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Genital Mycoplasmal Disease in the Newborn John Baier M.D. University of Manitoba.

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Presentation on theme: "Genital Mycoplasmal Disease in the Newborn John Baier M.D. University of Manitoba."— Presentation transcript:

1 Genital Mycoplasmal Disease in the Newborn John Baier M.D. University of Manitoba

2 Characteristics of Mycoplasmas n Mycoplasmas are the smallest self replicating organisms n Do not have a cell wall like other bacteria Do not Gram stainDo not Gram stain n Small genome and lack enzymes needed to synthesize may compounds Complex nutritional requirementsComplex 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

3 Mycoplasmas in Human Disease n Difficulties in culturing have made establishing a pathogenic role of mycoplasmas difficult n Diseases caused by mycoplasmas acute Mycoplasma pneumoniaeacute Mycoplasma pneumoniae often subacute or chronicoften subacute or chronic lack well defined clinical presentationslack well defined clinical presentations

4 Mycoplasmas in Human Disease n Diseases potentially caused by mycoplasmas Periodontal diseaseMycoplasma salivariumPeriodontal diseaseMycoplasma salivarium ArthritisMycoplasma arthitidis, Mycoplasma fermentansArthritisMycoplasma arthitidis, Mycoplasma fermentans Urethritis, cervicitisMycoplasma hominis, Ureaplasma urealyticumUrethritis, cervicitisMycoplasma hominis, Ureaplasma urealyticum PrematurityMycoplasma hominis, Ureaplasma urealyticumPrematurityMycoplasma hominis, Ureaplasma urealyticum Recurrent pregnancy lossMycoplasma hominis, Ureaplasma urealyticumRecurrent pregnancy lossMycoplasma hominis, Ureaplasma urealyticum AIDS related diseasesMycoplasma penetrans, Mycoplasma fermentansAIDS related diseasesMycoplasma penetrans, Mycoplasma fermentans Chronic lung diseaseMycoplasma hominis, Ureaplasma urealyticumChronic lung diseaseMycoplasma hominis, Ureaplasma urealyticum

5 Mycoplasmas Colonizing the Genital Tract n Ureaplasma urealyticum/ Ureaplasma parvum premature laborpremature labor pneumoniapneumonia meningitismeningitis BPDBPD n Mycoplasma hominis premature laborpremature labor pneumoniapneumonia meningitismeningitis BPD?BPD? n Mycoplasma fermentans no known association with perinatal diseaseno known association with perinatal disease n Mycoplasma genitalium Only detectable by PCROnly detectable by PCR no known association with perinatal diseaseno known association with perinatal disease

6 Epidemiology of Genital Tract Mycoplasmas n Commonly found 40-80% pregnancies colonized with Ureaplasma urealyticum40-80% pregnancies colonized with Ureaplasma urealyticum 5-50% pregnancies colonized with Mycoplasma hominis5-50% pregnancies colonized with Mycoplasma hominis n Increased colonization with increased number of sexual partnersincreased number of sexual partners earlier age of first intercourseearlier age of first intercourse isolation of other STDs (Chlamydia trachomatis)isolation of other STDs (Chlamydia trachomatis)

7 Transmission of Ureaplasma urealyticum to the Newborn n Vertical transmission 18-55% in term infants18-55% in term infants 29-55% in preterm infants29-55% in preterm infants n Factors that increase chance of transmission to fetus rupture of membranesrupture of membranes chorioamnionitischorioamnionitis vaginal deliveryvaginal delivery n Transmission rate varies with gestational age n Once acquired colonization of respiratory tract may persist for months untreated

8 Perinatal Transmission of Ureaplasma to Newborn Klein JO 1969

9 Consequences of Genital Mycoplasma Infections in the Newborn n Variable 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 development of chronic lung diseasechronic inflammatory response may lead to development of chronic lung disease

