Tom Rand’s presentationPerinatal infection continued:

Elusive cause of meningitis in a young infant

Contributed byIngrid Lundgren, MD, MPH

St. Luke’s Children’s Infections and Immune Deficiency Clinic

History

• 7-week-old term Hispanic male presents with fever to 102 F, fussiness

• Eating well, normal urine output, no V/D• Physical exam- essentially normal, except

appeared inconsolable in ED prompting complete septic workup

Birth History

• 39 weeks gestation, 7lbs 1oz• NSVD, no complications • Pregnancy - maternal hypertension, denied

h/o sexually transmitted diseases. • Prenatal labs normal• Mother recalled receiving antibiotics during

the delivery, but was afebrile and prenatal GBS negative

Past Medical History

• No prior hospitalizations• No surgeries• No past antibiotic prescription• No medications• No allergies• With birth dose hep B, immunizations up to

date• Diet: breast fed with Similac supplementation

Social/Family History

• Social History:– Lives with mother, father, 2-year-old sister in Marsing,

Idaho.– No known sick contacts. No travel or pets. – Parents originated in Mexico. Spanish speaking.

• Family History: – No relatives with severe infection, immune

deficiency, or infant death. – Healthy 2 year old sister. Mother and father 32 years

old and healthy.

Lab Evaluation

19.8

11.5

440

133 10

5.4 17 0.27

Differential: 33% Seg, 1% Band, 62% Lymph

116

CSF: WBC 1428 (85% neut, 6% lymph, 9% mono), RBC 37, protein 137, glucose 52.Gram stain: many WBC, no organisms seen.

Rapid Influenza/RSV negative

Chest x-ray: Bilateral perihilar mild infiltrate. No focal consolidation

Hospital course• Given IV vancomycin, cefotaxime, and dexamethasone for meningitis• Clinicians’ subjective impression bacterial meningitis and intention to treat for

full course• Admitted to Children’s Hospital, defervesced quickly• Gradual improvement in irritability• Thought to be baseline fussy infant

• Final Lab Results: – CSF culture: no growth – Bagged urine culture: mixed flora 80,000 colonies/ml with predominant

Staphylococcus aureus. – Blood culture: no growth– Urine pneumococcal and GBS antigens: negative.– CSF HSV PCR: negative.

• Completed 10 day course of IV cefotaxime

2 days after discharge…

• Fussiness and fever to 102 F returned• Normal neurologic signs except irritability• CSF: WBC 3480 (84% neut, 4% lymph, 12%

mono) RBC 13, glucose 37, protein 267• CSF Gram stain: many WBC, no organisms.• Initially treated IV ampicillin, gentamicin,

cefotaxime, and acyclovir

Testing 2nd hospital admission

• CSF, blood, and urine cultures: no growth • CSF enterovirus, paraechovirus, HSV, West Nile

Virus PCR negative

• Brain MRI: Slightly prominent fluid overlying the frontal lobes and temporal lobes

Recurrent, culture-negative meningitis in young infant DDX?

• Regular bacterial pathogens GBS, E. coli, pneumococcus with failure of treatment of the first meningitis episode (10 days cefotaxime)

• Other fastidious GNR (HACEK group)• Listeria• TORCH – Toxoplasma, Syphilis, CMV, HSV, HIV • Viral meningitis• Tuberculosis• Parameningeal focus of infection or anatomic

abnormality – CSF communication

Further testing 2nd hospital admissionAnatomic EvaluationMRI of the spine: No epidural abscess, no abnormality of vertebraeConsultation and physical exam by pediatric neurosurgeon -No signs of

lumbosacral defects or any other communication with CNSTORCH EvaluationToxoplasma IgG and IgM negative, Toxo PCR on CSF negativeRule-out congenital syphilisTreponemal antibody screen positiveTreponema pallidum particle agglutination (TPPA) positiveSerum and CSF VDRL non-reactive, serum RPR non-reactiveLong bone films, brain MRI, ophthalmologic exam, and hearing test normalMaternal RPR negative at prenatal 9 week visit, subsequent maternal RPR

positive postpartum Conclusion: Mother acquired syphilis infection during pregnancy. Infant not

infected.

