Microbial causes of

hematologic infection
TITLE:
HAEMATOLOGY MODULE

MODULE CODE: ---

NOMINAL DURATION: 4 WEEKS
• In your curriculum, the issue is mentioned as :

• Ricketisia, Brucellosis, Borrelia &

• causes of septicaemia and bacteremia (2hrs)
Genus Brucellae

 Causes infection in cattle (zoonosis)

 Acquired through aerosol, percutaneous and oral routes of exposure
 Brucellosis
 Primarily seen with animal handlers and those who handle animal
products
 ingested in raw milk, fresh cheese, cream or other milk products
 can be transmitted through unbroken skin
 easy to disseminate and cause moderate morbidity, but low mortality

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 Gram negative, short rods, coccobacilli
 Non-motile, non-spore forming, non-capsulated
 Aerobic, require complex media (amino acid, thiamine, nicotinamide)
 Growth enhanced (serum/blood)
 Many require CO2 for growth ,Catalase +ve, oxidase +ve
 characteristically located intracellular
 Cause disease primarily in animals
 Bacteremia and septicaemia in humans

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 Brucella species and their preferred host

 B. abortus- cattle, horse, buffalo

 B. melitensis- goat, sheep, camel
 B.suis- swine, hare, rodents
 B. canis- dogs
 B.ovis- sheep
 B.neotomae- rodents
 B. abortus, B. melitensis, and B.suis causes human brucellosis

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 Antigenic Structure

 There are at least two antigenic determinants-A (abortus) and M

(melitensis)-present on the lipopolysaccharide (LPS) protein
complex
 They are present in different amounts in the three major species. B.
abortus contains about 20 times A as M, Br. melitensis about 20
times M as A. B. suis has an intermediate antigenic pattern.

 Antigenic cross reactions exist between Bruceliae and V.

cholerae, with E. coli O: 116; O: 157, Salmonella, Y.
enterocolitica, and F. tularensis

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Pathogenesis and clinical manifestation
 The modes of infection are by ingestion, contact, inhalation or
accidental inoculation. Occurred ingested in raw milk, fresh cheese,
cream or other milk products

 Person to person spread does not ordinarily occur, but very rarely
transmission has been reported through the placenta, breastfeeding
and sex.

 Intracellular organisms infecting reticuloendothelial cells the spleen,

liver, kidneys and bone

 The disease in humans, brucellosis (undulant fever, Malta fever)

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 Chxd by an acute bacteremic phase followed by a chronic stage
that may extend over many years and may involve many tissues

 Chxd by fever which may be continuous, intermittent,

undulating or irregular

 Acute infection may resemble severe influenza with headache,

sweating (especially at night, urogenital symptoms may occur

 Often the patient is anemic and leukopenic with a relative

lymphocytosis
 Untreated infections can become chronic with musculoskeletal
symptoms (back pain, arthritis, arthralgia)
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Microbiologic diagnosis of brucella infections can be made by
Microscopy is insensitive
Culture (blood, bone marrow, infected tissue if localized
infection) is sensitive and specific if prolonged incubation is used
(minimum of 3 days to 2 weeks)
Isolation is extremely rare in chronic brucellosis.
Serology (such as the Rose Bengal Test (RBT) can be used to
confirm the clinical diagnosis;
 Four fold increase in titer or single titer ≥1:160; high titers can
persist for months to years;
 cross-reactive with other bacteria
nucleic acid amplification assays.
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 Brucella
Treatment, Prevention, and Control
Recommended treatment is
 doxycycline combined with rifampin for a minimum of 6
weeks for nonpregnant adults;
 trimethoprim-sulfamethoxazole for pregnant women and for
children younger than 8 years
Human disease is controlled by
 eradication of the disease in the animal reservoir through
vaccination and serologic monitoring of the animals for
evidence of disease;
 pasteurization of dairy products; and
 use of proper safety techniques in clinical laboratories
working with this organism
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Sources of Brucella infection
Rickettsiae
 The genus Rickettsiae found on the family Rickettsiacea

 Rickettsia species are small, structurally similar to Gram-negative

bacilli

 Obligate intracellular parasites of eukaryotic cells

 Found in ticks, lice, fleas, mites, and mammals

 Grow readily in yolk sacs of embryonated eggs or cell culture

 Most Rickettsiae survive only for short times outside of the vector
or host

 Quickly destroyed by heat, drying, and bactericidal chemicals

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 Rickettsia species cause

– Epidemic typhus: R. prowazekii

– Murine typhus: R. typhi

– Scrub typhus: R. tsutsugmushi

– Rocky Mountain spotted fever: R. ricketsii

– Other spotted fevers

 Virulence factors of R. prowazekii

 Intracellular growth protects the bacteria from immune clearance

 Replicates in endothelial cells with resulting vasculitis

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Clinical disease:
Epidemic typhus

