Case Report

Neonatal Ureaplasma parvum meningitis: a case report and

literature review
Qiu Wang1#, Kai Wang1#, Yuanbo Zhang1, Chaosheng Lu1, Yana Yan1, Xiaoxia Huang1, Jing Zhou2,
Lijiang Chen3, Dan Wang1
1
Department of Pediatrics, 2Department of Obstetrics, 3Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou
325000, China
#
These authors contributed equally to this work.
Correspondence to: Dan Wang, MD. Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Road,
Wenzhou 325000, China. Email: [email protected].

Abstract: Ureaplasma parvum (U. parvum) is common commensal in the female genitourinary tract. Despite
U. parvum has been associated with chorioamnionitis, abortion, prematurity and perinatal complications, the
invasive central nervous system (CNS) infection is rare in neonates. Diagnosis of U. parvum meningitis can
be difficult for the atypical presentations and sterile cultures by conventional methods. Metagenomic next-
generation sequencing (mNGS) could identify a broad range of human pathogens in a target-independent
manner. Here, we performed mNGS to search for the infectious etiology in a term infant presenting with
fever and seizure. U. parvum genome was identified by mNGS and further confirmed by PCR in the same
cerebrospinal fluid (CSF) sample. As the quick and timely diagnosis, the baby was successfully treated
with erythromycin for 4 weeks without complication. The clinical follow-up has showed that the physical
and mental development are normal. In conclusion, mNGS may a promising diagnostic technology for
U. parvum meningitis. As mNGS is able to identify diverse microbes in a single run, it could be a useful
strategy to detection the clinical causative pathogens with atypical features in neonates.

Keywords: Neonate; meningitis; metagenomic next-generation sequencing (mNGS); Ureaplasma parvum

(U. parvum); case report

Submitted Nov 29, 2019. Accepted for publication Jan 18, 2020.
doi: 10.21037/tp.2020.02.04
View this article at: http://dx.doi.org/10.21037/tp.2020.02.04

Introduction as pneumonia, bacteremia and central nervous system

(CNS) infection (2,3). However, the invasive infection in
Ureaplasma species (spp.), including Ureaplasma urealyticum
neonates with U. parvum has been rarely presented. The
(U. urealyticum) and Ureaplasma parvum (U. parvum), are the
diagnosis of U. parvum meningitis is complicated by the
smallest free-living organisms, lacking cell-wall, colonizers atypical manifestations and the inherent biologic properties
of the mucosal epithelial cells of genitourinary tract (1). of this organism. U. parvum cannot be demonstrated on
They have been associated with a serial of obstetrical Gram staining and may not grow in conventional culture
complications, including chorioamnionitis, premature media. Unlike traditional assessment for specific pathogen,
rupture of membranes, prematurity, miscarriage, still birth, metagenomic next-generation sequencing (mNGS) screens
and perinatal morbidity and mortality (1,2). Since the first for nearly all potential CNS infections and can identify
case report of U. urealyticum meningitis in newborn in 1986, novel or unexpected microbes. mNGS is being used
several researches have been indicated that U. urealyticum increasingly for the clinical diagnosis of CNS infection in
could be a causative pathogen of invasive disorders, such adults. Here, we present a rare case of U. parvum meningitis

© Translational Pediatrics. All rights reserved. Transl Pediatr 2020;9(2):174-179 | http://dx.doi.org/10.21037/tp.2020.02.04

Translational Pediatrics, Vol 9, No 2 April 2020 175

Ureaplasma parvum 1.24% total coverage intravenous oxacillin (50 mg/kg/dose, q8h) and sulperazon
10
(50 mg/kg/dose, q8h) were started for bacterial meningitis.
No microorganism was detected on Gram staining or
8 cultures of blood and CSF samples. On the day 4 of
hospitalization, the infant presented local seizures and
his anterior frontal became full and bulging. A cranial
Reads number

