Emergency Treatment of Group B Streptococcal Disease

Symposium on The Newborn

Emergency Treatment of Group B Streptococcal Disease Tim C. Miller, M.D., F.A.A.P.*

The plethora of recent journal space devoted to group B streptococcal disease in the neonate attests to the impact which this organism has recently made on perinatal mortality and morbidity. Many reports have concentrated on inborn populations associated with established neonatal care units. In referral units providing intensive care for large geographic areas, such as rural perinatal centers,16 as many as 75 per cent of infants admitted may be transferred from distant areas. The establishment of true intensive care support may therefore be prolonged for varying amounts of time. Stabilization of sick neonates prior to transport becomes, of necessity, a primary concern in programs developed for educational outreach to level I and level II hospitals. With this in mind, a review of our experience with group B streptococcal sepsis in such a rural perinatal center was undertaken.

The Disease Depending upon techniques for culturing and specimen collection sites, from 4.6 to 29 per cent of pregnant women have been shown to be carriers of group B streptococci. 4 , 5,15 Fortunately, it appears that the attack rate for serious infection in infants colonized at birth remains low. 18 ,22 Although colonization rates of 1.2 to 37 per cent have been reported, only 2 to 2.9 per 1000 live births appear to develop serious disease. However, combined morbidity and mortality in this group of infants is estimated to be 50 per cent. 19 The division of neonatal infection into early and late onset groups has been well described. 15 A high incidence of type I-a isolates in early onset disease and of type III strains in the delayed or meningitic form of disease has also been established. 3 , 22 It has become frighteningly apparent to physicians and nurses in neonatal intensive care units that acute onset group B streptococcal disease is clinically indistinguishable from

':'Director. Newborn High-Risk Nursery, St. Francis Hospital; Assistant Professor, Department of Pediatrics, University of Illinois College of Medicine, Peoria School of Medicine, Peoria, Illinois

Pediatric Clinics of North America- Vol. 24, No.3, August 1977

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severe forms of respiratory distress syndrome. I, 25 Indeed there is some pathologic evidence that the streptococcal organism itself might be a stimulus for hyaline membrane formation. 21 We have learned in our regionalization efforts that the association of severe respiratory distress with an infectious process is not well recognized by physicians in smaller hospitals.

Description of the Region Studied In order to describe the impact of this organism on the delivery of rural perinatal care it is necessary to briefly describe the region served. 20 St. Francis Hospital-Medical Center is centrally located in a region of Illinois which serves 23 countries and 33 hospitals in their delivery of perinatal care. The special referral nursery associated with this hospital consists of 15 intensive care beds and 25 intermediate care beds which accept sick neonates from a delivery population of over 18,000 per year, three-fourths of which are referred from smaller hospitals. Transfers occur over a radius of up to 150 miles and are accomplished by trained nurses utilizing either ambulance or helicopter transportation. Of the 32 hospitals referring infants to the center, only two perform more than 1000 deliveries each year. The remaining 30 hospitals are almost equally divided into those which deliver more or less than 500 babies per year. The region is served by approximately 40 obstetricians and 20 pediatricians, with the remaining physicians who care for the pregnant women and infants being classified as general or family practitioners. Misconceptions Identified In conjunction with outreach perinatal team visits to most referring hospitals, an initial assessment of the knowledge of group B streptococcal sepsis in neonates was collected. It became apparent that two major misconceptions were frequently held by many of the physicians and nurses providing immediate neonatal observation and stabilization. The first of these asserts that the premature infant with respiratory distress has hyaline membrane disease until another disease entity is proved to be causing the symptomatology, that is, either by x-ray evidence of pneumonia or by positive culture reports (if indeed cultures were ever taken). Second, with increasing awareness of the pathogenic potential of streptococcal organisms in some newborn infants, the misconception has arisen that only organisms exhibiting beta hemolysis are dangerous to the newborn. Again, recent evidence is clarifying this type of streptococcal classification. The addition of new typing methods in the laboratory has led to the classification of this disease entity as group B streptococcal disease, not B-hemolytic streptococcal sepsis. It will be shown that both of these misconceptions must be clarified before an accurate assessment of this disease process can be brought to bear on smaller hospitals referring sick infants to neonatal intensive care units. Laboratory Techniques With the recognition that clinical and epidemiological evaluation required a rapid and effective way to detect group B streptococci, im-

EMERGENCY TREATMENT OF GROUP

Table 1.