 Lice acquire R. prowazekii when they ingest a blood meal

from a rickettsemic patient

multiply in the mid gut

epithelial cells of the louse

spill over into the louse defecates

louse feces during its blood meal

patient auto inoculates the

organisms by scratching

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 Initially had non specific symptoms:
 Within 1 to 3 days, high fever, severe headache, chills, myalgias,
arthralgia, and anorexia developed

 Complications of epidemic typhus include myocarditis and

central nervous system dysfunction, if untreated

 Brill-Zinsser disease: Reactivation of epidemic typhus can

occur years after the initial disease
 Milder than epidemic typhus

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• Pathogenesis is associated with spread of the organism
via the blood (bacteremia) to various organs, especially
the heart, joints, and central nervous system.
• No exotoxins, enzymes, or other important virulence
factors have been identified.

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Epidemiology:
 Humans are the primary reservoir, with person-to-person
transmission by louse vector
 It is believed that sporadic disease is spread from squirrels to
humans via squirrel fleas
 People at greatest risk are those living in crowded, unsanitary
conditions, poor general health, lacking proper supportive medical
care
 Disease is worldwide, with most infections in Central and South
America and Africa

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Laboratory Diagnosis

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Treatment, prevention, control:

 Doxycycline is the drug of choice

 Controlled through improvements in living conditions and

reduction of the lice population through use of insecticides

 Inactivated vaccine is available for high-risk populations

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 Genus Borrelia
Structure:

 Spirochetes measure 0.2 to 0.5 × 8 to 30 μm

 Can be seen when stained with aniline dyes and are gram negatives

 Can grow in culture, but bacteria are microaerophilic and have complex
nutritional requirements

 Transmitted by infected arthropods

 Many species, few pathogen Borrelia species are:

 B. recurrentis: Epidemic or louse borne relapsing fever

 Other 15 species (B. hermsii and B. turicatae): Endemic relapsing fever, soft ticks
- vector

 Other species (B.burdorferri, B.garinii, B.afzelii): Lyme disease

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 Several species of Borrelia occur as commensals on the buccal and
genital mucosa.
 Although pathogens for mammals and birds, Borrelia are the
causative agents of tick borne and louse borne relapsing fever and
tick borne Lyme disease in humans.

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Virulence factors:
 Antigenic shift: Alter their serotype specific outer envelope
proteins through gene rearrangement.
 Escape immune clearance

 Endotoxin: for the clinical manifestations of the disease

 Immune reactivity against the Lyme disease agents may be

responsible for the clinical disease

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 Two types of relapsing fever:

 Louse born: epidemic relapsing fever

 Usually a single relapse and

 Mortality is high (50%)

 Thick born: endemic relapsing fever

 Pruritic eschar may develop at the site bite and repeated relapses

 Mortality 5%

 Splenomegaly and hepatomegaly are common

 Death result due to cardiac failure, hepatic necrosis or cerebral hemorrhage

 Outcome related to patients’ underlying poor state of health

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Clinical diseases caused:

Relapsing fever:
 After 1 week IP, the disease is heralded by the abrupt onset of
shaking chills, fever, muscle aches and headaches

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Lyme disease:
 It is defined as:

 Erythema migrans (∼5 cm in diameter): flat red border and

central clearings Skin lesion (papule)
 At least one late manifestation (i.e., musculoskeletal,
nervous system, or cardiovascular involvement) and
laboratory confirmation of infection

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Epidemiology:
 Epidemic relapsing fever:
 Transmitted person-to-person; reservoir-humans; vector-human body
louse
 Endemic relapsing fever:
 Transmitted from rodents to humans; reservoirs-rodents, small mammals,
and soft ticks; vector-soft ticks
 Individuals at risk for relapsing fever include
 People exposed to lice (epidemic disease) in crowded or unsanitary
conditions
 People exposed to ticks (endemic disease) in rural areas
 Lyme disease: transmitted by hard ticks from mice to humans; reservoir-
mice, deer, ticks

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 Individuals at risk for Lyme disease include people exposed
to ticks in areas of high endemicity
 Seasonal incidence corresponds to feeding patterns of
vectors
 Lyme disease and endemic relapsing fever has worldwide
distribution
Diagnosis:
 Isolation of Borrelia species on microscopy and for some on
culture
 Demonstration of diagnostic levels of immunoglobulin (Ig)M
or IgG antibodies to the spirochetes
 Significant increase in antibody titer between acute and
convalescent serum samples

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 Borrelia spps in blood films

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Treatment, Prevention, and Control
 For relapsing fever, treatment is with tetracycline or erythromycin

 For early localized or disseminated Lyme disease, treatment is with

amoxicillin, tetracycline, cefuroxime;
 Late manifestations of Lyme disease: treated with intravenous
penicillin or ceftriaxone
 Exposure to the insect vector can be decreased by using
 Insecticides and applying insect repellents to clothing and

 By wearing protective clothing that reduces exposure of skin to insects

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 If the level of spirochetes is high at the time treatment is initiated, a
systemic febrile reaction called Jarisch-Herxheimer
 This is resembling Gram-negative sepsis.
 It occurs in 15% of patients following antibiotic therapy
 It makes difficult to manage relapsing fever
 This is felt to be due to rapid lysis of the organisms with release of
outer membrane LPS.
 It is more common in louse-borne than tick-borne relapsing fever.