6 magnetic resonance image (MRI) identified ventriculitis

and mild dilatation of right lateral ventricle, but no abscess
or bleeding. A new CSF was analyzed and results showed
4
880 WBC/mm3 (48% of neutrophils), 2.6 g/L protein, and
<1.11 mmol/L glucose. Antibiotic therapy was modified
2 to intravenously administered vancomycin (15 mg/kg/
dose, q8h) and meropenem (30 mg/kg/dose, q8h); and
phenobarbital was added to suppress seizure. Again,
0 bacteriological cultures of blood and CSF still negative.
0 month 0.2 months 0.4 months 0.6 months
Nucleotide position along ureaplasma parvum genome After 7 days treatment of vancomycin and meropenem,
the infant had a sustained fever of 38.0 ℃ and somnolent,
Figure 1 Sequence reads mapped to U. parvum by mNGS data. A
a third CSF was collected, which showed 205 WBC/mm3
total of 188 reads mapped to U. parvum in the reference database,
(44% of neutrophils), protein at 1.9 mg/L, and glucose at 1.9
corresponding to a total coverage of 1.24%.
mmol/L. Given CSF culture failed to reveal a pathogen, a
CSF sample was collected and sent for the unbiased mNGS
(BGI, Shenzhen, China), with a classification reference
diagnosed by mNGS in a neonate. As the timely diagnosis,
databases downloaded from NCBI (ftp://ftp.ncbi.nlm.ni-h.
the baby was successfully treated with erythromycin
gv/genomes/) containing 1,424 whole genome sequence of
without complication. This report aims to discuss the
viral taxa, 2,406 bacterial genomes or scaffolds, 199 fungi related
characteristics of neonatal U. parvum meningitis, including
to human infection and 135 parasites associated with human
clinical features, new methods for microbial diagnosis,
diseases (5). Within 72 hours, the mNGS produced 36.1 million
pathogenicity, and the challenges of appropriate treatment.
reads and detected 188 reads of U. parvum, covering 1.24%
We present the following case in accordance with the
(9,306/751,719) of the U. parvum genome (Figure 1). To further
CARE Guideline (4).
verify the presence of this pathogen, a specific PCR analysis was
conducted with the same CSF sample and the PCR product
Case presentation was assessed by Sanger sequencing. The PCR primers were
5'-CATTGATGTTGCACAAGGAGAAA-3' and 5'-TTA
A 11-day-old male infant (birth weight 3,390 g) was admitted GCACCAACATAAGGAGCTAAATC-3', which target a U.
to hospital for a sudden onset of fever (38.7 ℃) and floppy. parvum specific region of 16S rRNA gene. Based on these
The baby was born by spontaneous vaginal delivery to a results, the patient was diagnosed of U. parvum meningitis
41-year-old gravida 0 para 0 mother at 40 weeks of gestation. and was administered with intravenous erythromycin
He did not have surface anomalies and was vigorous at birth (10 mg/kg/dose, q6h); other antibiotics were weaned. On day
with Apgar scores of 8 at 1 min and 9 at 5 min. Maternal 3 and 7 of erythromycin treatment, the fever subsided and
pregnancy was complicated by gestational diabetes mellitus CSF test recovered, respectively; and his condition continued
and premature rupture of the membranes for 40 hours. favorably. After the 4 weeks course of erythromycin, the
The Blood analysis revealed leukocytosis (15,740/mm 3), repeated CSF was without biochemical abnormalities and
and elevated C-reactive protein (10.4 mg/L) with normal baby was discharged home. The timeline of this case was
level of procalcitonin (0.04 ng/mL). Cerebrospinal fluid shown in Figure 2. The infant developed well without
(CSF) assessment showed leukocytosis (410 WBC/mm3 with abnormal neurological signs during the follow-up until
55% of neutrophils), elevated protein level (2.0 g/L), and 18 months old. His head MRI at the age of 6 months showed
reduced glucose (<1.11 mmol/L). Combined treatments of the resolution of ventriculitis and hydrocephalus.

© Translational Pediatrics. All rights reserved. Transl Pediatr 2020;9(2):174-179 | http://dx.doi.org/10.21037/tp.2020.02.04

176 Wang et al. A case report of U. parvum meningitis in neonate and brief literature review

Fever
Floppy Seizure Sustained mild fever No fever

Day 1 Day 4 Day 7 Day 13

Day 10 Day 17 Day 38

Abnormal blood analysis MRI Abnormal CSF Normal CSF test Stop erythromycin
U. parvum confirmed
Abnormal CSF test Abnormal CSF test test Discharge home
erythromycin
Oxacillin, sulperazon Vancomycin, meropenem mNGS

Figure 2 The timeline of this case, including clinical presentations, tests and treatments.

Table 1 Characteristics of published cases with Ureaplasma parvum meningitis

No. Gender Onset time Presentation Identification Treatment Complication Others Ref.

