Rheumatic Fever

Dr Deepashree R
Assistant Professor of Microbiology
Surveillance officer, HIC
JSS Medical College, Mysore
(Book Author Essentials of Hospital Infection Control & Essentials
of Antimicrobial Stewardship)
Editor – Essentials of Medical Microbiology (Dr Apurba Sastry)
Acute Rheumatic Fever

• Multisystem disease that occurs in people previously infected

with streptococcal (group A) sore throat, as a result of an

autoimmune reaction.

• Almost all of the manifestations resolve completely; except

the cardiac valvular damage - is called as rheumatic heart

disease (RHD). 2
 Pathogenesis

• Mainly a disease of children age 5–14 years.

• Rare in persons aged more than 30 years.

• Recurrent episodes of ARF - more common in adolescents and

young adults.

• More commonly affects females.

• ARF results following upper respiratory tract infection with group

3
 Pathogenesis
• Genetic predisposition may play a role; people with HLA-DR7 and HLA-DR4 appear to be
more susceptible as compared to others.

• Autoimmune theory: Pathogenesis is based on theory of molecular mimicry—

• Antibodies targeted against streptococcal antigens (M protein) cross react with

human tissue antigens (e.g. heart and joint).

• These cross reactive antibodies bind to valvular endothelium, leading to damage of

the heart valves

• Cytotoxic theory: Streptococcal toxins (e.g. streptococcal pyrogenic toxin) and enzymes
(streptolysin O) are directly toxic to human heart.
4
 Clinical Manifestations

• Usually appear after period of ~3 weeks following precipitating

group A streptococcal infection.

• Prior streptococcal infection may be either subclinical (more

common) or presents as sore throat.

• Heart, joints, skin and brain.

5
 Clinical Manifestations

• Common manifestations:
— Migrating polyarthritis-It is the most common manifestation,
characterized by migratory polyarthritis (hot, swollen, red, and/or
tender joints), which moves from one joint to another over a period
of hours. It is asymmetric and affects the large joints—most
commonly the knees, ankles, hips, and elbows
— Pancarditis-affecting endocardium, pericardium, or myocardium.
Valvular damage is the hallmark; leading to mitral regurgitation
(most common) and aortic regurgitation. Myocardial inflammation 6
 Clinical Manifestations

• Common manifestations:

— Subcutaneous nodules-Occur as painless, small, mobile lumps

beneath the skin overlying bony prominences, particularly of the

hands, feet, and elbows

— Chorea (Sydenham’s)-It is an abnormal involuntary movement

disorder, mainly affecting head and limbs

7
— Erythema marginatum: They are pink macular rashes that appear
 Modified Jones Criteria (2015)
Diagnostic Criteria for ARF Low risk
-ARF incidence <2 per 1L
Major criteria school-aged children /year, or
Low-risk population High-risk population -All-age prevalence of RHD of
≤1 per 1,000 population / year
Carditis (clinical or subclinical) Carditis (clinical or subclinical)
Arthritis—only polyarthritis Arthritis —monoarthritis or
polyarthritis
Polyarthralgia
Chorea Chorea

Erythema marginatum Erythema marginatum

Subcutaneous nodules Subcutaneous nodules

8
Modified Jones Criteria (2015)
Diagnostic Criteria for ARF
Major criteria
Low-risk population High-risk population
Polyarthralgia Monoarthralgia
Hyperpyrexia (≥ 38.5ºC) Hyperpyrexia (≥ 38.0ºC)

ESR ≥ 60 mm/h and/or CRP ≥ 3.0 mg/dL ESR ≥ 30 mm/h and/or CRP ≥ 3.0 mg/dL

Prolonged PR interval Prolonged PR interval

Diagnostic criteria
Initial ARF Two major or One major + two minor

Recurrent ARF (with a reliable past Two major or One major + two minor or
history of ARF/RHD) Three minor criteria

9
Treatment

• Penicillin - drug of choice - given orally (as penicillin V or

amoxicillin for 10 days) or intramuscularly as single dose of

1.2 million units of benzathine penicillin G.

• Supportive treatment (e.g. aspirin) - given for arthritis,

arthralgia, and fever.

