Genital Mycoplasmal Disease in the Newborn John Baier M.D. University of Manitoba.
-
Upload
cortez-britnell -
Category
Documents
-
view
213 -
download
0
Transcript of Genital Mycoplasmal Disease in the Newborn John Baier M.D. University of Manitoba.
Genital Mycoplasmal Genital Mycoplasmal Disease in the NewbornDisease in the Newborn
John Baier M.D.John Baier M.D.
University of ManitobaUniversity of Manitoba
Characteristics of Characteristics of MycoplasmasMycoplasmas
Mycoplasmas are the smallest self replicating Mycoplasmas are the smallest self replicating organismsorganisms
Do not have a cell wall like other bacteriaDo not have a cell wall like other bacteria• Do not Gram stainDo not Gram stain
Small genome and lack enzymes needed to Small genome and lack enzymes needed to synthesize may compoundssynthesize may compounds
• Complex nutritional requirements Complex nutritional requirements
• Require host cells and their productsRequire host cells and their products
• Difficult to culture outside of hostsDifficult to culture outside of hosts
• Will not grow on routine bacteriologic mediaWill not grow on routine bacteriologic media
Mycoplasmas in Human Mycoplasmas in Human DiseaseDisease
Difficulties in culturing have made establishing a Difficulties in culturing have made establishing a pathogenic role of mycoplasmas difficultpathogenic role of mycoplasmas difficult
Diseases caused by mycoplasmasDiseases caused by mycoplasmas• acute acute Mycoplasma pneumoniaeMycoplasma pneumoniae
• often subacute or chronicoften subacute or chronic
• lack well defined clinical presentationslack well defined clinical presentations
Mycoplasmas in Human Mycoplasmas in Human DiseaseDisease
Diseases potentially caused by mycoplasmasDiseases potentially caused by mycoplasmas• Periodontal diseasePeriodontal disease Mycoplasma salivariumMycoplasma salivarium
• ArthritisArthritis Mycoplasma arthitidis, Mycoplasma Mycoplasma arthitidis, Mycoplasma fermentansfermentans
• Urethritis, cervicitisUrethritis, cervicitis Mycoplasma hominis, Mycoplasma hominis, Ureaplasma Ureaplasma urealyticumurealyticum
• PrematurityPrematurity Mycoplasma hominis, Mycoplasma hominis, Ureaplasma Ureaplasma urealyticumurealyticum
• Recurrent pregnancy lossRecurrent pregnancy loss Mycoplasma hominis, Ureaplasma Mycoplasma hominis, Ureaplasma urealyticumurealyticum
• AIDS related diseasesAIDS related diseases Mycoplasma penetrans, Mycoplasma Mycoplasma penetrans, Mycoplasma fermentansfermentans
• Chronic lung diseaseChronic lung disease Mycoplasma hominis, Mycoplasma hominis, Ureaplasma Ureaplasma urealyticumurealyticum
Mycoplasmas Colonizing Mycoplasmas Colonizing the Genital Tractthe Genital Tract
Ureaplasma urealyticum/ Ureaplasma parvumUreaplasma urealyticum/ Ureaplasma parvum• premature laborpremature labor• pneumoniapneumonia• meningitismeningitis• BPDBPD
Mycoplasma hominisMycoplasma hominis• premature laborpremature labor• pneumoniapneumonia• meningitismeningitis• BPD?BPD?
