two cases of delayed diagnosis of postpartal streptococcal...

Two cases of delayed diagnosis of postpartal streptococcaltoxic shock syndrome

Wolfram Schummer and Claudia Schummer

Clinic for Anesthesiology and Intensive Care Medicine, Friedrich-Schiller University, Jena, Germany

Background: Puerperal sepsis due to group A b-hemolytic streptococcal (GAS) toxic shock syndrome isassociated with very high morbidity and mortality. Luckily it is now rare, but diagnosis is not always easy. Thisreport demonstrates the problem of recognizing this disease, and summarizes the current knowledge on thepathomechanism and management of streptococcal toxic shock syndrome.Case: Two cases of postpartum streptococcal toxic shock syndrome due to GAS are described. In both casesthe correct diagnosis was delayed for several days. The first patient was sent home with the diagnosis of Germanmeasles; the second patient was transferred to our neurological intensive care unit with the diagnosis of meningitis.Both patients were admitted to the intensive care unit in profound shock, both developed multiple organ failure,and one patient died.Conclusions: GAS may produce virulence factors that cause host tissue pathology. Besides aggressive modernintensive care treatment, early diagnosis and correct choice of anti-streptococcal antibiotics are crucial. A possibleadverse effect of non-steroidal anti-inflammatory agents requires confirmation in a multicenter study.

Key words: PUERPERAL SEPSIS; STREPTOCOCCAL INFECTIONS; BACTERIAL ANTIGENS; NON-STEROIDAL

ANTI-INFLAMMATORY AGENTS; ADVERSE EFFECTS

INTRODUCTION

Puerperal sepsis is a preventable postpartal compli-cation, if early signs are recognized and treatedadequately. The most serious postpartal infection isthe streptococcal toxic shock syndrome (TSS),characterized by the sudden onset of septic shockwith multiple organ failure and the isolation ofgroup A b-hemolytic streptococci (GAS) from anormally sterile body site. The dramatic nature ofthis severe, life-threatening infection is illustratedby the following two cases. Knowledge ofthe pathomechanism of invasive streptococcalinfections might help to understand the course ofthis disease.

CASE 1

After normal vaginal delivery of a healthy boy, thefirst patient (gravida two, para two) developedfever, combined with a macular rash especially ofthe trunk, 3 days postpartum. She was givennon-steroidal anti-inflammatory drugs (NSAIDs)against her fever and was discharged home earlywith the diagnosis of German measles (Figure 1).Seven days postpartum she was readmitted withthe features of septic shock: hypotension, tachy-cardia, tachypnea, and pyrexia. She was put onmetronidazole in combination with mezlocillin.Despite treatment with fluids and vasoactive drugsunder early invasive hemodynamic monitoring she

Infect Dis Obstet Gynecol 2002;10:217–222

Correspondence to: Wolfram Schummer, MD, DEAA, EDIC, Clinic for Anesthesiology and Intensive Care Medicine,Friedrich-Schiller University, Bachstr. 18, 07743 Jena, Germany. Email:[email protected]

Case report 217

progressed to organ dysfunction (Table 1). Theabdomen was soft; the uterus was bulky,anteverted, and tender. Since the focus of infectionwas considered to be the uterus, a hysterectomywas performed. When the diagnosis of a Group Ab-hemolytic streptococcal infection was con-firmed from blood cultures and abdominal swabs –both taken on the day of admission to the intensivecare unit (ICU) (day 1) – penicillin G was added to

the antimicrobial regimen 24 hours later. This wasdone because the activity of Penicillin G againstGAS is four times the activity of Mezlocillin. Withregard to surgery, it was decided against a narrow-ing of antimicrobial therapy. Her stay in theICU was initially characterized by septic shock,disseminated intravascular coagulation (DIC), andmultiple organ failure, including acute renal failurewith the need for continuous veno-venoushemofiltration. The severity and course of illnessare depicted in Figures 2 and 3, respectively.Secondary, left ventricular decompensation due topost-streptococcal myocarditis and critical illnesspolyneuropathy characterized her further stay inthe ICU. After 28 days, she returned to the wardprior to discharge home.

