A 5-Year Review of Recurrent Group B Streptococcal Disease: Lessons from Twin Infants

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1 282 A 5-Year Review of Recurrent Group B Streptococcal Disease: Lessons from Twin Infants Edina H. Moylett, 1 Marisol Fernandez, 1 Marcia A. Rench, 1 Melissa E. Hickman, 1 and Carol J. Baker 1,2 From the 1 Section of Infectious Diseases and Department of Pediatrics and the 2 Department of Microbiology and Immunology, Baylor College of Medicine, Houston, Texas Recurrent invasive disease due to group B Streptococcus (GBS) in twin infants has not been reported. We report 2 cases of recurrent GBS afflicting both siblings of a set of dichorionic twin infants. The maternal and infant colonizing and invasive strains were identical by serotyping and pulsed-field gel electrophoresis (PFGE). Despite attempts at eradication with different antibiotic regimens, the infants remained colonized after treatment of the second episode. A 5-year review of recurrent invasive GBS disease in infants in our affiliated hospitals was undertaken, and 6 further cases were identified. Serotyping and PFGE of isolates from initial and second episodes were genotypically identical for each case. Three infants each had GBS serotype Ia or V disease and 2 had GBS serotype III disease. The exact pathogenesis of recurrent GBS disease remains unclear, but our data support the hypothesis that persistent mucosal colonization with the original GBS strain rather than new acquisition is a pivotal factor in disease recurrence. Group B Streptococcus (GBS) or Streptococcus agalactiae remains an important pathogen in young infants. It is estimated that the incidence of early-onset GBS infection is 1.4 per 1000 live births, whereas that of late-onset GBS disease (at 17 days of life) is 0.4 per 1000 live births [1]. Case-fatality ratios remain high despite advances in intensive care, and neurological sequelae following severe meningitis continue to occur. Invasive infection with this microorganism is most commonly manifested as bacteremia with or without focal infection, such as pneumonia, meningitis, cellulitis-adenitis, osteomyelitis, or arthritis [2]. Among factors increasing the risk for invasive GBS disease in neonates and young infants, twin births has been reported, albeit uncommonly [3, 4]. Another uncommon phenomenon relating to systemic GBS infection in infants is recurrent infection. A prospective active surveillance program in Maryland from 1991 through 1993 revealed an incidence of 0.4% for recurrent episodes of GBS disease in infants [5], and numerous cases of recurrence following early- and late-onset infection have been recorded [6 12]. Although several hypotheses have been proposed to explain these recurrent infections in young infants, definition of the underlying mechanism dictating this uncommon entity remains elusive. To our knowledge, recurrent GBS disease in twin infants has Received 10 May 1999; revised 13 September 1999; electronically published 28 January Reprints or correspondence: Dr. Edina Moylett, Section of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Room 302A, Houston, TX (emoylett@bcm.tmc.edu). Clinical Infectious Diseases 2000;30: by the Infectious Diseases Society of America. All rights reserved /2000/ $03.00 not been reported. In an attempt to further define the pathogenesis of disease recurrence, we describe fraternal twins, each of whom had 2 episodes of invasive infection despite appropriate therapy, and we summarize 6 other cases with recurrences in infants from 1994 through Serotyping and genotyping of GBS strains confirmed that each episode was caused by the original strain rather than by a newly acquired strain. Case Report: Disease in Twins Twin B of fraternal male twins was admitted to our hospital at 20 days of age after 1 day of irritability and a rash on his lower abdomen. Before his arrival, a physician had administered im ceftriaxone. The infant was irritable and afebrile. Examination revealed a 5 5 cm area of erythema, induration, and tenderness of the skin over the left iliac fossa and extending to the proximal aspect of the thigh. The remainder of the physical examination findings were unremarkable. Laboratory studies revealed a total WBC count of 2400/mm 3, with 6% polymorphonuclear leukocytes (PMNs), 50% band forms, and 37% lymphocytes. CSF analysis showed 11 WBCs/ mm 3 with 30% PMNs and 68% monocytes; the protein and glucose levels were normal. Blood, urine, and CSF cultures were sterile. The infant received a 10-day course of parenteral penicillin G (200,000 U/kg/d); response to therapy was apparent by the second hospital day, with almost complete resolution of the cellulitis. Throat and rectal cultures obtained just before discharge yielded GBS. GBS was not isolated from this infant from a normally sterile site probably because of pretreatment with ceftriaxone. However, the clinical picture in addition to

