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Group B Streptococcal Infections
https://t.me/medicina_free
inChildren andHearing Loss
EdaKaradağ Öncel, MineUzunsoy Duzgol,
AyşeEnginArısoy, andVishakhaSabharwal
27.1 Introduction
Streptococcus agalactiae, also known as group B streptococcus (GBS), is an important cause of bacterial infection—in neonates and early infancy. In this early period,
GBS may cause sepsis, meningitis, pneumonia, and other focal infections [1]. It
commonly colonizes the gastrointestinal and genital tracts of pregnant women.
Vaginal and cervical colonization is usually asymptomatic; however, maternal colonization is the primary risk factor for GBS infection in neonates and young infants
[2]. The clinical disease can present as bacteremia, meningitis, pneumonia, septic
arthritis, osteomyelitis, cellulitis, and adenitis. Moderate or severe neurodevelopmental impairment is common among survivors with GBS meningitis; 18% of survivors with an average follow-up of 18months are affected [3]. Hearing loss may
also occur in patients with GBS meningitis. The frequency and complications of
meningitis may vary according to the time of infection [1].
27
E. Karadağ Öncel (*)
Section of Pediatric Infectious Diseases, Tepecik Training and Research Hospital, University
of Health Sciences, İzmir, Türkiye
e-mail: dredakaradag@gmail.com
M. Uzunsoy Duzgol · V. Sabharwal
Division of Pediatric Infectious Diseases, Department of Pediatrics, Chobanian & Avedisian
School of Medicine, Boston University, and Section of Pediatric Infectious Diseases, Boston
Medical Center, Boston, MA, USA
e-mail: mineduzgol@gmail.com; Vishakha.Sabharwal@bmc.org
A. E. Arısoy
Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Kocaeli University,
Kocaeli, Türkiye
e-mail: arisoyengin@yahoo.com
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
A. E. Arısoy et al. (eds.), Hearing Loss in Congenital, Neonatal and Childhood
Infections, Comprehensive ENT, https://doi.org/10.1007/978-3-031-38495-0_27
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E. Karadağ Öncel et al.
27.2 Etiology
Group B streptococci, gram-positive diplococci, usually create a limited beta hemolysis zone on 5% sheep blood agar. There are ten different types according to the
structures of capsular polysaccharides. In the United States of America (USA), the
most seen types, which account for approximately 99%, are Ia, Ib, II, III, IV, and V
in newborns [1]. Type III causes about 30% of early-onset GBS disease (EOD) and
60% of late-onset GBS disease (LOD).
27.3 Epidemiology
27.3.1 Maternal Colonization
Vaginal, rectal, urethral, and pharyngeal asymptomatic colonization develops within
approximately one-third of healthy young females [4]. Vaginal and cervical colonization is usually asymptomatic; however, identifying risk factors is critical to predicting neonatal disease. The main risk factors for vaginal colonization are African
American ethnicity, obesity, frequent sexual intercourse, multiple sex partners,
male-to-female oral sex, tampon use, and uncommon hand washing [4]. Colonization
prevalence is high in women under 20years [4]. Studies in pregnant women show
that colonization in vagina or rectum ratios differs between 18% and 35% [4]. This
variable rate depends on the region where the sample was taken, the microbiological
method used, and the trimester of pregnancy in which the cultures were obtained.
Culture samples taken 5 weeks before term pregnancy are ideal for predicting colonization at birth. Another signicant colonization is in the urinary system, which
may manifest as asymptomatic bacteriuria, and it causes an increase in the risk of
developing EOD in newborns [4–7].
