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Genital tract sepsis has been identified as the leading cause of direct maternal deaths in the UK in the last triennium (2006–8).1 Most cases were associated with community-acquired group A streptococcal (GAS) infection. Onset of this infection is often insidious, with women displaying few or no clinical symptoms initially. The infection has the distinctive potential, however, to progress rapidly to a life-threatening invasive infection, toxin-mediated shock and end organ failure, even before clinical signs become apparent.2 Early recognition and prompt intervention are, therefore, necessary to limit the progress of the disease and prevent severe morbidity and maternal mortality.
This review article highlights the key features, prevention strategies and management options for GAS infection, while emphasising the rapidity with which it can cause devastating effects.
There is a wide range of GAS infections, from non-invasive pharyngitis to severely invasive necrotising fasciitis. Puerperal sepsis was one of the most important manifestations of the infection between the 18th and 20th centuries and was the leading cause of maternal morbidity in the developed world.3 In the 1840s, Ignaz Semmelweis achieved a dramatic decline in the prevalence of puerperal sepsis by implementing a system of hand washing that prevented person to person spread.4 The introduction of penicillin in the mid 1940s was the next significant step in controlling the mortality rate of GAS infections.4 The overriding trend through the last century has been for a dramatic decline in severe GAS infections in general.
The incidence of GAS infections is now estimated to be about 3–4 cases per 100 000 population every year in developed countries.5 In the UK, a national enhanced population-based surveillance was commenced in 2003–4 by the Health Protection Agency (HPA), as part of a Europe-wide initiative (Strep-EURO programme).6 The survey reported an overall incidence of 3.33 per 100 000 population of severe GAS infections in the UK during 2003–4, which was similar to that noted in the rest of Europe.7
Two percent of all GAS infections in the UK (or 5% of all GAS infections in adults) during 2003–4 manifested as puerperal sepsis.8 The corresponding data for the USA, although not in comparable units, comes from a recent study9 which estimated that 220 cases of postpartum invasive GAS disease occur annually (0.06 cases per 1000 live births).
While the incidence rate may seem relatively low, GAS infections are significant because of their relatively high mortality rate. The HPA survey5 confirmed the rapid mortality associated with these infections, with 20% of women dying within 7 days of diagnosis. More relevant to the obstetrician are the findings in the Saving Mothers' Lives report1 published in 2011, which highlights that GAS infection was the leading cause of deaths due to puerperal sepsis. This report mentions 26 direct deaths from maternal sepsis (1.13 per 100 000 maternities) during the 2006–8 triennium, 13 of which were due to GAS infection; 6 of these were GAS puerperal sepsis. In a study from the Netherlands of maternal mortality due to sepsis between 1993–2006, Kramer et al.10 reported a maternal mortality ratio of 0.73 per 100 000 live births from sepsis. Group A streptococcus was recognised as an important cause of direct maternal mortality from sepsis, accounting for about 42% of maternal deaths due to puerperal sepsis.
More recently, the incidence of GAS has gained prominence owing to periodic upsurges. An increase in the number of severe cases of GAS infection in the UK was reported in December 2008 and again in December 2010 by the HPA.11–13 The reasons behind these increases are still poorly understood. The potential for a change in the virulence of strains remains possible. In addition, the significant influenza activity in the UK during the seasonal period may have contributed by either increasing transmission of GAS and/or rendering individuals with influenza more susceptible to secondary infections with GAS. One of the distinctive characteristics of GAS infections is, indeed, the seasonal pattern of occurrence. Reviewing data from Europe, USA and Canada, Lamagni8 notes that invasive disease patterns have a higher frequency between late winter and early spring and substantially lower frequency in summer and autumn.
Group A streptococcus (β-haemolytic Streptococcus pyogenes) is a Gram-positive coccus that grows in long chains or pairs. It is classified in the broad category of β-haemolytic streptococci owing to its ability to cause complete disruption of erythrocytes when cultured on a blood agar medium. The bacterium is a commensal of the throat and skin.1 Transmission occurs through inhalation of large droplets from infected patients or through skin to skin contact.
