Serious Group A β-Hemolytic Streptococcal Infections Complicating Varicella

ORIGINAL ORIGINAL CONTRIBUTION CONTRIBUTION

Serious Group Group A p-Hemolytic [3-Hemolytic Streptococcal Infections Complicating Varicella Varicella Division of Pediatric Pediatric From the Division Emergency Medicine, Medicine, Department Emergency of Pediatrics, Pediatrics, University University of Texas Texas Southwestern Medical Medical Center at Dallas, and Children's Medical Dallas, Children's Medical Center of Dallas, Dallas, Dallas, Dallas, Texas. Texas.

Receivedfor publication April 19, 1993. Revision received 1993. Revision received August 5, 1993. 1993. Acceptedfor publication August 20, 1993. publication

Michael RCowan, R Cowan, DO DO

Study objective: To Toalert practicing practicing emergency emergency physicians physicians to

Patricia Patricia A Primm, Primm, MD

an an important and possibly possibly increasing increasing relationship relationship between between lifethreatening group A p-hemolytic ~-hemolytic streptococcal infecgroup A streptococcal (GABHS) (GABHS)infections and children children recovering recovering from from varicella. varicella.

Susan Susan M Scott, Scott, MD MO Thomas Thomas J Abramo, Abramo, MD Robert Robert AWiebe, A Wiebe, MD

Design: A A case case series series of six patients managed managed from from January through through March March 1993. 1993. Setting: Setting: AA university-affiliated pediatric pediatric specialty specialty emergency emergency

department. Type of of participants: participants: Six previously previously healthy immunocompeimmunocompe-

tent children children between between 1and 1 and 5years 5 years of age seen seen in our ED ED over over a nine-week period. period. Results: Six children children had onset onset of varicella varicella two days days to two

weeks before before developing developing a serious serious life-threatening GABHS GABHS infection. Children Children presented presented with clinical symptoms symptoms of invasive invasive GABHS infection with bacteremia (one patient); streptococcal GABHS bacteremia (one patient); streptococcal toxic shock shock syndrome syndrome with negative negative blood blood culture (two). (two), pneupneumonia with pleural effusion and streptococcal toxic shock monia pleural streptococcal toxic shock syndrome syndrome (one). (one), pneumonia pneumonia with pleural pleural effusion (one). (one), and pyomyositis pyomyositis of the thigh thigh (one). (one). Four Four of six patients required required intensive intensive care care admissions admissions and and aggressive aggressive support support of vital signs. signs. All six survived. survived. Conclusion: Conclusion: Emergency Emergencyphysicians physicians should should be be aware of the

association association between between varicella and and serious serious GABHS GABHS infections infections and be be prepared prepared to recognize recognize and and aggressively aggressively manage manage serious serious comcomplications should should they they occur. occur. [Cowan Abramo TJ, [Cowan MR, MR, Primm Primm PA, PA, Scott SM, Abramo TJ, Wiebe RA: RA: Serious A p-hemolytic ~-hemolytic streptococcal Serious group group A streptococcal infections complicatcomplicating varicella. Ann Emerg April 1994;23:818-823.] varicella. Ann EmergMed Med April 1994;23:818-823.]