CASE 2

The second patient (gravida two, para one) wasadmitted to the labor ward with premature ruptureof membranes in week 38 of gestation. Shedelivered vaginally a healthy girl within 24 hoursafter rupture of membranes. She did not receiveany antimicrobial therapy. Three days later shecomplained of a frontal headache and muscle achein all limbs combined with a fever up to 39.5°Cthat was treated initially with a NSAID. When shebecame stuperous another 3 days later she wastransferred to a neurological ICU with the diag-nosis of meningitis. On admission she wascomatose, in severe shock and needed immediateintubation (Table 1). Aggressive organ supportwas initiated immediately. A computed cranialtomogram was normal, the cerebrospinal fluid wasclear, she showed 158/3 cells with an increase ingranulocytes, 584 mg/l protein, and a massive

Puerperal sepsis still exists Schummer and Schummer

218 INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY

Figure 1 Patient 1 on readmission: petechial rash ofright foot

Patient 1 Patient 2

Characteristics Day 1 Day 2 Day 1 Day 2

Temperature (°C)Pulse rate (bpm)Blood pressure (mmHg)White blood cell count (109/l)Urine output (ml/6h)

40.1192

80/408.9 (29% bands)

45

39180

100/508.6130

40.4160

70/3021.770

39.4180

110/5012.4—

Table 1 Patient characteristics on admission (day 1) and after 1 day of aggressive supportive intensive care therapy(day 2)

elevated lactate. For streptococcal TSS (puerperalsepsis) she was directly administered piperacillin,sulbactam, and clindamycin for 6 days. After24 hours gram-positive, catalase-negative cocciwere grown from two vaginal swabs and bloodcultures confirmed the diagnosis. The colonies dis-played a strong b-haemolysis; classification of thebacteria, which had been identified as Streptococcuspyogenes, detected Lancefield Group A antigen.Sequencing of the emm gene revealed type 77/27L.The genes for the exotoxins SPE C and SPE Fcould be detected by polymerase chain reaction.Multiple organ failure (cardiovascular, respiratory,renal) and DIC had already been established atadmission to the ICU. Acute anuric renal failureindicated continuous venovenous hemofiltrationfrom day 2 onwards. Severely compromised respi-ratory and cardiovascular function necessitatedcontinuous therapeutic intervention. The severityand the course of illness are again demonstrated byFigures 2 and 3. Organ functions stabilized after12 days but then, unfortunately, she had massiveinfratentorial bleeding which lead to brain deathon day 16.

DISCUSSION

Puerperal infection due to GAS became a raredisease in the 20th century. In recent years GAShave been more important as a cause of perinatalmaternal mortality, and in the last decade there hasbeen again an increase of GAS infection1. The onlyprospective population-based surveillance ofinvasive GAS disease was performed in Canada in1992–32. Invasive GAS disease was defined by theisolation of S. pyogenes from a normally sterile bodysite. The annual incidence of GAS was 1.5 cases

per 100 000 population; the rate for puerperalGAS sepsis was 0.5 infections per 10 000 deliver-ies; and 0.2 GAS infections per 10 000 met thecriteria for streptococcal toxic shock syndrome(streptococcal TSS) (Table 2)3. Here the overallmortality rate was 81%.

