Fulminant infection and toxic shock syndrome caused by Streptococcus pyogenes

The Journal of Emergency Medicine, Vol. 22, No. 4, pp. 357–366, 2002 Copyright © 2002 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/02 $–see front matter

PII S0736-4679(02)00436-5

Clincial Communications

FULMINANT INFECTION AND TOXIC SHOCK SYNDROME CAUSED BY STREPTOCOCCUS PYOGENES Kevin L. Fox,

MD,*

Michael W. Born,

MD,†

and Merrill A. Cohen,

MD*

*Department of Emergency Medicine and †Section of Plastic Surgery, York Hospital, York, Pennsylvania Reprint Address: Merrill A. Cohen, MD, Emergency Department, York Hospital, P.O. Box 15198, York, PA 17405-7198

e Abstract—Two patients presented to the Emergency Department (ED) with features of toxic shock syndrome, including hypotension, acute respiratory distress syndrome (ARDS), renal and hepatic insufficiency and disseminated intravascular coagulation (DIC). Computed tomography (CT) scan identified the source of infection in one patient. At laparotomy, pelvic peritonitis and massive edema of the pelvic retroperitoneal tissue was found. The other patient had myonecrosis of the forearm necessitating amputation. Intra-operative cultures of tissue in each case yielded Streptococcus pyogenes, Group A. These patients were treated early with clindamycin and intensive supportive care as well as surgery, and both made a full recovery. Because of the necessity of early recognition of the varied presentation of these infections, the clinical features as well as essential interventions are emphasized. We review the pathophysiology of invasive Group A streptococcal infection to increase awareness of these uncommon but fulminant and often lethal infections. © 2002 Elsevier Science Inc.

tion. It is thought to be caused by massive cytokine release stimulated by bacterial exotoxin acting as a superantigen (1,2). Initially, it was recognized to be due to toxins produced by Staphylococcus aureus but the syndrome is caused by the exotoxins of Streptococcus pyogenes as well. Streptococcal toxic shock syndrome is one manifestation of a group of invasive infections caused by highly virulent strains of Group A streptococci. The popular press terms these the “flesh-eating bacteria.” Stevens, who has studied a large number of these cases, writes, “The speed with which Group A streptococci induce local infection, multi-organ failure, and death cannot be matched by any other infectious organism” (3). These aggressive infections that have severe morbidity and mortality increasingly are being encountered, and early recognition of their varied presentations is essential for good outcome. We report two cases of fulminant, invasive infection complicated by toxic shock syndrome (TSS). One occurred in a female patient who presented with lower abdominal pain, shortness of breath, vomiting, fever, and hypotension. Pelvic peritonitis and phlegmonous involvement of the outer half of the uterus was identified at laparotomy. The second case is a young man who had severe pain of the elbow, shortness of breath, fever and hypotension. He had myonecrosis of the forearm. Group A, ␤-hemolytic streptococci were cultured from the tissues of both patients.

e Keywords—streptococcal toxic shock syndrome; group A streptococcal infection; toxic shock syndrome; peritonitis; myonecrosis

INTRODUCTION Toxic shock syndrome (TSS) is a dramatic host response characterized by hypotension and multi-organ dysfunc-

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RECEIVED:

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CASE REPORTS Patient 1 A 39-year-old woman presented with a 5-day history of worsening lower abdominal pain. The pain began abruptly two days after the conclusion of her last menstrual period. That menstrual period had lighter flow than usual and she used tampons, but no tampon remained in place for longer than 8 to 12 h. Because of the pain she consulted her family doctor who ordered an ultrasound of the pelvis, which showed that the uterus was larger than on a previous sonogram and there was a small amount of free fluid. The patient then was seen again by her primary care physician who clinically suspected a diagnosis of pelvic inflammatory disease (PID) and began treatment with ofloxacin and metronidazole. The patient vomited twice that afternoon. Her abdominal pain dramatically increased throughout the day, and she was brought by ambulance that evening to the Emergency Department (ED) complaining of severe lower abdominal pain. The patient was also short of breath. Past history included anemia because of menorrhagia for which the patient was not taking iron supplements, candidal vaginitis, and recurring genital herpes simplex. The last herpetic outbreak was one month earlier and it was brief and not unusual. A tubal ligation had been performed 6 years earlier. There was no history of recent sore throat, although her son had been treated for “strep throat” about 4 months before this illness. Initial vital signs included an oral temperature of 37.2°C (99°F), pulse of 130 beats/min, respiratory rate of 40 breaths/min, blood pressure of 80/40 mm Hg, and pulse oximetry of 89% saturation on room air. Physical examination was significant for crackles at the base of the lungs and the abdominal findings. The lower abdomen was moderately distended and very tender with guarding and rebound tenderness. The upper abdomen was soft and not tender. The patient experienced a great deal of pain with uterine cervical motion. Laboratory values included a white cell count of 8,700/mm3, hemoglobin of 7.9 g/dL, hematocrit of 24.8%, and platelet count of 184,000/mm3. The MCV was 72 and the MCH was 22.8. The blood smear demonstrated anisocytes, schistocytes, ovalocytes, Dohle bodies, and bands. The prothrombin time was mildly prolonged (INR 1.6) and the PTT was twice the normal level. The blood urea nitrogen was 34 mg/dL, and the creatinine was 1.6 mg/dL. An arterial blood gas on high-flow oxygen by face mask showed an arterial pH of 7.33, pO2 of 106 mm Hg, pCO2 of 34 mm Hg, and bicarbonate of 17 mmol/L. The chest X-ray study showed interstitial and early alveolar edema, with normal heart size, consistent with acute respiratory distress syndrome (ARDS). Rapid infusion of normal saline was

Figure 1. CT scan of the pelvis of patient 1, performed shortly after arrival in the ED, showing prominent ovaries and uterus, extensive infiltration of peri-uterine and pelvic fat, and intra-peritoneal fluid. The findings suggest an infectious process.

begun and the patient was sent for an emergency computed tomography (CT) scan of the abdomen and pelvis. This study demonstrated an enlarged uterus and fluid in the intra-peritoneal, retro-peritoneal, peri-rectal, and presacral regions. The source of the fluid was not identified but it was presumed to be inflammatory. Edema and infiltration of the pelvic soft tissues was striking. The interpretation of the CT scan was severe PID (see Figure 1). Treatment with clindamycin and piperacillin/tazobactam was begun. The patient was taken to the operating room (OR). Emergency laparotomy revealed extremely boggy uterus, ovaries, and adnexal structures. Purulent fibrinous exudate was noted on the uterine serosa, in the adnexal regions, and along the lateral border of the uterus. There was massive edema of the pelvic retroperitoneal tissues and lateral walls. The appendix and other viscera were normal. Supra-cervical hysterectomy and bilateral salpingo-oophorectomy were performed. The abdomen could not be closed because of the development of abdominal hypertension. Tissue and peritoneal cultures obtained at laparotomy demonstrated S. pyogenes. M-typing of the isolate was not done. No other organisms were isolated. Blood cultures yielded no growth. Pathologic examination of the uterus showed acute suppurative inflammation of the outer half of the myometrium with focal small abscesses, and parametritis, but there was no endometritis and no salpingitis. The ovaries showed stromal edema and focal abscess, and there was inflamma-

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Figure 2. Photograph of the elbow of patient 2, showing tense swelling, erythema, and focal areas of ecchymosis and hemorrhagic bullae.

tion on all serosal surfaces. Gram’s stain on tissue sections revealed Gram-positive cocci in chains consistent with streptococci. The day after admission the patient developed fever and a red “sunburn-like” rash on the trunk and thighs. The face and limbs became swollen. The leukocyte count rose to 19,700/mm3 and the platelet count fell to 93,000/ mm3. Additional laboratory studies shortly after admission included bilirubin of 2.7 mg/dL (direct of 2.0), alkaline phosphatase of 209 U/L, ALT 56 U/L, AST 115 U/L, calcium 6.0 mg/dL, ionized calcium 0.9 mmol/L, albumin 1.24 g/dL, and magnesium of 1.1 mg/dL. Fibrin split products was reported as ⬎40 ng/mL. Yeast were noted on urinalysis. Cervical gonococcal DNA probe and Chlamydia detection studies (polymerase chain reaction) at admission were negative. The hospital course was complicated by acute respiratory distress syndrome (ARDS), oliguria, lactic acidosis (with lactate level as high as 9.3 mmol/L), and disseminated intravascular coagulation (DIC). Dopamine, neosynephrine and epinephrine were needed to maintain an adequate blood pressure. The patient was extubated on the twelfth day, and she was discharged from the hospital on the seventeenth day. During recovery there was desquamation of the skin of the hands and feet, especially of the distal fingers.