Mycoplasma fermentansMycoplasma fermentans• no known association with perinatal diseaseno known association with perinatal disease
Mycoplasma genitaliumMycoplasma genitalium• Only detectable by PCROnly detectable by PCR• no known association with perinatal diseaseno known association with perinatal disease
Epidemiology of Genital Epidemiology of Genital Tract MycoplasmasTract Mycoplasmas
Commonly foundCommonly found• 40-80% pregnancies colonized with 40-80% pregnancies colonized with Ureaplasma urealyticumUreaplasma urealyticum
• 5-50% pregnancies colonized with 5-50% pregnancies colonized with Mycoplasma hominisMycoplasma hominis
Increased colonization withIncreased colonization with• increased number of sexual partnersincreased number of sexual partners
• earlier age of first intercourseearlier age of first intercourse
• isolation of other STDs (isolation of other STDs (Chlamydia trachomatisChlamydia trachomatis))
Transmission of Transmission of Ureaplasma Ureaplasma urealyticumurealyticum to the Newborn to the Newborn
Vertical transmissionVertical transmission• 18-55% in term infants18-55% in term infants
• 29-55% in preterm infants29-55% in preterm infants
Factors that increase chance of transmission to Factors that increase chance of transmission to fetusfetus
• rupture of membranesrupture of membranes
• chorioamnionitis chorioamnionitis
• vaginal deliveryvaginal delivery
Transmission rate varies with gestational ageTransmission rate varies with gestational age Once acquired colonization of respiratory tract Once acquired colonization of respiratory tract
may persist for months untreatedmay persist for months untreated
Perinatal Transmission of Perinatal Transmission of UreaplasmaUreaplasma to Newborn to Newborn
010
20304050
607080
90100
Per
cent
Tra
nsm
issi
on
<1500 1501-2000
2001-2500
2501-3000
3001-3500
3001-3500
>3500
Birth WeightKlein JO 1969
Consequences of Genital Consequences of Genital Mycoplasma Infections in the Mycoplasma Infections in the
NewbornNewborn
Variable response to infectionVariable response to infection• self limited with no long term effectsself limited with no long term effects
• acute pneumoniaacute pneumonia
• chronic inflammatory response may lead to chronic inflammatory response may lead to development of chronic lung diseasedevelopment of chronic lung disease
Ureaplasma urealyticumUreaplasma urealyticum as a as a cofactor in the development of cofactor in the development of
BPDBPD BPD is a multifactorial diseaseBPD is a multifactorial disease
• Uu is not THE CAUSE of BPDUu is not THE CAUSE of BPD
Conflicting data in the literatureConflicting data in the literature• different culture sites/methodsdifferent culture sites/methods
– single culture vs. multiple culturesingle culture vs. multiple culture
– tracheal aspirate vs. nasal aspiratetracheal aspirate vs. nasal aspirate
– reliability of culturesreliability of cultures
– PCR vs. culturePCR vs. culture
• different populationsdifferent populations
– not a disease of larger infantsnot a disease of larger infants• colonization with Uu is of no significance (generally) in a otherwise colonization with Uu is of no significance (generally) in a otherwise
healthy term infanthealthy term infant
– different frequencies of organisms causing preterm birth different frequencies of organisms causing preterm birth
Ureaplasma urealyticumUreaplasma urealyticum as a cofactor as a cofactor in the development of BPDin the development of BPD
Overall, isolation of Uu Overall, isolation of Uu from airways is from airways is associated with a 2-3 associated with a 2-3 fold increase in the fold increase in the incidence of oxygen incidence of oxygen dependency at 28 days dependency at 28 days of ageof age
Associated with a lesser Associated with a lesser but still significant but still significant increase in the incidence increase in the incidence of oxygen dependency of oxygen dependency at 36 weeks PCAat 36 weeks PCA
01020
30405060
708090
100
Per
cen
t B
PD
Uu present
Uu absent
LSU 1992-94LSU 1992-94
*
*p<0.001
Mechanisms of lung injury Mechanisms of lung injury caused by Mycoplasmascaused by Mycoplasmas Live and heat killed mycoplasmas induce inflammatory Live and heat killed mycoplasmas induce inflammatory
cytokine production in a variety of lung cell typescytokine production in a variety of lung cell types• mononuclear cells (alveolar macrophages)mononuclear cells (alveolar macrophages)
• respiratory epitheliumrespiratory epithelium
• fibroblastsfibroblasts
In most mycoplasmas the cytokine inducing activity is In most mycoplasmas the cytokine inducing activity is been determined to be membrane lipoproteinsbeen determined to be membrane lipoproteins
• slight similarity to LPSslight similarity to LPS
• utilize LPS receptors (toll like receptors)utilize LPS receptors (toll like receptors)
The component that stimulates cytokine production has The component that stimulates cytokine production has not been determined for not been determined for Ureaplasma urealyticumUreaplasma urealyticum
In vitroIn vitro infection with infection with U. urealyticumU. urealyticum preterm monocyte cytokine releasepreterm monocyte cytokine release
Monocytes from preterm cord blood (24 to 32 weeks) were incubated with CRPMI-10% FCS alone, U. urealyticum at 103 CCU (UU3) (low inoculum) or 106 CCU (UU6) (high inoculum), or LPS (100 ng/ml) with or without U. urealyticum for 24 h. (A) TNF- ; (B) IL-6; (C) IL-10; (D) IL-8. Results are expressed as percentages of the LPS positive control value n = 6). *, P < 0.05 versus medium control; , P < 0.05 versus LPS.
