Toxic Shock Syndrome in Children Aged 10 Years or Less

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Received for publication March 15, 1983; accepted Sept 12, 1983. Reprints will not be available.

PEDIATRICS (ISSN 0031 4005). Copyright © 1984 by the American Academy of Pediatrics.

Toxic

Shock

Syndrome

in Children

Aged

10

Years

or Less

Andrew

M. Wiesenthal,

MD, and James

K. Todd,

MD

From the Departments of Pediatric Infectious Diseases, Pediatrics, and Microbiology/ Immunology, University of Colorado School of Medicine, and The C. Henry Kempe Center for Investigative Pediatrics and Departments of Pediatrics and Pathology, The Children’s Hospital of Denver, Denver

ABSTRACT.

Eight children aged 10 years or less had toxic shock syndrome, and medical records were reviewed for seven of them. There were four boys and three girls, ranging in age from 5/i2 to 10A2 years; all seven met the Centers for Disease Control case definition oftoxic shock syndrome. One boy died. The illness was generally char-acterized by fever, followed by erythroderma,

gastrointes-tinal complaints, and mucous membrane hyperemia.

Based on the need for supplemental oxygen or mechanical ventilation, the girls tended to have milder courses than the boys. In four of four cultures performed prior to the institution of antibiotic therapy, Staphylococcus aureus

grew from one or more sites. One boy also met the case definition of Kawasaki syndrome and has had multiple

coronary artery aneurysms demonstrated in early and

late follow-up. Toxic shock syndrome in these children was similar to published descriptions of toxic shock syn-drome in series of adult patients, except that, as a group, the children had a greater incidence of respiratory em-barrassment. Pediatrics 1984;74:1 12-1 17; toxic shock syn-drome, mucocutaneous lymph node syndrome.

With the advent of widespread recognition of toxic shock syndrome (TSS), there have been

flu-merous published reports describing the clinical

and laboratory findings, primarily in menstruating females.’8 However, other than the initial report

by Todd et al9 and that by Reingold et al,’#{176}there has been little descriptive information relating to TSS in preadolescent children. Because of the con-tinued relevance of TSS to pediatric patients, we have reviewed all available material relating to

pa-tients aged 10 years or less at the onset of TSS.

METHODS

Patients with TSS become known to us in at

least one of three ways. Some are admitted to The Children’s Hospital of Denver and caned for directly

by us. Others are reported to us by their primary

care physicians in the process of clinical consulta-tion. The remainder are reported to the Colorado

Department of Health which, in turn, reports them

to us as part of an ongoing collaborative study. Virtually all patients of whom we are specifically aware reside within the referral area of The

Chil-dren’s Hospital-the entire State of Colorado and

part or all of seven neighboring states.

Vigorous attempts were made to obtain complete

information on all patients aged 10 years or less for whom a diagnosis of TSS could be confirmed. The diagnosis was confirmed utilizing the Centers for Disease Control (CDC) collaborative case defini-tion.” Records of all hospitalizations and records, both for the prodromal and convalescent period, from the patients’ private physicians were reviewed, for a standard set of historical, clinical, and labo-ratory parameters for each day of the acute illness, from onset through discharge from the hospital.

All tables and figures in which the duration of

particular findings is reported should be interpreted

as minimum estimates. Due to the retrospective

nature of this analysis, the possibility exists that the absence of a particular finding on a particular day in the medical record may mean that observers failed to note the finding even though it was pres-ent, that they failed to document a finding even though it was noted, or that the laboratory test appropriate to the documentation of the finding was not performed.

Interpretation of laboratory values was restricted

to determining whether or not a specific result lay

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Fever >38.5 C Dsp M.D 55 55 44 6I3 3 5 4 4 141412 7 4 33 2 6 2 2 5 2 7I A

131 31 1

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Diarrhea Vomiting 7 4 7 4

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-z-6 15 jlL77 IIA Conjunctival Hyperemia 4 Pharyngeal a Hyperemia ______ Hypotension a

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Figure. Aggregated course of selected clinical parameters by day. -4 1 A 1 --A 4

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[414 5 5 5 5 5 4 4 4 6]

Because several different laboratories were used by

physicians caning for these patients, the high like-lihood of methodologic variability made quantita-tive comparisons inappropriate.

RESULTS

Eight patients, 10 years of age on younger at the

onset of their illness, satisfied the CDC collabora-tive case definition of TSS; records for seven of the

eight were available for review. Some of the clinical features of these patients are shown in the Figure.