B

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Serological Identification of Streptococci IMMUNOFLUORESCENT POSITIVE

GROUP'

NO. STUDIED

Number

Per Cent

A B C D E

21 46 29 72 41 18 38 84

21 46 29 72 40 18 36 84

100.0 100.0 100.0 100.0 97.6 100.0 94.8 100.0

F G Otherst

CIE Number 21 46 28 72 39 17 35 84

POSITIVE

Per Cent 100.0 100.0 96.6 100.0 95.1 94.4 92.1 100.0

*Lancefield technique. t Streptococci other than groups A through G.

munofluorescence detection was evaluated and finally instituted for the identification of all streptococcal organisms isolated from newborn infants and pregnant women. Formerly, the classic Lancefield method of grouping streptococcal organisms required up to 72 hours for identification. 23 ,24 For a preliminary period, all isolates from our patient population were grouped by comparing counterimmunoelectrophoresis1o , 17 and immunofluorescent techniques27 ,28 to the standard Lancefield grouping technique. 9 There was complete concurrence between Lancefield group B typing and the methodology utilizing immunofluorescence or counterimmunoelectrophoresis (Table 1). Further comparison between Lancefield grouping and the nonserological grouping methods commonly used in other laboratories such as Bacitracin sensitivity, Hippurate hydrolysis, bile-esculin hydrolysis, and 6.5 per cent sodium chloride tolerance failed to show this 100 per cent correlation. Indeed these methods failed to detect a small but significant number and gave false identification to group B organisms. For that reason and because of convenience, the immunofluorescent technique was adopted. By utilizing this method, a significant percentage of group B streptococci were identified in organisms exhibiting alpha and gamma as well as beta hemolysis. 6 This finding has also been reported by others. 12: 26 Table 2 shows the percentage of isolates which were identified as group B in each of the common groups of organisms as identified by an evaluation of the amount of hemolysis present. As demonstrated, a full 20 per cent of the organisms did not exhibit beta hemolysis; therefore, the importance of this observation has significant implications for clinical and epidemiological evaluation of this disease process in perinatal patients. Infants with Respiratory Distress Syndrome More recently, a careful retrospective analysis was undertaken of the charts of all infants less than 30 days of age who had group B streptococci cultured from any site. All infants judged to be clinically normal and thought only to be exhibiting colonization were eliminated. Twenty-six infants exhibited a significant degree of clinical respiratory

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distress. These infants were divided into three groups. Fifteen infants had positive blood cultures, with an additional two infants yielding positive postmorten blood cultures after an initial negative culture. The last group of nine infants consisted of all neonates whose primary symptomatology was related to respiratory distress and who additionally had positive cultures of the ear, nose, and throat but had negative blood cultures. Three of the infants in group 1 who had positive blood cultures also had positive spinal fluid cultures. Gestational ages ranged from 27 to 40 weeks with birth weights ranging from 1100 to 4900 grams; two infants were small and two were large for gestational age, respectively. These infants were transferred either from our own delivery suite, from as close as another hospital across the street, or from as far away as 150 miles. Therefore, no weight or gestational age was spared the consequences of group B streptococcal disease. Seventeen of twenty-six infants had positive premortem or postmortem blood cultures. Twelve of the seventeen infants with either positive pre mortem or postmortem blood cultures died. The nine remaining infants had positive upper airway cultures. Four of the nine infants with upper airway cultures also died. Autopsies were performed on 13 of the 17 infants. If only those infants with positive blood cultures are included, the overall mortality was 67 per cent. However, two thirds of all infants with some sign of respiratory distress and who had group B streptococci cultured from blood or upper airway did not survive the neonatal period. Of the 13 infants autopsied, there was only one in whom gram-positive cocci in chains could not be identified in final preparation of lung tissue. It is important that two infants with negative blood cultures but with positive upper airway cultures who were autopsied had organisms present on microscopic lung specimens. We feel strongly that an infant with respiratory distress and positive upper airway cultures might be infected with group B streptococcal disease, in spite of a negative blood culture. This impression is enhanced by the identical clinical presentation of those babies exhibiting respiratory distress and by the association of autopsy findings compatible with streptococcal pneumonia. Infants with Proven Sepsis The remaining discussion analyzes factors which might be associated with survival including only infants with positive blood cultures. Our experience did not compare favorably with previously reported ma-