Pulmonary Inflammation and isolation of Pulmonary Inflammation and isolation of Ureaplasma urealyticumUreaplasma urealyticum
0
500
1000
1500
2000
2500
3000
MC
P-1
pg
/ug
Sec
1 3 5 9 14 21
Age (Days)
No UuUu
Induction of CC chemokines by Induction of CC chemokines by M hominis and U M hominis and U urealyticum:urealyticum:
Cord blood mononuclear cellsCord blood mononuclear cells
0
1000
2000
3000
4000
5000
6000
7000
8000
Cyto
kin
e (
pg/m
l)
Control Uu Control Mh
MIP-1 alphaMIP-1 betaMCP-1MCP-2MCP-3
UuUu increases inflammatory increases inflammatory responses in animal modelsresponses in animal models
Yoder et al 2003Yoder et al 2003• Intra-amniotically infected premature baboonsIntra-amniotically infected premature baboons
• Increased inflammatory cell infiltrate in Increased inflammatory cell infiltrate in UuUu +ve animals compared to +ve animals compared to controls of controls of UuUu – ve animals – ve animals
• Predominately monocytic cellsPredominately monocytic cells
Factors determining “pathogenicity” of Factors determining “pathogenicity” of Genital MycoplasmasGenital Mycoplasmas
Gestational ageGestational age• animal models suggest that immature animals develop more severe diseaseanimal models suggest that immature animals develop more severe disease
• clinically this is a disease of the smallest infantsclinically this is a disease of the smallest infants
– reduced transfer of maternal IgGreduced transfer of maternal IgG
– immature immune responsesimmature immune responses
Surfactant deficiencySurfactant deficiency• infants with mature lungs rarely develop problemsinfants with mature lungs rarely develop problems
• lack of mycoplasmacidal effects of surfactant proteinslack of mycoplasmacidal effects of surfactant proteins
Oxygen administration/Mechanical ventilationOxygen administration/Mechanical ventilation• synergistic effect between oxygen and infectionsynergistic effect between oxygen and infection
Maternal immune responseMaternal immune response• low antibody production in mother increases risk of disease in newbornlow antibody production in mother increases risk of disease in newborn
Genetic Factors?Genetic Factors?• Variations in cytokine or pathogen pattern recognition genesVariations in cytokine or pathogen pattern recognition genes
– IL-1RA (maternal)IL-1RA (maternal)
– TLR2TLR2
Biovar or serotype does not play a roleBiovar or serotype does not play a role• no specific pathogenicity factor knownno specific pathogenicity factor known
Surfactant protein A: Surfactant protein A: mediation of mediation of mycoplasmacidal activity of alveolar mycoplasmacidal activity of alveolar
macrophagesmacrophages
Hickman-Davis et al 1998
Clinical Presentation Clinical Presentation
Transient colonizationTransient colonization Non resolving HMD/Persistent Non resolving HMD/Persistent
colonizationcolonization Rapid development of BPD like changesRapid development of BPD like changes Pneumonia Pneumonia PPHN (rare)PPHN (rare) Apnea Apnea
Transient respiratory Transient respiratory tract colonizationtract colonization
Incidence is not knownIncidence is not known May constitute ~ 25% of culture positive infantsMay constitute ~ 25% of culture positive infants Present with mild-moderate respiratory distressPresent with mild-moderate respiratory distress
• HMD or TTNHMD or TTN
• Positive culture for Uu/Mh incidentalPositive culture for Uu/Mh incidental
Rapid resolution without sequelaeRapid resolution without sequelae Culture results return after patient is extubated Culture results return after patient is extubated
and relatively welland relatively well Require no treatmentRequire no treatment
Non resolving HMD/Persistent Non resolving HMD/Persistent colonizationcolonization
Represents largest proportion of infantsRepresents largest proportion of infants Initial presentation of typical HMDInitial presentation of typical HMD Incomplete resolutionIncomplete resolution May have multiple cultures positiveMay have multiple cultures positive
• initial may be negativeinitial may be negative
Infants with persistent Infants with persistent UuUu are are more likely to develop BPDmore likely to develop BPD
Ou
tco
me
(p
erc
en
t)
0
20
40
60
80
100
Follow up Uu culturenegative or indeterminate
Follow up Uu culturepositive
O2 at 28 daysO2 at 36 weeks
Baier RJ et al 2003
Rapid development of Rapid development of BPD like changesBPD like changes
Initial presentation of typical HMDInitial presentation of typical HMD• does not have to be severedoes not have to be severe
Poor resolutionPoor resolution Development of cystic appearance by first weeks Development of cystic appearance by first weeks
of lifeof life• can be confused with PIEcan be confused with PIE
• likely represents pneumonialikely represents pneumonia
Worse prognosis?Worse prognosis?