Patient 2 A 36-year-old healthy man began to experience symptoms of generalized aches, anorexia, nausea, vomiting, and pain in the right elbow. The next day he developed diarrhea, malaise and fever. The patient attributed the persistent elbow pain to shoveling snow because there had been a snowstorm several days before its onset. The other symptoms were thought to be because of the “flu.” After six days, because of worsening elbow pain extending proximally into the brachium and distally into the forearm, as well as lightheadedness and diaphoresis, he was brought to the ED. While in the ED the patient’s pain became increasingly severe, and a diffuse erythematous rash appeared on the back and spread to the shoulders. On examination, the systolic blood pressure was 70 mm Hg. The pulse was 115 beats/min, and the respiratory rate 24 breaths/min. He was alert, oriented, illappearing and in agonizing pain. Physical examination was significant for the blanching rash, slight scleral icterus, mild right upper quadrant abdominal tenderness, and the findings on the right upper limb. The proximal forearm was swollen, tense and very tender (see Figure 2). Erythema developed in the area while the patient was in the ED. The hand was cool and dusky. The radial pulse

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was present, and sensation to light touch and power in the hand were intact. Laboratory testing revealed many abnormal values. The leukocyte count was 7,000/mm3, hemoglobin 16.4 g/dL, hematocrit 47.4%, and platelet count 84,000/mm3. Six metamyelocytes, one melocyte, toxic granulation, Dohle bodies, and bands were seen on the peripheral blood smear. The prothrombin time was 13.9 s, and the PTT was 36.2 s. The blood urea nitrogen was 33 mg/dL, and the creatinine was 2.3 mg/dL. Electrolytes were significant for a potassium of 2.9 mmol/L and bicarbonate of 17 mmol/L. Liver studies included a total bilirubin of 6.7 mg/dL, alkaline phosphatase 134 U/L, AST 379 U/L and ALT 249 U/L. Arterial blood gases on room air revealed pH of 7.39, pO2 70 mm Hg, pCO2 29 mm Hg, and O2 saturation 93%. Except for mild proteinuria, the urinalysis was unremarkable. Myoglobinuria was not present. An infusion of normal saline was started, narcotic analgesics were administered, and ED consultations were urgently obtained. Because of concern for compartment syndrome, the patient was taken to the OR and emergency fasciotomy was performed. The fascia, when incised, was found to exude a slight amount of serosanguinous fluid. The muscle appeared normal, soft and viable, and a sample was taken for pathology and for culture. A Gram’s stain of the fluid that exuded was negative. While in the OR, the patient’s body temperature climbed to 40.5°C (105°F) and he became markedly tachycardic with a heart rate of 160 beats/min. The patient was taken to the intensive care unit (ICU). He was very dyspneic. A chest radiograph revealed bilateral perihilar densities suggestive of early heart failure, although the heart size was normal. A repeat chest X-ray study hours later revealed extensive bilateral interstitial edema and alveolar densities, consistent with ARDS. By then, the skin was diffusely erythematous. Antibiotic therapy for the probability of sepsis consisted of clindamycin, vancomycin, and ciprofloxacin. Further laboratory evaluation at admission included fibrin split products ⬎40 ␮g, creatine kinase 134 U/L, calcium 7.2 mg/dL, ionized calcium 2.7 mmol/L, and lactate 5.8 mmol/L. Albumin was 1.7 g/dL and the magnesium 0.9 mg/dL. Pressors were needed to support the blood pressure. DIC and severe hepatic dysfunction (with bilirubin climbing to a high of 45 mg/dL) developed. The patient became anuric requiring dialysis. S. pyogenes, Group A, was cultured from the forearm muscle tissue and from the blood, urine, and stool. No other organisms were isolated. Because of a tumultuous course including hypotension, lactic acidosis, ARDS, DIC, liver and kidney failure, and inspection of the forearm wound showing hemorrhagic necrosis of the muscle, and bullae and skin