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INTRODUCTION

self-limited disease disease maniVaricella is usually a benign and self-limited fested by mild systemic systemic symptoms, characteristic characteristic rash, fested low-grade fever. fever. Because of its highly contagious and low-grade nature, children with varicella varicella often are considered unwelemergency department. Although minor comcome in an emergency plications are common, serious problems related to variimmunocompetent patient are relatively relatively rare. cella in the immunocompetent 1.4:100,000 The varicella death: case ratio is estimated at 1.4: 100,000 11 common serious complicain normal children. The most Common tions include soft-tissue infections, pneumonia, dehydrainvolvement. 1-4 >4 tion, and central nervous system involvement. A number of recent reports have noted an apparent increase in the number of patients with invasive group A [3-hemolytic streptococcal (GABHS) (GABHS) infections in nonvari~-hemolytic 8 celia patients. 55-s cella - In addition to blood-borne and tissue GABH5 infections, there have been several reports of a GABHS 12 syndrome.99-12 toxic shock-like syndrome There also have been several sporadic case reports of invasive streptococcal disease as a complication of varicella. 13-16 13-16 We report our experience with six patients seen between January 19 and March 27,1993, 27, 1993, in a pediatric ED. All six patients were previously healthy and had recently recovered or had had active varicella infection at GABHS complications occurred. Two Two of the six the time GABHS patients were improperly triaged as having only varicella initial management of with delay in the recognition and initial shock. These patients offer a valuable lesson to emergency emergency physicians and nurses who may be complacent when triaging varicella patients. Although varicella is generally a benign and self-limited illness, illness, emergency emergency physicians and nurses must be aware of the increasing risk of serious GABHS GABHS complications. CASE REPORTS Case 11 A A 3-year-old girl presented to our ED with a fiveday history of varicella and a two-day history of large bullous lesions on the upper upper trunk. She also had anorexia and decreased urine output. She was treated by her pediatrician with acyclovir on the day before admission. Vital signs were blood pressure, 79/41 79/41 mm Hg; pulse, 205; respirations, 60; and temperature, 39.6°C. 39.6'C. The patient was lethargic and difficult to arouse. The extremities were cool to the touch, with a capillary refill of six seconds. The skin was diffusely erythematous with a fine sandpaper-like rash on the abdomen and scattered areas of sloughing skin on the upper upper chest. Varicella lesions were present in various evolutionary stages.

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Initial laboratory results revealed revealed a WBC of 3,200 cells/mm cells/mm33 and serum sodium of 126 mmoliL. mmol/L. Other test results, including prothrombin time, partial thromboplastin time, and liver transaminases, were normal. Blood and throat cultures subsequently grew GABHS. GABHS. In the ED ED the patient was given a total of 80 mUkg mL/kg of isotonic volume replacement replacement before before capillary refill and perfusion returned to normal and her mental status improved. The patient was admitted to the pediatric ICU. She subsequently required intubation and massive volume support (240 mUkg mL/kg in the first 24 hours) and was placed on vasopressor infusions. By By day 3 in the pediatric ICU, the patient had a consumption coagulopathy and massive pulmonary hemorrhage, and she developed acute respiratory distress syndrome. syndrome. After a prolonged stay requiring high ventilatory setting and multiple thoracostomy thoracostomy tubes to manage her pulmonary disease, she recovered recovered uneventfully. uneventfully. Case 2 A A l-year-old 1-year-old girl presented to an outside ED two weeks after the onset of varicella with a two-day history of fever, fever, malaise, decreased appetite, and difficulty difficulty breathing. On examination, the patient was in moderate respiratory distress with nasal flaring, subcostal retractions, and decreased breath sounds over the left lung. Vital signs were blood pressure, 134/66 mm Hg; pulse, 160; respirations, 42; temperature, 39.TC; 39.7°C; and oxygen saturation, 90% on room air. air. The infant was irritable and lethargic, Dry, crusted skin lesions were all that but arousable. Dry, remained as evidence of varicella. The patient was given a single dose of ceftriaxone at the referring hospital and brought by our transport team to mUkg normal our ED. En route, the patient was given 20 mL/kg saline because of lethargy and a capillary refill of four to five seconds. mUkg of In the ED, the patient was given a total of 90 mL/kg crystalloid in one hour, intubated, and given vasopressor infusions. A chest radiograph revealed the presence of a left pleural effusion, and a thoracostomy tube was inserted. Seropurulent material obtained from the pleural GABHS. Blood cultures were negaspace was positive for GABH5. tive. After stabilization with volume and vasopressor support, the patient was admitted to the pediatric ICU, where she continued to require blood, albumin, and fresh frozen plasma for 48 hours. Recovery was uneventful. A 3-year-old previously healthy boy with a sixCase 33 A day history of varicella was referred to our ED from an outside ED for evaluation of abdominal pain, cough, diffi39.soC. culty breathing, and fever to 39.5°C.