Table 2. HEMOLYSIS

Beta Alpha Gamma Total

Hemolytic Pattern of Group B Streptococci NO. OF ISOLATES

PERCENTAGE

207 9 47 263

78.7 3.4 17.9 100.0

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ternal, infant, and laboratory findings associated with group B streptococcal disease. Prolonged rupture of membranes did not correlate with outcome; indeed, in several of the infected infants, the membranes ruptured immediately prior to the final minutes of delivery. Maternal complications and Apgar scores were not significantly different in those who survived versus those who died. X-rays in most instances were indistinguishable from the classic reticulogranular appearance of hyaline membrane disease. Complete blood counts, platelet counts, and IgM were not significantly different in predicting the outcome. There did appear to be an association with total white counts below 6000 in most infants. As reported recently, compliance of the lungs in septic infants appears to be greater than that of infants exhibiting pure hyaline membrane disease.! Because we were not using volume ventilation, we could only notice that lower pressures than usual could be utilized in adequately ventilating these infants. Since no specific parameters utilized after admission of the infant to the intensive care unit appeared to be associated with an accurate prognosis, it was decided to review charts sent with each infant from the referring hospital for an evaluation of symptomatology and decisions made prior to transfer. In this way, it was thought that severity of the disease process might be related to the timing of care delivered to each infant. From evaluation of nurse's notes from the minute each infant arrived in the respective nurseries, it was determined that all infants with the exception of four were immediately recognized as having respiratory distress, evidenced by retractions, cyanosis, and grunting. These four exceptions will be discussed later. The appearance of immediate symptoms in most infants did not appropriately identify those infants who were to survive. Accordingly, the following three timed episodes or events which could influence outcome were tabulated: (1) age when seen by a physician; (2) age when a decision was made to transfer; and (3) age at arrival in the intensive care unit. None of the events correlated with survival. There was extreme variation in all of these parameters - some being transferred after immediate examination in the delivery room, others being given oxygen orders over the telephone with a subsequent decision to transfer after oxygen was shown to fail to relieve symptoms, and still others being recognized as exhibiting significant respiratory distress, but not being transferred until after apnea developed.

Apnea and Time of Antibiotic Administration As this infectious etiology for respiratory distress would appear to be influenced by the administration of antibiotics, the age of the infant at the time of antibiotic administration was evaluated. This parameter appeared to show some significant differences in whether or not the infant survived. The earlier the use of antibiotics, the greater the chance of survival. 2 .!3 Four infants did not receive antibiotics until 24 hours or greater. Each of these babies exhibited no immediate respiratory distress and exhibited symptomatology characteristic of a gradual onset of sepsis-increasing lethargy, failure to retain feedings and, finally,

