) are important for diagnosis
serologic tests like ELISA are msot practical for diagnosis but they’re only effective after humoral response has occurred
you can’t culture this bacteria!!!
FLASHCARD: microbiology, pathology, epidemiology, clinical, diagnosis and treatment of bartonella
MICROBIOLOGY: Curved, pleomorphic Gram – bacillus, poor Gram strain (Warthin-Starry in tissues), fastidious growth (use chocolate agar for 14 days), infect erythrocytes and endothelial cells in humans, different species transmitted by different arthropod vectors
PATHOLOGY: Infects endothelial cells after introduced into skin by vector (B.h.-flea, B.q.-human louse, B.b.-sandfly). Released at intervals into bloodstream to infect erythrocytes (RBCs). Disease severity is related to relative ability of each strain to achieve high numbers in blood and/or lyse RBCs; B.h. is mild, B.q. is moderate, and B.b. is severe
EPIDEMIOLOGY: B.h. is found in more temperate zones and associated with animal-transmission via fleas or biting/scratching. Mainly transmitted to human via cat-scratch, and most cases are children. B.q. is only transmitted via louse, so seen in areas with poor hygiene or war-associated populations. B.b. is only found in valleys of Andes mountains, where transmitted via bite of sandfly
CLINICAL: Cat scratch disease (B.h.) is usually mild and self-limiting, with swollen lymph nodes; however, immunosuppressed can develop more severe disease and vascular tumors (bacillary angioedema). Trench fever (B.q.) exhibits a “Quintana”, where every ~5 days see onset of severe headache, pain in shin bones, and elevated temperature that lasts 3-7 days, followed by ~5 days normal; debilitating, but not fatal. B.b. cause two disease: Oroya fever (acute) has massive invasion & lysis of RBCs, fever, headache, shin pain. Splenomegaly; highly fatal febrile anemia. Second is verruga peruana (chronic) where form large numbers of vascular tumors (bacillary angioedema)
DIAGNOSIS: Mainly diagnose by symptoms and epidemiology for each. Culture is impractical. Can stain lesions (Wartin-Starry) or test for antibodies for each bacteria. Treat Oroya fever ASAP!
TREATMENT: CSD is usually self-limited. DOC is doxycycline, or erythromycin
which genuses are in the anaplasmataceae family?
- anaplasma
- ehrlichia
- neorickettsia
- wolbachia
which bacteria cause human ehrlichioses?
- Ehrlichia chaffeensis**
- Ehrlichia ewingii
- Anaplasma phagocytophilum**
- Neorickettsia sennetsu
all of these are in the anaplasmataceae family
what is the microbiology of anaplasmataceae family?
gram (-) cocci
obligate intracellular pathogens = can’t grow them on media outside of a cell
lack LPS and peptidoglycan*
how are anaplasmataceae family bacteria transmitted?
all transmitted by ticks
what cell type do anaplasmataceae family bacteria infect?
they infect different leukocyte populations
they remain in phagocytic vacuoles and prevent fusion with lysosome
then they divide to form vacuole-bound colonies known as morulae –> a single cell can havae 3-15 morulae
**morulae are diagnostic for anaplasmataceae infection!!
they look like little spots inside neutrophils
how are Ehrlichia chaffeensis and Anaplasma phagocytophilum transmitted?
Wild rodents are reservoirs for A. phagocytophilum
deer are reservoirs for E. chaffeensis (yellow)
each bacteria are usually transmitted to humans by the bite of infected ticks that have acquired the infection by taking a blood meal from respective reservoir wild animals
A. phagocytophilum and E. chaffeensis infect primarily granulocytes and monocytes, respectively
these infected leukocytes circulate throughout the body to cause systemic diseases
human brain infection is rare, but E. chaffeensis has been observed in human cerebrospinal fluid mononuclear cells
which cells do Anaplasma phagocytophilum infect?
granulocytes = neutrophils, basophils, eosinophils
which cells do Ehrlichia chaffeensis infect?
monocytes
what is a marker for cell death?
elevated aminotransferase levels
what disease does ehrlichia chaffeensis cause?
human monocytic ehrlichiosis (HME)
what disease does anaplasma phagocytophilum cause?
- human granulocytic anaplasmosis (HGA)
2. tick borne fever
what are the symptoms of HGA?