Ureaplasmal pneumoniaUreaplasmal pneumonia
May present at birthMay present at birth• indistinguishable from HMDindistinguishable from HMD
• pneumonic appearancepneumonic appearance
May present several weeks after birthMay present several weeks after birth• apneaapnea
• respiratory distressrespiratory distress
• may progress to chronic lung diseasemay progress to chronic lung disease
No other agent is culturedNo other agent is cultured
Adverse CNS Outcomes in infants with Adverse CNS Outcomes in infants with Ureaplasma urealyticumUreaplasma urealyticum
0
10
20
30
40
50
60
70
Inci
den
ce (
%)
All IVH Severe IVH Hydrocephalus Shunt
Uu Positive
Uu Negative
*
*
*
*p<0.02
Interaction between isolation of Interaction between isolation of UuUu and IL-1and IL-1 –511T polymorphism –511T polymorphism
0
5
10
15
20
25
30
35
40
45
Inc
ide
nc
e (
%)
IVH PVL IVH or PVL
Uu negative and 511T negative Uu negative and 511T positiveUu Positive and 511T neagtive Uu Positive and 511T positive
Diagnosis and Diagnosis and Management of Management of
Mycoplasmal InfectionsMycoplasmal Infections
Diagnosis of Genital Diagnosis of Genital Mycoplasma infectionsMycoplasma infections
Who to culture?Who to culture?• RoutineRoutine
– Infants with birth weight less than 1500 gramsInfants with birth weight less than 1500 grams
– mechanical ventilationmechanical ventilation
– preterm labor ± ROM, chorioamnionitispreterm labor ± ROM, chorioamnionitis
• Suspect genital mycoplasmasSuspect genital mycoplasmas
– early BPD like changesearly BPD like changes
– non resolution of HMDnon resolution of HMD
– culture negative pneumoniaculture negative pneumonia
Diagnosis of Genital Diagnosis of Genital Mycoplasma infectionsMycoplasma infections
What to culture?What to culture?• Tracheal aspirateTracheal aspirate
• Blood ?Blood ?
• Little predictive value of positive cultures from nose, throat, Little predictive value of positive cultures from nose, throat, rectum, gastric aspiraterectum, gastric aspirate
Value of repeated cultures?Value of repeated cultures?• Persistent positive cultures correlate better with development Persistent positive cultures correlate better with development
of BPDof BPD
• frequently initial culture at birth may be negativefrequently initial culture at birth may be negative
• 3x during first week if intubated3x during first week if intubated
Diagnosis of Genital Diagnosis of Genital MycoplasmasMycoplasmas
Culture methodsCulture methods• Mycoplasmas are not hardy Mycoplasmas are not hardy
organisms organisms – fresh specimensfresh specimens
• specialized transport mediaspecialized transport media– frozenfrozen– bloodblood– CSFCSF
• frequently there are natural frequently there are natural inhibitors to growthinhibitors to growth
– serial dilutionsserial dilutions– multiple mediamultiple media
• cultures are difficult to interpretcultures are difficult to interpret– require microscopic require microscopic
examination of colony examination of colony formationformation
– color change in media may be color change in media may be from other organismsfrom other organisms
Polymerase Chain Reaction (PCR)Polymerase Chain Reaction (PCR) UreaplasmaUreaplasma
• Urease geneUrease gene
• Multiple banded antigenMultiple banded antigen
– distinguishes between distinguishes between U. urelyticum and U. parvumU. urelyticum and U. parvum
Mycoplasma hominisMycoplasma hominis• 16S rRNA gene16S rRNA gene
Diagnosis of Genital Diagnosis of Genital MycoplasmasMycoplasmas
PCR for Ureaplasma based on Urease gene
PCR vs CulturePCR vs Culture
PCRPCR• rapid results <24 hoursrapid results <24 hours
• biovar informationbiovar information
• very sensitivevery sensitive
– relevance of detecting ~ 10 organismsrelevance of detecting ~ 10 organisms
CultureCulture• may take longer than a week for positive IDmay take longer than a week for positive ID
• no biovar informationno biovar information
• false negatives may be common depending on lab false negatives may be common depending on lab experience and specimen handlingexperience and specimen handling
• less sensitiveless sensitive
– detects larger numbers of viable organismsdetects larger numbers of viable organisms
Treatment StrategiesTreatment Strategies
Should you treatShould you treat
Whom to treat?Whom to treat?
