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Keywords:

  • clinical immunology;
  • infection immunity;
  • pathogenesis;
  • toxin

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Since 1992, many neonates in neonatal intensive care units in Japan have been developing fever and systemic exanthema. Immunological analyses of neonates with these symptoms has revealed that the bacterial superantigen, toxic shock syndrome toxin-1 (TSST-1) is the cause. The name neonatal TSS-like exanthematous disease (NTED) has been applied to this condition. The most striking clinical finding has been that none of the term neonates have developed shock or died of NTED. The timing of NTED epidemics has coincided with the spread of emerging TSST-1-producing methicillin-resistant Staphylococcus aureus clones in Japan. The low frequency of pregnant women with positive anti-TSST-1 antibody titers could be one reason for the spread of NTED in Japan. Neonates have immune tolerance against TSST-1 and may actively suppress the immune response to NTED with interleukin-10. According to the T cell responses in infants or young children with diseases induced by TSST-1, the pathophysiology of TSST-1-related diseases may be age-dependent. The precise mechanism of anergy and deletion of specific T cells stimulated with TSST-1 should be investigated in neonates infected with NTED. Both NTED and TSS might provide good models for analyzing the mechanism(s) of neonatal immune tolerance and the age-dependence of human immunity. This disease has not only become representative of diseases caused by superantigens, but has also yielded a considerable amount of evidence about human immune reactions against superantigens.


List of Abbreviations
Abs

antibodies

APC

antigen-presenting cells

CDR

complementarity determining region

CRP

C-reactive protein

IL

interleukin

MHC

major histocompatibility complex

MRSA

methicillin-resistant Staphylococcus aureus

MSSA

methicillin-sensitive Staphylococcus aureus

NICUs

neonates in neonatal intensive care units

NTED

neonatal TSS-like exanthematous disease

S. aureus

Staphylococcus aureus

TCR

T-cell receptor

TSS

toxic shock syndrome

TSST-1

toxic shock syndrome toxin-1

HISTORY

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Neonates in neonatal intensive care units in Japan started to develop fever and systemic exanthema during 1992. The symptoms usually appeared during the first post-natal week and were frequently associated with thrombocytopenia. Figure 1 shows the exanthema typical of a patient with this condition. The symptoms were similar to those of viral diseases; however, extensive efforts to isolate viruses from any patients' samples all failed. This clinical entity was described as a new disease entity in 1995 [1, 2]. Studies subsequently determined that almost all patients with this neonatal disease were colonized by MRSA producing TSST-1 [3]. However, MRSA carrier rates were very high in Japanese NICUs at that time, and a large proportion of MRSA carriers did not show any signs of the new disease.

image

Figure 1. Typical exanthema in a patient with NTED. Macular erythema generally spreads and tends to fuse.

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The bacterial superantigen TSST-1 [4-6] is now known to be the major causative toxin of life-threatening infectious TSS [7-9]. In contrast to TSS, most patients with the new disease entity developed less severe symptoms and signs and the condition usually regressed spontaneously in neonatal patients without active treatment. Notably, TSST-1 was not detected in blood samples from any of these neonatal patients. Because TSST-1 exposure would cause expansion of this T cell population, the expression of Vβ2 in T cells from affected patients was investigated to confirm a role for TSST-1 in NTED [10]. Immunological analysis of data of infected neonates confirmed that TSST-1 did indeed cause this disease [11].

Although the pathogenic mechanisms are fundamentally the same in this disease and TSS, the clinical criteria differ and the former is specific to neonates. Therefore, the name neonatal TSS-like exanthematous disease (NTED) was proposed to describe this disease and it has generally been accepted [11-14]. Since 1992, NTED became epidemic and neonates were infected in 85.6% of the 90 major NICUs surveyed in Japan during 1998 [14].

In addition to becoming a representative disease caused by a superantigen, NTED has also yielded much important evidence about human immune reactions against superantigens. The pathophysiology of superantigen-related diseases may be age-dependent. This review summarizes the basic and clinical findings in NTED. We present an overall picture of the disease and perspectives on it based upon current accumulated information.