10 Ureaplasma urealyticum as a cofactor in the development of BPD n BPD is a multifactorial disease Uu is not THE CAUSE of BPDUu is not THE CAUSE of BPD n Conflicting data in the literature different culture sites/methodsdifferent culture sites/methods –single culture vs. multiple culture –tracheal aspirate vs. nasal aspirate –reliability of cultures –PCR vs. culture different populationsdifferent populations –not a disease of larger infants colonization with Uu is of no significance (generally) in a otherwise healthy term infantcolonization with Uu is of no significance (generally) in a otherwise healthy term infant –different frequencies of organisms causing preterm birth

11 Ureaplasma urealyticum as a cofactor in the development of BPD n Overall, isolation of Uu from airways is associated with a 2-3 fold increase in the incidence of oxygen dependency at 28 days of age n Associated with a lesser but still significant increase in the incidence of oxygen dependency at 36 weeks PCA LSU * * p<0.001

12 Mechanisms of lung injury caused by Mycoplasmas n Live and heat killed mycoplasmas induce inflammatory cytokine production in a variety of lung cell types mononuclear cells (alveolar macrophages)mononuclear cells (alveolar macrophages) respiratory epitheliumrespiratory epithelium fibroblastsfibroblasts n In most mycoplasmas the cytokine inducing activity is been determined to be membrane lipoproteins slight similarity to LPSslight similarity to LPS utilize LPS receptors (toll like receptors)utilize LPS receptors (toll like receptors) n The component that stimulates cytokine production has not been determined for Ureaplasma urealyticum

13 In vitro infection with U. urealyticum preterm monocyte cytokine release Monocytes from preterm cord blood (24 to 32 weeks) were incubated with CRPMI-10% FCS alone, U. urealyticum at 10 3 CCU (UU3) (low inoculum) or 10 6 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.

14 Pulmonary Inflammation and isolation of Ureaplasma urealyticum

15 Induction of CC chemokines by M hominis and U urealyticum: Cord blood mononuclear cells

16 Uu increases inflammatory responses in animal models n Yoder et al 2003 Intra-amniotically infected premature baboonsIntra-amniotically infected premature baboons Increased inflammatory cell infiltrate in Uu +ve animals compared to controls of Uu – ve animalsIncreased inflammatory cell infiltrate in Uu +ve animals compared to controls of Uu – ve animals Predominately monocytic cellsPredominately monocytic cells

17 Factors determining “pathogenicity” of Genital Mycoplasmas n Gestational 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 IgG –immature immune responses n Surfactant 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 n Oxygen administration/Mechanical ventilation synergistic effect between oxygen and infectionsynergistic effect between oxygen and infection n Maternal immune response low antibody production in mother increases risk of disease in newbornlow antibody production in mother increases risk of disease in newborn n Genetic Factors? Variations in cytokine or pathogen pattern recognition genesVariations in cytokine or pathogen pattern recognition genes –IL-1RA (maternal) –TLR2 n Biovar or serotype does not play a role no specific pathogenicity factor knownno specific pathogenicity factor known

18 Surfactant protein A: mediation of mycoplasmacidal activity of alveolar macrophages Hickman-Davis et al 1998

19 Clinical Presentation n Transient colonization n Non resolving HMD/Persistent colonization n Rapid development of BPD like changes n Pneumonia n PPHN (rare) n Apnea

20 Transient respiratory tract colonization n Incidence is not known n May constitute ~ 25% of culture positive infants n Present with mild-moderate respiratory distress HMD or TTNHMD or TTN Positive culture for Uu/Mh incidentalPositive culture for Uu/Mh incidental n Rapid resolution without sequelae n Culture results return after patient is extubated and relatively well n Require no treatment

21 Non resolving HMD/Persistent colonization n Represents largest proportion of infants n Initial presentation of typical HMD n Incomplete resolution n May have multiple cultures positive initial may be negativeinitial may be negative

22 Infants with persistent Uu are more likely to develop BPD Baier RJ et al 2003

23 Rapid development of BPD like changes n Initial presentation of typical HMD does not have to be severedoes not have to be severe n Poor resolution n Development of cystic appearance by first weeks of life can be confused with PIEcan be confused with PIE likely represents pneumonialikely represents pneumonia n Worse prognosis?