As is shown by our cases, early signs and symp-toms of puerperal sepsis due to GAS are apparentlyuntypical and are often misinterpreted due to thelow incidence of this fulminating disease (Table 3).Both patients received NSAIDs against theirunspecific symptoms. In case 1 the diagnosis wasmade 4 days after the occurrence of an erythemaand in case 2, 3 days after the onset of the firstsymptoms. In our two cases, diagnosis of GAS was


INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 219

37 36

24 25

1923

1722

Day 1 Day 3 Day 5 Day 7

40353025201510

50

Poin

ts

Patient 1Patient 2

Figure 2 Course of Acute Physiology and ChronicHealth Evaluation (APACHE) II scores

1513

15 15

11 119 9

Day 1 Day 3 Day 5 Day 7

20

15

10

5

0

Poin

ts (m

ax. 2

4)Pa tient 1Pa tient 2

Figure 3 Course of Multiple Organ DysfunctionScores (MODS)

A IsoIation of group A streptococcus

(1)(2)

From a sterile siteFrom a non-sterile body site

B Clinical signs of severity

(1)(2)

HypotensionClinical and laboratory abnormalities (requirestwo or more of the following:

(a)(b)(c)(d)(e)

(f)

Renal impairmentCoagulopathyLiver abnormalitiesAcute respiratory distress syndromeExtensive tissue necrosis, i.e. necrotizingfasciitisErythematous rash)

Definite case: A1 + B(1+2)Probable case: A2 + B(1+2)

Table 2 Streptococcal toxic shock syndrome isdefined as any group A streptococcal infection associatedwith the early onset of shock and organ failure15

confirmed by blood cultures and abdominal andvaginal swabs. At that time both patients sufferedalready from septic shock according to ACCP/SCCM criteria4 and multiple organ failure. Todemonstrate the severity and the course of illnessand organ dysfunction we applied the AcutePhysiology and Chronic Health Evaluation(APACHE) II and the Multiple Organ Dys-function Score (MODS) (Figures 2 and 3). TheAPACHE II model uses information on physio-logical variables, age, surgical status, and previoushealth status to assign a score to the patient

(Table 4). The APACHE II is the most commonlyused outcome prediction model5. The organfailure scores were developed to quantify organfailure in critically ill patients. A commonly usedscore is the Multiple Organ Dysfunction Score(MODS). This sophisticated score describesincreasing dysfunction of individual organs,measured as a continuum ranging from normalitythrough dysfunction to complete failure6.

GAS may produce virulence factors that causehost tissue pathology. These virulence factors havebeen grouped into four families: adhesins,aggressins (i.e. streptolysin O), impedins (i.e.superantigens), and invasins. The streptococcalpyrogenic exotoxins (SPEs) are polypeptides,produced by certain group A streptococci andbelong to the group of substances known assuperantigens7. They have the capacity to super-stimulate the immune system and thereby induce acascade of cytokines. The action of cytokines isassumed to be responsible for the induction ofthe TSS. Superantigens such as the streptococcalpyrogenic exotoxins do not require processing byantigen-presenting cells before they can stimulateT-cells. These superantigens cause an aberrant



Clinical signs suggestive of puerperal sepsis

Pains: symphyseal, limbs, joints, sore throat, headacheMalaise, flu-like symptomsShort fever, or noneErythematous rashObstipation, diarrhoeaAcral mottlingAltered mental stateTachycardia

Table 3 Early clinical signs suggesting puerperal sepsis

APS/points +4 +3 +2 +1 0 +1 +2 +3 +4

Temperature (°C)Mean arterial pressure

(mmHg)Heart rate (bpm)Respiratory rate

(per minute)Oxygenation: if FiO2 ³0,5A: AaDO2

FiO2 < 0,5: PaO2

(mmHg)Arterial pHNa+ (mmol/l)K+(mmol/l)Creatinine (mg/dl)

(acute renal failure: ´ 2)Hematocrit (%)White blood cells (109/ l)15 – Glascow Coma Scale