SUPERANTIGENS

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

The concept of superantigens was proposed in 1989 [10, 15, 16] and they comprise bacterial and viral types [4-6]. Several bacterial superantigens are the pathogenic toxins of some infectious diseases that manifest acute and systemic clinical symptoms such as TSS, scarlet fever and systemic Yersinia pseudotuberculosis infection [4-6]. T cell activation induced by superantigens produced by many types of bacteria is a primary component in the pathogenesis of these diseases [4-6]. S. aureus produces many superantigens, including TSST-1 [5, 6] and staphylococcal enterotoxins [4-6, 15, 16]. Cytokines such as γ–interferon and α–tumor necrosis factor are thought to mediate the disease process in response to superantigen stimulation [5, 6].

Intact superantigens bind to major histocompatibility complex class II molecules outside the antigen-binding groove without being fragmented by antigen-presenting cells [4-6]. Superantigens bypass the orthodox CDRs of TCRs and interact exclusively with particular Vβ elements outside CDRs in TCR β chains [10, 15, 16]. This unique ability of superantigens leads to activation of very much greater numbers of T cells than occurs in response to conventional peptide antigens. For example, TSST-1 selectively activates Vβ2+ T cells, which comprise over 10% of all T cells [5, 6].

CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Expression of Vβ2 in T cells of infected neonates has been investigated to confirm the role of TSST-1 in NTED. Far more Vβ2+ T cells were found in the patients than in controls [11]. However, the ratio (%) of Vβ2+ T cells rapidly changed during the clinical course of the disease. To further define the role of TSST-1, CD45RO expression on Vβ2+ T cells was analyzed using flow cytometry. Because neonatal T cells are usually naïve T cells that do not express CD45RO, CD45RO expression by these cells indicates T cell activation [17]. The more numerous Vβ2+ T cells in neonates with NTED reportedly express large amounts of CD45RO [11, 18, 19].

When individuals are exposed to superantigens, specific T cells expand in a polyclonal manner. The DNA of many cloned Vβ2+ TCR-β chain genes randomly obtained from patients has been sequenced to confirm that a superantigen causes NTED. These researchers found heterogeneous usage of Dβ and Jβ gene segments in expanded Vβ2+ T cells [11]. These findings indicate that the superantigen TSST-1 causes NTED.

DIAGNOSIS

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Proposed clinical criteria for NTED are based on this disease's distinctive features, namely, erythema together with one of thrombocytopenia, low-positive CRP concentrations or fever together with exclusion of other known disease processes [1]. The clinical diagnostic criteria for NTED and TSS are shown in Table 1. The most similar disease among neonates is enteroviral infection; in these cases it is important to obtain a history of transmission from the mother or from any other infants in the same neonatal ICU.

Table 1. Clinical diagnostic criteria for NTED and TSS
 NTED TSS
  1. CNS, central nervous system; CSF, cerebrospinal fluid.

1Skin rash, generalized macular erythema1Diffuse rash, intense erythrodema, blanching
2Positive for one or more of these three clinical items2Body temperature >38.9°C
 Fever (>38.0 °C)3Systolic blood pressure <90 mm Hg
 Thrombocytopenia (<150 × 103/μL)4Desquamation 1–2 weeks after onset
 Low positive concentration of C-reactive protein (1–5 mg/dL)5Involvement of three or more of these organ systems
   Gastrointestinal
   Muscular
   Mucous membrane hyperemia
   Renal failure
   Hepatic inflammation
   Thrombocytopenia
   CNS involvement
3Other known disease processes excluded6Negative results of
   blood, throat, and CSF cultures for other bacteria
   negative serology for rickettsia infection, leptospirosis and measles

Complementing clinical diagnosis, double staining for Vβ2+ and CD45RO in peripheral blood T cells using flow cytometry is useful for making a rapid and definitive diagnosis of NTED [19]. Figure 2 shows representative flow cytometry findings of a phase-by-phase time course of Vβ2+ T and CD45RO+ T cells in a neonate with NTED [19]. During the early acute phase, Vβ2+ T cells are obviously depleted in the peripheral blood [19, 20]. Figure 3 shows chronological changes in the ratio (%) of Vβ2+ T cells among 19 neonates with NTED [19]. Vβ2+ T cells rapidly increased in number for 1–2 days after their initial depletion from the peripheral blood and remained numerous for a few days. The large numbers of T cells then rapidly declined to comprise a very small proportion of peripheral blood cells. Both the percentage of Vβ2+ T cells in CD4+ T cells and the absolute number of Vβ2+ T cells in the peripheral blood show the same chronological pattern as depicted in Figure 3.