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Physical examination revealed an alert and active child in moderate respiratory distress with multiple erythematous, crusted varicella lesions over the face, trunk, and extremities. Breath sounds were decreased over the right posterior lung field. The remainder of the examination was unremarkable. Laboratory results included a WBC count of 31,200 cells/mm % segmented neutrophils and 1% cells/ram33 with 81 81% bands. Chest radiograph revealed a right pleural effusion and right lower lobe pneumonia. A thoracostomy tube was placed; the pleural fluid contained 5,320 WBCs/mm33 and 28,150 RBCs/mm 33.. Cultures of the pleural fluid and varicella skin lesions were positive for GABHS. GABHS. Blood cultures were negative. He was admitted to the ward and thereafter made an uneventful recovery. Case 4 A 2-year-old boy presented to a local ED with a six-day history of varicella and a two-day history of vomiting, decreased activity, decreased urine output, and lethargy. Two Two days before this visit, he had been seen in the same ED for a seizure associated with fever. fever. The examination was unremarkable and the patient was discharged. On the second presentation to the local ED, vital signs were blood pressure, 120/60 mm Hg; pulse, 160; respirations, 32; temperature, 37.9'C; 37.9°C; and capillary refill, three seconds. Positive physical phYSical findings included an erythematous throat and mottled skin with four purpuric lesions measuring 0.5 to 2 em cm in diameter on the right shoulder and buttock. There were varicella lesions in various stages on the face, trunk, and extremities. The patient was given 10 mLlkg mL/kg normal saline and cefotaxime cefotaxime at the referring ED and then transferred to our ED. On arrival, he had poor perfusion, with a capillary refill of five five seconds. The patient received received volume resusciduring the first hour and was given tation of 80 mLlkg mL/kg vasopressor support with some improvement. Initial laboratory results revealed a WBC of 19,200 cells/mm33 with 37% segmented neutrophils, 42% bands, and a serum sodium of 125 mmollL. mmol/L. Cultures of the skin and throat were positive for GABHS. GABHS. Blood, cerebrospinal fluid, and urine cultures were sterile. The patient was admitted to the pediatric lCU, ICU, where he ultimately required endotracheal intubation and aggressive volume and vasopressor support. He was transferred to the ward on day 5 and eventually made an unremarkable recovery. Case 5 A 3-year-old boy presented to our ED with a three-day history of varicella and increasing right-sided abdominal pain, vomiting, and decreased activity over the past several hours.

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Initial examination revealed an alert, crying child with cm by 10 em cm erythematous erySipelas-like erysipelas-like rash a tender 8 em over the right abdominal wall. Vital signs were blood pressure, 88/67 mm Hg; pulse, 165; respirations, 42; tem'C; and capillary refill, five perature, 39.1 39. I°C; five seconds. The pharynx, tongue, and palate were erythematous. erythematous. There were multiple varicella lesions over the trunk and extremities that were noninfected and undergoing normal evolution. Initial laboratory studies revealed a WBC of 20,500 41% cells/mm 33 with 41 % segmented neutrophils and 28% bands. Throat culture had a heavy growth of GABHS. GABHS. The patient was given a total of 60 mLlkg mL/kg normal during the first hour and was given a vasopressor saline dUring infusion. He continued to require fluid and vasopressor support during the first 48 hours of pediatric lCU ICU management and then had an uneventful recovery. recovery Case 6 A 5-year-old girl with a five-day five-day history of varicella presented to our ED with right leg pain and tenderness. 127/75 mm Hg; pulse, Vital signs were blood pressure, 127/75 140; respirations, 24; and temperature, 3TC. 37°C. She was unable to bear weight on her right leg. There was tenderness and erythema over the anteromedial aspect of the right thigh. There were multiple varicella lesions over the face, trunk, and extremities in normal evolution, and none appeared secondarily infected. Initial laboratory results revealed a WBC of 18,900 cells/mm 33 with 74% segmented neutrophils and 16% bands. The patient was admitted with a diagnosis of cellulitis, cellulitis, and oxacillin was started. Because of continued fever, fever, a magnetic resonance imaging scan of the right hip and thigh was performed. This revealed a collection of fluid surrounding and involving most of the musculature of the thigh but sparing the posterior compartment. Needle aspiration revealed purulent material with a WBC of 47,000/mm ceils. 47 ,000/mm33,, all of which were polymorphonuclear cells. The patient required surgical drainage of 50 mL of purulent material that was positive for GABHS. GABHS. Blood cultures were negative. The wound was left open for drainage, and the patient recovered without problems. DISCUSSION Varicella is generally generally a benign and self-limited illness affecting an estimated 3.5 million individuals annually.3 annually. 3 affecting The majority of these cases resolve with little more than patient discomfort and parental anxiety. However, it is