The bacterium can also be present in the vagina, although vaginal–rectal colonisation in late pregnancy is rare (colonisation rates are reported at 0.03%, compared with group B streptococcus, which has a colonisation rate of 20.1%).14 The mere presence of the bacteria in the vaginal flora, however, is not sufficient to cause the disease. An immunocompromised state of the host, commonly a breach in the mucosa or other perineal trauma, is necessary for bacterial invasion. Parturition is usually the time for a breach in the mucosal barrier to occur and the infection reaches the uterus via the endocervix or tissue planes. Septicaemia ensues when the infection reaches the vascular implantation site.
Group A streptococcus has several virulence factors that enable it to colonise, rapidly multiply and spread in its host by confusing the immune system and evading phagocytosis. The capsule of GAS is composed of hyaluronic acid, which allows the bacterium to adhere to and invade human skin and mucosa.15 Resistance to phagocytosis is also facilitated by the M protein, found on the bacterial cell surface, blocking the binding of complement to the underlying peptidoglycan.15 There are over 130 known serotypes of M protein. M proteins are unique to each strain and identification can be used clinically to confirm a strain causing an infection or outbreak.
Among other key virulence factors are pyrogenic exotoxins, which play a major role in the rapid onset of toxic shock syndrome.16 These toxins act as ‘superantigens', which interact with T-cell receptors in a domain outside the antigen recognition site. Unlike conventional antigens, the superantigens do not require processing by the antigen-presenting cells and they interact directly with T-cell receptors, causing massive stimulation of host T cells with a corresponding release of cytokines and interleukins.
Chronic carriers are potential sources of relapsing/recurring GAS infections.17 The streptococci also tend to survive in blankets and personal articles, although their infectivity tends to decrease in the surrounding environment. Hence it is necessary to adhere to strict hygiene and hand washing techniques to prevent hospital-acquired cross infection.
Group A streptococcal infections cause varying degrees of symptoms which range from mild respiratory, cutaneous and soft tissue infections to serious invasive infections. Invasive group A streptococcus (iGAS) infection is defined as an infection associated with the isolation of the bacteria from a normally sterile body site.5 Three clinical syndromes are described (Box 1).5
Table Box 1 . Clinical syndromes resulting from iGAS infection:5 all of these complications have been reported in the puerperium
Streptococcal toxic shock syndrome
• Differentiated from other types of iGAS infections by shock and multi-organ system failure early in the course of the infection
• Extensive local necrosis of subcutaneous soft tissues and skin
Other invasive disease
• Bacteraemia with/without identified focus of infection: the infections are characterised by the isolation of bacteria from a sterile body site in patients not meeting the criteria of streptococcal toxic shock syndrome or necrotising fasciitis
A new case ascertainment definition of severe GAS disease is used for reporting by the HPA,18 which now includes isolation of GAS from a non-sterile site or from a sterile site in combination with a severe clinical presentation (streptococcal toxic shock syndrome, necrotising fasciitis, pneumonia, puerperal sepsis, septic arthritis or meningitis). This definition is a slight expansion on the previous definition of invasive disease (iGAS), which was limited to cases with infection in sterile sites only.
Group A streptococcal puerperal sepsis has diverse manifestations. Typically, the woman presents within the first 48 hours of delivery with fever, rigours and tachycardia. Women can, however, present up to 7 days postpartum. It should be noted that the World Health Organization definition spans an even wider period of presentation: puerperal sepsis is defined as an infection of the genital tract occurring at any time between rupture of membranes or labour and the 42nd day postpartum.19 The earlier the woman presents, the more likely it is that the infection is endogenous in origin, barring the possibility of the risk of a birth attendant being the source of infection.20 Considering that the incubation period of severe GAS infections is usually short, at 1–3 days,21 later puerperal presentations, especially those beyond 7 days, are more likely to be of community origin.