image

Figure 2. Typical flow cytometry findings of a patient with NTED [19]. This patient developed a high fever on post-natal day 8, at which time Vβ2+ T cells decreased in the peripheral blood. The percentage of Vβ2+CD45RO+ T cells was 1.4% of CD4+ cells as shown in the top left panel. At this time, the absolute number of Vβ2+CD45RO+ T cells was only 42/μL of peripheral blood. This period is referred to as the early acute phase. Exanthema occurred on post-natal days 9–12, and Vβ2+ T cells increased greatly in number and were activated on post-natal day 12. The percentage of Vβ2+CD45RO+ T cells was 22.2% in CD4+ cells as shown in the top right panel. At this time, the absolute number of Vβ2+CD45RO+ T cells was 1663/μL of peripheral blood. This period is referred to as the acute phase. Vβ2+ T cells were decreased in the peripheral blood on post-natal day 37. The absolute numbers of Vβ2+ T cells and Vβ2+CD45RO+ T cells were only 105 and 10.5/μL, respectively. This period is referred to as the recovery phase (lower left panel) [19].

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image

Figure 3. Chronological changes in Vβ2+ T cells in CD4+ T cells from 19 patients with NTED [19]. Ratios of Vβ2+ T cells rapidly and significantly changed during the course of NTED. Shaded area indicates range of 14 controls (12.0 ± 3.2, mean ± 2SD). Both the absolute number and percentage of Vβ2+ T cells show similar chronological changes.

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Figure 4 shows the ratio of Vβ2+ T cells and CD45RO expression in samples from 75 patients collected throughout Japan and controls [19]. “Definitive NTED” is indicated when the ratio of Vβ2+ T cells has selectively increased to >15.2% of CD4+ T cells and when these cells have been activated, that is, CD45RO+ cells comprise >8.6% of the Vβ2+ T cells [19].

image

Figure 4. Ratios of Vβ2+ T cells and Vβ2+ T cells expressing CD45RO in 75 patients with clinically diagnosed NTED [19]. %TCR Vβ2, ratio of CD4+ cells expressing Vβ2; %CD45RO, ratio of Vβ2+ T cells expressing CD45RO.

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CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Table 2 shows clinical data accumulated from 262 term and 268 preterm infants studied in nationwide surveys in Japan [21]. Rates of fever were high and significantly more common in term infants than in preterm infants. The prevalence of low platelet counts (<150 × 103/μL) was very high in both preterm (87.2%) and term infants (81.0%), the mean minimum platelet count being significantly lower in the former. The prevalence of low grade positive CRP was high in both term and preterm infants. A case control study has confirmed the relationship between these clinical findings and NTED [21].

Table 2. Clinical profiles of Japanese neonates with NTED (data from nationwide surveys [21]
 Term (n = 262)Preterm (n = 268)p
  1. GA, gestational age (weeks); BW, birth weight (g); Age of onset of NTED (day of life); low platelets, prevalence of <150 × 103/μL of platelets; CRP, C-reactive protein; low positive CRP, prevalence of 10-50 mg/L of CRP; DIC, disseminated intravascular coagulopathy; shock, prevalence of patients requiring catecholamines or volume infusion; tracheal stenosis, prevalence of patients with extubation difficulties or requiring tracheostomy.

GA (weeks)37.4 ± 3.432.9 ± 2.6<0.001
BW (g)2588.8 ± 754.91742.3 ± 489.3<0.001
Age at onset (days)4.4 ± 3.65.0 ± 4.90.017
Fever (>38.0°C)183/254 (72.0%)153/262 (58.4%)0.001
Low platelets137/169 (81.0%)164/188 (87.2%)0.144
Platelets (×103/μL)102.0 ± 80.086.0 ± 0.00.031
CRP (mg/L)23.8 ± 23.416.7 ± 24.30.006
Low-positive CRP108/168 (64.2%)75/107 (70.1%)0.360
Antibiotics199/239 (83.2%)228/253 (89.1%)0.033
γ-Globulin7/239 (2.9%)47/253 (18.6%)<0.001
Platelet transfusion5/239 (2.1%)25/253 (9.9%)<0.001
DIC7/262 (2.7)11/268 (4.1%)0.474
Shock0/262 (0.0%)7/268 (2.6%)0.015
Tracheal stenosis5/262 (1.9%)9/268 (3.4%)0.418
Death0/262 (0.0%)3/268 (1.1%)0.249