27.3.2 Infant Colonization
The most critical factor for colonization and infection in newborns is the presence
of high inoculum of GBS within maternal genitourinary or gastrointestinal tracts of
the mother at birth [6]. Although only 1–12% of newborns of non-colonized mothers are colonized, vertical transmission from colonized mothers to their infants averages 50%, reported between 41% and 72% [4, 8, 9]. Ingestion of the GBS by the
infant occurs during ascending via the ruptured membranes before birth or while
passage through the birth canal. Dense maternal inoculum, 105 colony-forming
units/mL, in the genital tract signicantly increases vertical transmission and colonization to newborns [8, 10]. The most crucial risk factors in developing EOD are
premature birth, a history of premature membrane rupture ≥18 h, a history of
27 Group B Streptococcal Infections inChildren andHearing Loss
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intrapartum fever (≥38°C), intra-amniotic infection, bacteriuria of GBS throughout
the last pregnancy, or a history of invasive GBS disease in a previous infant [1]. In
some studies, multiple pregnancies have been revealed to increase the GBS disease
risk [11]. Maternal intrapartum antibiotic administration generally reduces the vertical transmission of GBS [4, 7].
Rarely, community-acquired or healthcare-associated horizontal transmissions
may be seen. Transmission from infants or healthcare personnel with colonization
to newborns may develop, but such outbreaks are sporadic [12]. After discharge,
neonates and young infants can acquire GBS horizontally from mother or colonized
household contacts and develop late-onset bacteremia, meningitis, or other focal
infections. Breast milk may be a mode of transmission for LOD, and postpartum
mastitis of the mother has been found in most reported cases. However, the role of
breast milk in LOD has not yet been established [13].
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27.3.3 Incidence ofDisease
Worldwide, the incidence of GBS diseases in infants is nearly 0.5 per 1000 live
births [14, 15]. Still, the incidence varies from region to region, with the highest
incidence in Africa and the lowest incidence in Asian countries [14]. The disease
burden is very high all over the world. In the USA in 2015, 205,000 (uncertainty
range [UR]: 101,000–327,000) EOD and 114,000 (UR: 440,00–326,000) LOD
were diagnosed in newborns. Of whom, approximately 7000 (UR: 0–19,000) had
neonatal encephalopathy, and 57,000 (UR: 12,000–104,000) had fatal infection and/
or miscarriage [16]. A study conducted in the USA between 1998 and 2007 showed
that GBS was the cause of meningitis in 86% of infants under 2 months, and the
infection was fatal in 11% of cases [17]. Africa accounted for 54% of estimated
cases and 65% of fetal/infant deaths [17].
Intrapartum antibiotic prophylaxis (IAP) for EOD was implemented in 1996
with joint consensus by the American Academy of Family Physicians (AAFP),
the American Academy of Pediatrics (AAP), the American College of NurseMidwives (ACNM), the American College of Obstetricians and Gynecologists
(ACOG), and other stakeholder organizations [18]. With universal maternal antenatal screening and IAP, the national EOD incidence, GBS in the USA, fell from
1.8 cases per 1000 live births in 1990 to 0.23in 2015 [19]. Nonetheless, the
effect of IAP on the incidence of LOD is unknown. In 2018, the incidence of
LOD exceeded that of EOD at 0.28 cases per 1000 live births [1]. Almost 30% of
neonates with EOD and up to 55% of newborns with LOD and late-late-onset
GBS disease (late-LOD) are premature infants [20–22]. The schema of classication and the transmission of GBS disease vertically in infants after using IAP
is shown in Fig.27.1. Late-late-onset GBS disease constitutes 7–13% of pediatric GBS infections [23, 24].
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E. Karadağ Öncel et al.
MaternalGBS colonization
(25%)
Non-colonized
infant
50%
Asymptomatic
Sepsis
80-85%
Pneumonia
50%
Colonized infant
98%
Early-onset disease Late-onset disease
10-15%
1-2%
Invasive GBS
50%50%
Meningitis
5-10%
disease
Bacteremia of
unknown
focus
Meningitis
25-30%
65%
Focal
infections
5-10%
Fig. 27.1 Flow chart of vertical transmission and disease classication of group B streptococcal
(GBS) disease in infants after using intrapartum chemoprophylaxis. (Adapted and modied from
Refs. [4, 7])
27.4 Terminology
Early-Onset GBS Disease (EOD): Infection is usually seen in the rst 24h follow-
ing birth but includes infections that develop up to 6days after delivery [1, 2].
Late-Onset GBS Disease (LOD): The term covers infections between the 7th–89th
days. Infection is usually seen until the 4th–5th weeks following birth [1, 2].