Women can also present with abrupt severe limb22 or chest pain and lower abdominal pain, with or without foul-smelling lochia. Occasionally, early symptoms are like those of influenza or the woman has an altered mental state, prior to deteriorating rapidly and developing streptococcal toxic shock syndrome. The characteristic features of septic shock are highlighted in Box 2.2
Table Box 2 . Characteristic features of septic shock2
Tachycardia: >90 beats/minute
Tachypnoea: >20 breaths/minute
Hypotension: systolic blood pressure ≤ 90 mmHg in the absence of other causes
Elevated serum lactate level
Abnormal liver and renal functions
Positive blood cultures
Severe metabolic acidosis
Life-threatening complications of severe sepsis include disseminated intravascular coagulation and adult respiratory distress syndrome. Recognised complications of this sepsis also include septic ovarian thrombosis and septic arthritis.23
Several atypical presentations such as necrotising fasciitis involving the cervix and uterus24 or caesarean section wounds25 have been reported. Group A streptococcus-infected episiotomy wounds have also been a cause of puerperal sepsis.26
Puerperal toxic shock syndrome causing myositis, rhabdomyolysis, coagulation failure and adult respiratory syndrome due to GAS has been reported.27 Retroperitoneal fasciitis due to GAS infection can occur in the puerperal period.22 Finally, among the rarest presentations, one case of GAS infection complicated by generalised Shwartzman reaction (a rare tissue reaction to endotoxins causing tissue necrosis) caused by GAS has been reported.28
The identification of these complications is vital, as early surgical intervention by hysterectomy or wound debridement may be necessary to limit the disease progression. Recognition of early iGAS infection is, therefore, crucial in planning surgical intervention to restrict progression.
Women presenting postnatally with puerperal sepsis should be promptly investigated. It is essential to do a baseline full blood count; renal function tests, C-reactive protein test; vaginal, placental and wound swabs; and blood cultures at presentation. If the presentation is peripartum, neonatal swabs are essential as well. Neutropenia, altered renal function (raised urea, low total carbon dioxide and high C-reactive protein) can be early predictors of severe sepsis. It is vital to collect blood cultures under aseptic conditions as contamination by skin flora can lead to inappropriate treatment.29 Arterial blood gas analysis is useful to assess morbidly sick women. A coagulation profile is also necessary if there is suspicion of severe sepsis. Other common causes of infection, such as urinary tract infection, pyelonephritis, mastitis and endometritis, must be ruled out based on clinical findings and appropriate investigations.
Further localising signs in the woman can guide the clinician to other investigations. Imaging of the abdomen and puerperal uterus gives a guide to retained products or abscess collection in the pelvis. Ascites due to severe abdominal sepsis would be evident in abdominal scans. Soft tissue swelling presenting with swinging temperatures must invoke a rare clinical suspicion of necrotising fasciitis. While the diagnosis of necrotising fasciitis is mainly clinical, investigations such as X-rays can help in ruling out other conditions and indicate the extent of the disease. X-rays of the affected area may show soft tissue gas in the later stages and may be useful in ruling out septic conditions such as osteomyelitis.
Computed tomography or magnetic resonance imaging of the affected area can help in assessing the extent of involvement and planning surgical debridement. Doppler sonography is useful if thrombosis is suspected.
A swab or blood culture showing group A streptococcus is essential for diagnosis. Gram stains will show Gram-positive cocci in chains or pairs. Culture of the organism on blood agar will show complete haemolysis of the red cells surrounding the colony. To distinguish the organism from other β-haemolytic streptococci, Lancefield grouping should be done, which tests for the presence of group-A-specific polysaccharide in the bacterium's cell wall. If there are outbreaks of GAS puerperal sepsis it is useful to apply molecular characterisation techniques which identify different strains.30
It is vital to understand the different stages through which sepsis progresses when managing a septic woman:1,31
• Bacteraemia occurs when viable bacteria are present in the bloodstream; this progresses to a systemic inflammatory response syndrome when there is an acute inflammatory response in the woman.
• Sepsis occurs when the systemic inflammatory response syndrome is present with an identifiable organism; this progresses to severe sepsis when there is evidence of organ dysfunction or hypoperfusion and hypotension is present.
• Septic shock is sepsis-induced hypotension, despite there being adequate arterial perfusion.
• Multiple organ failure is dysfunction of organs in an acutely ill woman in whom homeostasis cannot be achieved without intervention.
The key characteristic that distinguishes GAS infections from other sepsis is rapid deterioration in the clinical condition of the woman in spite of conservative therapy.2 Another important characteristic is that there may not be any distinguishing risk factors for puerperal infection and women may be fit and well a few hours prior to admission.