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Bacteremia and Endotoxemia
• Bloodstream is sterile in health
• The presence of circulating microorganisms in the blood
is either a part of the natural history of the infectious
disease or a reflection of serious, uncontrolled infection.
• Depending on the class of agent involved, this process is
described as viremia, bacteremia, fungemia, or
parasitemia.
• The terms sepsis and septicemia refer to the major
clinical symptom complexes generally associated with
bacteremia
• The presence of bacteremia defines some of the most serious and life-
threatening situations in medical practice, and it has a marked impact
on the management and outcome of bacterial infections.

• Viremia is usually a very early, even prodromal, event accompanied by

fever, malaise, and other constitutional symptoms, such as muscle
aches.

• Usually the detection of viremia does not play a role in the diagnosis
or management of viral infections.
Suppurative Thrombophlebitis
•is an inflammation of a vein wall frequently associated with
thrombosis and bacteremia. Intravenous catheter often
associated with thrombophlebitis
•There are four basic forms:
•superficial,
•pelvic,
•intracranial venous sinus, and
•portal vein infection (pylephlebitis).
 Diagnosis and Treatment
• The diagnosis is often suspected on clinical grounds.
• Direct cultures of the infected site or blood cultures usually yield the
infecting organism, because bacteremia is often present.
• The choice of antimicrobial agents is based on culture and
susceptibility test results. And removal of possible offending sources,
such as intravenous catheters is recommended
• Many cases are preventable. Unnecessary, long-term intravenous
cannulation should be avoided
Intravenous Catheter Bacteremia
• A variant of intravascular infection develops when a
medical device such as an intravenous catheter or any of
several types of monitoring devices placed in the
bloodstream becomes colonized with microorganisms.
• Skin flora most commonly involved, S. epidermidis,
Corynebacterium jeikeium, or S. aureus.
Bacteremia From Extravascular
Infection
• most cases of clinically significant bacteremia are the
result of overflow from an extravascular infection
• Bacteremia may be high despite mild manifestations
• Bacteremia is overflow from respiratory, urinary,
wound, and other primary sites of infection
SEPSIS AND SEPTIC SHOCK
• Sepsis is defined as a systemic disease caused by
microorganisms or their products in the blood
• or, as life-threatening organ dysfunction caused by dysregulation
of the immune response to infection.
• Septic shock is a subset of sepsis in which particularly
profound circulatory, cellular, and metabolic abnormalities
are associated with a greater risk of mortality.
SEPSIS AND SEPTIC SHOCK
•Sepsis is the suspicion (or proof) of infection and evidence
of a systemic response to it (eg, tachycardia, tachypnea,
hyperthermia, or hypothermia).
•If the process remains uncontrolled, there is subsequent
progression to septic shock (development of hypotension)
•Sepsis from both bacterial and non-bacterial infection is one
of the most common causes for DIC (Disseminated
intravascular coagulation).
DIC has now been described in a variety of Gram -ve = classical,
Gram +ve, very rarely, viral and rickettsial disease infections.
• Laboratory findings that are hallmark of acute DIC are
thrombocytopenia, prolonged prothrombin time (PT),
activated partial thromboplastin time (aPTT), elevated D-
Dimer or fibrinogen degradation products (FDP) and
reduced plasma fibrinogen level.
• A peripheral blood smear will show presence of
microangiopathy.
• Other findings include prolonged thrombin time and
reduced levels of antithrombin (AT), protein C, protein S,
factor V and Factor VIII.
BLOOD CULTURE
• The primary means for establishing a diagnosis of sepsis
is by blood culture.
• sample of the patient’s blood is obtained by aseptic
venipuncture and cultured in an enriched media.
Growth is detected, and the organisms are isolated,
identified, and tested for antimicrobial susceptibility.
• Parvovirus and Colorado tick virus (Reovir) are known to
infect and destroy the hemopoietic progenitor cells
• Thrombocytopenia can be either from decreased
production or increased destruction of platelets.
• Decreased production has been observed in those who have
Dengue, Parvovirus, Rubella, Mumps, Varicella, Hepatitis C,
Epstein-Barr virus, etc.
• Direct megakaryocytic infection has been demonstrated in
Parvovirus, HIV and Dengue
Prevention of infection in hematology patients consists of
• antimicrobial prophylaxis,
• prevention of exposure to infectious agents, and
• immune prophylaxis (vaccination; Ig: immunoglobulin).