J Pediatr Adolesc Gynecol (2004) 17:289–292

Opinions in Pediatric and Adolescent Gynecology

Edited by Hatim Omar, MDProfessor of Pediatrics and Ob/Gyn, Director of Adolescent Medicine & Young Parent Programs, J422, Kentucky Clinic, University of Kentucky,Lexington, KY 40536

Back in the late 70s when toxic shock syndrome wasinitially described, much attention was paid to the subject;most physicians and trainees were paying significantattention to it and cases were detected on a routine basisin most clinics. During that period, most of the cases, ifnot all, were connected or related somehow to tamponuse. This trend continued until about mid to late 80s.In the late 90s and the start of the new millennium,somehow, cases of toxic shock syndrome were less andless common and it seemed at some point that physicianshad forgotten about its existence. Meanwhile, severalreports during that time have showed that toxic shocksyndrome can be associated with many other etiologiessuch as injuries or foreign bodies and even body piercingor tattooing. Despite that, for the last 3–4 years, wehave seen several cases of toxic shock syndrome that weremissed by primary care providers mainly because of notthinking about the disorder.

One specific case is that of a 15-year-old white femalethat was referred to the adolescent clinic for evaluationof what the primary care provider referred to as persistenturinary tract infection. The patient was seen by her physi-cian 3 weeks prior to referral for some urinary symptomssuch as dysuria and on and off fever; the symptoms hadstarted a few days after her last menstrual period. Patientwas started on antibiotic for presumed urinary tract infec-tion based on a urinalysis that showed high number ofwhite blood cells. Patient continued to have the samesymptoms for 3 or 4 more days and was seen again byher physician who changed the antibiotic based on theassumption that the bacteria was not responding appropri-ately to this antibiotic. Maybe it was not responsive;however, no urine culture was obtained at either visit.The symptoms of the patient continued and she startedhaving persistent fever initially around 101 and 102ºF(38.3–38.9ºC); then the temperature continued to rise andfinally she was referred to the adolescent clinic.

On her arrival to our clinic, her temperature was104ºF (40ºC) and the blood pressure was 81/60, whichvery quickly started plummeting; the patient went intoshock less than 10 min after arriving in our clinic. Pa-tient’s exam after hospital admission and taking the neces-sary urgent management steps showed remnants of a

� 2004 North American Society for Pediatric and Adolescent GynecologyPublished by Elsevier Inc.

tampon that was forgotten in the vagina and severe muco-sal edema with sloughing of the tissue in the vaginalarea especially in the vaginal walls. Subsequently, patientrecovered after aggressive treatment in the intensive careunit for toxic shock syndrome that was caused by staphy-lococcus aureus in this case.

As seen in this case, if the provider had consideredthe possibility of toxic shock syndrome, it probablywould have been detected a lot earlier. In light of allthis, I thought that discussing or revisiting toxic shocksyndrome would be very appropriate for this section sincemany of our readers are also primary care providers otherthan pediatric and adolescent gynecologists. I have in-vited a guest opinion from Dr. Chris Nelson, who isan associate professor of pediatrics and a specialist inpediatric infectious disease at the University of Kentuckyto share his thoughts and experience on early detection oftoxic shock syndrome. Since this is an invited opinionwith no opposing opinion, we would welcome any feed-back or comments in this regard; they may be addressed tothe “Letters to the Editor” section of this journal.

doi:10.1016/j.jpag.2004.07.001

Early Recognition andTreatment of Staphylococcaland Streptococcal Toxic Shock

Chris Nelson, MDDepartment of Pediatrics, University of Kentucky Chandler MedicalCenter, Lexington, Kentucky, USA

A diverse array of human infection is caused by Staphylo-coccus aureus and Streptococcus pyogenes, from minorskin and soft tissue infections to disseminated, invasivedisease associated with significant morbidity and mortal-ity. The term toxic shock syndrome is used to describeserious, life-threatening illness associated with particularstrains of Staphylococcus aureus and Streptococcus pyo-genes that demonstrate the ability to excrete a variety of

1083-3188/04/$22.00doi:10.1016/j.jpag.2004.06.002

290 Omar: Opinions in Pediatric and Adolescent Gynecology

toxins capable of inducing rash, shock, focal pyogenic,and/or necrotizing infection and multi-organ system fail-ure. It has been my experience that in many cases oftoxic shock syndrome, early clinical clues are missed,leading to unnecessary delays in diagnosis and initiationof specific anti-staphylococcal and streptococcal antimi-crobial therapy. The key to effective management of toxicshock syndrome lies in the early recognition of telltalesymptoms and physical findings so that treatment inter-ventions can be initiated early enough to have a significantimpact on the considerable morbidity and mortality asso-ciated with this disease.