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slippage over the olecranon, on the third hospital day the right upper limb was amputated at the level of midhumerus. Pathologic examination of the submitted specimen revealed acute necrotizing and hemorrhagic myositis of the muscles of the forearm, dermal necrosis, and venous thrombi. The arteries were normal. All the patient’s toes became ischemic and had to be amputated. The course then was one of intensive support, and the patient left the hospital 4 weeks later. He continued to gain strength at home and eventually was able to return to work.

DISCUSSION PID is an acute infection, usually sexually acquired, that ascends from the cervix to involve the upper tract. In the case of our first patient, however, pathologic examination of the surgical specimen showed that the infection did not reach the uterus by ascending. The endometrium was normal on histologic examination, as were the inner half of the myometrium and the fallopian tubes. The infection in this patient reached the pelvis by the hematogenous route from an unknown remote portal. Primary peritonitis in the otherwise healthy individual is often hematogenous (4 – 6). Indeed, case reports of tubo-ovarian abscess (TOA) in children (presumably not sexually acquired) because of S. pneumonia, which is non-vaginal flora, and cases of TOA in adults who have had remote hysterectomy must be blood-borne (7,8). One other report documents the occurrence of fulminant, blood-borne, Group A streptococcal infection of the myometrium. Ooe and Udagawa reported two cases of explosive purulent myometritis because of S. pyogenes infection that arose in the pharynx (9). Pathologic examination of the uteri at autopsy revealed, as in our case, no evidence of endometritis or salpingitis. Fikrig et al. also report a case of Group A streptococcal peritonitis and salpingitis, which may have been blood-borne, complicated by toxic shock syndrome (10). The second patient we report had no evident portal of entry either. There probably was transient bacteremia, and bacteria that perhaps originated in the pharynx translocated to the elbow or forearm, possibly because of strain associated with shoveling snow several days earlier. Gaffield et al. report a case of Group A streptococcal deep infection following an acute muscle strain (11). Because infections such as these occur spontaneously, a clinician encountering the patient could suspect some other process and not recognize it as infectious. Our second patient initially was thought to have compartment syndrome. The early appearance of deep infection of the soft tissues of a limb because of Group A streptococci can resemble deep vein thrombophlebitis, bursitis, ten-

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donitis, or an envenomation as well as compartment syndrome.

Pathophysiology of Streptococcal Infection Group A streptococcal infections exhibit a broad spectrum of clinical manifestations. Some persons, for example, carry Group A streptococci harmlessly, some develop pharyngitis, or impetigo, and others develop benign scarlet fever. At the other end of the spectrum are the fulminant infections such as necrotizing fasciitis, myonecrosis, peritonitis, and TSS, which are characterized by a rapid course and high mortality. The complex interaction between the virulence factors of the microbe and the immune state of the host differentiates benign Group A streptococcal illness from the malignant and explosive infections (3). Some S. pyogenes organisms have an M protein, a filamentous coiled macromolecule, on the surface of the cell wall. The M protein is thought to be one of the major virulence factors of Group A streptococci (12,13). Strains that have these hair-like surface projections resist phagocytosis by polymorphonuclear (PNM) leukocytes and cause disease; strains that lack them are nonvirulent. Many antigenically different M protein serotypes exist. M types 1 and 3 have been identified as the most virulent of these proteins and cause invasive infection. Strains with M types 1 and 3 are most often isolated from patients with streptococcal TSS. Some S. pyogenes also have the ability to produce single chain proteins termed streptococcal pyrogenic exotoxin A (SPEA), B (SPEB), or C (SPEC). These exotoxins not only cause fever and rash but have been shown to powerfully induce mononuclear cells to produce various cytokines. The streptococcal pyrogenic exotoxins have been termed superantigens because they are able to super-stimulate the host’s immune system to produce an exaggerated response of T cell activation and cytokine production. Normally, antigens are processed by an antigen-presenting cell and that is followed by a specific, restricted interaction with a T-cell receptor, and cytokines are produced. Perhaps 0.01% to 0.1% of the body’s T-cells are thus activated. However, superantigens bypass the normal immune response by non-specifically binding T-cells, and from 5% to 25% of the body’s T-cell population is activated, producing a massive quantity of cytokines (14 –17). The cytokines then mediate shock and tissue injury (1,2,18,19). Other virulent factors produced by Group A streptococci include streptolysin O, which stimulates cytokine production, streptococcal superantigen (SSA), another exotoxin recently isolated, and perhaps an extracellular enzyme that disrupts host cellular metabolism (19 –21).

