Resurgence of pertussis in adult

8/13/2019 Resurgence of pertussis in adult

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CASE

A 53-year-old male developed symptoms of malaise, fatigue,

and mild cough while on vacation in DELHI with his family.

Six days after the onset of symptoms, the patient returned

home to BIKANER still ill and complaining of a headache,

low grade fever, chest pains, and a cough.

Pt treated in line of the viral fever.

At day 10, the patient had a cough with the production of

purulent sputum.

A sputum specimen was collected and sent to the laboratory

for culture. Thepatientssymptoms persisted despite treatment

with ampicillin-clavulanic acid [Augmentin(R)].


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At day 14 of his illness, developed paroxysmal cough,

occasional vomiting after cough, and subconjunctival

hemorrhage.

At day 15 his illness was complicated by episodes of seizure,

with clonic movements of the arms and legs, brief loss of

consciousness, and confusion. The episodes were triggered by

mild, unremarkable coughing paroxysms.


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The Gram stain of sputum revealed Gram negative

coccobacilli.

The nested PCR from two different site of the nasophyrnx andsputum showed Bordetella pertussis.

This was supported by culture on LR media and serology.


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WHAT THIS CASE

INDICATES.


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RESURGENCE OF BORDETELLA PERTUSSIS IN ADULTS

PRESENTOR-Dr MAHAVEER SINGH

MODERATOR-Dr S.ANURADHA


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PERTUSSIS INCIDENCE IN USA

FROM 1990 TO 2011(AGE WISE) PROPORTION OF ADULT CASES


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PERTUSSIS INCIDENCE AND GENOME

ANALYSIS


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BORDETELLA PERUSSIS

Bordetella is a small (approximately 0.8 m by 0.4 m), rod-

shaped, coccoid, or ovoid gram negative bacterium that is

encapsulated and does not produce spores.

While nine species of Bordetellahave been identified to date,

only three additional members, B. bronchiseptica, B.

parapertussis, and B. holmesii, have been associated with

respiratory infections in humans and other mammals.

B. bronchiseptica produces infection in immunocompromised

and AIDS.


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VIRULENCE FACTOR OF

BORDETELLA PERTUSSIS

THE BVG -AS TWO

COMPONENT SYSTEM

ADHESIONS

1. FILAMENTOUS

HAEMAGGLUTININ

2. FIMBRIAE

3. PERTACTIN

TOXINS

1. ADENYLATE CYCLASE

2. PERTUSSIS TOXIN

3. DERMATONECROTIC

TOXIN

4. TRACHEAL CYTOTOXIN

LIPOPOLYSACCHARIDE

SECRETORY SYSTEMS


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Bvg-AS TWO COMPONENT SYSTEM

Bvg locus encodes proteins that

transmit extracellular signals to

the cellular transcription

machinery, causing changes in

gene expression. With theexception of tracheal cytotoxin,

expression of virulence factors is

coordinately regulated by the

products ofthe bvglocus. BvgS is a 135 kDa periplasmic

sensor histidine kinase.

BvgA, the response regulator, is a

23-kDa cytoplasmic protein .


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FILAMENTOUS HEAMAGGLUTININ-

Filamentous hemagglutinin is a

large (220 kDa) protein that formsfilamentous structures on the cell

surface. FHA binds to galactose

residues on a sulfated glycolipid

called sulfatide which is verycommon on the surface of ciliated

cells(respiratory epithelia).

Mutations in the FHA structural

gene reduce the ability of the

organism to colonize, and

antibodies against FHA provide

protection against infection


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FIMBRIE

B.pertussis fimbriae are

submicroscopic proteinaceousappendages that protrude from the

cell surface. They are comprised of

a major and a minor subunit.