Late-Late-Onset (or Very Late-Onset) GBS Disease: Infection occurs in infants
over 3months [1, 2]. It is usually seen in infants born before the 28th gestational
week and those with a history of immunodeciency [23, 25]. Group B strepto-
coccal disease is rare in infants and children over 3 months and lacks sufcient
information [26].
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27.5 Clinical Manifestations
27.5.1 Clinical Manifestations inEarly-Onset Disease
Early-onset GBS infection most commonly manifests as generalized sepsis, pneumonia, or meningitis. In more than 90% of cases, clinical signs appear in the rst
24h after birth. Newborns of mothers who receive IAP are less likely to develop
sepsis, need ventilator support, or have proven GBS bacteremia [27]. Early-onset
GBS disease presents with sepsis in 80–85% of patients. The clinical signs of sepsis
are nonspecic; it can present with irritability, lethargy, respiratory symptoms,
hyper- or hypothermia, circulatory disorder, and hypotension. Pneumonia occurs in
approximately 10% of patients with EOD, usually manifesting with difcult breathing, hypoxia, and increased respiratory effort [28]. In addition, GBS pneumonia can
cause persistent pulmonary hypertension in infants. Meningitis occurs in 7% of
patients with EOD [28]. Classic central nervous system ndings of meningitis are
not generally seen in newborns with EOD, and patients often present with respiratory system ndings [29]. Payne etal. [30] determined that birth weight<2500g,
apnea, hypotension, absolute neutrophil count <1500 cells/mm3, initial pH <7.25,
and presence of pleural effusion in chest X-ray on admission are associated with
fatal outcomes in EOD.
27.5.2 Clinical Manifestations inLate-Onset Disease
Sixty-ve percent of infants with GBS infection present with bacteremia without a
focus [28]. Meningitis (25–30%) and focal infections can also be seen [31]. Compared
with those with EOD, infants with LOD with meningitis are less likely to be in shock
and more likely to have clinically signicant seizures [32]. The clinical manifestations
of meningitis are often indistinguishable from those in neonatal sepsis. The most common clinical ndings are hyper- or hypothermia, irritability or lethargy, and vomiting.
Typical clinical ndings of meningitis, such as bulging fontanel, nuchal rigidity, and
focal neurological ndings, are more common in LOD than in EOD.Upper respiratory tract infection ndings can be seen in 20–30% of patients with LOD [33]. Focal
infections, including arthritis, osteomyelitis, and cellulitis-adenitis syndrome, may
occur in infants with LOD [7]. Less common clinical syndromes are urinary tract
infections, sometimes concomitant with structural abnormalities, otitis media, necrotizing fasciitis, endocarditis, and other conditions [1, 2, 4, 7].
27.5.3 Clinical Manifestations inLate-Late-Onset Disease
The late-late-onset GBS disease most commonly develops in premature neonates,
especially <28weeks of gestation. Infants generally present as bacteremia without
a focus, but rarely focal sites of infection may be seen. A comparison of characteristics of early-, late-, and late-late-onset GBS infections is depicted in Table27.1.
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E. Karadağ Öncel et al.
Table 27.1 Comparison of early, late, and late-late-onset group B streptococcus (GBS) infection
characteristics
Disease
characteristics
Age at onset <7days; mean, 8h;
Maternal
obstetric
complications
Frequency of
prematurity
Clinical ndings Acute respiratory
Clinical
diagnosis
Common
capsular type
Case fatality rate 5–15% 2–6% <5%
a
Adapted and modied from Refs. [4, 7]
a
Early-onset GBS
disease (EOD)
median, 1h
Common Preterm delivery Varies
Frequent (≈25%) Frequent (≈50%)
distress, apnea, and
hypotension common
– Septicemia
(80–85%)
– Pneumonia
(10–15%)
– Meningitis (5–10%)
Ia, II, III, V III (>50%), Ia, V III, Ia, V
Late-onset GBS disease
(LOD)
7–89days; mean,
36days; median,
27days
Fever, irritability,
nonspecic signs,
occasionally fulminant
– Bacteremia without
focus (65%)
– Meningitis
(25–35%)
– Soft tissue, bone,
joint infection, or
pneumonia (5–10%)
Late-late-onset GBS
disease
≥90days
Typical
Fever, irritability,
nonspecic signs
– Bacteremia
without focus
(common)
– Bacteremia with
a focus
(occasional)
Group B streptococcal infections can also affect older infants, children, and
pregnant and non-pregnant women. Invasive disease due to GBS in non-pregnant
adults presents with skin, soft tissue, and bone infections in 36%, unidentied bacteremia in 30%, urosepsis in 14%, pneumonia in 9%, peritonitis in 7%, septic arthritis in 4%, meningitis in 4%, catheter infection in 3%, and endocarditis in 2% [34].