Management 2nd hospital admission• Further CSF testing not done as no remaining fluid available• Treatment:

– Acyclovir stopped – CSF HSV PCR negative, MRI normal– 10 days of ampicillin then 10 days of penicillin, 7 days of

gentamicin during 21 days of cefotaxime treating possibilities GBS, syphilis, Listeria, fastidious GNR, pneumococcus

• Repeat lumbar puncture performed after 3 days of antibiotics: RBC 0, WBC 0, glucose 30 and protein 94.

• Discharged home, seen in follow-up 1 week later, doing great

• Happy, not fussy, eating well, gaining weight, development on track

4 weeks after discharge…

• The patient is now 4 months old• Fever 100.4 F, mild rhinorrhea/congestion• Seizure- left-sided facial twitching of forehead and eyelids,

drooling and generalized shaking.• ED: generalized tonic-clonic seizure for 30 min, rectal

Diastat given• CSF: 660 WBC (85% neut, 13% lymph), 338 RBC, glucose 39,

protein 125• Gram stain: many WBC, no organisms seen• Negative antigens: pneumococcus, GBS, Hib and Neisseria

meningitidis

3rd Time’s a charm?Expanded DDX?

• Relapsed CNS congenital syphilis• Viral – enterovirus, parechovirus, CMV, rotavirus,

astrovirus, VZV, EBV, HTLV ½, HIV, respiratory viruses• Genital Mycoplasma and Ureaplasma • Other spirochete• Cryptococcus• Malignancy – astrocytoma, lymphoma, etc.• Immune deficiency• Autoimmune – sarcoidosis, SLE, NOMID, other

Management 3rd hospital admission

• Vancomycin, cefotaxime, acyclovir, and penicillin G IV

• Repeat LP after 48 hours: WBC 82 (59% neut, 18% lymph, 22% mono), RBC: 0, Gucose: 39, Protein 138

Additional Lab StudiesCSF: NEGATIVE STUDIESBacterial, fungal, AFB cultureVDRLHSV PCREnterovirus parechovirus PCRCMV PCR HHV-6 PCRCryptococcal antigenCytology

SEROLOGIES: NEGATIVE CMV IgG and IgM, and PCRToxoplasma IgG and IgMHIV antibody, and PCRCryptococal AntigenMycoplasma pneumoniae IgMHTLV ½ antibody

Other - NEGATIVE:Stool cultureRotavirus antigenUrine CMV cultureRespiratory virusesPPD

IMMUNOLOGIC - NORMALQuantitative immunoglobulins Lymphocyte subsetsComplement CH 50

RADIOLOGY STUDIESSpine MRICT temporal boneRepeat Brain MRI – slight increase extra-axial fluid

MRI Findings

Small bilateral subdural effusions

Small 2 mm focal hyperintensity along frontal dura – This may represent a tiny subacute hemorrhage or short segment focal venous thrombosis.

Then ….

• Mycoplasma hominis identified by PCR of CSF: Positive by Mycoplasma-specific primers and universal 16S bacterial primers

• Treated with 6 weeks of moxifloxacin and rifampin, initially IV followed by PO

• CSF PCR negative on therapy at 14 days• Clinic follow-up over 12 months after

completion of therapy – normal development

Mycoplasma hominis• Genital mycoplasmas (M. hominis, M. genitalium, and Ureaplasma)

found in female genital tract, often in conjunction with other STIs. Considered co-pathogen in chorioamnionitis and other genital tract infection.

• Very rare neonatal CNS pathogen (premature infants)• 1988 study of 100 preterm infants with suspected meningitis – 5 M.

hominis, 8 Ureaplasma by culture• Another study 318 neonatal meningitis – 9 M. hominis, 5

Ureaplasma• Most cases cleared meningitis without directed therapy• Clinical course variable – asymptomatic to neurologically devastating• Chronic infection has been observed

Perinatal infection of term infant with Mycoplasma hominis?

