Tom Rand’s presentation
Perinatal infection continued:
Elusive cause of meningitis in a
young infant
Contributed by
Ingrid 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
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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
Differential: 33% Seg, 1% Band,
62% Lymph
11.5
440
19.8
Rapid Influenza/RSV negative
133
10
116
5.4
17
0.27
CSF:
WBC 1428 (85% neut, 6% lymph, 9% mono),
RBC 37, protein 137, glucose 52.
Gram stain: many WBC, no organisms seen.
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 admission
Anatomic Evaluation
MRI of the spine: No epidural abscess, no abnormality of vertebrae
Consultation and physical exam by pediatric neurosurgeon -No signs of
lumbosacral defects or any other communication with CNS
TORCH Evaluation
Toxoplasma IgG and IgM negative, Toxo PCR on CSF negative
Rule-out congenital syphilis
Treponemal antibody screen positive
Treponema pallidum particle agglutination (TPPA) positive
Serum and CSF VDRL non-reactive, serum RPR non-reactive
Long bone films, brain MRI, ophthalmologic exam, and hearing test normal
Maternal 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 Studies
CSF: NEGATIVE STUDIES
Bacterial, fungal, AFB culture
VDRL
HSV PCR
Enterovirus parechovirus PCR
CMV PCR
HHV-6 PCR
Cryptococcal antigen
Cytology
Other - NEGATIVE:
Stool culture
Rotavirus antigen
Urine CMV culture
Respiratory viruses
PPD
SEROLOGIES: NEGATIVE
CMV IgG and IgM, and PCR
Toxoplasma IgG and IgM
HIV antibody, and PCR
Cryptococal Antigen
Mycoplasma pneumoniae IgM
HTLV ½ antibody
IMMUNOLOGIC - NORMAL
Quantitative immunoglobulins
Lymphocyte subsets
Complement CH 50
RADIOLOGY STUDIES
Spine MRI
CT temporal bone
Repeat 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
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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.