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If a host has antibody to the specific M type surface protein, invasive infection will not occur. Likewise, if an infecting organism is of a less virulent strain (M type 4, for example), only localized infection such as pharyngitis would result, but if the strain also produced SPEA, for example, scarlet fever might occur, depending on whether or not the host had antibody to the exotoxin. Infection by M1, SPEA-producing Group A streptococci in a host lacking antibody to either factor would result in rampant, rapidly progressive invasive disease (3). It is likely that other host factors affect susceptibility to severe streptococcal disease (1,22). Studying small outbreaks of invasive Group A streptococcal infection, Cockerill and DiPersio observed that the same strain in different hosts causes completely different manifestations, spanning the spectrum of Group A streptococcal infection (23,24). Young children may be especially susceptible to invasive Group A streptococci because they do not yet have protective antibody, and the very elderly likewise may be more susceptible because of waning immunity (2). A number of other factors also have been identified that are thought to represent inherent host predisposition to invasive infection; this may account for the fact that most cases of fulminant streptococcal infection occur sporadically (19). The attenuation in severity of streptococcal infection until the last decade of the 20th century may have been because of the relative distribution of strains of S. pyogenes that express the several virulent factors, or it is because of a change in herd immunity (19,25,26).

Invasive Streptococcal Infection The virulent Group A streptococci that increasingly are being encountered cause invasive and aggressive infections (27). Invasive Group A streptococcal infections include necrotizing fasciitis, myonecrosis, bacteremia, various deep infections such as pneumonia and peritonitis, and TSS (3). Infections of the limb or trunk because of Group A streptococci affect either the skin (cellulitis) or the deeper soft tissue (necrotizing fasciitis or myonecrosis). Necrotizing fasciitis, an infection of the subcutaneum that destroys fat and underlying fascia, is an extremely rapidly progressing infection with high mortality. Systemic toxicity frequently accompanies the infection. Many organisms such as Gram-negative rods, Clostridia, and other anerobes can cause necrotizing fasciitis, but Group A streptococcus is the cause of perhaps half of all cases (28,29). Most cases occur in persons with chronic underlying illness and result from a local injury that permits bacteria to invade the deeper soft tissue (27).