10
Prevention

Primary Prevention:
• Includes timely and complete treatment of group A
streptococcal sore throat with antibiotics (penicillin) within 9
days of sore throat onset.

Secondary Prevention:The mainstay of controlling ARF and

RHD is secondary prevention. Patients with ARF are at much
higher risk of developing recurrent ARF
11
Prevention

ARF without carditis: For 5 years after the last attack or 21

years of age (whichever is longer)

ARF with carditis but no residual valvular disease: For 10

years after the last attack, or 21 years of age (whichever is
longer)

ARF with persistent valvular disease: For 10 years after the

last attack, or 40 years of age (whichever is longer) or 12
Classification

13
Virulence Factors and Pathogenicity

▰ Virulence factors of S. pyogenes can be categorized into:

➢ Cell wall antigens

➢ toxins

➢ enzymes.

14
Cell Wall Antigens

▰ Lipoteichoic acid: Helps in adhesion to pharyngeal epithelial cells

▰ C-carbohydrate antigens: Group-specific - basis of Lancefield grouping

▰ M protein: Principle virulence factor of group A Streptococcus.

▰ Other cell wall proteins such as:

➢ Fimbriae and F factor (fibronectin binding protein)- help in adhesion
➢ M protein-associated protein (opacity factor)- associated with skin
infections. 15
Cell Wall Antigens (Cont..)

▰ Capsule: Some strains of group A Streptococcus are capsulated, made up

of hyaluronic acid - produce mucoid colonies

➢ Capsule is antiphagocytic, but not antigenic

➢ It helps group A streptococci to colonize the pharynx by binding to

CD44, a hyaluronic acid-binding protein expressed on epithelial cells.

16
M protein

▰ It is the principle virulence factor of group A Streptococcus.

▰ It inhibits complement mediated opsonisation by phagocytes

▰ Antibody to M protein - protective in nature and promotes phagocytosis

17
Toxins - Hemolysins
Streptolysin (SL-O) Streptolysin (SL-S)

Oxygen labile (hence named as Oxygen stable

streptolysin-O) Serum soluble (hence
Heat labile named as streptolysin-S )
Strongly antigenic Not antigenic

Antistreptolysin-O antibodies (ASO) Not useful for

are raised in most of the streptococcal serological diagnosis of
infections and are used as a standard streptococcal infections
marker for retrospective diagnosis of
streptococcal infections (except in
glomerulonephritis and pyoderma
where ASO titer is low)

18
Clinical Manifestations

▰ Group A Streptococcus (GAS) produces both suppurative and non-

suppurative manifestations .

▰ Throat - primary site of invasion by GAS.

▰ Infection occurs through respiratory droplets.

19
Suppurative and non-suppurative manifestations
of Streptococcus pyogenes
Suppurative Non-suppurative
Respiratory infections: Acute rheumatic fever
➢ Pharyngitis/sore throat
➢ Scarlet fever Acute
➢ Others (rare): Pneumonia, empyema, quinsy, glomerulonephritis
sinusitis and otitis media

Skin and soft tissue infections Guttate psoriasis

(Superficial):
➢ Impetigo (pyoderma) Reactive arthritis
➢ Cellulitis and erysipelas

20
Suppurative and non-suppurative manifestations
of Streptococcus pyogenes (Cont..)
Suppurative Non-suppurative
Deep soft tissue infections: PANDAS
➢ Necrotizing fasciitis (Pediatric Autoimmune
➢ Streptococcal myositis Neuropsychiatric
Disorders Associated
Bacteremia leading to endocarditis,
with Streptococcal
osteomyelitis, septic arthritis,
infections)
meningitis, etc.
Toxic shock syndrome

Puerperal sepsis (rare)

21
Antigenic cross reactivity between streptococcal antigens
and the corresponding human antigens

Streptococcal antigen Human antigen

Cell wall M protein (of serotypes Myocardium

M1, M5, M6, and M19) (tropomyosin and myosin)