The mainstay of treatment is aggressive antimicrobial therapy. Antibiotics need to be commenced immediately, even prior to definitive microbiological diagnosis. Delayed treatment as a result of misdiagnosis of key signs of deep-seated GAS infection is associated with increased likelihood of death.32
It is reasonable in the first instance to give high doses of broad-spectrum antibiotics such as cefuroxime and metronidazole prior to bacteriology results.1 The expert advice of a microbiologist should be sought at an early stage and bacteriology results obtained as soon as possible. Once the diagnosis is confirmed, as all group A streptococci are sensitive to penicillin, intravenous benzylpenicillin is the drug of choice.8 Clindamycin has been shown to suppress the expression of some exoproteins (superantigens) which play a major role in toxic shock syndrome and should be given in addition to benzylpenicillin in severe cases.8,33 In the event of the woman being allergic to penicillin, cephalosporins or vancomycin can be used.8 The choice of additional broad-spectrum antibiotics to combat superimposed bacterial infections in severe disease would need to be discussed with the microbiologist.
While women are initially managed in the labour ward, rapidly deteriorating women need to be transferred to the intensive care or high dependency unit (depending on severity and response). Kramer et al. report that GAS sepsis often requires admission to an intensive care unit.10 Supportive management with generous hydration and analgesia should be given. Strict fluid management is necessary to ensure a balance between adequate hydration and fluid overload. It is mandatory for the woman to be monitored on a one-to-one basis, with observations monitored using the Scottish Early Warning Score chart or the Modified Obstetric Early Warning Scoring System.1 It is also necessary to involve the critical care team, anaesthetists and medical team for multidiscplinary input. Non-steroidal anti-inflammatory agents (NSAIDs) need to be used with caution in invasive streptococcal infections as they can mask the presentation, which can lead to a delay in intervention.34 Moreover, in a septic woman whose renal function or coagulation profile is deranged, the use of NSAIDs is contraindicated.
If the woman does not respond to initial treatment or shows signs of deterioration in spite of aggressive conservative treatment, then it is necessary to look for signs of deep infection. It may be necessary to consider radical surgical interventions such as hysterectomy in the case of invasive endometrial infection or infarction (Figure 1). Occasionally, removal of adnexal tissue may have to be carried out in extensive infection leading to long-term morbidity.23 Surgical wound drainage/debridement and irrigation may be necessary to prevent further tissue damage if there is necrotising fasciitis.
The principles of management of women in critical care are beyond the scope of this article. However, a few interventions specific to GAS are mentioned below.
The use of hyperbaric oxygen in puerperal necrotising fasciitis has not been established. A North American study35 of a series of cases of cervical necrotising fasciitis, however, concludes that hyperbaric oxygen is a useful adjunct to surgical wound debridement and that it can lead to a decreased hospital stay.
The use of intravenous immunoglobulins in invasive streptococcal infections is also still in the experimental stages. This has the potential to neutralise some superantigens and, therefore, to moderate tissue damage.36 It has been proven to be a useful adjunct and a reduction in mortality was noticed in small trials associated with streptococcal infections.36,37
Supportive treatment of the woman and the family is important. Breastfeeding is not contraindicated if the woman is clinically stable, but if there is clinical deterioration then this issue must be addressed.
Transmission of GAS infection is usually through direct contact with droplets of saliva, nasal secretions or infected lesions of people with the condition. Contamination of the perineum is also likely when the organism is transferred from the upper respiratory infection of the woman or close contacts to the perineum via the woman's hands. Women need to be made aware of this and of the need for personal hygiene.1
As mentioned previously, chronic carriers are potential sources of relapsing/recurring GAS infections. A Danish study reported a 7-month outbreak of relapsing postpartum infections with GAS which were ultimately linked to a healthcare worker who was harbouring the bacterium in her dermatitis lesions.17 About 5–12% of all severe GAS infections are found to be associated with health care.38 If more than one case of GAS puerperal sepsis occurs on the same unit within 6 months and typing shows the cases to be caused by the same strain, the possibility of a birth attendant being the source of infection may need to be considered.38 This makes management of the healthcare environment and close community contacts a cornerstone of prevention of GAS infections.
In the UK, the GAS Guideline Development Working Group38 has drafted a set of guidelines for the control and prevention of spread of GAS infection in acute healthcare settings. The key recommendations from this consultation document, which was released in May 2010, are:
• All cases of identified GAS infection should be referred to the infection prevention and control team.