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However, streptococcal necrotizing fasciitis also can occur spontaneously in previously healthy individuals because of bacteremia originating at a remote or unidentified site (29). Streptococcal necrotizing fasciitis manifests early as severe pain along with marked tenderness of the affected area. Because infection initially spreads along fascial planes with no or minimal skin involvement, early in its course the extent of disease may not be recognized. Swelling then develops, followed by erythema. Infarction of superficial nerves in the subcutaneum causes anesthesia of the overlying skin (30). Hemorrhagic bullae in the overlying skin point to this diagnosis, but they occur late. Patients are febrile and appear toxic, and they can be hypotensive (27). The infection undermines skin. A hemostat placed through a small incision into an area of necrotizing fasciitis will pass without resistance in the fascial plane (30). Patients with necrotizing fasciitis can have concomitant myonecrosis (1,31–34). Early aggressive excision of infected, necrotic tissue is essential for survival, but mortality is high for elderly patients and for those who develop TSS (27,34 –36). Streptococcal myonecrosis is rare (32). It results from spontaneous hematogenous spread of Group A streptococci to the muscle, probably from the pharynx, although most patients reported to have this condition did not have clinical pharyngitis. Unlike clostridial myonecrosis, which occurs in patients with malignancy or leukemia or following injury, streptococcal myonecrosis occurs spontaneously in healthy adults (37,38). Fever, if not toxicity, is present. The affected part is severely painful, tender, swollen, and warm. Muscle compartment syndrome develops very rapidly. Pathologic examination shows purulent infiltrates replacing necrotic, perhaps hemorrhagic muscle and fascia (32). The patient’s condition deteriorates rapidly, and mortality is between 80 and 100% (3). Crepitus, if present, points to clostridial or other gasproducing infection instead. The distinction between necrotizing fasciitis and myonecrosis is indistinct because features of both often are seen in any individual case. In the case we report, the creatine kinase at admission was normal and the muscle appeared normal at fasciotomy, but pathologic examination of the submitted amputation specimen revealed extensive myonecrosis, raising the possibility the process began as necrotizing fasciitis but rapidly extended from the investing fascia to the muscle itself. Piepmeier and colleagues report a fatal case of combined necrotizing fasciitis and myonecrosis in which the infection visibly spread as they were amputating the patient’s limb (39). Group A streptococcal bacteremia occurs as a complication of a medical procedure but more commonly it is associated with a cutaneous lesion such as chickenpox, cellulitis, ulcer or dermatitis (40,41). Bacteremia without

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a primary focus of infection (“cryptogenic”) has been observed as well (42– 44). Most patients have an underlying chronic illness or malignancy. All patients are febrile and many have septic shock. Streptococcal TSS can be associated. The incidence of Group A streptococcal bacteremia in children is 0.6 per 100,000 persons/ year, and it is 1.6 per 100,000 persons/year in the elderly. In the middle age group, it is mostly because of injection drug use (41). The mortality of Group A streptococcal bacteremia is almost 30%, but if septic shock results, the mortality jumps to 60% (45). Although rare, Group A streptococcal deep infection such as peritonitis and involvement of organs including uterus, heart, lung, bone and eye occur (46). Moskovitz et al. recently have identified 15 previously reported cases of primary peritonitis due to Group A streptococcus in healthy adults, but additional cases have been reported (6,43). Many of these patients are in shock or have TSS.

Streptococcal Toxic Shock Syndrome TSS was first described by Todd et al. in 1978 (47). The clinical syndrome consists of shock and multi-system involvement characterized by abrupt onset of fever, rash, mental state changes, vomiting, and diarrhea, with desquamation during convalescence. The syndrome was associated with either infection or colonization by toxinproducing S. aureus. Recognizing that the exotoxins produced by S. pyogenes have biologic properties similar to those elaborated by Staphylococcus aureus, Willoughby and Greenberg in 1983 suggested the possibility of a streptococcal TSS (48). In 1987, Cone and coworkers identified 2 cases of almost the same syndrome caused by S. pyogenes (25). Two years later Stevens et al. reported a series of 20 cases of streptococcal TSS, and since then many more cases have been described (46). Both cases we report fulfill the criteria established by The Working Group for Streptococcal TSS (49). In most cases of streptococcal TSS the patients are previously healthy, and the site of infection is usually skin or soft tissue, although some are puerperal or, rarely, pharyngeal (50 –52). Approximately half of cases of TSS are associated with necrotizing fasciitis (27). Streptococcal TSS occurs in the very elderly, and it also occurs in children, usually as a complication of chickenpox (40,42,53). The portal of entry of many cases of streptococcal TSS is a wound or the pharynx, but in about 40% of cases no portal can be identified, as in our two cases (36). The clinical features of streptococcal TSS, like those of staphylococcal TSS, are shock and multiple organ dysfunction. ARDS, toxic cardiomyopathy, renal failure,