2 CID 2000;30 (February) Recurrent GBS Disease in Infants 283 heavy GBS colonization implied a case of probable invasive GBS infection. Twin A, the 3-week-old brother of twin B, presented to our hospital 24 h after twin B s admission with a 1-day history of fever, irritability, and a rash on the neck. There was a 3 4 cm area of cellulitis over the right posterior auricular region, with obvious discomfort on palpation. The rest of the physical examination findings were normal. Laboratory studies revealed a WBC count of 11,400/mm 3 and normal CSF parameters. GBS was isolated in the blood culture; CSF and urine cultures were sterile. The cellulitis rapidly resolved after administration of parenteral penicillin G (200,000 U/kg/d) for 10 days. A throat culture performed at the time of discharge yielded GBS, but the rectal culture did not. Four days after he was discharged from the hospital, twin B was noted to be fussy and febrile. A 5 5 cm area of erythema involving the right lateral cervical region was noted, and there was tenderness on palpation. The remainder of the physical examination findings were unremarkable. He was readmitted to the hospital, and the WBC count was 6600/mm 3 with 31% PMNs and 19% band forms. The blood culture yielded GBS; CSF and urine cultures were sterile. A CT scan of the neck revealed soft-tissue swelling without abscess formation. The infant initially received iv broad-spectrum antimicrobial therapy. When results of the blood culture became available, penicillin G (200,000 U/kg/d) was substituted to complete a total of 10 days of therapy. Throat and rectal cultures preformed after parenteral therapy remained positive for GBS. Twelve hours after twin B s second admission, twin A was readmitted to the hospital because of irritability and fever of 6 hours duration. The physical examination findings were unremarkable, and the WBC count was 20,000/mm 3 with 27% PMNs and 33% band forms. The blood culture yielded GBS; CSF and urine cultures were sterile. A 10-day course of parenteral penicillin G (200,000 U/kg/d) was administered. A throat culture performed at hospital discharge still yielded GBS. GBS colonization persisted in both twins after completion of treatment for the recurrent GBS disease, despite 2 outpatient courses of oral rifampin (20 mg/kg/d), 1 of 4 days and another of 7 days duration, and 1 of oral clindamycin (30 mg/kg/d for 1 week). Quantitative immunoglobulin and total hemolytic complement values were normal. Both twins remained well during the 9 months of follow-up after their second episodes of GBS infection. The early neonatal period for both twins had been unremarkable except for delivery at 36 weeks gestation. The maternal GBS colonization status was unknown, but a single dose of ampicillin was administered 4 h before delivery of twin A. Ten days postpartum, the mother was admitted to a hospital for treatment of endometritis. Her recovery was rapid after antibiotic therapy was initiated, and she completed treatment at home. Vaginal and rectal swab culture specimens obtained from the mother immediately before her twin infants were discharged from their first period of hospitalization yielded GBS. Methods Study population. Infants at our affiliated hospitals who have 11 episode of invasive GBS infection have been prospectively identified since A recurrent episode of GSB infection was defined as a new illness associated with isolation of GBS from a usually sterile site, occurring at any interval after completion of apparently successful therapy for the initial episode. Strain identification and serotyping. GBS isolates from cases were received from the hospital microbiology laboratory and were serogrouped and serotyped by the capillary-precipitin method [13]. The isolates were stored in Todd-Hewitt broth (Becton Dickinson Microbiology Systems, Cockeysville, MD) with 20% glycerol at 80 C until further study. Chromosomal analysis by pulsed-field gel electrophoresis (PFGE). GBS isolates were thawed and subcultured onto 5% sheep blood agar plates. Subsequently, isolates were prepared for chromosomal digestion by SmaI, as described elsewhere [6]. Melted prepared DNA slices were placed into wells of 1% agarose (IDNa agarose; Intermountain Scientific Corporation, Rockland, ME). Chromosomal DNA fragments then were separated with a contour-clamped homogenous electric field (CHEF-DR II; Bio-Rad Laboratories, Hercules, CA) [6]. Pulse times were ramped from 2 to 55 s over h, at 6 volts/cm. The gels were then stained with ethidium bromide, photographed under ultraviolet light, destained overnight, and rephotographed. Interpretation of the gels was performed by one of us (C.J.B.), who did not know the identities of the specimens. Isolates were designated genetically indistinguishable if their restriction patterns had the same number of bands and if the corresponding bands were the same apparent size. A difference of 1 or 2 bands between