Data on the frequency of GBS disease in children beyond infancy are limited. In
a population-based evaluation of invasive GBS disease in Atlanta, 219 (52%) of 424
patients were children, and 205 (48%) patients were adults [22]. The study reported
that 46% of all patients were newborns, 4% were infants aged 1–12months, and 2%
were children aged 1–17years. In another study, 143 pediatric patients with a positive GBS culture from the normally sterile body uid were identied, and medical
records of 18 (13%) patients >3months old with their rst GBS infection were
reviewed [23]. The age range was 15weeks to 18years, with the median age being
13months. Five infants had premature birth, and two were infected with the human
immunodeciency virus (HIV). The most common (50%) clinical manifestation
was bacteremia without a focus, seen in nine patients. Other clinical manifestations
were sepsis and bullous desquamation in one infant with HIV infection, meningitis
in two adolescents with ventriculoperitoneal shunts (VPS), septic arthritis, endocarditis, central venous catheter, and ventriculostomy infections. Apart from the diseases described above, GBS can present other infections in infants and children in
very different localizations, as depicted in Table27.2 [4, 7, 35–37].
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Table 27.2 Unusual clinical features of infants and children with group B streptococcal infection
Localization and type of infection
Central nervous
system
Abscess Epiglottitis Renal abscess
Cerebritis Supraglottitis Urinary tract infection
Chronic meningitis Tracheitis Epididymo-orchitis
Eosinophilic meningitis Pleural empyema Skin and soft tissue
Subdural empyema Cardiovascular Breast abscess
Ventriculitis Endocarditis Bursitis
Diabetes insipidus Myocarditis Cellulitis/adenitis
White matter injury
Transverse myelitis
Eye Adrenal abscess Impetigo neonatorum
Conjunctivitis Delayed-onset diaphragmatic
Endophthalmitis Gallbladder distention Omphalitis
Ear and sinus Peritonitis Rhabdomyolysis
Ethmoiditis Scalp abscess
Otitis media/mastoiditis
a
Adapted and modied from Refs. [4, 7]
b
Ref. [37]
c
Ref. [35]
d
Ref. [36]
Respiratory tract Genitourinary tract
infection
c
Pericarditis Dactylitis
d
Abdomen Fasciitis
Purpura fulminans
hernia
b
a
27.6 Laboratory Investigation andDiagnosis
The denitive GBS infection diagnosis requires a GBS culture obtained from a
normally sterile region, including blood, CSF, pleural uid, bone aspirate, joint
uid, or soft tissue. Detection of GBS in the skin, umbilicus, or mucous membranes
does not always support the actual infection, so these results should be evaluated
with caution. Blood culture is recommended in infants with suspected GBS disease.
A complete blood count (CBC) is benecial in suspected EOD or LOD, mainly
when used with other sepsis biomarkers. Leukopenia, neutropenia, or a high proportion of immature-to-total neutrophils may be seen; however, their sensitivities are
insufcient. In EOD, the test’s sensitivity is increased when the CBC is analyzed
6–12h after birth [38].
Lumbar puncture (LP) should be performed before antibiotic administration if
there is strong clinical suspicion of infection. It is challenging to distinguish meningitis accompanying early neonatal sepsis from bacteremia without a focus clinically; also, meningitis is detected in only 10–38% of patients without bacteremia
[39]. Therefore, an LP should be performed regardless of whether there is evidence
of meningeal infection if there is clinical suspicion of disease. Even in infants with
focal infection signs, concomitant meningitis can be detected; GBS was isolated in
the CSF in 24% of patients followed up for cellulitis and/or adenitis [40]. Cell count,
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protein and glucose levels, Gram staining, and culture tests in the CSF should be
performed.