Patients 1 and 2 (Table 1) have been briefly described elsewhere.9 The seven patients had the

Erythroderma

1313

I 21212

onset of their illness between March 1977 and

August 1981, and they ranged in age from 5/12 years

to 108/12 years (mean 76/12 years) at the onset of

TSS. There were four boys and three girls; all were

white. Excluding patient 1, who died, and patient

7, whose hospitalization was prolonged by the need

for extensive debnidement and grafting of the post-operative wound infection which was the probable

source of his TSS, the mean duration of illness for

the remaining five patients was 12.6 days, and the mean duration of hospitalization was 9.2 days.

The prodromal historical and clinical findings, up to the day of admission to the hospital, are summarized in Table 2. As can be inferred from

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Finding Prodrome

Patients with Mean Days

Finding/Total Present (Range) Patients

Admission: Patients with Finding/Total

Patients

Subsequent Course At any Time:

Patients with Finding/Total

Patients Patients with

Finding/Total Patients

Mean Days Present (Range)

ini’;g 5/7 2.0 (1-4) 5/7 3/7 1.3 (1-2) 5/7

Diarrhea 5/7 2.2 (1-4) 5/7 5/7 1.4 (1-2) 6/7

Myalgia 2/7 1.5 (1-2) 2/7 2/7 1.0 (1) 3/7

Dizziness 2/7 1.5 (1-2) 2/7 1/7 .. . (1) 2/7

Erythroderma 7/7 2.7 (1-5) 7/7 7/7 4.7 (2-11) 7/7

Conjunctival hyperemia 6/7 2.5 (1-5) 7/7 4/5 5.8 (2-10) 7/7

Pharyngeal hyperemia 7/7 1.3 (1-2) 7/7 6/7 3.5 (1-8) 7/7

Vaginal hyperemia 0/3 . . . 0/3 0/3 .. . 0/3

Fever 38.5C 7/7 3.7 (3-5) 7/7 7/7 2.7 (1-6) 7/7

Hypotension or shock 4/7 7/7 3.0 (1-7) 7/7

Desquamation* 1/7 3/3 8.0 (5-10) 3/3

* Of the four patients not examined for convalescent desquamation, patient 1 died acutely, patient 7 had extensive debridement (as described in text), and patients 2 and 3 were lost to appropriate follow-up.

Table 2, all of the patients had fever, erythroderma,

and mucous membrane (excepting vaginal)

hyper-emia by the day of admission, and most had had

vomiting or diarrhea. Two patients experienced

dizzyness or myalgia. Fever was the initial

symp-tom, followed by erythroderma, gastrointestinal

complaints, and mucous membrane involvement.

The clinical and laboratory findings present on

the day of admission are shown in Tables 2 and 3.

As was the case prior to admission, the most

corn-mon clinical findings on admission included fever,

erythroderma, mucous membrane hyperemia, and

gastrointestinal disturbances. Only four of the

seven patients had hypotension. Of interest is the

fact that patient 4 had already begun to desquarnate

by the time he was admitted to the hospital on day

6 of his illness.

Although these patients were relatively similar

at the time of admission, their hospital courses were

somewhat more divergent (see Tables 2 and 3).

Patient 1 had acute onset of irreversible shock and

respiratory distress secondary to pulmonary edema

and died on the fourth day of hospitalization.

Pa-tient 7 had necrosis of his operative site (a plastic

surgical modification of his left ear, performed 15

hours prior to the onset of his TSS) and of the skin

TABLE 1. Patient Data

Pa- Date of Age at Sex Length Length

Out-tient Onset Onset of of come

No. (yr) Illness

(d)

Hospital-ization

(d)

1 3/26/77 8 ‘%2 M 5 4 Died

2 11/28/77 108/12 F 9 5 Survived

3 5/20/79 6 /12 F 11 7 Survived

4 7/5/79 6 2/,2 M 14 10 Survived

5 8/16/79 5 /12 F 10 8 Survived

6 1/14/80 7 /12 M 19 16 Survived

7 8/21/81 7 /12 M 40 39 Survived

TABLE 2. Clinical Findings

of his distal extremities, all of which required ex-tensive grafting and prolonged his hospitalization.

He was not noted to have convalescent

desquarna-tion, but the debnidement, grafting, and

concorni-tant bandaging may have precluded such an

obser-vation. The three girls, patients 2, 3, and 5, had apparently milder illnesses than the boys. The girls

showed a trend (not statistically significant) toward fewer therapeutic supportive measures-none were given steroids or pressors and only one required

supplementary oxygen-and toward a shorter

du-ration of hospitalization (Table 1). Three of the

four boys required steroids and pnessors, and all

four needed oxygen or ventilatory support.

