Management of Primary Group A Streptococcal Peritonitis: A Systematic Review

Abstract

Background:

Over the past 20 years, there has been a global increase in the incidence and severity of group A streptococcal diseases. Primary group A streptococcal peritonitis is a life-threatening disease that may present in previously healthy individuals and progress to shock and severe organ dysfunction within a few hours. Our goal was to develop recommendations regarding the care of this group of patients.

Methods:

A systematic review of all adult cases of primary group A streptococcal peritonitis described in the English-language literature between January 1990 and December 2011.

Results:

Thirty-two patients with a median age at diagnosis of 38 years and a male:female ratio of 1:4 are described. Exploratory laparotomy was performed in 25 patients, 17 of whom had undergone abdominal computed tomography (CT). Laparoscopic peritoneal lavage was performed in five patients, and, in two patients, no operative interventions were undertaken.

Conclusion:

The worrisome increase in invasive group A streptococcal disease means that presentations of primary group A streptococcal peritonitis are likely to become more common. The challenge for the treating surgeon is to consider the possibility of this diagnosis. In the current era of multi-detector CT technology, secondary peritonitis from an intra-abdominal source may be excluded reliably using abdominal CT. Exploratory laparotomy is not mandated, and paracentesis is sufficient to confirm the diagnosis and avoid operative morbidity in patients with localized intra-peritoneal fluid collections. Laparoscopic peritoneal lavage should be reserved for patients with widespread intra-peritoneal free fluid or whose condition deteriorates despite antibiotic therapy.

Group A streptococcus (GAS; Streptococcus pyogenes) is a ubiquitous organism that causes a range of infections, from non-invasive pharyngitis to severely invasive necrotizing fasciitis. Over the past 20 years, the incidence of invasive GAS infections, defined as the isolation of GAS from a normally sterile site, has increased globally secondary to the emergence of new, more virulent strains [1]. Recently, periodic upsurges in invasive GAS infections have been reported in several countries across Europe and North America. An increase in the number of severe cases of GAS infection in the United Kingdom in both December 2008 and December 2010 prompted the chief medical officer to write to hospitals emphasizing the need for clinical vigilance, early diagnosis, and rapid initiation of treatment in suspected cases [2].

Primary GAS peritonitis is a fulminant process that presents sporadically in previously healthy individuals and progresses to shock and severe organ dysfunction within a few hours. It is defined as an isolate-proved peritonitis occurring in a patient without ascites or an intra-abdominal source of infection (for example, appendicitis). Whereas primary GAS peritonitis is a rare manifestation of GAS sepsis, the increasing global incidence and severity of GAS infections over the past two decades means that presentations are likely to become more common [3,4]. A systematic review of adult cases of primary GAS peritonitis published between 1990 and 2010 was undertaken with regard to the pathogenesis, diagnosis, and treatment of this disease in order to develop recommendations regarding the care of this group of patients.

Patients and Methods

Relevant primary studies were identified by conducting an electronic search of the MEDLINE, PubMed, and Embase databases using combinations of the following search terms: “Streptococcus pyogenes,” “group A streptococcus/streptococcal,” “primary/spontaneous,” and “peritonitis”. The search was limited to articles published in English between January 1990 and December 2011. A comprehensive hand-based search of reference lists of published articles and review articles was performed to ensure inclusion of all possible studies and to exclude duplicates.

The inclusion criteria were peritonitis (without established ascites or an intra-abdominal source of infection) in an adult patient (>16 years of age) with isolate-proved GAS infection. This was defined as a pure monomicrobial growth of GAS on culture of blood, peritoneal fluid, or debrided tissue, or the presence of purely gram-positive cocci on gram stain of peritoneal fluid.

Data were extracted using a standardized electronic form. The following were recorded: The patient's age, gender, and medical history; the presumed source of GAS infection; gram stain and culture results; radiologic investigations; operative management; and clinical evidence of streptococcal toxic shock syndrome (STSS, skin erythema/rash/desquamation).

Results

The search strategy identified 23 articles [5 –27] that were suitable for analysis. Outcomes of 32 adult cases of primary GAS peritonitis were examined. A summary of the characteristics of each of the included patients is shown in Table 1.

Table 1.