In the study of Levent etal. [41], three of 53 patients with GBS meningitis died,
and 11 were followed up with severe neurologic disorders such as resistant seizures
and hypertonicity. These 14 patients who died or had neurological complications at
discharge were more likely to present with seizures during the admission hours,
require pressor support, have a coma or semicoma, and have an initial CSF glucose
<20mg/dL, or protein ≥300mg/dL than were the 39 infants with normal neurologic
examinations.
Lumbar puncture is usually unnecessary in evaluating EOD in newborns appearing well [2]. There is no growth in CSF culture for various reasons in some patients,
but the yield of diagnosis can be increased if polymerase chain reaction (PCR) is
used. The diagnosis rate may increase with new molecular methods, but more studies are needed. A chest radiograph is recommended for newborns with respiratory
symptoms and urine culture with a urinary catheter or suprapubic aspiration for
infants aged over 6days [2]. Imaging methods can be used because surgical drainage may be required in infants with bone and joint infections. Radiographic examination of the kidneys and urinary system may be needed in those with urinary tract
infections.
E. Karadağ Öncel et al.
27.7 Treatment
27.7.1 Empirical andSpecific Treatment
Empirical treatment for possible bacterial agents should be started in newborns and
infants with suspicion of infection. The combination of ampicillin plus gentamicin
used in neonatal infections is effective in GBS infection. However, when GBS is
demonstrated by culture growth, treatment with penicillin G or ampicillin alone is
sufcient [4, 7]. Penicillin G is effective in GBS disease and has less effect in altering the microbiome than ampicillin, which can be used as an alternative for bloodstream infection.
Regardless of gestational age, high-dose ampicillin (300mg/kg/day) with gentamicin should be given to newborns with suspected meningitis and clinical conditions when LP is unsuitable [4]. Although ampicillin plus cefotaxime or ceftriaxone
combination is generally preferred in LOD, if vancomycin is preferred in empirical
therapy and GBS meningitis cannot be excluded, penicillin or ampicillin should be
added to treatment because vancomycin is inhibitory rather than bactericidal invitro
and CSF concentrations may not exceed the minimal inhibitory concentration
(MIC) if a high inoculum of GBS is present [32].
Initial empirical therapy, denitive therapy, and duration of treatment for GBS
infections are shown in Table27.3. Ten days of treatment is sufcient in GBS bacteremia, and the course of antibiotic therapy is 14days in uncomplicated meningitis.
If meningitis due to GBS has been diagnosed, it is recommended to perform a
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Table 27.3 Initial empirical and denitive therapy and duration of treatment for group B streptococcus (GBS) infection
Empirical treatment
Septicemia
Early onset Ampicillin (150mg/kg/day) plus
Late onset (term
infant readmitted)
Late onset
(inpatient)
Meningitis
Early onset Ampicillin (300mg/kg/day) plus
Late onset Ampicillin (300mg/kg/day) plus
Specic treatment
Bloodstream
infection
Meningitis Penicillin G (400,000–500,000U/kg/day) 14–21days
Arthritis Penicillin G (200,000–300,000U/kg/day) 2–3weeks
Osteomyelitis Penicillin G (200,000–300,000U/kg/day) 3–4weeks
Endocarditis Penicillin G (200,000–300,000U/kg/day) 4weeks
a
Adapted and modied from Ref. [7]
b
Empiric therapy is always followed by denitive treatment
c
Assumes that lumbar puncture to exclude meningitis has been performed and that cerebrospinal
uid has no detectable abnormalities
c
a
b
Antibiotics
gentamicin
Ampicillin (300mg/kg/day) plus
gentamicin or cefotaxime until meningitis
is excluded; then ampicillin
Vancomycin plus gentamicin or amikacin 10–14days
gentamicin plus cefotaxime
gentamicin or amikacin plus cefotaxime
Ampicillin (150mg/kg/day) or penicillin
G (200,000U/kg/day)
Duration
10days
10days
Until cerebrospinal uid
sterility and penicillin
susceptibility documented
Until cerebrospinal uid
sterility and penicillin
susceptibility documented
10days
follow- up LP to show that the CSF has become sterile after 24–48h. Babies with a
positive culture should be evaluated for very high bacterial inoculum, severe infection such as ventriculitis accompanied by an obstruction, cerebritis, subdural empyema, septic thrombophlebitis, and an insufcient dose of antibiotics. When
polymorphonuclear leukocytes in CSF are over 30% of the total cells, and the protein level is >200mg/dL, a new evaluation may be required; the duration of the
antibiotics should be extended [32]. If complications develop, the course of treatment can be extended [1].