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estimated that varicella results in more than 4,000 hospitalizations per year in the United States. 17 lr Recent reports have documented that serious morbidity and mortality can occur from the complications of varicella celia infection. Jackson et all al 1 reviewed 103 cases of patients hospitalized with varicella during a ten-year period. Thirty-one percent had soft-tissue infections, 21 % skin infections, 15% central nervous system compli21% cations, 10% dehydration, 10% pneumonia, 5% sepsis, and 6% Reye's Reye's syndrome. These findings were consistent al, 2 who found similar results in with those of Fleisher et al,2 a study published ten years earlier. In a classic review of complications of varicella by Bullowa and Wishik,4 Wishik, 4 133 of 2,534 2,534 patients with varicella (5.2%) had significant complications. There are many sporadic cases reported of GABHS GABHS invasive disease in previously preViously healthy patients. In recent years there have been numerous reports of the increasing incidence of invasive GABHS GABHS in children. Givner et aIS al 5 GABHS in described this apparent increase in invasive GABHS 1987. 1987. Since that time, the incidence of invasive GABHS GABHS relatively rare. appears to have increased but still remains relatively Recent estimates from Colorado and South Carolina indicate an incidence of three to seven cases per 100,000 100,000 persons per year with GABHS GABHS bacteremia or toxic shock syndrome. 66 Invasive GABHS GABHS infections complicating varicella have ,13-l6 Although this is a recogbeen described in the past. S8,~3-~6 nized complication, case reports are sporadic, and even in large referral centers one case annually of serious GABHS GABHS complications from varicella is unusua1. ,7,S The vast unusual. 55,r,8 majority of serious GABHS GABHS infections have occurred predominantly in healthy adolescent or adult populations.iS populations. 1S Shulman provided definitions and differentiation differentiation between the clinical entity of streptococcal toxic shock syndrome and invasive group A streptococcal infection with bacteremia. 19 19 The patient with streptococcal toxic shock syndrome most often has a soft-tissue focus focus of infection. Bacteremia may be present but is not necessary for the diagnosis as it is a toxin-mediated form of shock. The most consistent feature of streptococcal toxic shock syndrome is hypotension with progression to multiple failure if not aggreSSively aggressively managed. The organ system failure fever is generscarlatiniform rash characteristic of scarlet fever ally not present with streptococcal toxic shock syndrome. differentiate this entity from This allows the clinician to differentiate staphylococcal toxic shock syndrome, which is often associated with a fine fine erythematous rash. Invasive GABHS GABHS infection usually is associated with a specific focus of infection, and bacteremia is often documented.

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Three of our patients (nos. 2,4, 2, 4, and 5) presented with symptoms consistent with streptococcal toxic shock syndrome. All three were hypotenSive, hypotensive, clearly in shock, and reqUired required from 60 to 90 mUkg mL/kg of isotonic fluid resuscitaGABHS, tion. Patient 2 had pleural fluid positive for GABHS, patient 4 had cultures positive from both skin and throat, and patient 5 had a classic erYSipelas-like erysipelas-like rash and a positive throat culture for GABHS. GABHS. Patient 2 presented in shock two weeks after the onset of varicella. It was not clear precisely when the varicella infection resolved completely, completely, but dry and crusted lesions remained at the time she presented to the ED in shock. On presentation, the patient already had a large pleural effusion and pneumonia, so we included this patient in our series as a possible complication of varicella. It is possible that this GABHS GABHS infection is not related to the antecedent varicella. More recently, there has been an increased awareness of invasive and toxin-related diseases caused by GABHS. GABHS. Streptococcal toxic shock syndrome has been reported l3 Bradley et al l3 a113 recently by several investigators. 99q3 reported a case of a 6-year-old with varicella who developed streptococcal toxic shock syndrome. Begovac et al ll 1~ reported two patients with varicella who developed streptococcal toxic shock syndrome that resulted in progression to multiple organ system failure. The apparent increase in incidence and virulence of invasive GABHS GABHS is thought to be a result of an increase in the number of virulent serotypes. Schwartz et apo al2° described a shift in the proportions of M types 1, 3, and 18 during the past 20 years and documented that these strains were more likely to cause invasive and fatal infections. There was no consistency in M and T typing of GABHS in our patients. GABHS It appears that the incidence of both invasive GABHS GABHS and streptococcal toxic shock syndrome are increasing. We report a possible and very concerning association between GABHS GABHS and varicella. During the three-month period of our study, there were two additional nonvaricella celia admissions with serious GABHS GABHS infections or sequelae. Although this case series supports a relationship between GABHS GABHS and varicella, further epidemiologic studies are needed to document a true association. The possible pOSSible increasing relationship between serious GABHS GABHS and patients with varicella must be recognized early and treated aggressively. Patients with varicella who look ill, have prolonged capillary refill, or are hypotensive have altered mental status and high fever, fever, or are febrile beyond the first 72 hours of varicella infection should be considered for possible pOSSible GABHS GABHS complications. To avoid