Characteristics of 32 Adult Patients with Primary Group A Streptococcal Peritonitis

Ref (year)	Age/gender	Presumed source	CT?	Laparotomy?	Cultures	Notable medical history	STSS?
5 (1990)	44/M	Pharyngitis	No	Yes	P+, B+	Alcoholism	No
6 (1990)	50/F	Unidentified	No	Yes	P Gm+, B+	None	Yes
6 (1990)	58/F	Unidentified	No	Yes^a	B+	Immunosuppression for RA	No
7 (1990)	87/F	Unidentified	No	Yes	P+, B+	None	No
7 (1990)	42/F	Unidentified	Yes	No (paracentesis)	P Gm+	Alcoholism, type II DM	No
8 (1995)	39/F	Aerosol^b	No	Yes	P+	None	Yes
9 (2000)	39/F	Vaginal	No	Yes	P Gm+, V+, B+	None	No
10 (2001)	33/F	Vaginal	No	Yes	P Gm+, V Gm+, B+	None	No
11 (2001)	36/F	Vaginal	No	No (laparoscopy)	P+, V+, B+	None	No
12 (2001)	39/F	Unidentified	Yes^a	Yes^a	P+, T+	None	Yes
13 (2001)	52/F	Unidentified	Yes	Yes	P Gm+	None	No
14 (2001)	34/M	Unidentified	Yes	No (laparoscopy)	P+	None	No
15 (2004)	29/F	Aerosol^b	Yes^a	Yes^a	P+	1 month post-CS	No
16 (2004)	40/M	Aerosol^b	Yes	Yes	P+	None	Yes
17 (2005)	54/F	Unidentified	Yes	No (laparoscopy)^c	B+	None	Yes
17 (2005)	82/F	Unidentified	Yes	No	B+	Lung cancer	No
18 (2006)	38/F	Unidentified	Yes	Yes	P+	3 months post-CS	No
18 (2006)	30/F	Vaginal	Yes^a	Yes	P+, V+, B+	3 months post-CS	Yes
19 (2006)	23/F	Unidentified	Yes	Yes	B+	None	No
20 (2008)	28/F	Vaginal	No	Yes	P+, V+, B+	None	No
21 (2008)	35/F	Unidentified	No	No (laparoscopy)^c	P+	IUCD in situ^d	No
22 (2009)	36/M	Unidentified	Yes	Yes	P+, B+	None	Yes
23 (2009)	38/M	Insect bite	Yes	Yes^a	P+, B+	None	No
24 (2010)	27/F	Unidentified	Yes	Yes^a	B+	None	No
25 (2010)	39/F	Unidentified	Yes^a	Yes	B+	None	Yes
26 (2010)	35 (23–43)^e/1M 5 F	Fasciitis (2 patients) Unidentified (4 patients)	Yes (6 patients)	Yes (6 patients)	P+, B+	None	Yes (5 patients)
27 (2011)	23/F	Pharyngitis	Yes	No (laparoscopy)	P+	None	No

Retroperitoneal involvement seen on CT or at laparotomy (psoas thickening/edema/microabscess formation).

Patients with children with concomitant group A streptococcal pharyngitis.

Delayed laparoscopy.

Device not cultured.

Median age (range) for six patients.

B=blood; CS=caesarean section; CT=computed tomography; DM=diabetes mellitus; Gm+= gram-positive cocci; IUCD=intrauterine contraceptive device; P=peritoneal; RA=rheumatoid arthritis; STSS=streptococcal toxic shock syndrome (description of skin erythema/rash/desquamation); T=tissue; V=vaginal.

The median age at diagnosis was 38 years (range 23–87 years) with a male:female ratio of 1:4. The source of infection was identified presumptively in 13 patients, being vaginal in five patients [9 –11,18,20], pharyngitis in two patients (on the basis of a history of recent upper respiratory tract infection) [5,27], superficial soft tissue infection in one patient [23], and necrotizing fasciitis in two patients [26]. Aerosol transmission of infection was presumed in the cases of three patients with children with concomitant GAS pharyngitis [8,15,16]. The portal of entry of GAS was obscure in 19 patients. One patient was immunosuppressed secondary to long-term corticosteroid therapy [6]. A further four patients had risk factors for altered host defences (diabetes mellitus, alcoholism, malignant disease, or advanced age) [5,7,17].