Contrast-enhanced neuroimaging should be performed before treatment discontinuation in patients with delayed CSF sterilization, prolonged signs of infection, fever
duration >5days, cerebritis, abscess, subdural empyema, or venous thrombosis [4].
Generally, analyzing the MIC and minimal bactericidal concentration (MBC) of
penicillin for GBS isolates is unnecessary. Insufcient clinical or bacteriologic
improvement despite penicillin or ampicillin usage, unexplained relapse or recurrent infection, and the disease developed in a congenital or acquired immunodeciency infant, necessitates studying MIC and MBC [7].
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27.7.2 Supportive Treatment
Although clinical practices usually focus on the specic treatment, prompt and
effective supportive treatment is also very important. Because pneumonia can be
present, especially in EOD, early respiratory failure ndings should be reviewed,
and necessary respiratory support should be started. In the presence of constant
metabolic acidosis or delayed capillary rell time, the initiation of shock therapy
should be considered. Patients with respiratory and circulatory failure signs or meningitis should be admitted to the neonatal intensive care unit. Severe anemia, acidosis, and hypoxemia should be corrected, and anticonvulsant therapy should be
initiated promptly for concurrent seizures. Lastly, in persistent pulmonary hypertension or failure of conventional respiratory therapy, extracorporeal membrane oxygenation (ECMO) might be regarded [4].
27.7.3 Adjunctive Treatment
Adjunctive therapy should be considered in infants with life-threatening infections.
These treatment approaches were not proven and not in the guidelines but can be
used as a supplement on a case-by-case basis. Several adjunctive therapies reported
in the literature are intravenous immunoglobulin (IVIG), monoclonal antibodies to
GBS polysaccharide antigen, growth factors including granulocyte colonystimulating factor (G-CSF), and granulocyte-monocyte colony-stimulating factor
(GM-CSF) for neutropenia and leukocyte transfusion [4, 7].
27.8 Recurrent Infection
Recurrent GBS infection might develop in 0.5–4.5% of infected newborns [42]. The
pathogenesis of the recurrent infections remains unclear. In a population-based
study, 14 (24%) of 84 infants with recurrent invasive GBS disease were twins or
triplets, in 64 (76%) bacteremia, in 16 (19%) meningitis and bacteremia, in three
(4%) meningitis, in six (7%) cellulitis (ve had a positive blood culture) were determined [43]. Among the infants with available information, 42 of 74 (57%) were
preterm, 30 of 50 (60%) were boys, and 28 of 42 (67%) were delivered vaginally.
Recurrence of GBS disease occurred at a median age of 40 (8–141) days. The third
episode of GBS disease was seen in 11 (13%) infants. In this study, multiple births
were an important risk factor for recurrent infection [43].
Recurrent GBS disease is attributable to subclinical persistent mucosal colonization associated with several factors, such as decient host immunity, inadequate
therapy dose or period, microbial hypervirulence, or resistance [44]. Neonatal GBS
infection associated with high relapses can also be attributed to repeated exposition
to exogenous causes, such as contaminated breast milk [44, 45]. Recommendations,
when faced with recurrent infection, are as follows: validate the isolate’s penicillin
sensitivity via MIC testing, evaluate serum immunoglobulins and HIV status,
administer empiric treatment 1 week more than the usual regimen, and regard oral
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