The patients’ clinical courses for selected

pararn-eters are shown in the Figure. The numbers in the

boxes correspond to the patient numbers. Although

most abnormalities were evident prior to on on the

day of admission, it is interesting to note that

evidence for hypotension was more likely to be

present subsequent to that time. Abnormalities of

pulmonary function sufficient to require therapeu-tic intervention, either supplementary oxygen alone

on oxygen and mechanical ventilation, had their

onset between the second and seventh days of

hos-pitalization (mean 4.4 ± 1.8 days).

The results of bacterial cultures in the seven

patients consistently showed Staphylococcus aureus

to be the only pathogen isolated from any of them. S aureus grew from pleural fluid obtained from patient 1 after death; it grew from a throat culture

from patient 2; it grew from two blood cultures of

patient 5 (all six other patients had repeatedly

sterile blood cultures); and it grew from an infected

postoperative wound at the ear of patient 7.

Pa-tients 3, 4, and 6 all had sterile cutures of all sites, but all had had prior treatment with

antistaphylo-coccal antibiotics. The pet cat of patient 3 had an

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TABLE 3. Selected Laboratory Findings

Admission: Patients with

Finding/ Total Patients

Subsequen t Course At any Time:

Patients with Finding/

Total Patients Patients with

Finthng/ Total Patients

Mean Days Present (Range)

Renal function:

5 WBC/HPF on urinalysis 3/4 2/4 1.5 (1-2) 4/6

1 RBC/HPF on urinaylsis 2/4 2/4 1.5 (1-2) 3/6

2+ protein on urinalysis 2/4 1/3 . .. (1) 3/6

Elevated BUN 3/3 6/7 2.3 (1-5) 6/7

Elevated creatinine 2/4 2/6 1.5 (1-2) 3/6

Hepatic function:

Elevated alkaline phosphatase 0/2 0/2 . .. 0/4

Elevated lactic dehydrogenase 2/2 3/4 2.0 (1-4) 3/4

Elevated SGOT 4/4 4/5 3.5 (1-6) 4/5

Elevated SGPT 1/1 2/2 1.5 (1-2) 2/2

Elevated bilirubin 4/5 4/4 1.75 (1-4) 5/5

Decreased total protein 1/2 3/4 1.7 (1-3) 4/4

Decreased albumin 0/1 4/4 4.0 (1-6) 4/4

Hematologic and clotting function:

Elevated WBC count 4/7 6/7 4.0 (1-10) 6/7

Elevated % ofpolymorphonuclear 3/7 5/7 3.8 (1-8) 5/7

leukocytes

Elevated % of band cells 5/7 6/7 2.8 (1-5) 7/7

Decreased platelets 2/7 3/7 4.0 (2-7) 3/7

Prolonged prothrombin time 2/3 3/5 3.0 (1-7) 4/5

Prolonged partial thromboplastin 3/4 5/5 1.6 (1-2) 5/5

time Serum electrolytes:

Hyponatremia 5/5 5/7 3.8 (1-10) 7/7

Hypocalcemia 1/2 3/4 5.0 (2-6) 3/5

Hypophosphatemia 1/2 2/4 1.5 (1) 2/4

Hyperphosphatemia 1/2 1/4 . . . 2/4

Other:

Abnormal arterial blood gases 0/1 5/5 3.4 (1-7) 5/6

Elevat3d creatine phosphokinase 0/0 2/3 1.0 (1) 2/3

3 had TSS. Patient 4 had a clear-cut cervical ad-enitis, not cultured prior to antistaphylococcal then-apy, for which S aureus would have been a plausible

etiologic agent. Prior to the initiation of antibiotic therapy, patient 6 had a throat culture that grew “wound flora” but no organisms were specifically identified. Of the three girls (patients 2, 3, and 5), two (patients 2 and 3) had vaginal cultures per-formed (patient 2 prior to antistaphylococcal then-apy). In neither case did S aureus grow. Viral cul-tunes of urine, nasopharyngeal, or throat, and nec-turn were obtained for patients 2 and 4, and no viruses were grown.

All patients received large quantities of intrave-nous fluid, especially in the first 48 hours. Six of the seven patients received antistaphylococcal

an-tibiotics at some point during the course of their illness. Patient 1 (who died) did not receive anti-staphylococcal antibiotics. Five patients received other antimicrobial agents as well. Patients 1, 6,

and 7 required pressors, and patients 4, 6, and 7

were given systemic steroids for varying periods of

time. Six of the patients were given aspirin, the only antipynetic used.