HGA = human granulocytic anaplasmosis which is caused by anaplasma phagocytophilum
- fever, chills, malaise
- thombocytopenia
- elevated aminotransferase
- rash, circular skin lesion
- intracytoplasmic inclusions in neutrophils
where in the US are anaplasma phagocytophilum infections most common?
they cause human granulocytic anaplasmosis
areas where HGA may occur is based on distribution of vector tick species = ixodes scapularis
this distribution is consistent with the fact that the vector of HGA also transmits Borrelia burgdorferi = often see co-infection
most of the recognized HGA cases have originated from states that also have a high incidence of Lyme disease = Connecticut, Massachusetts, New York, Minnesota, and Wisconsin
in the western United States, the HGA agent is transmitted by the western blacklegged tick = ixodes pacificus
which age group is more susceptible to anaplasma phagocytophilum infections?
elderly
what are the symptoms of HME?
HME = human monocytic ehrlichiosis which is caused by ehrlichia chaffeensis bacteria
it’s called chaffeensis because it was first seen at fort chaffee during boot camp
fever, headache, pharyngitis, nausea, vomiting & dehydration 3 days after onset
PE revealed prominent cervical lymphadenopathy, splenomegaly, and no rash
CBC showed significant left shift = lots of immature cells = active infection
how is ehrlichia chaffeensis transmitted?
lone star tick = western US
NOT efficiently transmitted to egg; larvae have to feed on an infected deer
disease distribution directly correlates with the geographic distribution of the Lone Star tick
where are ehrlichia chaffeensis often seen in the US?
Arkansas, Missouri, Oklahoma, North Carolina, South Carolina, and Georgia
what is the reservoir of ehrlichia chaffeensis?
deer
but can also be found in dogs, foxes, coyotes, wolves, raccoons, opossums, goats, and mice
vector = lone star tick
what are the similarities between HME and HGA disease?
HME = caused by ehrlichia chaffeensis; infects monocytes/macrophages
HGA = caused by anaplasma phagocytophilum; infects granulocytes
symptoms appear 1-21 days after infection (tick-bite)
most common symptoms are fever, headache, chills, muscle aches and pains, fatigue, and malaise
rash is infrequent (more common for HME)
common clinical findings are thrombocytopenia (71%), leukopenia (49%), anemia (37%), and elevated hepatic transaminase levels (71%)
what are the effects on the immune system that HME and HGA have?
HME infects monocytes while HGA infects granulocytes so the immune system is adversely affected due to infection and killing of leukocytes
this lessens the ability to fight other infections so you see many complications and getting sick from other diseases
is HME or HGA more deadly?
Hospitalization is required for 50% of symptomatic patients with both diseases
but HME mortality rate is higher
rates higher in elderly
how do E. chaffeensis and A. phagocytophilum infect cells?
they infect different cell types but they both:
bind to surface receptors that promote non-inflammatory uptake
then they’re both internalized into endosome but do not fuse with lysosome
they replicate within endosomal vacuole to form morulae
what virulence factors do E. chaffeensis and A. phagocytophilum have?
both bacteria lack LPS and peptidoglycan
so they do not elicit a strong initial inflammatory response
they also downregulate ROI in monocytes and granulocytes, respectively
plus both can inhibit apoptosis of respective host cell types
describe the biphasic life cycle of E. chaffeensis and A. phagocytophilum
kind of like chlamydia!!
initially, small dense-cored cells bind to host cells, are internalized and develop into large reticulate cells = EB
reticulate cells then mature into dense-cored cells or compact into clumps = RB –> formation of morulae!!
which of the following have two different cell phases during their normal life cycle?
A. orientia tsutsumagushi
B. rickettsia rickettsi
C. neisseria gonorrheae
D. coxiella burnettii
E. bacillus anthracis
D. coxiella burnettii
how do diagnose HME and HGA?
indirect immunofluorescence assay (IFA) is generally considered the reference standard but it takes a while for antibodies to develop….