Toxic shock syndrome was first described in 1978 asa complication of infection with Staphylococcus aureus.1

Early association was made between toxic shock syn-drome and concomitant tampon use in menstruatingwomen. Ironically, the strength of the association in theminds of many physicians of staphylococcal toxic shockand tampon use may at least partially explain why toxicshock syndrome remains under-recognized in patientsother than menstrual-aged females. However, even in theearliest series of reports of toxic shock syndrome, the term“non-menstrual” was used to describe cases that were notassociated with menstruation, tampon use, or indeed withfemale patients at all. After several revisions, a case defi-nition of staphylococcal toxic shock was published in1982.2

The clinical criteria published in this case definitionare shown in Table 1. It is important that physiciansfamiliarize themselves with these criteria in order to enter-tain a possible diagnosis of toxic shock early in the courseof evaluation of any seriously ill patient.

Toxic shock syndrome also is a recognized complica-tion of infection with Streptococcus pyogenes (group A,Beta-hemolytic streptococcus). The original associationof group A streptococci with toxic shock is credited toCone et al., who in 1987 described two patients withsevere group A streptococcal infections who had featuresin common with staphylococcal toxic shock syndrome.3

Several case series were subsequently published demon-strating the link between serious group A streptococcalinfections and toxic shock syndrome. In 1993 the WorkingGroup on Severe Streptococcal Infections, an informalgroup of clinicians, microbiologists, and epidemiologists,published a consensus case definition for group A strepto-coccal toxic shock.4 Their proposed case definition isshown in Table 2.

Early recognition of key clinical features common toboth staphylococcal and group A streptococcal toxicshock should be the focus of clinicians caring for patientswith these life-threatening disorders. An important basicfact is that toxic shock strikes without particular predi-lection for sex, age, or in females, menstrual status.

Table 1. Case Definition for Staphylococcal Toxic ShockSyndrome*

Fever: temperature �38.9º C (102º F)Rash: diffuse macular erythrodermaDesquamation 1 to 2 weeks after onset of illness, particularly of

palms and solesHypotension: systolic blood pressure �90 mm Hg for adults or

below fifth percentile by age for children below 16 years of age,orthostatic drop in diastolic blood pressure �15 mm Hg fromlying to sitting, orthostatic syncope, or orthostatic dizziness

Multisystem involvement: three or more or the following:Gastrointestinal: vomiting or diarrhea at onset of illnessMuscular: severe myalgia or creatine phosphokinase level at

least twice the upper limit of normal for laboratoryMucous membrane: vaginal, oropharyngeal, or conjunctival

hyperemiaRenal: blood urea nitrogen or creatinine at least twice the upper

limit of normal for laboratory or urinary sediment with pyuria(�5 leukocytes per high-power field) in the absence of urinarytract infection

Hepatic: total bilirubin, SGOT, SGPT at least twice the upperlimit of normal for laboratory

Hematologic: platelets �100,000/mm3

Central nervous system: disorientation or alterations inconsciousness without focal neurologic signs when fever andhypotension are absent

Negative results on the following tests, if obtained:Blood, throat, or cerebrospinal fluid cultures (blood culture may

be positive for Staphylococcus aureus)Rise in titer to Rocky Mountain spotted fever, leptospirosis,

or rubeola

*Toxic shock syndrome is considered definite or confirmed when thecase meets all the criteria of the case definition

The rapid onset of toxicity, shock, and multi-organ failurefollowing a non-specific prodromal illness are the hall-marks of toxic shock, and this syndrome should be sus-pected in all patients presenting with this set of findings.Clinical signs and symptoms that provide valuable cluesto the early clinical diagnosis of toxic shock include fe-ver (temperature �38.7ºC), tachypnea, tachycardia, ery-thematous rash, hyperemia of mucous membranes (mostcommonly conjunctivae), orthostatic dizziness, altered con-sciousness, vomiting, and diarrhea.