isolates was interpreted as representing possible variants of the same strain [14]. Results Eight infants with recurrent invasive GBS infection, including the set of fraternal twins, were identified from January 1994 through December Table 1 summarizes the demographic, clinical, and microbiological findings for these infants. Seven infants (87%) were born before 37 weeks gestation (mean, 30 weeks), and each had a birth weight!2500 g. Seven (87%) were male. Each of the episodes represented late-onset GBS infection. The mean age at initial presentation was 38 days (range, days). One-half of initial infections were nonfocal. Typically the findings for these infants were nonspecific and prompted evaluation for serious bacterial infection. GBS was isolated from the blood of 7 (87%) of the infants (the eighth patient had received im ceftriaxone a few hours before a blood culture specimen was obtained). One patient (patient 5) had GBS isolated from both blood and CSF. Another infant (patient 6) had a central venous catheter at the time of the first episode. Subsequent to antibiotic therapy, his

3 284 Moylett et al. CID 2000;30 (February) Table 1. Patient no., sex Clinical and microbiological features of 8 infants with recurrent group B streptococcal infection. Birth weight, g Gest. age, w First episode Age, d Syndrome Site (serotype) Days of iv antibiotics Second episode Interval, d Age, d Syndrome Site (serotype) 1, M Sepsis Blood (Ia/c) Sepsis Blood (Ia/c) 10 2, M a Cellulitis None b Sepsis/cellulitis Blood (Ia/c) 10 3, M a Sepsis/cellulitis Blood (Ia/c) Sepsis Blood (Ia/c) 10 4, M Sepsis/cellulitis Blood(III) Sepsis Blood (III) 10 5, M Sepsis/meningitis Blood (III); CSF (III) Sepsis/meningitis Blood (III) 21 6, M Sepsis Blood (V) Sepsis Blood (V) 12 7, M Sepsis Blood (V) Sepsis Blood (V) 21 8, F Sepsis Blood (V) Sepsis Blood (V) 14 NOTE. Gest., gestational. a Twin siblings. b Infant treated with ceftriaxone before blood culture was performed. Days of iv antibiotics signs of infection promptly resolved, but the central catheter remained in place after therapy was discontinued; this may have served as a source for the second episode of bacteremia. The catheter was removed during therapy for the recurrence. Three patients (37%), including the twins, had cellulitis at initial presentation. Apart from prematurity, none of the infants had underlying medical conditions. The mean interval between episodes of invasive GBS disease was 9.4 days (range, 4 19 days), and the mean age at presentation with the second episode was 57 days (range, days). Each infant had GBS isolated from blood at disease recurrence. Seven infants had the same clinical syndrome with each episode, even though at recurrence 1 of the twins had cellulitis involving a different anatomic area. Disease recurrence was not associated with fatal outcome or serious sequelae. Each of the infants with bacteremia and/or cellulitis at first presentation received therapy for at least 10 days (mean, 12.5 days; range, days) with a b-lactam antibiotic, most often penicillin G or ampicillin. The doses per day prescribed were as follows: penicillin G, 200,000 U/kg; vancomycin, 45 mg/kg; ampicillin, mg/kg; and piperacillin, 200 mg/kg. The infant with late-onset meningitis (patient 5) received iv ampicillin (300 mg/kg/d) and tobramycin (7.5 mg/kg/d) for 2 weeks, followed by a further 7 days of treatment with ampicillin alone. This infant received 21 days of treatment with cefotaxime for presumed meningitis at recurrence. The second episodes of GBS disease were treated in a similar manner for most patients, with 6 patients receiving vancomycin for the first 48 h as empirical treatment for late-onset sepsis. As a component of an ongoing study, cultures of throat and rectum specimens from the twin siblings were performed immediately after completion of parenteral antibiotic therapy for the first episode of GBS disease. These cultures, the blood culture from twin A, and the vaginal and rectal specimen cultures from the mother all yielded type Ia/c GBS, as did the blood cultures performed for each twin at admission for recurrent infection. Each blood culture isolate of GBS and the throat and rectal isolates obtained before the second episodes were analyzed by PFGE. The GBS isolates from the twins had identical genomic patterns (figure 1), as did the maternal vaginal, and rectal isolates (data not shown). The GBS capsular polysaccharide type was the same for each of the first and second episodes of infection (table 1). Three infants each had disease with type Ia and type V, and 2 had disease with type III. Furthermore, each patient s first isolate was genotypically identical to the second by PFGE (figures 1 3). The digestion patterns for the 2 infants with type III infections and for the 1 infant with type Ia/c (figure 3), as well as for the twins (figure 1), appeared electrophoretically similar by serotype. This was not