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periods of apnea. Three of four infants also had positive spinal fluid cultures. These were the only infants in the study to have meningitis. As specific typing of the organisms which were isolated was not available, the subgrouping of the organisms responsible for this "semiacute" group B streptococcal disease cannot be determined. It would be interesting to postulate that these organisms might have been subgrouped as the type III organism which has been isolated from delayed onset meningitis seen later in neonatal life. The remaining infants can be grouped as to whether or not they received antibiotics prior to or after 8 hours of life. This was a purely arbitrary decision utilizing one nursing shift as to ability to diagnose and treat quickly. Two infants received no antibiotics and both died. All of the infants who died were born in a referring hospital. None of the infants born at our own hospital died. With only one exception, infants who received antibiotics prior to 8 hours lived. In the reverse order, with one exception, infants who received antibiotics after 8 hours died. This left us with an incomplete but clinically significant prognostic indicator- with only two exceptions the earlier the infant was given antibiotics, the better were his chances for survival. On further analysis of the remaining infants, it was found that all infants who exhibited acute respiratory distress persisting past the first hour after delivery and who then developed apnea prior to the first 24 hours of life died. On the other hand, the four infants who had immediate respiratory distress but who did not develop apnea, even if antibiotics were administered after 8 hours, all survived. Thus it appears that apnea associated with group B streptococcal disease is extremely ominous. To await the appearance of apnea in an infant with respiratory distress immediately after delivery before administering antibiotics appears to be untenable.

Protocol for Immediate Management of Respiratory Distress We have recently established a protocol for the immediate treatment of an infant of any gestational age with respiratory distress after one hour of age. This protocol divides infants into two groups: Infants at high risk for infection (ampicillin and gentamiCin) 1. Apnea < 24 hours of age 2. Asphyxia- Apgar:=; 7 at 5 minutes 3. Shock - blood pressure:=; 2 S.D. from mean 4. Bag of water rupture 2:12 hours 5. Maternal infection and/or fever (2:100 4 ) 6. Foul-smelling amniotic fluid 7. Positive gastric aspirate 8. Prematurity « 34 weeks) Infants at low risk for infection (penicillin G) N one of above

Since the risk factors encompass the possibility of gram-negative infection as well as group B streptococcal disease, a broad spectrum antibiotic is added to penicillin. On the other hand, if the infant does not have any of the factors associated with a high risk for infection but is still exhibiting respiratory distress, the possibility of group B streptococ-

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cal pneumonia should be entertained and penicillin alone is' administered. A plan for the emergency treatment of acute respiratory distress in the newborn infant to be delivered in community hospitals was initiated and entails the following points: (1) In any newborn of any weight or gestational age who is exhibiting respiratory distress (such as increasing Silverman score and cyanosis in room air) after the first 30 to 60 minutes of neonatal adaptation, it becomes mandatory that this patient be seen and assessed by a physician. (2) Immediate cultures are obtained (routine septic work-up plus a spinal tap for high risk infants and blood culture and nasal culture for low risk infants). (3) Penicillin or ampicillin, with or without gentamicin, is then administered immediately. (4) Finally, transfer arrangements are made and the infant, along with the culture samples, is sent to the high risk nursery. This allows for appropriate evaluation of culture and grouping reports at the referral center.