The minor subunit, named FimD

binds to the integrin Vla-5, located

on monocytes. The major subunitbinds to sulfated sugars like heparan

sulfate, chondroitin sulfate and

dextran sulfate which are ubiquitous

in the respiratory tract


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PERTACTIN

Pertactin, a 69 kDa nonfimbrial

outer membrane protein, under

the control of the bvg locus, is

partly responsible for the

adhesion of the bacteria to the

host cells.

The mature protein has two

Arginine-Glycine-Aspartic acid

(RGD) sequences, at 225-227and 665-667. These sequences

mimics sequences on proteins

like fibronectin, vitronectin and

fibrinogen.


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PERTUSSIS TOXIN

PTx is a two component, A+B

bacterial exotoxin. The A subunit

(S1) is an ADP ribosyltransferase. The B component,

composed of five polypeptide

subunits (S2 through S5), binds

to specific carbohydrates on cell

surfaces. The A subunit gains enzymatic

activity and transfers the ADP

ribosyl moiety of NAD to the

membrane-bound regulatory

protein Gi that normally inhibits

the eukaryotic adenylate cyclase

and intracellular Levels of cAMP

increases.


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This has the effect to disruptcellular function, and in the caseof phagocytes, to decrease their

phagocytic activities such as

chemotaxis, engulfment, theoxidative burst, and

bacteridcidal killing

Systemic effects of the toxin

include lymphocytosis andalteration of hormonal activitiesthat are regulated by cAMP,such as increased insulin

production (resulting in

hypoglycemia) and increasedsensitivity to histamine(resulting in increased capillary

permeability, hypotension andshock).


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ADENYLATE CYCLASE

This toxin is a 45 kDa protein that may be cell-associated or

released into the environment. It is active only in the presenceof a eukaryotic regulatory molecule called calmodulin.

This toxin acts locally to reduce phagocytic activity and

probably helps the organism initiate infection.

TRACHEAL CYTOTOXIN

The tracheal cytotoxin is a peptidoglycan fragment, which

appears in the extracellular fluid where the bacteria are

actively growing. The toxin kills ciliated cells and causes their

extrusion from the mucosa. It also stimulates release of

cytokine IL-1, and so causes fever.


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DERMATONECROTIC TOXIN

The lethal toxin is a 102 kDa protein composed of four

subunits, two with a mw of 24kDa and two with mw of 30

kDa.

It causes inflammation and local necrosis adjacent to sites

whereB. pertussisis located.

LIPOPOLYSACCHARIDE

As a Gram-negative bacterium Bordetella pertussis possesses

lipopolysaccharide (endotoxin) in its outer membrane.

It is heterogeneous, with two major forms differing in the

phosphate content of the lipid moiety.

The unfractionated material elicits the usual effects of LPS

(i.e., induction of IL-1, activation of complement, fever,

hypotension, etc.


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PATHOGENESIS OF BORDETELLA PERTUSSIS

CLINICAL FEATURE


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Length Clinical Features

Stage 1: Catarrhal Usually 7-10 days; range

of 4-21

Characterized by:

Coryza

Low-grade fever

Mild, occasional cough (which gradually becomes more severe)

Stage 2: Paroxysmal Usually lasts 1-6 weeks,

but may persist for up to

10 weeks

Characterized by:

Paroxysms of numerous, rapid coughs due to difficulty expelling thick mucus from

the tracheobronchial tree.

Long aspiratory effort accompanied by a high-pitched "whoop" at the end of the

paroxysms

Cyanosis

Vomiting and exhaustion

Paroxysmal attacks:

Occur frequently at night, with an average of 15 attacks per 24 hours.

Increase in frequency during the first 1-2 weeks, remain at the same frequency for

2-3 weeks, and then gradually decrease.

Stage 3: Convalescent Usually 7-10 days; range

of 4-21

Characterized by:

Gradual recovery

Less persistent, paroxysmal coughs that disappear in 2-3 weeks

Paroxysms often recur with subsequent respiratory infections for many months after theonset of pertussis.