• Risk factors : prematurity, maternal chorioamnionitis

• Presence of syphilis may have predisposed to ascending infection with M. hominis, with inflammation of placenta and genital tract

Unique features of case• Clinical response to beta-lactam antibiotic

with recrudescence after each of 2 full courses. Successful treatment with fluoroquinolone.

• Purulent CSF in typical bacterial range (700 to 3000 WBC neutrophil predominant)

• Congenital syphilis was evaluated due to untreated maternal syphilis, but ultimately not consistent with serologic evaluation.

• Molecular diagnosis of culture-negative CSF

References• Krausse R, Shubert S. In vitro activities of tetracyclines, macrolides, fluoroquinolones and clindamycin

against Mycoplasma hominis and Ureaplasma ssp isolated in Germany over 20 years. Clin Micro and Infect. 2009

• Bayraktar et al. Prevalence and antibiotic susceptibility of Mycoplasma hominis and Ureaplasma urealyticum in pregnant women. Intl. J Infect Dis. 2010.

• Hata et al. Mycoplasma hominis meningitis in a neonate: Case report and review. J of Infection.2008.• Wolthers et al. A case of Mycoplasma hominis meningo-encephalitis in a full-term infant: rapid recovery

after start of treatment with ciprofloxacin. Eur J Pediatr. 2003.• Waites K, et al. Congenital and opportunistic infections: Ureaplasma species and Mycoplasma hominis.

Sem in Fetal and Neonatal Med. 2009.• Watt K, et al. Pharmacokinetics of Moxifloxacin in an infant with Mycoplasma hominis meningitis. Pediatr

Infect Dis J. 2012.• Knausz et al. Meningo-encephalitis in a neonate cuased by maternal Mycoplasma hominis treated

successfully with chloramphenicol. J. Med Microbiol. 2002.• Chong et al. Successful treatment of multiple subdural empyemata caused by Mycoplasma hominis in a

newborn. Neonatology 2009.• Waites et al. Mycoplasmal infections of cerebrospinal fluid in newborn infants from a community hospital

population. Pediatr Infect Dis J. 1990.• Waites et al. Chronic Ureaplasma urealyticum and Mycoplasma hominis infections of central nervous

system in preterm infants. Lancet 1988.

Case example is ideal for molecular diagnosis by PCR (polymerase chain reaction)

• M. hominis culture not readily available and not very sensitive – Even the reference lab would rather do PCR

• Also detected by universal bacterial PCR for 16S ribosomal sequences

Will PCR replace all other testing for infections? Answer: nope

Where you would not use PCR

• Well standardized diagnostic approach detects with clinically appropriate sensitivity/specificity– Antigen (throat swab for group A Strep)– Antibody (West Nile virus meningoencephalitis)– Culture (abscess I&D)

• Main hazard of PCR is cross-contamination that is eliminated by proper lab practices

Apply the best test for the specimen

• Cutaneous HSV lesion: viral culture for HSV appropriate sensitivity, cost and availability

• CSF for HSV encephalitis: PCR necessary for sufficient sensitivity

You may have learned• Recommendations for neonatal HSV have

become more aggressive – dose and duration of IV acyclovir– pre-emptive treatment of known perinatal exposure– suppressive oral acyclovir after IV treatment

• Congenital CMV causes delayed-onset hearing loss missed by newborn hearing screening.

• Antiviral therapy is used selectively for symptomatic congenital CMV. Valganciclovir oral dosing allows duration of therapy that may prevent progressive hearing loss.

You may have learned

• Perinatal prophylaxis for hepatitis B with HBIG and HB vaccine fails to prevent infection 5% of cases, so follow-up testing for infant is important. Role for maternal antiviral therapy is developing and appears to be safe.

• No consistent consequences on infant neurodevelopment result from Lyme disease in pregnancy.

• Ebolavirus in pregnancy is nearly always associated with death of mother and fetus.

• Molecular testing by PCR identifies some perinatal infections that traditional microbiology or serology testing fails.