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organ system system failure, shock shock must must be be treated treated withwithmultiple organ out delay. Rapid and and aggressive early early fluid resuscitation resuscitation is out the most most important important aspect aspect of of early early shock shock management in in the 21 children. 21 Drugs directed at improving the cardiac index Drugs directed at the cardiac index and combating toxin-mediated vasodilatation should should also and be considered as early therapeutic interventions. be be important important in in early Antibiotics to cover GABHS may be care of the seriously ill child presenting presenting with with varicella. SUMMARY

Serious GABHS complications of varicella may be increasing. We report six cases of life-threatening GABHS infections in children occurring during a nine-week period. Cases included two patients with pneumonia and pleural effusion (one with toxic shock), one patient with pyomyositis, two patients with a streptococcal toxic shock syndrome, and one patient with GABHS and bacteremia. The emergency physician should be aware that healthy children recovering from varicella can develop life-threatening invasive infections caused by GABHS.

16. 16. Gradon Gradon JD, JD, Chapnick Chapnick EK, EK. Lutwick Lutwick LI, L1, et et al: al: Group Group AAstreptococcal streptococcal meningitis meningitis complicating complicating varicella. ;10:786-787. varicella. Pediatr Pediatr Infect Infect Dis Dis JJ1991 1991;10786-787 17. J, et 17. Guess Guess HA, HA, Broughton Broughton DD, DO, Melton Melton III III LLJ. et ah al: Population-based Population-based studies studies of of varicella varicella complications. complications. Pediatrics Pediatrics 1986;78 1986;78 (suppl):723-727. (suppl):723-727 18. Stevens Stevens DL: Invasive Invasive Group Group AAstreptococcus streptococcus infections. Clin Clin Infect Infect Dis DIS 1992;14:2-13. 1992;14:2-13. 19. Shulman Shulman ST: ST: Invasive Invasive and and toxin-related toxin-related disease disease caused caused by group group AAstreptococci. streptococci. Pediatr Pediatr Infect Dis Dis JJ 1991;10:528-531. Infect 20. 20. Schwartz Schwartz B, B. Facklam Facklam RR, RR, Breiman Breiman RF: RF: Changing Changing epidemiology epidemiology of of group group AAstreptococcal streptococcal infection in the 1990;336:1167-1171. the USA. USA. Lancet Lancet1990;336:1167-1171 21. 21. Carcillo Carcillo JA, JA. Davis Davis AL, AL, Zaritsky Zaritsky A: A: Role Role of of early early fluid fluid resuscitation resuscitation in pediatric pediatric septic septic shock. shock. 1991 ;266:1242-1245. JAMA 1991 The authors acknowledge George McCracken, McCracken, Jr, MD, MD, for time time spent in manuscript manuscript review and Debbie Woodby for for her excellent manuscript manuscript preparation.

Reprint Reprint no. 47/1/53848 47/1/53848 Address Address for for reprints: reprints: Robert AAWiebe, Wiebe, MD Division of Pediatric Pediatric Emergency Medicine Department of Pediatrics Pediatrics

UTSWMC 5232 Harry Hines Boulevard

Dallas, Texas 75235 75235 214-640-2014 214-640-2014

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