An exploratory laparotomy was performed in 25 patients, 17 of whom had undergone abdominal computed tomography (CT) scanning. Diagnostic laparoscopy was performed acutely in three patients [11,14,27]. In two patients, antibiotic treatment was initiated on the basis of gram-positive cocci seen on staining of peritoneal fluid obtained by paracentesis [7,21]. One of these patients subsequently underwent diagnostic laparoscopy five days post-admission to exclude an underlying gynecologic etiology [21]. Two patients who had undergone abdominal CT scanning to exclude a surgical cause of peritonitis were commenced on antibiotics on the basis of positive blood cultures [17]. Diagnostic laparoscopy was performed on one of these patients on Day 3 post-admission because of deterioration in her clinical condition despite intravenous antibiotics [17].

In seven of 32 patients with primary GAS peritonitis, there was objective evidence of associated retroperitoneal inflammation on abdominal CT or at laparotomy that ranged from psoas thickening and retroperitoneal edema to microabscess formation [6,12,15,18,23 –25]. A description of the skin manifestations of STSS was noted in 13 of 32 patients [6,8,12,16 –18,22,25,26]. All of the patients in this review were reported to have survived.

Discussion

Recent epidemiologic data suggest that the incidence of invasive GAS disease is rising. Although primary GAS peritonitis accounts for only 2% of invasive GAS infections [3,4], the generalized increase in the incidence and severity of GAS infections means that presentations are likely to become more common. A systematic review was therefore undertaken to summarize the knowledge on this topic and provide recommendations regarding its management.

Pathogenesis

The pathogenesis of primary GAS peritonitis remains controversial, and, in concordance with other manifestations of streptococcal sepsis, the portal of entry is obscure in more than 50% of cases [28]. Ascending infection from the vagina has been implicated, as there is a female preponderance of reported cases, and GAS is an occasional colonizer of the female genital tract [29]. Although GAS is not part of the normal bowel flora, direct transluminal spread from the colon in cases of streptococcal proctocolitis also has been postulated as a cause of primary GAS peritonitis [7].

Primary GAS peritonitis also may arise as a result of hematogenous spread of GAS from a distant site, most commonly the upper respiratory tract. Although there may be a history of pharyngitis [5,27], a transient asymptomatic bacteremia from occult throat colonization as a result of being close to a child with tonsillitis may be sufficient for GAS to seed to the peritoneum [8,15,16]. The presence of minor skin trauma (for example, an insect bite [23]) or the development of necrotizing fasciitis of an extremity [26] also may raise the suspicion of streptococcal infection in a patient with peritonitis.

Interestingly, seven of the 32 cases of primary GAS peritonitis described above also exhibited retroperitoneal inflammatory changes. Whereas polymicrobial retroperitoneal necrotizing fasciitis typically arises from local pericolic or perirectal sepsis [30], GAS retroperitoneal inflammation reflects the hematogenous spread of GAS from a distant site to the retroperitoneum. From here, GAS organisms may translocate across the peritoneum and cause primary GAS peritonitis.

Different GAS strains exhibit variable virulence, with some serotypes more commonly associated with invasive GAS disease [31]. The M protein of GAS is a major virulence factor that confers resistance to phagocytosis, with M types 1, 3, 12, and 28 the most common isolates in patients with shock and multiple organ dysfunction syndrome [1]. Patients who lack protective humoral immunity to GAS virulence factors also may be more susceptible to invasive GAS disease. Several studies have shown that patients with invasive GAS disease have significantly lower serum titers of antibodies against M proteins and GAS bacterial toxins than do sera from patients with non-invasive disease [32,33].

The GAS bacterial toxins can act as superantigens, bypassing normal major histocompatibility antigen-restricted antigen processing and stimulating the repetitive cycle of immune-cell expansion and rampant cytokine release that causes STSS. In 13 of the reported cases of primary GAS peritonitis, a description of the skin manifestations of STSS was recorded. However, this probably is an underestimation of its prevalence, as the current definition of STSS includes streptococcal toxin-mediated hypotension and organ dysfunction [34].

Necrotizing fasciitis occurs when hemolysins, deoxyribonucleic acid (DNA)-ase, proteases, and collagenases released by streptococci embedded in tissue undermine surrounding tissue rapidly and progressively by a process of coagulative necrosis [35]. Hypoalbuminemia caused by the ensuing disseminated intravascular coagulation and capillary leak syndrome results in edema, hypotension, and respiratory distress [36]. Both STSS and necrotizing fasciitis may present in previously healthy people as primary GAS peritonitis, with severe septic shock and multiple organ dysfunction emerging in just a few hours [28].