• All cases of iGAS should be notified to the local health protection specialist.
• Healthcare workers should wear protective equipment, including disposable gloves and an apron when in contact with the woman or her equipment and her immediate surroundings.
• Healthcare workers should adhere to a strict hand hygiene policy.
• Visitors should adhere to standard infection control practice, including a hand hygiene policy.
• Women with GAS infection should be isolated, in most cases for a minimum of 24 hours of effective antibiotic therapy.
• The isolation room and equipment should be cleaned thoroughly and the linen and other waste must be handled as infected waste in accordance with the local policy.
• Prophylaxis should be considered for healthcare workers who sustain a needle stick injury with potentially infectious material.
• All healthcare workers in contact with the woman should be considered as possible sources of hospital-acquired GAS.
• Healthcare workers in contact with a case of GAS should be asked to present for screening if they suffer a sore throat, skin infection, skin lesion or vaginitis during the period in question.
• In the event of the screening of a healthcare worker being positive, antibiotics must commence for eradication. The most appropriate antibiotic for eradication of the infection has not been established; however, the recommended antibiotics for a healthcare worker with pharyngeal carriage of the bacterium are:
• oral penicillin V 500 mg four times a day for 10 days or
• amoxicillin 500 mg three times a day for 10 days or
• clindamycin 300 mg four times a day for 10 days or
• azithromycin 12 mg/kg/day (maximum of 500 mg per day) for 5 days.
For non-pharyngeal carriage, penicillin alone may be insufficient. Oral clindamycin or azithromycin may be given (similar dosages as above). Screening to evaluate eradication of infection must be carried out at 24 hours after completing treatment and at 1, 3, 6 and 12 weeks following the end of treatment. Eradication is not essential if the healthcare worker is carrying a different strain to that of the outbreak.
An outbreak should be considered if there is a cluster of two or more cases of suspected GAS infection related by person or place. The interval between case presentations may vary between 1–6° months. Emm sequence typing must be carried out to prove that the cases are related. Recommendations for chemoprophylaxis must be decided by the outbreak control team on a case by case basis.
Figure 2 shows a flow chart published by the HPA, which captures the interim UK guidelines on management of close community contacts very well.5
To reiterate, the key points from the interim guideline are that:
• Antibiotics should be administered both to the mother and baby if either develops iGAS disease in the neonatal period (the first 28 days of life).
• Antibiotics should not be routinely administered to all contacts of GAS cases.
• Close contacts must be educated regarding the signs and symptoms of GAS and asked to report them, if any, in the following 30 days.
Should household contacts of women with group A streptococcus be given prophylactic treatment? The risk of invasive disease among household contacts from an index patient who has invasive disease has not been established. Health authorities have differing views.
The interim Strep-EURO report from 2003, which is based on a comprehensive literature review, concludes that 2000 household contacts would have to be treated to prevent one case of invasive disease. The evidence did not, therefore, support giving chemoprophylaxis to all household contacts.5 Addressing this ethical issue, a further report from the HPA in 2005 suggested educating household contacts about early warning signs and seeking medical advice if they have any.39 Similarly, the Center for Disease Control and Prevention in Atlanta, USA, held a workshop for the prevention of iGAS disease and concluded that routine screening or chemoprophylaxis of patients were not recommended but that practitioners could choose at-risk patients and offer chemoprophylaxis.40
Group A streptococcus has been the cause of sporadic cases of fatal puerperal sepsis. There have been reports of an increasing incidence, especially during winter months following outbreaks of viral infections.
Clinicians must maintain a high degree of suspicion and investigate cautiously when evaluating a septic woman. Parenteral antibiotics are the first line of management, even before diagnosis can be established, to combat rapid progression of this disease. If a woman does not respond to antibiotics, other localising signs must be looked for and acted upon promptly.
Multidisciplinary input is vital and, therefore, all relevant specialties must be alerted. If clusters of septic women present, epidemiological investigation must be carried out to identify strains and investigations must be carried out to identify potential chronic carriers. Healthcare workers are possible sources or carriers of infection. Where they are in contact with infected women, healthcare workers need to be screened and treated.