surprising, given the reported limited diversity of strains within serotypes Ia and III [2, 6]. Similarly, the digestion patterns for the type V isolates were genotypically identical (figure 2). The 3 patients with type V disease had no known epidemiological relationship; each patient was infected during different years. Discussion Recurrence of GBS disease, first reported in the Englishlanguage literature in the mid-to-late 1970s, remains an unusual manifestation of both pediatric [6] and adult GBS infection [5]. The earliest reports of recurrent GBS disease in infants [7, 8] were followed by a plethora of cases [9 12]. However, to our knowledge, this is the first report of this entity afflicting both siblings in a set of dichorionic twins. Walker et al. [8] reported recurrent GBS meningitis affecting 1 member of a set of twin girls, 10 days after type III late-onset meningitis occurred in each infant at 14 and 18 days, respectively. Reports of fatal GBS meningitis occurring in newborn twin infants, both monochorionic and dichorionic, highlighted the increased risk for invasive GBS disease in this group of infants [15]. Vaginal GBS colonization rates are comparable for mothers in twin and singleton pregnancies [4]. However, twin infants have been shown to be at an increased risk for the development of invasive disease, often within h of onset in the index sibling [3, 4]. Among prematurely born twins, in particular, there is a significantly increased incidence of GBS disease as compared with

4 CID 2000;30 (February) Recurrent GBS Disease in Infants 285 is considered an appropriate drug, dosage, and duration of parenteral therapy [17]. The possibility of recurrence of infection caused by persistent mucosal colonization rather than reinfection with a new GBS strain was raised by Green et al. [6]. Five of their 6 patients infected with the same serotypes had genotypically identical GBS isolates by PFGE; for 1 there was evidence that the recurrent disease was caused by an unrelated strain. Repeated infection with an identical strain, as determined by DNA restriction enzyme analysis, was also noted by Denning et al. [18], suggesting that recurrent disease resulted from persistent mucosal colonization. Similar molecular techniques have been used to study adults with recurrent GBS disease. Harrison et al. [5] reported that 13 of 18 isolate pairs were identical. These investigators also noted that the timing to second infection was shorter if recurrent infection was caused by the same strain that was responsible for the first episode. We found (by PFGE) identical genotypes for isolate pairs from the first and second episodes of GBS disease, as well as an even shorter mean interval (9 days) between episodes than in previous series [5, 6]. Since only 1 of our 8 infants had a potential source for disease recurrence (patient 6, who had central venous catheter related sepsis treated in situ during the first episode), Figure 1. Pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA from GBS serotype Ia/c isolates from twin siblings. Lane S, molecular weight standards; lanes A C, patient 3, first- and second-episode GBS blood isolates and throat-colonizing strain at end of treatment for first episode, respectively; lanes D F, patient 2 secondepisode GBS blood isolate and throat- and rectum-colonizing strains at end of treatment for first episode, respectively. that among their term counterparts [4]. It is hypothesized that premature rupture of membranes, with exposure of the second twin to GBS on descent through the birth canal, coupled with genetically dictated host factors and low levels of maternally derived antibodies to GBS capsular polysaccharide, accounts for enhanced risk of disease in some twins [16]. Because of this risk, some experts recommend that the sibling of the index case, if symptomatic, undergo diagnostic evaluation and receive empirical parenteral therapy until results of systemic cultures become available [17]. In a previous report of infants with recurrent GBS disease [6], the mean duration of antibiotic therapy for the first episode was 14 days (median, 14 days; range, days), and each infant in that series received what are considered to be optimal doses of penicillin or ampicillin. The majority of infants with recurrent GBS infection in earlier reports [6 12] in the Englishlanguage literature received low doses of penicillin or ampicillin, in comparison with today s advised dosages [17]. This latter fact may have played a role in recurrent disease in some infants, but each of the infants in our study was treated with what now Figure 2. Pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA from pairs of GBS isolates obtained during initial and recurrent episodes of GBS serotype V infection. Lane S, molecular weight standards. Lanes A and B, patient 7 (blood isolates); lanes C and D, patient 6 (blood isolates); lanes E and F, patient 8 (blood isolates).