³ 41³ 160

³ 180³ 50

³ 500

³ 7.7³ 180

³ 7³ 3.5

³ 60³ 40

39–40.9130–159

140–17935–49

350–499

7.6–7.69160–179

6–6.92–3.4

110–129

110–139

200–349

155–159

1.5–1.9

50–59.920–39.9

38.5–38.9

25–34

7.5–7.59150–1545.5–5.9

46–49.915–19.9

36–38.470–109

70–10912–24

< 200

> 70

7.33–7.49130–1493.5–5.41.6–1.4

30–45.93–14.9

34–35.9

10–11

61–70

3.3–3.4

32–33.950–69

55–696–9

7.25–7.32120–1292.5–2.9< 0.6

20–29.91–2.9

30–31.9

40–54

55–60

7.15–7.24111–119

£ 29.9£ 49.9

£ 39£ 5

< 55

< 7.15£ 110

< 2.5

< 20< 1

Table 4 The APACHE II is the most commonly used outcome prediction model. Acute Physiology Score (APS), thelargest component of the APACHE II score, is derived from 12 clinical measurements that are obtained within 24 hoursafter admission on the ICU. The most abnormal measurement is selected to generate the APS component5

proliferation of specific T-cell subsets and candirectly activate thousands of times more T-cells(up to 25% of the total T-cell population) thanconventional antigens, to produce an acceleratedcascade of cytokines such as interleukins and tumornecrosis factor (TNF)8. At this stage, antibioticsalone can’t control GAS infection.

Additionally we would like to report on anobservation concerning NSAIDs. We have treatedseven patients with proven GAS-TSS either aspuerperal sepsis or as necrotizing fasciitis. Allpatients had ingested NSAIDs while showing earlysigns of their illness. For us it is suggestive thatNSAIDs taken at the early stage of invasive GASinfection may accelerate the cascade systemsand play a contributory role in the onset ofshock, organ failure, cytokine production, andinflammation9. This observation would requireconfirmation in a multicenter study.

Other streptococcal factors, such as streptolysinO, contribute to production of TSS because thissubstance can, at least in vitro, induce TNF andseems to function synergistically with exotoxin10.Due to their virulence factors, GAS spread rapidlyand stimulate the cascade systems maximally11. Theuterus might be the site of initial infection but afterthe rapid hematological spread the uterus is nolonger considered the focus of infection. There-fore currently hysterectomy is not part of first-linetreatment. With streptococal TSS due to puerperalsepsis a patient should be stabilized within 24–48hours. If a patient’s condition deteriorates despiteadequate intensive care therapy (antibiotics: peni-cillin G and clindamycin, and support of failingorgans), hysterectomy should be performed12.

The therapeutic management of severe GASinfections requires high doses of intravenous

antibiotics. Penicillin G traditionally has been theagent of choice, because there is no high-levelresistance among the group A streptococci.Patients allergic to penicillin may be treated with afirst-generation cephalosporin, vancomycin, orclindamycin. Recently, clindamycin has beenrecommended in addition to penicillin for allpatients. Experimental evidence indicates thatclindamycin may be more effective than penicillinat inhibiting these organisms when they are presentin a high inoculum and not dividing rapidly.Evidence comes from in vitro observation of the‘Eagle effect’ as well as animal models. Harry Eaglefirst showed that streptococci present at highinoculum (> 107 cfu/mL) are very slowly killed bypenicillin. Animal models suggest that clinda-mycin, with its inhibition of protein synthesis, hasgreater activity than penicillin against organisms ina stationary phase of growth and may reduceproduction of toxins, and TNF13. Clindamycinalone is not recommended because some strains areresistant, especially in regions where macrolides areused extensively in outpatients. Invasive strepto-coccal TSS is fulminating and may not respond todelayed antibiotic therapy; therefore it is obviousthat antibiotics and aggressive intensive care treat-ment should be started as early as possible.

Immunoglobulin preparations have been givento patients with the intention of neutralizing thestreptococcal toxins, but none of the reports onthis practice is conclusive14. However, ordinaryhuman immunoglobulin preparations containconsiderable amounts of toxin-neutralizing anti-bodies and, given at an early stage of invasivedisease, might have a beneficial effect15. No humanstudies on intravenous immunoglobulins forstreptococcal TSS have been performed so far. And


INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 221

Characteristic/points 0 1 2 3 4

PaO2/FiO2

Serum creatinine (mg/dl)Serum bilirubin (mg/dl)PARPlatelet count (per mL)Glascow Coma Score*