What to treat with?What to treat with?
Treatment of Genital Treatment of Genital MycoplasmasMycoplasmas
Treatment of genital mycoplasmas is Treatment of genital mycoplasmas is controversialcontroversial
No studies have been done to show that it alters No studies have been done to show that it alters outcomeoutcome
• diagnosis and treatment is often delayeddiagnosis and treatment is often delayed
– not considerednot considered
– cultures take 5-7 dayscultures take 5-7 days
• distinguishing between colonization and infectiondistinguishing between colonization and infection
• strains ofstrains of Ureaplasma Ureaplasma may be resistant to antimicrobialsmay be resistant to antimicrobials
Treatment of Genital Treatment of Genital Mycoplasmas: StrategiesMycoplasmas: Strategies Empiric treatment of at risk infantsEmpiric treatment of at risk infants
• no studiesno studies
• possible benefit of early treatmentpossible benefit of early treatment
• treatment of infants who won’t develop disease with broad treatment of infants who won’t develop disease with broad spectrum antibioticsspectrum antibiotics
– increased risk to develop yeast infections?increased risk to develop yeast infections?
Treatment of culture positive or persistently Treatment of culture positive or persistently positive infantspositive infants
• delay of treatment after much of the damage may be donedelay of treatment after much of the damage may be done
• the few studies done show little or no benefitthe few studies done show little or no benefit
Treatment of Genital Treatment of Genital MycoplasmasMycoplasmas
Ureaplasma urealyticumUreaplasma urealyticum• sensitive to macrolide sensitive to macrolide
antibioticsantibiotics• erythromycin 30-40 mg/kg/dayerythromycin 30-40 mg/kg/day
– 10-14 days (no studies)10-14 days (no studies)– Failure to clear organismFailure to clear organism
• azithromycinazithromycin– no datano data– 10mg/kg day 1 then 10mg/kg day 1 then
5/mg/kg/day x 6days?5/mg/kg/day x 6days?• insensitive to clindamycininsensitive to clindamycin• sensitive to chloramphenicol sensitive to chloramphenicol
and tetracyclinesand tetracyclines– resistant cases or resistant cases or
meningitis?meningitis?
Time after start of treatment(days)
Day 0 Day 5 Day 10 Day 15P
ositi
ve T
A c
ultu
re (%
)
0
20
40
60
80
100
Baier RJ et al 2003
Treatment of Genital Treatment of Genital MycoplasmasMycoplasmas
Mycoplasma hominisMycoplasma hominis• insensitive to macrolidesinsensitive to macrolides
• may be sensitive to gentamicin (not reliable)may be sensitive to gentamicin (not reliable)
• sensitive to clindamycinsensitive to clindamycin
• sensitive to chloramphenicol and tetracyclinessensitive to chloramphenicol and tetracyclines
– resistant cases or meningitis?resistant cases or meningitis?
SummarySummary Genital mycoplasmas frequently colonize and Genital mycoplasmas frequently colonize and
infect the respiratory tract of preterm infantsinfect the respiratory tract of preterm infants Infants may develop self limited disease from Infants may develop self limited disease from
infection or may have chronic inflammation that infection or may have chronic inflammation that may predispose to the development of BPDmay predispose to the development of BPD
Identification and treatment of infants with these Identification and treatment of infants with these organisms is frequently delayed or missed organisms is frequently delayed or missed because of specialized culture requirementsbecause of specialized culture requirements
The benefits of treating these infants have not The benefits of treating these infants have not been determined although treatment of infants been determined although treatment of infants with pneumonia or chronic inflammation may be with pneumonia or chronic inflammation may be warrantedwarranted