Cell wall C carbohydrate Cardiac valves

Cytoplasmic membrane Glomerular vascular intima

Peptidoglycan Skin antigens

Hyaluronic acid Synovial fluid

22
Laboratory diagnosis of S. pyogenes infections

▰ Specimen collection and transport: Depends on the site of the infection

▰ Direct smear microscopy: Pus cells with gram-positive cocci in short

chains

▰ Culture:

➢ Blood agar: Pinpoint colony with a wide zone of β-hemolysis

➢ Selective media: Crystal violet blood agar

23
Laboratory diagnosis of S. pyogenes infections
(Cont..)
▰ Culture smear: Gram-positive cocci in short chains

▰ Identification:

➢ Biochemical identification: It is catalase negative, bacitracin sensitive,

CAMP test negative

➢ Automation methods such as MALDI-TOF and VITEK

24
Laboratory diagnosis of S. pyogenes infections
(Cont..)
▰ Typing:

➢ Lancefield grouping: Shows group A Streptococcus

➢ Typing of group A Streptococcus: Griffith and emm typing

▰ Serology: ASO antibodies and anti-DNase B antibodies

▰ Antimicrobial susceptibility testing.

25
Laboratory diagnosis of S. pyogenes infections
(Cont..)

A. In Gram stained smear of pus;

B. In culture smear showing gram-positive cocci in chains
26
Laboratory diagnosis of S. pyogenes infections
(Cont..)

A B C D E

A. Growth on blood agar with wide

zone of beta-hemolysis around the
pin point colonies; B. Bacitracin
sensitive.
27
Treatment of S. pyogenes infections

▰ Penicillin - drug of choice for pharyngeal infections as well as for

suppurative complications.

▰ Resistance to penicillin – not reported yet.

▰ Failure to penicillin occur due to: (i) noncompliance, if discontinued before

10 days of full course of oral penicillin V, (ii) β-lactamases produced by
normal throat flora such as Moraxella
28
Treatment of S. pyogenes infections
(Cont..)
▰ Macrolide - erythromycin is given to patients allergic to penicillin.

▰ Resistance to macrolides - common

▰ Treatment shortens the clinical syndrome - reduces transmission to others,

decreases the risk of suppurative and non-suppurative sequelae such as
ARF.

▰ However, treatment does not reduce the risk of PSGN.

29
 30
Essentials of Medical Microbiology
 31
Essentials of Medical Microbiology
 32
Essentials of Medical Microbiology
 33
Essentials of Medical Microbiology
 34
Essentials of Medical Microbiology
TWO Terminologies

• CRBSI-
• Used clinically (for lab diagnosis and treatment purpose)

• CLABSI-
• Used for surveillance purpose only.

• Treatment should never be based on CLABSI criteria.

crbsi
• Bacteremia/ fungemia in a patient with an intravascular catheter

• Associated clinical manifestations (i.e., fever, chills, and/or hypotension), and

• No apparent source for the BSI except the catheter.

• Local signs of inflammation –absent in 70% of cases of CRBSI.

Sources of infections

Intrinsic contamination Extrinsic contamination

During device or fluid production and At the time of insertion
before use
Result of faulty sterilisation or damage Poor sterile precautions during drug or
during manufacture IV fluid admixture
Klebsiella spp, Enterobacter spp or Skin commensals like CoNS and
Pseudomonas [Link]
 Risk
factors
Patient related Device related
HCW related
• Immunodeficiency
• Duration of CL • Poor hand
• Severe underlying
• Site
illness hygiene
• Catheter composition /
• Loss of skin construction
• Lack of infection
integrity • Microbial adherence control practices
property (e.g. bundle care)
• Type of catheter
• Number of lumens
• Emergency/ elective
Reference: Damani’s Manual of infection prevention and control,
38 3rd
 Interpretation of simultaneous blood cultures
from CL and PV by DTP
Simultaneous blood
cultures from CL and the
peripheral vein

PV –ve PV +ve
PV –ve PV +ve
CL + ve CL -ve
CL -ve CL +ve
(same organism)
? Skin
contaminants
? Colonization DTP
of CL CL < 2hrs of PL
Sterile CL > 2hrs of PL
CRBSI Ruled out
Source of BSI is CRBSI
other than CL