1 Female 18 days after Fever, cardiovascular PCR ERY + CIP × Grade III IVH Preterm, fetoscopic (5)
birth instability and apnea 3 weeks and HCP surgery at 21
gestational weeks

2 Female 4 weeks after HCP and developmental PCR CHL × 3 weeks HCP and Preterm, maternal (6)
birth delay developmental delay cervical insufficiency
and cerclage

3 Unknown 10 days after Fever, rhinitis, PCR and CIP ×7 weeks + HCP Term (7)
birth conjunctivitis and culture THI ×3 weeks
focal seizure

4 Male 16 days after Fever, headache, PCR LVFX ×3 weeks None Adult, (8)
surgery photophobia and craniopharyngioma
meningeal irritation ablation
IVH, intraventricular hemorrhage; HCP, hydrocephalus; ERY, erythromycin; CIP, ciprofloxacin; CHL, chloramphenicol; THI, thiophenicol;
LVFX, levoflfloxacin.

Discussion with histological chorioamnionitis, abortion, stillbirth,

preterm birth and perinatal complications (1,2), the invasive
Here, we describe a rare case of neonatal meningitis
infection is rare. According to the literature, there are
resulting from U. parvum infection. Like the most previous
four cases of U. parvum meningitis have been previously
cases of U. parvum meningitis (6-9), the common cultures
of blood and CSF were negative. But after the pathogen was reported (Table 1) (6-9). One is in an adult after surgical
identified by mNGS and confirmed by PCR, the baby was ablation of a craniopharyngioma (9). Other three cases
successfully treated with erythromycin. are in neonates (two prematurity and one term) (6-8). In
Despite U. parvum has been consistently associated with all reported neonatal cases, no other pathogen was found
chorioamnionitis, abortion, stillbirth, premature rupture of despite extensive microbiological diagnostics. Infection
membranes and prematurity. with U. parvum in neonates has been documented to be
Despite Ureaplasma spp have been consistently associated late onset meningitis and has variable clinical presentation
with histological chorioamnionitis, abortion, stillbirth, preterm including fever, apnea, cardiovascular instability, rhinitis,
birth and perinatal complications, Despite Ureaplasma spp have conjunctivitis, seizure and hydrocephalus. In this case, the
been consistently associated with histological chorioamnionitis, full-term boy also had manifestations of fever, floppy and
abortion, stillbirth, preterm birth and perinatal complications. seizure. The results of initial CSF analysis might with the
Despite U. parvum has been consistently associated predominance of leukocytes or lymphocytes and the glucose

© Translational Pediatrics. All rights reserved. Transl Pediatr 2020;9(2):174-179 | http://dx.doi.org/10.21037/tp.2020.02.04