CLINICAL FEATURE


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VIDEO OF ADULT WHOOPING COUGH


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Classification of coughing episodes involving

pertussis based on cultures, serology, family

exposure, and clinical symptoms

1. B. pertussisisolated from the nasopharynx.

2. At least one of the following criteria fulfilled:

Significant increase in PT IgG.

Significant increase in FHA IgG without other criteria forparapertussis.

Both PT IgG and FHA IgG 6,000 in the same convalescentserum.

Family member with pertussis verified by culture or serology.


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3.Clinical pertussis with at least 3 weeks of paroxysmal cough and

known exposure to pertussis outside the family; serum samples

lacking or suboptimal timing in relation to onset of symptoms.

4.Known exposure to pertussis within or outside the household;

clinical symptoms not evaluable because of early erythromycin

treatment


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BORDETELLA PERTUSSIS IN ADULTS

Most cases of adult pertussis occur in those who have a history

of past pertussis vaccination or infection. Pertussis has been

found to be the cause in 1320% of adults presenting with

prolonged cough.

Adults and adolescents usually present late in the course of the

infection, often after 4 or more weeks of coughing


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COMPLICATIONS

The most frequent complication observed in children is

pneumonia, which occurs in 6% of cases.

In the first 2 months of life, pneumonia, seizures and

encephalopathy have been reported in 25%, 3% and 1% of

cases, respectively.

After childhood, the risk of complications increases with age.

Pneumonia has been observed in 2% of patients less than 30

years of age, as compared with 5%9% of older patients.


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Other complications observed in adults are syncope,urinary incontinence, back pain, rib fracture and

hernia.

Severe paroxysm, post-tussive cyanosis, whooping,

posttussive vomiting, apnea, pneumonia and seizures

are the most frequent reasons patients are admitted tohospital, regardless of age


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Complications

Children

Hypoxia

Apnea

Pneumonia

Seizures

Adults

Pneumonia

Rib Fracture

Weight LossHernias

Urinary Incontinence


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DIAGNOSIS OF BORDETELLA PERTUSSIS

CULTURE

Culture is considered to bethe gold standard.

Its sensitivity decreasessteeply if the specimen istaken more than 2 weeks

after onset of cough and isreduced by prior immunityfrom disease orimmunisation.

Results can be available in72 h, especially in high titreinfection, but 2 weeks arerequired before culture maybe definitively reported asnegative.


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DNA PCR

Polymerase chain reaction (PCR)methods enhance the probability ofidentification ofB.pertussis.

Conventional-semi nested (CsnPCR) andreal-time PCR (RtPCR) are two PCRtools employed for the detection of B.

pertussis with the former detecting

amplified target gene products visualizedby ultra violet (UV) light followingagarose gel electrophoresis and the lattermonitoring the fluorescence emittedthroughout PCR reaction phases

indicating gene amplification


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Novel real-time PCR assays targeting the Bordetella pertussis

insertion sequence IS481, the toxin promoter region and

Bordetella parapertussis insertion sequence IS1001 were

designed.

PCR assays were capable of detecting 10 copies of target

DNA per reaction, with an amplification efficiency of 90%.

Since positive results may be obtained even when theorganism is no longer culturable.

However, the sensitivity of PCR decreases with the duration of

symptoms, since the method is based on the detection of themicroorganism.


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SEROLOGY

Infection of bordetella pertusis is followed by increase in the

concentrations in serum of IgA, IgG, and IgM antibodies to

specific antigens as well as to preparations of the whole

organism.

The antibodies measured to detect infection are directed

against FIM2/3, PRN, and LPS

In contrast to natural infection, the primary immunization of

children induces mainly IgM and IgG antibodies


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Serologic diagnosis of pertussis may be suspected by thedemonstration of an increase in agglutinin titer or the use of

ELISA, showing an increase in IgA or IgG antibody titer to

PT, FHA, PRN, FIM, or to sonicated whole organisms in two

serum samples collected 2 to 4 weeks apart.