Detailed information regarding the convalescent course of the six survivors is lacking in most

in-stances, primarily because evidence for long-term sequelae was nil in five of them. Patients 2, 3, 4, 5, and 7 all returned to normal function, and none of them are known to have had recurrences of TSS.

Patient 6 was an exception. His acute course was complicated by severe left-sided heart failure and pulmonary edema. He responded well to medical management and was discharged from the hospital on a regimen of digoxin. Four weeks later he un-derwent repeat cardiac evaluation, including chest roentgenogram, ECG, echocardiogram, and cardiac catheterization with aortic root cineangiography. Findings from the first three investigations were all normal, as were findings on the routine can-diac catheterization, but cineangiographic findings showed two aneurysms of the right coronary artery and two aneurysms of the left main coronary artery. Digoxin therapy was discontinued and the patient was given sulfinpyrazone (Anturane) for the next 2 years without any interruption of normal growth,

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to have persistence of all aneurysms previously noted. He is still receiving sulfinpynazone and will have repeat coronary angiography in approximately

3 years.

DISCUSSION

The clinical findings in these seven children tend

to support the notion that TSS is an “acute, febnile entity with a diffuse, desquamating erythroderma and mucous membrane hyperemia which may have

a prodrome of myalgia, vomiting, diarrhea, and pharyngitis and can progress rapidly to hypotension and multiorgan system dysfunction.”2 Further,

these children demonstrated many of the same laboratory abnormalities found in older patients by other investigatons.”37 These included renal (ab-normal findings on urinalysis, elevated level of BUN), hepatocellular (elevated levels of lactic de-hydrogenase [LDH], SGOT, SGPT, and bilirubin; decreased levels of albumin and total protein), clot-ting (prolonged prothrombin time [PT] and PTT), and electrolyte (hypocalcemia and hyponatremia) abnormalities. Although these findings, especially the electrolyte abnormalities, provoked therapeutic interventions in some of our patients, it is not clear that such interventions were necessary. As an ex-ample, despite evidence for renal impairment in all but one of these children and severe oligunia in several of them, none required dialysis. Further, although all patients appropriately observed had laboratory evidence of a coagulopathy, none had clinically important bleeding, and none required blood or blood products because of bleeding.

The extent of the pulmonary dysfunction in our patients differed somewhat from that described by

others. Chesney et al3 mentioned that only two of their 22 patients required mechanical ventilation. Three of the eight patients described by Fisher et al5 needed similar intervention, whereas two of the 15 patients reported by Tofte and Williams7 were ventilated. The latter two papers described these particular patients as resembling patients with

adult respiratory distress syndrome. Five of the seven patients in our series required some thera-peutic intervention for pulmonary embarrassment,

and three of these required mechanical ventilation for between 24 and 72 hours (patient 1 died after approximately 24 hours on a ventilator). Given the fact that this problem arose subsequent to hospi-talization and several days of therapy, it is reason-able to assume that, in our patients, it did represent a form of adult respiratory distress syndrome, pos-sibly related to the large quantities of fluid admin-istered during the initial stages of hospitalization.

The children in our study also differed from patients in other published series in that none had

TSS that was menstrually or tampon associated, and there were no vaginal isolates of S aureus. Three of the four children on whom cultures were performed prior to the initiation of antistaphylo-coccal antibiotics had major staphylococcal infec-tions (empyema, bacteremia, and a wound infec-tion), and the fourth had evidence for mucosal

colonization (a throat culture grew S aureus). These findings reinforce the idea that focal infection or colonization with S aureus is a necessary precon-dition for the development of TSS and that being

female, menstruating, and using tampons are not (although such characteristics, especially the last, probably increase the risk of developing TSS in

ways that are not yet fully clear).