It has been my experience that the clinical features ofpatients with toxic shock syndrome may be quite variablypresent in any one patient. It is also important to remem-ber that the case definitions for staphylococcal and strep-tococcal toxic shock syndrome are based primarily onfindings from studies of adults with these disorders. Theclinical presentation in children and adolescents maydiffer slightly from that seen in adults. In the publishedcase definitions, the rash associated with toxic shock,which is usually an early manifestation of disease, isdescribed as “diffuse, macular erythroderma” or a “gener-alized erythematous macular rash.” Although these de-scriptions may apply to children with toxic shock, whatI have seen most commonly in children with toxic shockis a diffuse erythroderma closely resembling the appear-ance of a total body “sun burn.” Less commonly, the rash

Omar: Opinions in Pediatric and Adolescent Gynecology 291

Table 2. Case Definition for Streptococcal Toxic ShockSyndrome*

I. Isolation of Group A streptococci (Streptococcus pyogenes)A. From a normally sterile site (e.g. Blood, cerebrospinal, pleural,

or peritoneal fluid, tissue biopsy, surgical wound, etc.)B. From a nonsterile site (e.g. Throat, sputum, vagina, superficial

skin lesion, etc.)II. Clinical signs of severity

A. Hypotension: systolic blood pressure �90 mm Hg in adultsor �5th percentile for age in children

ANDB. �2 of the following signs

1. Renal impairment: creatinine �177 µmol/L (�2 mg/dl)for adults or greater than or equal to twice the upper limitof normal for age. In patients with preexisting renal disease,a �2-fold elevation over the baseline level

2. Coagulopathy: platelets � 100 × 109/L (�100,000/mm3)or disseminated intravascular coagulation defined byprolonged clotting times, low fibrinogen level, and thepresence of fibrin degradation products

3. Liver involvement: alanine aminotransferase (SGOT),aspartate aminotransferase (SGPT), or total bilirubin levelsgreater than or equal to twice the upper limit of normal forage. In patients with preexisting liver disease, a �2-foldelevation over the baseline level

4. Adult respiratory distress syndrome defined by acute onsetof diffuse pulmonary infiltrates and hypoxemia in theabsence of cardiac failure, or evidence of diffuse capillaryleak manifested by acute onset of generalized edema, orpleural or peritoneal effusions with hypoalbuminemia

5. A generalized erythematous macular rash that maydesquamate

6. Soft-tissue necrosis, including necrotizing fasciitis ormyositis, or gangrene

*An illness fulfilling criteria IA and II (A and B) can be defined asa definite case. An illness fulfilling criteria IB and II (A and B) can bedefined as a probable case if no other etiology for the illness is identified.

of toxic shock appears as discrete macular lesions inpatients, satisfying the case definitions for staphylococcaland streptococcal toxic shock. It also is important toremember that because of the greater cardiac reserve andhigher maximal sustainable heart rate in children andadolescents relative to adults, development of hypoten-sion as a manifestation of toxic shock is a late, often im-mediately pre-terminal event in children and adolescents.

Just as maintaining a high index of clinical suspicionand early recognition are basic elements to the diagnosisof toxic shock syndrome, supportive care in an intensivecare unit by a skilled intensivist is basic to the clinicalmanagement of such patients. However, of equal impor-tance in the management of patients with toxic shock is theearly identification of the anatomical focus (or foci) orsource of infection, and the drainage and sterilization ofany identified foci. This often requires a completenessof physical examination and perhaps radiological imagingstudies beyond those performed in a routine patient evalu-ation. Focal infections important for the clinician to con-sider as the possible source of toxin-excreting bacteriain patients with toxic shock include bacteremia (often

without other identified focus), pneumonia, sinusitis,otitis, pharyngitis, tracheitis, empyema, meningitis, peri-tonitis, osteomyelitis, septic arthritis, pyomyositis, necro-tizing fasciitis or myositis, impetigo, post-operativewound and hardware infections, erysipelas, cellulitis, andvaginitis. Association of toxic shock syndrome with aninfected body piercing has even been described.4