It is now clear that antibody responses to FHA and PRN alsooccur following other Bordetella infections, so that isolated

increases in titers of antibody against these antigens are not

specific forB. pertussisinfection..


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In addition, high titers of antibody to FHA may be the result of

cross-reacting epitopes of nonencapsulated H.influenzae,

M.pneumoniae, C.pneumoniae, and perhaps other bacteria

The greatest sensitivity and specificity for the serological

diagnosis of B. pertussis infection is achieved by ELISA and

measurement of IgG and IgA antibodies to PT.

A significant rise in titer (greater than or equal to twofold)

between acute-phase and convalescent-phase sera needs to be

demonstrated. In adolescents and adults, single high values ofIgG or IgA antibodies to PT also indicate infection.


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SINGLE SERUM SPECIMEN

Single-sample serology tests for antipertussis toxin IgG mustbe collected at least two weeks after symptom onset. A highantibody titer more than two years following vaccination

supports the diagnosis of pertussis.

A solitary antibody concentration of IgG anti-PT greater than

100-125 EU/mL suggests recent B. pertussis infection orexposure. A study in the Netherlands showed that a titer of 100EU/mL against this antigen has a sensitivity of 76 percent andspecificity of 99 percent for the diagnosis of acute pertussis.


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SEROLOGICAL CRIETARIA

Significant increase in ELISA diagnostics

1. Controll serum interassay variation Acute to convalascent phaseincrease in AB

50%

100%

1. MINIMUM LEVEL FOR CONVALESCENT SERUM

A. 4 TIMES MLD FOR ANTIBODIES TO PT

B. 32 TIMES MLD FOR ANTIBODIES TO FHA


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MANAGEMENT OF BORDETELLA

PERTUSSIS


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SPECIAL GROUPS

Postexposure prophylaxis

The decision to administer postexposure chemoprophylaxis is

made after considering the infectiousness of the patient and theintensity of the exposure, the potential consequences of severe

pertussis in the contact, and possibilities for secondary

exposure of persons at high risk from the contact (e.g., infants

aged


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Coughing (symptomatic) household members of a pertussis

patient should be treated as if they have pertussis.

Postexposure prophylaxis should be administered in exposure

settings that include infants aged


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CLOSE CONTACT PROPHYLAXIS

A close contact of a patient with pertussis is a person who had

face-to-face exposure within 3 feet of a symptomatic patient.

Close contacts also can include persons who Have direct contact with respiratory, oral, or nasal

secretions from a symptomatic patient.

Shared the same confined space in close proximity with a

symptomatic patient for >1 hour.


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PERTUSSIS VACCINE

The pertussis vaccine is available as:

DTaP (Diphtheria Toxoid-Tetanus Toxoid-acellular

Pertussis vaccine)

DTaP in combination with Haemophilus influenzae type b

(Hib) vaccine

DTaP in combination with hepatitis B and inactivated

polio vaccines

DTaP in combination with Hib, hepatitis B and inactivated

polio vaccines

Tdap (Tetanus Toxoid reduced-Diphtheria-acellular

Pertussis vaccine)


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VACCINE RECOMMENDATIONWho should receive the vaccine?

Most infants and children younger than seven years of age

should receive DTaP beginning at two months of age.

Children 7-10 years of age who are incompletely immunizedagainst pertussis should receive Tdap.

11-18 year olds should receive a single dose of Tdap instead of

a Td booster if they have completed the recommendedchildhood DTP/DTaP immunization series and have not

received Tdap. The preferred age for Tdap vaccination is 11-12

years.


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Adults 19-64 years of age should also receive a single dose of

Tdap to replace a single dose of Td for booster immunization

if their most recent tetanus toxoid-containing vaccine was 10

or more years earlier.