Findings for patient 7 add to the growing body of

evidence concerning the incubation period of post-operative TSS-approximately 15 hours from the time of his surgery to the onset of fever. This is rapid compared with the range of one to four days in the series described by Reingold et al.’#{176}

Patient 6, the child who was found to have con-onary artery aneurysms, deserves further comment. There is no question that he qualifies as a case of TSS by virtue of fitting the criteria of the collabo-native case definition. He also fits the criteria for mucocutaneous lymph node syndrome as described by Kawasaki et al13 and Morens and Nahmias.’4 Coronary artery aneurysm formation has been shown to be associated with Kawasaki syndrome,13 and, to date, there have been no reports of early or late sudden death due to coronary artery aneurysm and thrombosis in patients felt to have TSS. This would seem to favor a diagnosis of Kawasaki

syn-drome in this child. However, the mean age of children with Kawasaki syndrome reported to the Centers for Disease Control is 3.1 years,14 and only

31/254 patients reported to them were 7 years of

age on older at disease onset’5 (14/31 were patients who were aged 12 years or older-recent experience suggests that most of these patients had TSS). Kawasaki et aP3 indicated that a reasonable upper age limit might be 5 years-fewer than 5% of Jap-anese patients are olden. At age 7/12 years, this patient was definitely older than most patients with Kawasaki syndrome. In addition, fewer than half of patients with Kawasaki syndrome reported in the United States had indications of significant renal and hepatic involvement,’5 dramatic features of the illness in patient 6, and there were no reports

of adult respiratory distress syndrome, a major feature of his illness. All of these factors suggest a diagnosis of TSS.

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per-haps an unrecognized earlier episode of Kawasaki syndrome followed by this episode of TSS, as it is unknown whether he had aneurysms prior to the illness described herein.

Thankfully, patient 6 seems to be the exception

that makes the rule-the other children in this series did not fulfill the criteria for Kawasaki syn-drome, and the distinction usually is not, in our experience, a difficult one to make clinically. This is particularly true when there is evidence for a focal staphylococcal infection, a factor clearly as-sociated with TSS and not with Kawasaki syn-drome (Dr Mary Ann Melish, personal communi-cation, 1983).

In summary, the clinical and laboratory findings

in preadolescent children with TSS do not appear to differ appreciably from those in older patients.

The exception to this may be a greater incidence of adult respiratory distress syndrome in the children.

Girls with TSS showed a trend toward less severe illness than boys. Making the distinction between TSS and Kawasaki syndrome may present prob-lems in individual cases, but it generally is not difficult.

ACKNOWLEDGMENT

The authors thank Carolyn V. Hudspeth and Lynda Donegan for their assistance in the preparation of this manuscript.

REFERENCES

1. McKenna UG, Meadows JA, Brewer NS, et al: Toxic shock syndrome; a newly recognized disease entity: Report of 11 cases. Mayo Clin Proc 1980;55:663-672

2. Abdul-Karim FW, Lederman MM, Carter JR, et al: Toxic

shock syndrome: Clinicopathologic findings in a fatal case. Hum Pathol 1981;12:16-22

3. Chesney PJ, Davis JP, Purdy WK, et al: Clinical manifes-tations of toxic shock syndrome. JAMA 1981;246:741-748 4. Chesney, RW, Chesney PJ, Davis JP, et al: Renal

manifes-tations of the staphylococcal toxic shock syndrome. Am J

Med 1981;71:583-588

5. Fisher RF, Goodpasture HC, Peterie JD, et al: Toxic shock

syndrome in menstruating women. Ann Intern Med 1981;

94:156-163

6. Fisher CJ, Horowitz BZ, Nolan SM: The clinical spectrum of toxic shock syndrome. West J Med 1981;135:175-182 7. Tofte RW, Williams DN: Toxic shock syndrome: Clinical

and laboratory features in 15 patients. Ann Intern Med 1981;94:149-156

8. Tofte RW, Williams DN: Toxic shock syndrome: Evidence of a broad clinical spectrum. JAMA 1981;246:2163-2167 9. Todd J, Fishaut M, Kapral F, et al: Toxic-shock syndrome

associated with phage group I staphylococci. Lancet 1978; 2:1116-1118.

10. Reingold AL, Dan BB, Shands KN, et al: Toxic shock

syndrome not associated with menstruation. Lancet 1982;

1:1-4

11. Follow-up on toxic shock syndrome. MMWR 1980;29:441-445

12. Todd JK: Toxic shock syndrome-Perspective through the

looking glass. Ann Intern Med, in press 1984

13. Kawasaki T, Kosaki F, Okawa 5, et al: A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) pre-vailing in Japan. Pediatrics 1974;54:271-276

14. Morens DM, Nahmias AJ: Kawasaki disease: A ‘new’ pedi-atric enigma, parts 1 and 2. Hosp Prac 1978;13:109-112, 119-120

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1984;74;112

Pediatrics

Andrew M. Wiesenthal and James K. Todd

Toxic Shock Syndrome in Children Aged 10 Years or Less

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1984;74;112

Pediatrics

Andrew M. Wiesenthal and James K. Todd

Toxic Shock Syndrome in Children Aged 10 Years or Less

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