5 286 Moylett et al. CID 2000;30 (February) Figure 3. Pulsed-field gel electrophoresis of SmaI-digested chromosomal DNA from pairs of GBS isolates obtained during initial and recurrent episodes of GBS serotypes III (patients 4 and 5) and Ia/c (patient 1) infection. Lane S, molecular weight standard; lanes A and B, patient 4 (blood isolates); lanes C E, patient 5 (CSF and blood isolates, respectively); lanes F and G, patient 1 (blood isolates). recurrence was probably caused by bloodstream invasion by a persistently colonizing strain. Serotype Ia/c was responsible for each of the episodes of invasive disease and was the serotype detected in specimens from the maternal genital tract and the respiratory or gastrointestinal tracts of the twins in the present investigation. These GBS strains had an identical genotype, again suggesting reinvasion from a colonizing site. The same GBS strain persisted despite attempts at eradication, underscoring the resilience of this organism as a member of the normal flora of the human host. Prematurity has long been recognized as an independent risk factor for invasive GBS disease. It has been estimated that preterm birth, at 36 weeks gestation, is associated with a 15% increase in the acquisition of invasive GBS disease [2]. Immaturity of the immune system, especially in relation to absent or very low concentrations of antibodies to GBS capsular polysaccharides, contributes substantially to this elevated risk. In addition to vertical transmission of GBS to the newborn, horizontal acquisition from mother to infant is another proposed mechanism. As demonstrated in this report, the twins mother s gastrointestinal tract was colonized with GBS, a finding supporting postpartum transmission as a possible mode of infant colonization. Serotype V has emerged as a frequent isolate from infants with GBS disease. This serotype was responsible for almost 40% of the recurrences among our patients. Although the numbers are small, these data support the reported shift in distribution of GBS serotypes that cause invasive disease in the United States [19 21]. Before the early 1990s, serotype III was the most frequent serotype causing invasive disease in neonates, especially late-onset infections [2, 17]. Recent data from the Centers for Disease Control and Prevention (Atlanta) have highlighted that the recent emergence of GBS disease caused by serotype V is not due to the appearance of a single clonal type [22]. These investigators examined 45 serotype V GBS isolates collected from 1986 to 1996 and found 17 different patterns by PFGE. They concluded that more than one-half of the strains were identical but that this clone had been in the United States since 1976 [22]. An interesting finding in our study was that each of our 3 infants with recurrent serotype V GBS disease had an identical pattern by PFGE, and this pattern appears related to the most common clonotype, highlighting the fact that more than one-half of type V strains in the United States have a single clonal pattern. Recurrence of GBS disease in neonates and young infants continues to be problematic for the pediatrician. The most likely pathogenesis relates to the persistence of mucosal carriage of GBS despite appropriate antimicrobial treatment for the invasive infection [23]. Recent attempts using oral rifampin for eradication of carriage following invasive GBS disease have been disappointing [24]. Extension of therapy beyond the currently recommended duration for invasive infection in an attempt to eradicate carriage is not recommended. This has previously been shown to be unsuccessful [23]. The duration of treatment for first episodes of early- or late-onset GBS infection should be determined by the clinical syndrome [17]. Finally, owing to the emergence of serotype V as a cause of early- and late-onset neonatal infection, inclusion of this serotype in currently formulated maternal GBS vaccines is of paramount importance. Acknowledgments We extend special thanks to Morven Edwards, M.D., for her critical review of the manuscript and Robin Schroeder for assistance in manuscript preparation. References 1. Centers for Disease Control and Prevention. Decreasing incidence ofperinatal group B streptococcal disease United States, Morb Mortal Wkly Rep 1997;46: Baker CJ, Edwards MS. Group B streptococcal infections. In: Remington JS, Klein JO, eds. Infectious diseases of the fetus and newborn infant. 3d ed. Philadelphia: WB Saunders, 1995: Edwards MS, Jackson CV, Baker CJ. Increased risk of group B streptococcal disease in twins. JAMA 1981;245:

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