> 300< 1.1< 1.19

< 10> 120

15

226–3001.11–2.29

1.2–3.510.1–15

81–12013–14

151–2252.3–3.99

3.51–715.1–20

51–8010–12

76–1504–5.7

7.01–1420.1–30

21–507–9

< 76> 5.7

> 14> 30< 21

< 7

Table 5 The Multiple Organ Dysfunction Score (MODS); PAR, pulse-adjusted heart rate = HR x (RAP/MAP); HR,heart rate; RAP, right atrial pressure; MAP, mean arterial pressure; *the best estimate in the absence of sedation6

there is still no evidence for the use of otherexperimental approaches like the application ofanti-TNF and plasmapheresis, respectively.

Conclusion: currently, an otherwise healthypatient, with rapid onset of shock and fever evenafter an otherwise normal delivery is at least likelyto suffer from streptococcal TSS. In the absence ofeffective methods of prevention of this devastatingdisease, a high index of suspicion, promptinitiation of antibiotic therapy with agents thatsuppress toxin production, and aggressive organ-supporting intensive care therapy constitute ourbest weapons to fight TSS.

ACKNOWLEDGEMENTS

The authors are grateful to Dr. A. Weiss for helpfulsuggestions and review of this work. The authorsalso would like to acknowledgeall of the staff of theICU who were involved in the care of thesepatients. We thank Dr. D. Mack, Institut fürMedizinische Mikrobiologie und Immunologie,Universitätsklinikum Hamburg-Eppendorf andDr. C. Brandt, Institut für Medizinische Mikro-biologie, Universitätsklinikum der Rheinisch-Westfälischen Technischen Hochschule Aachen,for the isolation and biochemical identification ofthe S. pyogenes strain of the second patient.

REFERENCES1. Stevens DL. Invasive group A streptococcus infec-

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group A streptococcal infections in Ontario,Canada. Ontario Group A Streptococcal StudyGroup. N Engl J Med 1996;335:547–54

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4. Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organfailure. Chest 1992;101:1481–3

5. Knaus WA, Draper EA, Wagner DP, et al.APACHE II: a severity of disease classificationsystem. Crit Care Med 1985;13:818–29

6. Marshall JC, Cook DJ, Christou NV, et al. Multipleorgan dysfunction score: a reliable descriptor ofa complex clinical outcome. Crit Care Med 1995;23:1638–52

7. Bohach GA, Fast DJ, Nelson RD, et al. Staphylo-coccal and streptococcal pyrogenic toxins involvedin toxic shock syndrome and related illnesses. CritRev Microbiol 1990;17:251–72

8. Schlievert PM. Role of superantigens in humandisease. J Infect Dis 1993;167:997–1002

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10. Hackett SP, Stevens DL. Streptococcal toxic shocksyndrome: synthesis of tumor necrosis factor andinterleukin-1 by monocytes stimulated withpyrogenic exotoxin A and streptolysin O. J InfectDis 1992;165:879–85

11. Sriskandan S, Kemball-Cook G, Moyes D, et al.Contact activation in shock caused by invasivegroup A Streptococcus pyogenes. Crit Care Med2000;28:3684–91

12. Petersen EE. Streptokokken-A-Puerperalsepsis.Der Gynäkologe 1999;32:512–17

13. Stevens DL, Gibbons AE, Bergstrom R, et al.The Eagle effect revisited: efficacy of clindamycin,erythromycin, and penicillin in the treatment ofstreptococcal myositis. J Infect Dis 1988;158:23–8

14. Stevens DL. Rationale for the use of intravenousgamma globulin in the treatment of streptococcaltoxic shock syndrome. Clin Infect Dis 1998;26:639–41

15. Stegmayr B, Bjorck S, Holm S, et al. Septic shockinduced by group A streptococcal infection:clinical and therapeutic aspects. Scand J Infect Dis1992;24:589–97

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RECEIVED 02/20/02; ACCEPTED 05/31/02



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