Antibiotics were frequently administered to both term and preterm infants, whereas γ-globulin was administered to 18.6% of preterm infants and rarely to term infants. Platelet transfusion was more frequently required in preterm (9.9%) than in term infants (2.1%). Although thrombocytopenia is a notable feature of NTED, rates of disseminated intravascular coagulopathy were not high in either term (2.7%) or preterm (4.1%) infants. The mechanism of the thrombocytopenia remains unclear.

The most striking clinical finding was that none of the term patients developed shock or died of NTED. Shock is a criterion for TSS in children; however, shock was not evident in term infants with NTED. None of the 262 term infants died, whereas 3 of the 268 preterm infants died. However, airway damage such as acquired tracheo-esophageal fistula due to necrotizing tracheobronchitis has been identified in patients with NTED [22]. This rare but serious complication might be associated with NTED in preterm infants. These findings suggest that NTED tends to be more severe in preterm than in term infants. The reason(s) for the difference in severity between term and preterm patients remains to be elucidated.

EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Soon after the first report in 1995 [1], NTED was recognized throughout Japan and several nation-wide questionnaires were disseminated. Neonates developed NTED in 25.7% and 85.6% of the 90 major NICUs surveyed in 1995 and 1998, respectively [14]. The number of NICUs in which neonates developed NTED increased threefold over these 3 years.

Table 3 shows the numbers of infected neonates in 90–145 responding major NICUs in Japan in 2000, 2002 and 2005 [21]. The frequency of NICUs that were positive for neonates with NTED was 52.2% in 2000, 44.1% in 2002 and 28.3% in 2005. During the year 2000, 120 term and 120 preterm patients became infected with NTED whereas the total number of patients decreased to 151 in 2002 and to 139 in 2005 [21]. To our knowledge, only one patient with NTED infection has been reported from Europe or countries other than Japan [12]. Therefore, NTED has reached epidemic proportions only in Japan.

Table 3. Variation in frequency of patients with NTED in NICUs in Japan [21]
YearSurvey (n)Reply (n)Positive (n, %)No. of patientsMean annual patients/unit (means ± SD)
TermPreterm
  • Mean number of patients in each NICU that had experience caring for patients with NTED.

20001629047 (52.2%)1201205.27 ± 4.90
200219410245 (44.1%)66853.36 ± 3.37
200519414541 (28.3%)76633.46 ± 3.43

MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

A molecular epidemiological analysis of 68 S. aureus strains from NTED patients in 40 Japanese neonatal care units in 2003 [23] showed that all of the isolates were MRSA containing the mec A gene. Most of them (98%) could be included in a single clone (type A) of coagulase type II, and the TSST-1 and SEC genes (tst and sec) were retained. This MRSA clone A has been isolated not only from NICUs but also from almost all hospital wards in Japan. The carrier rates of MRSA were more than 25% in over half of 47 Japanese NICUs during the 1990s [24]. During the period, this major MRSA clone also replaced the previous dominant MRSA clone in Japan, which was less resistant to β-lactams and lacked TSST-1 production [25]. These data suggest that the timing of NTED epidemics coincided with the spread of an emerging novel MRSA clone in Japan. Gbaguidi-Haore et al. recently reported that MRSA harboring the tst gene accounted for about 2% of all MRSA isolates in a university hospital in France [26]. The MRSA in Japan seems to be unique in terms of retaining the tst gene.

The number of patients with NTED has gradually decreased since 2000 (Table 2). A simultaneous investigation of the rate of MRSA isolation and NTED in Japanese NICUs revealed a decrease in the rate of MRSA isolation in NICUs between 2000 and 2005 [27]. This decline was largely caused by the general use of plastic gloves [27]. Furthermore, when portable alcohol-based hand disinfectants were implemented for staff in an NICU, MRSA colonization rates declined from 34.4% to 6.1% over a period of 8 months [28]. With the decrease of MRSA colonization rates in NICUs, no neonates have become infected with NTED since 2006 [28]. Preventing the spread of the TSST-1-producing MRSA clone was therefore crucial in stopping the spread of NTED in NICUs.