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capillary leak syndrome, and DIC occur (12). There are some differences between staphylococcal and streptococcal TSS, however. In streptococcal TSS a rash may not be present, and a flu-like prodrome may occur, as in our second case. The streptococcal form differs significantly from staphylococcal TSS in that the streptococcal form evidences infection at some site, such as cellulitis or necrotizing fasciitis. But if the infection is deep (such as pneumonia or peritonitis), the site may not be apparent at initial presentation. Also unlike staphylococcal TSS, in streptococcal TSS the blood culture is often positive. Whereas the mortality for staphylococcal TSS is approximately 3 to 6%, despite optimal treatment the mortality of streptococcal TSS is greater than 30% (1,3,19,54). Streptococcal TSS is differentiated from sepsis syndrome by the fact that in streptococcal TSS organ failure occurs early, usually by the time of initial presentation, not subsequently as in sepsis. Study of a series of cases of invasive streptococcal infection in Atlanta showed the overall annual incidence to be 5.2 cases per 100,000 population (55). The Center for Disease Control and Prevention estimates that 10,000 to 15,000 cases of invasive Group A streptococcal infection occur each year in the United States (56). Although small outbreaks have been reported, most cases occur sporadically (19,23,24,40,57).

Early Recognition and Intervention Essential to survival of patients with these aggressive infections are early diagnosis, initiation of appropriate antibiotic, and surgical removal of infected tissue. A number of clinical features aid early recognition. Flu-like symptoms including fever and perhaps diarrhea may occur; these symptoms could mislead the emergency physician into suspecting a viral syndrome or enteritis with dehydration. Pain is an initial presenting symptom of invasive streptococcal infections. The pain may be excruciating, perhaps out of proportion to other physical findings. Swelling, tenderness, erythema, and perhaps bullae may not be present, but if so, these features point to necrotizing fasciitis or myonecrosis. If there is no history of injury or evidence of skin wound, other, more benign conditions could be suspected. For example, early necrotizing fasciitis easily could be mistaken for deep vein thrombosis and time would be lost waiting for duplex vascular studies. The severe pain and tenderness, however, should differentiate invasive soft tissue infection from cellulitis, vascular occlusion, or other benign conditions. All patients with TSS are hypotensive either at presentation or very shortly thereafter. The patient with TSS at presentation usually also appears acutely ill or toxic and short of breath, but if not, becomes so in

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short course. An erythroderm is present initially in only a minority of patients with streptococcal TSS. It is the laboratory evidence of multi-organ dysfunction that early betrays the diagnosis (1,3,19). Renal insufficiency almost always is found at presentation, and this points to TSS because shock due to sepsis does not cause renal insufficiency until later. The leukocyte count may be normal, but if so there is a left shift with bands, metamyelocytes and myelocytes. Hypoalbuminemia and hypocalcemia occur early, perhaps at presentation. If myonecrosis is present, the creatine kinase may be elevated. Evidence of ARDS may be noted early on chest X-ray study. When faced with a sick-appearing patient who may have an invasive infection, the clinician should be liberal in use of the laboratory. Recognition of deep infection, as in case 1, also can be greatly aided by the use of imaging. In our case, ultrasound of the pelvis done earlier on the day of admission was not sensitive to the details provided by CT scan, such as tissue edema and diffuse infiltration of fat. High resolution cross-sectional imaging readily identifies intra-abdominal infectious processes, including tuboovarian abscess (58). When faced with a toxic patient who is in acute pain necessitating a parsimonious yet effective work-up, CT scan should be utilized. Besides revealing sites of infection, CT scan can disclose other acute conditions (ischemic bowel or ruptured viscus, for example) that, if present, mandate prompt surgical intervention. To aid the early diagnosis of soft tissue infection, CT scan has been used effectively, as has magnetic resonance imaging (MRI) (59 – 61). MRI may support a surgeon’s decision to operate, but such imaging also can be time-consuming and delay the immediate surgical debridement that patients with this condition need. The optimal role of imaging is to locate suspected deep infection, as in the first case we report. Also possibly useful in establishing a diagnosis in the case of deep soft tissue infection are muscle compartment pressure measurement and needle aspiration of fluid from inflamed tissue. Needle aspiration can be followed by either Gram’s stain or use of a rapid streptococcal diagnostic kit (31). New methods to rapidly identify bacteria without waiting 24 to 48 h for culture are being developed. Using a new technique not yet available to clinical laboratories, fluorescence in situ hybridization targeting bacterial ribosomal RNA, Trebesius et al. rapidly (within 2 to 3 h) and accurately detected the bacterial pathogens that cause necrotizing fasciitis (62). Also, anecdotally reported is the use of ultrasound in cases of myonecrosis; abnormal echoes with free fluid are found in the muscle tissue (63). Another key to survival is choice of antibiotic. Group A streptococci are extremely sensitive to penicillin, and penicillin is effective treating pharyngitis, impetigo, cel-