24 Ureaplasmal pneumonia n May present at birth indistinguishable from HMDindistinguishable from HMD pneumonic appearancepneumonic appearance n May present several weeks after birth apneaapnea respiratory distressrespiratory distress may progress to chronic lung diseasemay progress to chronic lung disease n No other agent is cultured

25 Adverse CNS Outcomes in infants with Ureaplasma urealyticum * * * * p<0.02

26 Interaction between isolation of Uu and IL-1  –511T polymorphism

27 Diagnosis and Management of Mycoplasmal Infections

28 Diagnosis of Genital Mycoplasma infections n Who to culture? RoutineRoutine –Infants with birth weight less than 1500 grams –mechanical ventilation –preterm labor ± ROM, chorioamnionitis Suspect genital mycoplasmasSuspect genital mycoplasmas –early BPD like changes –non resolution of HMD –culture negative pneumonia

29 Diagnosis of Genital Mycoplasma infections n What to culture? Tracheal aspirateTracheal aspirate Blood ?Blood ? Little predictive value of positive cultures from nose, throat, rectum, gastric aspirateLittle predictive value of positive cultures from nose, throat, rectum, gastric aspirate n Value of repeated cultures? Persistent positive cultures correlate better with development of BPDPersistent positive cultures correlate better with development of 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

30 Diagnosis of Genital Mycoplasmas n Culture methods Mycoplasmas are not hardy organismsMycoplasmas are not hardy organisms –fresh specimens specialized transport mediaspecialized transport media –frozen –blood –CSF frequently there are natural inhibitors to growthfrequently there are natural inhibitors to growth –serial dilutions –multiple media cultures are difficult to interpretcultures are difficult to interpret –require microscopic examination of colony formation –color change in media may be from other organisms

31 n Polymerase Chain Reaction (PCR) n Ureaplasma Urease geneUrease gene Multiple banded antigenMultiple banded antigen –distinguishes between U. urelyticum and U. parvum n Mycoplasma hominis 16S rRNA gene16S rRNA gene Diagnosis of Genital Mycoplasmas PCR for Ureaplasma based on Urease gene

32 PCR vs Culture n PCR rapid results <24 hoursrapid results <24 hours biovar informationbiovar information very sensitivevery sensitive –relevance of detecting ~ 10 organisms n Culture 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 experience and specimen handlingfalse negatives may be common depending on lab experience and specimen handling less sensitiveless sensitive –detects larger numbers of viable organisms

33 Treatment Strategies n Should you treat n Whom to treat? n What to treat with?

34 Treatment of Genital Mycoplasmas n Treatment of genital mycoplasmas is controversial n No studies have been done to show that it alters outcome diagnosis and treatment is often delayeddiagnosis and treatment is often delayed –not considered –cultures take 5-7 days distinguishing between colonization and infectiondistinguishing between colonization and infection strains of Ureaplasma may be resistant to antimicrobialsstrains of Ureaplasma may be resistant to antimicrobials

35 Treatment of Genital Mycoplasmas: Strategies n Empiric 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 spectrum antibioticstreatment of infants who won’t develop disease with broad spectrum antibiotics –increased risk to develop yeast infections? n Treatment of culture positive or persistently positive 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

36 Treatment of Genital Mycoplasmas n Ureaplasma urealyticum sensitive to macrolide antibioticssensitive to macrolide antibiotics erythromycin mg/kg/dayerythromycin mg/kg/day –10-14 days (no studies) –Failure to clear organism azithromycinazithromycin –no data –10mg/kg day 1 then 5/mg/kg/day x 6days? insensitive to clindamycininsensitive to clindamycin sensitive to chloramphenicol and tetracyclinessensitive to chloramphenicol and tetracyclines –resistant cases or meningitis? Baier RJ et al 2003

37 Treatment of Genital Mycoplasmas n Mycoplasma 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?

38 Summary n Genital mycoplasmas frequently colonize and infect the respiratory tract of preterm infants n Infants may develop self limited disease from infection or may have chronic inflammation that may predispose to the development of BPD n Identification and treatment of infants with these organisms is frequently delayed or missed because of specialized culture requirements n The benefits of treating these infants have not been determined although treatment of infants with pneumonia or chronic inflammation may be warranted


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