The nation-wide questionnaires revealed a significant increase in the rate of MSSA isolation among term neonates with NTED during 2005 [21]. These term patients with NTED caused by MSSA had not developed their symptoms in NICUs, but were inpatients who had been transferred from other clinics managed by obstetricians or midwives. This fact indicated that NTED was not only a result of hospital-acquired infection with MRSA in NICUs but was also a health care-associated infection caused by MSSA in Japan. Parsonnet et al. found that 9% of S. aureus isolates (mainly MSSA) obtained from 209 healthy Japanese women were TSST-1 producing strains [29]. Verkaik et al. reported that 12% of MSSA isolates harbored TSST-1 gene among 206 samples in Algeria [30]. Thus, MSSA might become an important cause of NTED in the future.

ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Anti-TSST-1 IgG Abs of maternal origin play a protective role in preventing the development of NTED [18]. Serum titers of anti-TSST-1 Abs in maternal serum and cord blood of their infants are closely correlated. Anti-TSST-1 Abs mainly consist of IgG1 and IgG4 subclasses [30].

The ratio of pregnant Japanese women positive for anti-superantigenic exotoxin Abs has been investigated [31]. Of more than 200 pregnant Japanese women at 30 weeks of gestation, around 40% were negative for anti-TSST-1 Abs [31]. Published reports show that around 90% of adult women are positive for anti-TSST-1 Abs in many countries [29, 32]. Parsonnet et al. reported a significant difference in the prevalence of Abs to TSST-1 between women in Japan and in the USA [29]. The low frequency of pregnant women with positive anti-TSST-1 Ab titers could be one reason for the spread of NTED in Japan. Vaccination against TSST-1 might prevent occurrence of NTED in term infants [33]. However, preterm infants might not receive a sufficient amount of maternal Abs before birth. Therefore immunoglobulin products with a high anti-TSST-1 Ab titer or humanized monoclonal anti-TSST-1 Ab might be required to prevent or treat NTED in preterm infants.

IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

The rapid complication-free recovery from NTED by most full-term infants is unique. Reactivity against TSST-1 of peripheral blood mononuclear cells from NTED patients has been investigated in vitro [18]. Table 4 shows that peripheral blood mononuclear cells of neonates with NTED have a low or absent response to TSST-1 re-stimulation and a substantial response to stimulation with the superantigen staphylococcal enterotoxin A [18]. These findings indicate that anergy is specifically induced in the numerous T cells activated by TSST-1 in NTED patients. Rasigade et al. recently reported that Vβ2+ T cells from an adult patient with TSS increased in number after re-stimulation with TSST-1 in vitro [34]. The immune response against re-stimulation with TSST-1 differs between T cell blasts produced from cord blood and adult peripheral blood [17].

Table 4. Expansion and anergy induction to TSST-1 in TCR Vβ2+ T cells from neonates with NTED [18]
 Ratio of Vβ2+ T cells (CD45RO+)IL-2 production§ (U/mL) period of stimulation (hr)
CD4+CD8+Toxin82448
  • Ratio (%) of Vβ2+CD4+ and Vβ2+CD8+ T cells among peripheral blood mononuclear cells.

  • CD45RO+ fraction among Vβ2+CD4+ and Vβ2+CD8+ T cells.

  • §

    Peripheral blood mononuclear cells (2 × 105/culture) from four patients and eight controls were stimulated in vitro with 10 ng of TSST-1 or staphylococcal enterotoxin A/mL for the indicated periods and IL-2 activity assayed in culture supernatants.

  • Mean ± SD in eight MRSA-free neonates on postnatal day 5 (controls).