Early recognition of toxic shock facilitates early initia-tion of specific antimicrobial and other therapeutic agents.Two recently published studies that highlight the impor-tance of appropriate, early, empiric antimicrobial therapyin patients with severe sepsis offer valuable lessons forpatients with staphylococcal or streptococcal toxic shocksyndrome.5,6 These studies show that appropriate earlyantimicrobial therapy is an important determinant of sur-vival in patients with bacterial sepsis. Stated simply, the“clock is ticking” in such patients and great care andconsideration should be given to early recognition of thesigns and symptoms of toxic shock as well as empiricantibiotic treatment decisions. From the perspective of aninfectious disease specialist, empiric antibiotic therapyfor patients suspected of having toxic shock syndromeshould include a bacteriocidal agent capable of rapidlydestroying Staphylococcus aureus and Streptococcus pyo-genes, in combination with an antimicrobial agent tar-geted at inhibiting protein (toxic shock toxin) production.In practical terms, the antibiotics usually given empiri-cally to toxic shock patients should include a parenteralanti-staphylococcal/streptococcal semi-synthetic peni-cillin such as nafcillin, or a first generation cephalosporinsuch as cefazolin, in combination with clindamycin. Withthe recent increase of infections in children and adoles-cents caused by community-acquired methicillin-resistantStaphylococcus aureus, consideration should be given toempiric treatment of patients with toxic shock with van-comycin in addition to—or in place of—an anti-staphylo-coccal/streptococcal penicillin or cephalosporin. Althoughdata to support efficacy is limited, toxic shock patients mayalso benefit from receiving intravenous immunoglobulinG therapy (IVIG).7 If IVIG is used, it should be given asearly in the clinical course as possible.

Due to the rapid clinical deterioration of patients withstaphylococcal and streptococcal toxic shock, it is impera-tive that early signs and symptoms of these diseases arequickly and easily recognized by health care professionalsevaluating such patients. From the perspective of an infec-tious disease specialist, toxic shock syndrome is not asdifficult to recognize as it is to successfully treat, due tothe fact that quite often the specialist becomes involvedin the management of such patients well into the courseof their disease when the most recognizable signs andsymptoms have fully developed and the patient is criti-cally ill. Therefore, it is the emergency room, primary careand other first-line physician who plays the most importantrole in influencing the outcome of the patient with toxicshock syndrome by maintaining a high index of suspicion

292 Omar: Opinions in Pediatric and Adolescent Gynecology

for the disease. It is imperative to remember that identifi-cation of a drainable infectious focus early in the courseof the infection is critical because abscesses and otherpurulent foci represent an ongoing reservoir of toxin-producing organisms that potentially may delay or preventresolution of toxic shock signs and symptoms. Initiation ofappropriate empiric antibiotic therapy early in the courseof disease may positively influence subsequent morbidityand mortality, lending further importance to early recogni-tion of the telltale signs and symptoms of toxic shock.

References

1. Todd J, Fishaut M, Kapral F, et al: Toxic-shock syndromeassociated with phage-group-I staphylococci. Lancet 1978;2:1116

2. Reingold AL, Hargrett NT, Shands KN, et al: Toxic shocksyndrome surveillance in the United States, 1980 to 1981.Ann Intern Med 1982; 96:875

3. Cone LA, Woodard DR, Schlievert PM, et al: Clinical andbacteriologic observations of a toxic shock-like syndromedue to Streptococcus pyogenes. N Engl J Med 1987; 317:146

4. McCarthy VP, Peoples WM: Toxic shock syndrome afterear piercing. Pediatr Infect Dis J 1988; 7:741

5. Harbarth S, Garbino J, Pugin J, et al: Inappropriate initialantimicrobial therapy and its effect on survival in a clini-cal trial of immunomodulating therapy for severe sepsis.Am J Med 2003; 115:529

6. MacArthur RD, Miller M, Albertson T, et al: Adequacy ofearly empiric antibiotic treatment and survival in severesepsis: Experience from the MONARCS trial. Clin InfectDis 2004; 38:284

7. Darenberg J, Ihendyane N, Sjolin J, et al: Intravenous immu-noglobulin G therapy in streptococcal toxic shock syndrome:A European, randomized, double-blind, placebo-controlledtrial. Clin Infect Dis 2003; 37:333