Translational Pediatrics, Vol 9, No 2 April 2020 177

level could be undetectable or normal, suggesting bacterial 40% (14). On account of the complex growth requirements
or viral meningitis. Similarly, the CSF was presented with and specific culture condition, the organism might avoid
pleocytosis and decreased glucose level in our case. Thus, detection. Broad range bacterial PCR is another method
the CSF profile of U. parvum meningitis may be various and for the Ureaplasma identification and superior to traditional
atypical. After the specific treatment of U. parvum, the CSF culture methods. But this hypothesis-driven molecular
profile has been reported to gradually normalize, paralleled testing may miss the pathogen when there is no consideration
by a continuous clinical improvement. Development of about the specifically targeted organisms or when the used
hydrocephalus with or without of hemorrhage also has been primers contain mismatches to the microbial strain involved,
reported in all neonatal cases, either at initial signs or in which decreases the sensitivity of detection. Above options
the clinical course. And the long-term outcome of neonatal for diagnosing infections caused by Ureaplasma are limited
U. parvum meningitis ranges from complete resolution to due to the shortcomings of both culture and PCR-based
progressive internal hydrocephalus or neurodevelopmental techniques. Thus, microbial diagnostics on Ureaplasma may
impairment (6,8). In accordance to the previous U. parvum be delayed by the difficulties in pathological detection. Here,
meningitis, the hydrocephalus gradually resolved and the we found U. parvum in CSF by mNGS analysis. mNGS, a
baby boy develops appropriately in this case. Only one high-throughput or massively parallel sequencing method, is
previous case which manifested with sustained meningitis beneficial for diagnosis in patients with suspected infectious
and progressive hydrocephalus had poor neurological but negative results for conventional assessments (5). It could
outcome (6,8), implying that continuous inflammation apply for hypothesis-free and universal pathogen detection,
is related to the adverse outcome. Thus, early diagnosis promising to improve infectious disease diagnostics,
and initiation of appropriate treatment are necessary to especially in immunocompromised neonates or critically ill
improving the prognosis. patients. This novel technique will enable timely diagnosis
Although Ureaplasma normally exist in a state of and treatment of invasive U. parvum infection and is expected
adherence to mucosal epithelial cells, they can disseminate to result in excellent outcomes, as presented in this case.
to other sites and cause invasive infection when there is a However, mNGS method also has inherent disadvantages,
disruption of the mucosa and/or an underlying defect in host including sequencing human host gene background, suffering
defenses, such as in the developing fetus or newborn. Their from the contamination with environmental species, and the
pathogenicity has been imputed to inflammatory response expensive cost.
by modulating the immune system in a complex way, not The treatment of invasive Ureaplasma infection in neonates
only promoting pro-inflammation, but also inhibit immune is particularly challenging. Previous cases of U. parvum
response (1,10). The balance between pro-inflammatory meningitis shows several therapeutic chemicals (Table 1).
cytokines (e.g., tumor necrosis factor-α, interleukin (IL)- Three reports in neonates used different antibiotic regimes:
1β, IL-2, IL-6, IL-8) and anti-inflammatory cytokines two preterm infants were treated by chloramphenicol
(e.g., IL-10) is disturbed by Ureaplasma infection (1). and the combination of erythromycin and ciprofloxacin,
In addition, they could also affect innate host immune respectively; the other term baby was administered with
by downregulating cell defense genes (e.g., antimicrobial ciprofloxacin and thiophenicol. Considering that Ureaplasma
peptides), decomposing the host cell membrane via are free of cell wall, the antibiotics targeting protein or DNA
phospholipase, and exerting cytotoxicity through ammonia synthesis may effective, such as macrolides, tetracyclines,
accumulation or PH-shift via hydrolyzing urea (11,12). clindamycin, chloramphenicol and quinolones (14).
In the previous U. parvum meningitis cases, the pathogen However, the potential side effects of above drugs have
in CSF was demonstrated by PCR in three cases and by the been taken into consideration when used in the newborn.
combination with PCR and culture in on case. Ureaplasma Tetracyclines can induce permanent dental discolorations or
are the smallest free-living organisms. They cannot be skeletal abnormalities; chloramphenicol may cause “gray baby
visualized by Gram stain since the lacking of cell wall (13). syndrome” or blood dyscrasias; and fluoroquinolones have
Given they are not surviving in standard culture media, in arthropathogenic effects. Thus, these drugs are generally
order to harvest these organisms, clinical specimens should avoided in neonates due to concerned toxicities. Macrolide
be inoculated immediately onto specialized culture media antibiotics are usually used in the Ureaplasma treatment.
before they are allowed to dry (7,13). And culture detection Here, we firstly treated the baby with erythromycin.
take long time intervals and positive rate can be as low as Erythromycin is not suggested for the treatment of

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178 Wang et al. A case report of U. parvum meningitis in neonate and brief literature review

Ureaplasma meningitis due to its poor liquor penetrance (14). Open Access Statement: This is an Open Access article
But some cases have been successfully treated with distributed in accordance with the Creative Commons
erythromycin (15), which may be explained by the increase Attribution-NonCommercial-NoDerivs 4.0 International
of blood-brain barrier permeability when meningitis is License (CC BY-NC-ND 4.0), which permits the non-
occurring. In addition, the appropriate duration of antibiotic commercial replication and distribution of the article with
therapy for Ureaplasma meningitis is not well understood. We the strict proviso that no changes or edits are made and the
choose erythromycin for 4 weeks, as is general practice in the original work is properly cited (including links to both the
treatment of other types of bacterial meningitis in neonates. formal publication through the relevant DOI and the license).
In other reports, the treatment duration may range from 2 to See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
6 weeks in infants (16).
In conclusion, neonatal Ureaplasma meningitis might be
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Cite this article as: Wang Q, Wang K, Zhang Y, Lu C, Yan

Y, Huang X, Zhou J, Chen L, Wang D. Neonatal Ureaplasma
parvum meningitis: a case report and literature review. Transl
Pediatr 2020;9(2):174-179. doi: 10.21037/tp.2020.02.04

© Translational Pediatrics. All rights reserved. Transl Pediatr 2020;9(2):174-179 | http://dx.doi.org/10.21037/tp.2020.02.04