For adults(>65) who have not received Tdap vaccine and are

likely to come in contact with infants suffering from pertussis,

a single dose of Tdap vaccine (2 weeks before the contact with

the infant) is indicated if 2 years or more have elapsed sincethe last dose of Td vaccination.

d b i i l h h i h


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Tdap may be given at an interval shorter than 10 years since the

last tetanus toxoid-containing vaccine in order to protect against

pertussis in special conditions

Women


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Who should not receive the vaccine?

Those with a history of a serious allergic reaction (such as

anaphylaxis) to any of the vaccine components.

Those with a history of encephalopathy (e.g. coma or

prolonged seizures) not attributable to an identifiable cause

within 7 days of administration of a vaccine withpertussis components.

People with the following conditions should discuss with their

health care professional whether they should receive

DTaP vaccine.


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Moderate or serious reaction after receiving DTP or DTaP in

the past.

Seizure or have a parent or sibling who has had a seizure.

Brain problem that is unstable or getting worse.

People who are moderately or severely ill should consult withtheir physician before receiving any vaccine.

VACCINATION SCHEDULE


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VACCINATION SCHEDULE

A DTaP vaccine is given to most children at two, four, and six

months of age. A fourth dose of DTaP is given between 15 and18 months, and a fifth dose is given at age four to six years.

Children younger than age seven who should not receive the

pertussis vaccine should receive the DT (diphtheria-tetanus) vaccine.

Between the ages of seven and nine, Tdapwhich contains

the same amount of tetanus vaccine as DTaP or DT, butcontains much less diphtheria toxoid is given to protect

against tetanus, diphtheria and pertussis.


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At age 11-12 years, a booster shot of tetanus-diphtheria-

acellular pertussis (Tdap) is needed. It should be given no later

than 16 years of age. Every 10 years and thereafter, a booster

of Td is needed to maintain protection against diphtheria

and tetanus.

One booster dose of Tdap is recommended for adults to

replace a Td booster. Every 10 years thereafter, a booster of Tdis needed to maintain protection against diphtheria and tetanus


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.


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ADVERSE REACTIONS

Mild Problems (Common) Fever, redness or swelling, soreness or tenderness fussiness,

tiredness or poor appetite, vomiting.

Moderate Problems (Uncommon) Seizure.

Non-stop crying, high fever.

Severe Problems (Very Rare) Serious allergic reaction. Long-term seizures, coma, or lowered consciousness.

Permanent brain damage.


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RECOMMENDED WHO CASE


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RECOMMENDED WHO CASE

DEFINATIONS OF PERTUSSIS

Clinical case definition

A case diagnosed as pertussis by a physician orA person with a cough lasting at least two weeks with at least

one of the following symptoms:

Paroxysms (i.e. fits) of coughing

Inspiratory whooping

Post-tussive vomiting (i.e. vomiting immediately aftercoughing) without other apparent cause


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Criteria for laboratory confirmation-

Isolation ofBordetella pertussisor

Detection of genomic sequences by means of the polymerase

chain reaction (PCR) or

Positive paired serology.


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Suspect Case-

A clinical syndrome or illness consistent or compatible withpertussis and without other apparent cause such as:

Any acute cough illness with paroxysmal cough or inspiratory

whoop. Any acute cough illness in a person who is a close contact to a

patient with a confirmed or probable case.

Any cough associated with apnea in an infant.

Any acute cough illness lasting 7 days when there is areported outbreak of pertussis in the community.

Any acute cough illness with positive PCR results for B.pertussis that does not meet the clinical case definition.

Clinical case definition of pertussis for


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Clinical case definition of pertussis for

surveillance purposes

RESURGENCE OF BORDETELLA


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RESURGENCE OF BORDETELLA

PERTUSSIS IN ADULTS


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CAUSES FOR RESURGENCE

VACCINES OFBORDETELLA PERTUSSIS?A CAUSE OFRESURGENCE .

VNTR CHANGES AND MODIFICATION OF BACTERIAL

GENOME.

TRANSITION IN VACCINE.