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lulitis and erysipelas. But penicillin can fail in the presence of a large microbial burden (64). The ␤-lactam antibiotics are effective when bacteria are in their active growth phase. It is thought that in these deep infections enormous numbers of streptococci are present and they are in a stationary phase, so penicillin may not be effective (19). Penicillin, moreover, does not halt the production of exotoxin. Clindamycin, a protein synthesis inhibitor, terminates production of M protein and pyrogenic exotoxin, the chief streptococcal virulence factors. For this as well as other reasons, clindamycin is the preferred antibiotic, and it should be started as soon as this condition is suspected (19). Because bacteria other than S. pyogenes can cause these infections, until culture results are available, empiric therapy should include a combination ␤-lactam antibiotic with a ␤-lactamase inhibitor, in addition to clindamycin (30,65). In the management of streptococcal TSS, massive fluid resuscitation is needed as well because of diffuse capillary leak of fluid. Many liters of crystalloid may be required in the initial hours. A recent anecdotal report from Germany describes the apparently beneficial use of C1-esterase inhibitor to reverse the capillary leak syndrome in cases of streptococcal TSS, but this product is not yet available in the United States (66). On the basis that streptococcal pyrogenic exotoxins mediate invasive disease, IV administration of pooled immunoglobulin to passively provide neutralizing antibody has been tried with varying success (67). If given early, some patients may benefit (22,68). Although some investigators have recommended hyperbaric oxygen (HBO) therapy for necrotizing fasciitis, Shupak and co-authors found that HBO affords no benefit (69,70). HBO has no clear role in the management of streptococcal TSS (1). Emergency surgery is essential for survival of the patient with invasive Group A streptococcal infection. These infections progress rapidly and have severe mortality. Early aggressive surgical excision of infected tissue is mandatory. Repeated debridement typically is needed. Patients in the ED suspected to have invasive soft tissue infection should be referred not to internal medicine for admission, but to a surgeon. “Infection spread even while we were working,” a surgeon observed while debriding a fatal case of necrotizing fasciitis (71).

CONCLUSION We present two patients who had invasive deep infection and a rapidly progressive, fulminant course. Both developed hypotension, acute respiratory distress syndrome, acute renal insufficiency, lactic acidosis, and dissemi-

nated intravascular coagulation. Group A streptococci were cultured from tissues of both patients and from blood in one. The patients made a full recovery from streptococcal toxic shock syndrome with appropriate antibiotics, including early use of clindamycin, surgical removal of infected tissue, and intensive supportive therapy. When evaluating patients who present with infection yet have toxicity, hypotension, and evidence of multiorgan dysfunction, the possibility of invasive Group A streptococcal infection including streptococcal toxic shock syndrome should be considered. Invasive Group A streptococcal disease should be suspected in anyone who presents with skin, soft tissue, or not readily categorized deep infection who is hypotensive or appears severely ill. Pain typically is severe and seems out of proportion to the physical findings. Initial antibiotic treatment should include clindamycin because of its ability to inhibit exotoxin production. In the case of patients presenting with abdominal pain, CT scan should be employed as early as possible in the evaluation to recognize the possible existence of deep infection as well as to identify other types of surgical emergency. Streptococcal TSS is a fulminant condition with high mortality occurring in otherwise healthy individuals because of infection that can occur at a number of sites. It must be recognized early so treatment can be initiated promptly to ensure a successful outcome.

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