Neonates with NTED
P127.236.7TSST-1<0.1<0.1<0.1
 (86.0)(86.2)SEA1.05.316.2
P229.529.0TSST-1<0.1<0.1<0.1
 (96.7)(69.7)SEA0.313.028.0
P325.426.4TSST-11.70.6<0.1
 (85.1)(85.6)SEA1.89.520.0
P425.721.7TSST-1<0.10.82.0
 (57.1)(44.2)SEA1.514.063.0
MRSA-free neonates (controls)
 11.5 ± 1.56.1 ± 0.9TSST-12.7 ± 0.933.6 ± 5.276.3 ± 13.4
 (5.1 ± 2.5)(1.0 ± 1.1)SEA2.8 ± 0.640.1 ± 8.886.0 ± 55.4

Serum concentrations of the anti-inflammatory cytokine IL-10 are selectively increased in patients with NTED (mean concentration >1200 pg/mL) [35]. Newborn infants may actively suppress the immune response induced by stimulation with the superantigen. Regulatory T cells may produce high concentrations of IL-10 in patients with NTED. Because no reports have been published in English about the cytokine profiles of adult patients with TSS, we cannot so far conclude this finding is specific to newborn patients. Figures 2 and 3 show that the Vβ2+ T cells reactive to TSST-1 almost disappear from the peripheral blood in the early phase of NTED. Responsive T cells might accumulate in lymphoid organs: findings in adult patients with TSS support this notion [34]. Whether this is true of other infectious diseases is of interest.

AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

In newborns with NTED, the initially numerous peripheral blood T cells resulting from stimulation with TSST-1 rapidly decline in number (Figures 2 and 3). In contrast, in adult patients with TSS, peripheral blood Vβ2+ T cells remain in a highly proliferative state and then gradually become less numerous [36, 37]. Therefore, T cell responses against TSST-1 in non-neonates should be evaluated. A French group identified an adult type of T cell response in a 12-year-old child with TSS [38]. Dateki et al. similarly described a 3-year-old child with TSS caused by a burn who had an adult type response [39]. On the other hand, Sato et al. reported a 3-month-old infant with an exanthematous disease caused by TSST-1 and a neonatal type of T cell response [40]. These findings suggest that the pathophysiology of superantigen-related diseases might be age-dependent.

FUTURE PERSPECTIVES

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES

Figure 5 summarizes the basic and clinical findings in NTED. Several issues remain to be elucidated. The first is whether NTED is truly absent outside Japan. Even in Japan, the number of NTED infections caused by MSSA has increased and the situation concerning NTED has changed. We hope that pediatricians around the world will become more aware of this disease.

image

Figure 5. Pathophysiology and immunology of NTED. MRSA or MSSA produce TSST-1 and MRSA predominantly produces TSST-1 in NTED. Maternal anti-TSST-1 Abs help to protect against NTED. TSST-1 binds to the outside of the binding groove of major histocompatibility complex Class II on antigen-presenting cells. TSST-1 simultaneously binds to the Vβ region of Vβ2+ T cells, which causes them to increase in number and express large amounts of CD45RO. These T cells are soon rendered anergic and rapidly depleted from peripheral blood of neonates with NTED. In contrast, the response of adult T cells to TSST-1 is sustained and the increased numbers prolonged. The clinical findings are more severe in TSS than in NTED. T cell responsiveness appears to be dependent upon host age. APC, antigen-presenting cell; MHC, major histocompatibility complex; Mo, month; Y, year.

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The precise mechanism of anergy and deletion of specific T cells stimulated with TSST-1 should be investigated in neonates infected with NTED. IL-10 might play a key role in the induction of anergy. Both NTED and TSS might provide good models with which to analyze the mechanism of neonatal immune tolerance and the age-dependence of human immunity.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. HISTORY
  4. SUPERANTIGENS
  5. CAUSE OF NEONATAL TOXIC SHOCK SYNDROME -LIKE EXANTHEMATOUS DISEASE
  6. DIAGNOSIS
  7. CLINICAL PICTURE OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  8. EPIDEMIC NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  9. MICROBIOLOGY AND PREVENTION OF NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  10. ANTIBODIES AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  11. IMMUNE REACTIONS IN NEONATAL TOXIC SHOCK SYNDROME-LIKE EXANTHEMATOUS DISEASE
  12. AGE DEPENDENCE OF RESPONSE AGAINST TOXIC SHOCK SYNDROME TOXIN-1
  13. FUTURE PERSPECTIVES
  14. ACKNOWLEDGMENT
  15. DISCLOSURE
  16. REFERENCES
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