ADAPTATION AND WANING IMMUNITY.

INCREASED DIAGNOSTIC EFFICACY.

VACCINES OF BORDETELLA PERTUSSIS


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VACCINES OF BORDETELLA PERTUSSIS

?A CAUSE OF RESURGENCE

Is polymorphism in pertactin and pertussis toxin driven by

host immunity, or is it the result of random fixation due to

genetic drift?

It is conceivable that the increase in fitness associated with

nonvaccine types of pertactin and pertussis toxin in vaccinated

populations is substantial enough to drive expansion of strains

carrying these protein variants.


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VNTR CHANGES AND MODIFICATION


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VNTR CHANGES AND MODIFICATION

OF BACTERIAL GENOME

The combined MAST-MLVA profiles were used to perform

clustering analyses of the DutchB. pertussisstrains isolated

before the introduction of the pertussis vaccine in 1953 and

isolates obtained before and after the pertussis epidemics in the

1990s, a period in which neither vaccine formulation norvaccine coverage have changed.

The analysis showed that the profiles from strains predating

the vaccination era were more diverse than those isolated inthe 1990s and only distantly related to the recent strains


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There was a strong decrease in diversity in the genotypes of

theB. pertussisstrains during and after the epidemics in the1990s, suggesting that these epidemics were caused by a

limited number of strains (clonal expansion).

MLVA markers may not reveal causal relationships but can be

helpful to signal clonal expansions and thus visualize the

spread of a subgroup of theB. pertussispopulation with

increased fitness, e.g., becauseB. pertussisis able to escape

host immunity.


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Previous studies showed that antibodies against Prn1, present

in the current vaccine, are less efficient in protecting against

pertussis in animals challenged with the other Prn variants.

Variation of theprngene is caused by variation in the number

and composition of the repeats in this virulence gene. Hence,this is an example of a VNTR within a virulence gene in which

variation results in antigenic change and possible vaccine

escape.

In biology, minimum spanning trees can easily be applied to

multistate data such as MLVA, MAST, or MLST profiles.


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MINIMUM SPANNING TREE


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ADAPTATION AND WANING IMMUNITY

The Ptx promoter showed a relatively high degree ofpolymorphism, suggesting that fine tuning of Ptx productionhas adaptive value.

Globally, ptxP1 and ptxP3 were the most prevalent ptxPalleles. The replacement of ptxP1 strains by ptxP3 strains inrecent times is a global phenomenon because it has beenobserved in 11 countries representing 4 continents; Asia,Europe, and North and South America.

When compared with ptxP1 strains, ptxP3 strains produced1.62 times more Ptx.


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INCREASED DIAGNOSIS AND


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INCREASED DIAGNOSIS AND

REPORTING

A recent study in Toronto, Canada, reports that a marked

increase in pertussis incidence in 2006 was associated with a

markedly increased volume of tests performed, primarily PCR-

based assays. Increased press reports and scientific literature

on the resurgenceofpertussis,as well as reports of pertussisvaccine trials and subsequent licensure of low dose acellular

pertussis vaccines for use in adults, may have also led to an

increase in clinician awareness and reporting.

TAKE HOME MESSAGE


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TAKE HOME MESSAGE

Pertussis is a respiratory infection which causes whoopingcough

Pertussis has its resurgence so it should be considered in caseof chronic cough of >2 week duration.

Typical symptoms are initially cold-like followed by a stage ofrapid coughing and finally a recovery stage of coughing whichcan last for weeks or months.

Diagnostics include a nasopharyngeal swab culture, DNAPCR, and ELISA test for antibodies.

Macrolides are the primary antibiotic used against an pertussisinfection.

Vaccination is still the single best way to prevent whoopingcough although not everyone will get an immune response andimmunity wanes with time. This means that people can still getwhooping cough if they have been vaccinated or if they havehad previous infection.


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Resurgence of pertussis in adult

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