Diagnosis

The initial clinical manifestations of primary GAS peritonitis are variable and can range from isolated peritonitis with normal hemodynamic status and no signs of streptococcal infection to fulminant sepsis with necrotizing fasciitis and STSS [26]. In patients with acute abdominal pain of unknown cause, abdominal CT reliably excludes secondary peritonitis from an intra-abdominal source [37]. The absence of a surgical cause for peritonitis raises the suspicion of a primary process (Fig. 1). In patients with suspected primary GAS peritonitis, a sample of intra-peritoneal fluid should be sent for urgent gram stain and culture. The presence of purely gram-positive cocci in chains on microscopy of peritoneal fluid provides rapid initial confirmation of the diagnosis. In patients with a localized fluid collection (for example, in the rectouterine pouch), peritoneal fluid may be obtained via ultrasound- or CT-guided paracentesis to avoid operative morbidity.

FIG. 1.

Algorithm for initial management of suspected primary peritonitis. OR=operating room.

Treatment

Although there is no evidence that peritoneal lavage improves the prognosis in primary GAS peritonitis (and the rarity of this infection means that comparative therapeutic trials are unlikely to be conducted), the importance of drainage to reduce the bacterial load has been underlined in STSS [38]. Therefore, in patients with widespread intra-peritoneal free fluid on CT, or whose condition deteriorates despite antibiotic therapy [17], peritoneal lavage should be undertaken. Laparoscopic lavage permits satisfactory management of peritonitis arising from diverticulitis and appendicitis [39,40] and is an appropriate surgical approach in primary GAS peritonitis.

Although antibiotic therapy may be guided by the gram stain of aspirates, rapid instigation of broad-spectrum empirical therapy with subsequent rationalization based on culture data is a pragmatic approach. Whereas GAS is almost invariably penicillin sensitive, the efficacy of these drugs in severe infections may be diminished as a result of the organisms being largely in the stationary phase [41]. Clindamycin switches off exotoxin production even in stationary-phase organisms and protects well against death in patients with GAS necrotizing fasciitis [41,42].

Early and aggressive fluid resuscitation is a vital intervention in patients with septic shock [43]. Whether the type of resuscitation fluid that is administered in very early septic shock influences survival remains controversial. There is convincing evidence that in this setting, hydroxyethyl starch fluids cause acute kidney injury, as defined by the requirement for renal replacement therapy, compared with crystalloid fluids [44]. In contrast, a subgroup analysis from a randomized controlled trial comparing 4% albumin with normal saline showed a reduction in the mortality rate in the albumin group [45]. These findings require confirmation in a large randomized trial [46].

Morbidity and mortality rate

Patients with severe invasive GAS infections requiring admission to an intensive care unit (ICU) have high rates of major organ dysfunction. A case series of 62 ICU patients at a referral center for GAS infections reported that acute respiratory distress syndrome developed in 34%, acute kidney injury in 55% (with renal replacement therapy required in 21%), hepatic dysfunction in 64%, and coagulopathy in 69% of patients [47]. The majority of the patients (81%) were intubated and placed on mechanical ventilation. Morbidity in non-ICU case series of invasive GAS differ widely but generally are lower than those quoted above.

A multinational epidemiological survey (Strep-EURO) of cases of severe GAS sepsis diagnosed in Europe in 2003 and 2004 reported a seven-day case fatality rate of 19% [1]. The development of STSS was strongly associated with death, with 44% of patients with STSS, versus 15% of those without, dying within seven days. Although the clinical presentations of primary GAS peritonitis were not categorized separately, case fatality rates for necrotizing fasciitis (32%) and puerperal sepsis (4%) were reported. All of the patients in this systematic review of case reports were reported to have survived; however, this may represent selection or publication bias or both.

Limitations

A systematic review of case reports is limited by the lack of a standardized method of reporting, incomplete information, possible selection bias within the reported cohorts, and possible publication bias.

Summary

The worrisome increase in invasive GAS disease means that presentations of primary GAS peritonitis are likely to become more common. The challenge for the treating surgeon is to consider the possibility of this diagnosis. In the current era of multidetector CT technology, secondary peritonitis from an intra-abdominal source may be excluded reliably using abdominal CT. Exploratory laparotomy is not mandated, and paracentesis is sufficient to confirm the diagnosis and avoid operative morbidity in patients with localized intraperitoneal fluid collections. Laparoscopic peritoneal lavage should be reserved for patients with widespread intra-peritoneal free fluid or whose condition deteriorates despite antibiotic therapy.

Footnotes

Author Disclosure Statement

No conflicting financial interests exist.

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