PCR is the most rapid and specific diagnostic assay for HME and HGA
E. chaffeensis and A. phagocytophilum can only be cultured in host cells
base treatment on epidemiologic and clinical clues = tick exposure, fever, general malaise (sometimes see variable rash, but not diagnostic), thrombocytopenia, decrease in lymphocytes, increased aminotransferase levels, anemia
morulae are only detected in blood smears in 60% of patients but if they’re there they are diagnostic!
how do you treat HME and HGA?
doxycycline!
how do you prevent HME and HGA?
no vaccine
so just avoid tick exposure
FLASHCARD: microbiology, pathology, epidemiology, clinical, diagnosis, and treatment of Ehrlichia chaffeensis & Anaplasma phagocytophilum
MICROBIOLOGY: Gram – coccobacilli, lack LPS & peptidoglycan, will not Gram-stain, obligate growth within either monocytes (E.c.) or neutrophils (A.p.) for growth/persist within morulae. Appear to have 2 forms, with inert small elementary body that infects host cell, then transform into larger reticulate body that multiplies within morulae before transform back to elementary body for release.
PATHOLOGY: After introduced into skin via tick-bite, migrate to bloodstream to infect either macrophages or neutrophils. Eventually cause reduction in these WBC, result in suppressed immunity. Can go on the infect multiple organs.
EPIDEMIOLOGY: E.c. is hosted/transmitted by Amblyomma americanum (Lone star tick) and A.p. by Ixodes ticks, and thus disease is only acquired within their ranges. Disease is more common in Spring-Summer, in males, and in elderly patients.
CLINICAL: E.c. (Human monocytic ehrlichiosis; HME) and A.p. (Human granulocytic ehrlichiosis; HGE) cause similar disease. After incubation of 1-2 weeks, become sick very quick. Most commonly see high fever, severe headache, fever, malaise, thrombocytopenia, and general illness, but often do not associate tick-bite. Rash is rare, but can occur. Commonly can lead to hospitalization. Fatal outcome is low if treat rapidly.
DIAGNOSIS: Difficult to diagnose. Cannot culture on medium. Initial diagnosis is on clinical symptoms and epidemiology. May be able to detect morulae within monocytes or neutrophils in blood smear. Eventually can detect antibodies in blood or PCR on blood cells. Ixodes ticks carry multiple pathogens (e.g. Borrelia, Babesia, Powassan virus), so should consider all options.
TREATMENT: DOC is tetracyclines (doxycycline)
what is the microbiology of babesiosis microti?
trick question
they are eukaryotic parasites, NOT a bacteria
how is babesiosis microti transmitted?
blacklegged tick = ixodesscapularis
same tick vector as B. burgdorferi and A. phagocytophilum
so an individual tick can carry and transmit any combination of these 3 pathogens
where are babesiosis microti infections seen in the US?
geographic distribution and seasonality is same as Lyme disease and Anaplasmosis
most U.S. cases are B. microti and seen in upper Midwest and Northeast U.S.
recent increase in Babesiosis most likely due to the expansion of the white-tailed deer population in endemic regions –> deer do not carry infection, just provide blood meal for ticks
what is the lifecycle of babesia microti?
- tick takes a blood meal from mouse
- diploid turns into gamete form in the mouse and then the tick takes another blood meal and ingests gametes
- fertilization in gut
- ookinete enters salivary gland
- tick bites human and sporozoites are introduced into host
- can be transmitted between humans via blood transfusion
what are the symptoms of babesiosis?
most patients develop non-specific symptoms 1-4 weeks after inoculation
intermittent fever, fatigue, malaise, headache, chills, sweats, myalgia
babesia causes lysis of RBCs so you often see splenomegaly, hemolytic anemia, lymphopenia, thrombocytopenia, elevated serum lactate dehydrogenase, and elevated RBC sedimentation rate
symptoms last for week to months (or longer) if untreated, but usually resolves
however, patients with complicating conditions can have severe or fatal disease
how do you prevent babesia microti infections?
no vaccine
avoid tick exposure
how do you diagnose babesiosis?
definitive initial test is Giemsa or Wright stain of thin blood smears – babesia too small to see on thick smear
PCR can be performed, if available
antibodies can be detected by IFA or immunoblot
if tests are negative & symptoms persist, can inject patient blood into small rodent
when should you consider babesiosis?
Residence/travel in endemic area
Received recent blood transfusion
Should be considered in patient with Lyme disease or HGA diagnosis since all pathogens are carried by the same tick co-infection is common
what do babesia look like on a thin blood smear?
you can see tetrads of replicating merozoites arranged in a cross-like pattern
maltese cross is diagnostic!
how do you treat babesiosis?
two combination options, both are great
- atovaquone + azithromycin
- clindamycin + quinine
7-10 days or 6 weeks if persistent relapsing infection