REFERENCES 1. Ablow, R. C., Driscoll, S. G., Effmann, E. L., et al.: A comparison of early-onset group B streptococcal neonatal infection and the respiratory-distress syndrome of the newborn. New Engl. J. Med., 294:65-70,1976. 2. Alojipan, L., and Andrews, B. F.: Neonatal sepsis. Clin. Pediat., 14:181-185, 1975. 3. Baker, C. J., and Barrett, F. F.: Group B streptococcal infections in infants. J.A.M.A., 230:1158-1160, 1974. 4. Baker, C. J., and Barrett, F. F.: Transmission of group B streptococci among parturient women and their neonates. J. Pediat., 83:919-925, 1973. 5. Baker, C. J., Barrett, F. F., and Yow, M. D.: The influence of advancing gestation on group B streptococcal colonization in pregnant women. Am. J. Obstet. Gynecol., 122:820-823, 1975. 6. Baman, S. I., Kelly, C. E., and Miller, T.: Group B streptococci isolates in neonates: Clinical bacteriologic and autopsy studies (abstract). Am. J. Clin. Pathol., 65:261, 1976. 7. Battaglia, F. C., and Lubchenco, L. 0.: Classification of newborns by birth-weight and gestational age and by neonatal mortality risk. J. Pediat., 71 :161,1967. 8. Behrman, R. E.: Group B streptococci: The new challenge in neonatal infections. J. Pediat., 82:703-706,1973. 9. Cropp, C. B., Zimmerman, R. A., et al.: Serotyping of group B streptococci by slide agglutination fluorescence microscopy, and microimmunodiffusion. J. Lab. Clin. Med., 84:594-603, 1974. 10. Edwards, E. A., and Larson, G. L., Serological grouping of hemolytic streptococci by counter-immunoelectrophoresis. Appl. Microbiol., 26:899, 1973. 11. Eickhoff, T. C., Klein, J. 0., et al.: The issue of prophylaxis of neonatal group B streptococcal infection . .T. Pediat.,83:1097-1100, 1973. 12. Facklam, R. R.: A review of the microbiological techniques for the isolation and identification of streptococci. Crit. Rev. Clin. Lab. Sci., 6:287-317, 1976. 13. Farquhar, J., and Andrews, B. F.: The changing bacteriologic pattern of newborn septicemia. J. Kentucky Med. Assoc., 73:657-659, 1975. 14. Feigin, R.: The perinatal group B streptococcal problem: More questions than answers. New Engl. J. Med., 294:106-107, 1976. 15. Franciosi, R. A., Knostman, J. D., and Zimmerman, R. A.: Group B streptococcal neonatal and infant infections. J, Pediat., 82:707-718,1973. 16. Hein, H. A., Christopher, C., and Ferguson, N. N.: Rural perinatology. Pediatrics, 55:769773,1975. 17. Hill, H. R., Riter, M. E., Menge, S. K., et al.: Rapid identification of group B streptococci by counterimmunoelectrophoresis. J. Clin. Microbiol., 1 :188, 1975. 18. Horn, K. A., Meyer, W. T., Wyrick, B. C., et al.: Group B streptococcal neonatal infection. J.A.M.A., 230:1165-1167, 1974. 19. Horn, K. A., Zimmerman, R. A., Knostman, J. D., et al.: Neurological sequelae to group B streptococcal neonatal infection. Pediatrics, 53:501-504, 1974. 20. Illinois Committee for Perinatal Health: A plan for perinatal health in Illinois. Illinois Department of Public Health, July, 1974.

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21. Katzenstein, A., Davis, C., and Braude, A.: Pulmonary changes in neonatal sepsis due to group B B-hemolytic streptococcus: Relation to hyaline membrane disease. J. Infect. Dis., 133:430-435, 1976. 22. Klesius, P. H., Zimmerman, R. A., Mathews, J. H., et al.: Cellular and humoral immune response to group B streptococci. J. Pediat., 83:926-932, 1973. 23. Lancefield, R. C.: A serological differentiation of human and other groups of hemolytic streptococci. J. Exp. Med., 57:571-595,1933. 24. Lancefield, R. C.: Loss of the properties of hemolysin and pigment formation without change in immunological specificity in a strain of Streptococcus haemolyticus. J. Exp. Med., 59:459-469, 1934. 25. Quirante, J., Ceballos, R., and Cassady, G.: Group B B-hemolytic streptococcal infection in the newborn. Am. J. Dis. Child., 128:659-665,1974. 26. Roe, M. H., Todd, J. K., and Favara, B. E.: Nonhemolytic group B streptococcal infections. J. Pediat., 89:75-76,1976. 27. Romero, R., and Wilkinson, H. W.: Identification of group B streptococci by immunofluorescence. Appl. Microbiol., 28:199, 1974. 28. Watson, B. K., Kunz, L. J., and Moellering, R. C.: Identification of streptococci: serogrouping by immunofluorescence. J. CUn. Microbiol., 1 :268, 1975. 29. Yow, M.: Group B streptococci: A serious threat to the neonate. J.A.M.A., 230:1177-1178, 1974. Director, Newborn High-Risk Nursery St. Francis Hospital 530 N.E. Glen Oak Avenue Peoria, Illinois 61637