Microbiol Immunol. 2013 Nov;57(11):737-45.

Overall picture of an emerging neonatal infectious disease induced by a superantigenic exotoxin mainly produced by methicillin-resistant Staphylococcus aureus.

Takahashi N, Imanishi K, Uchiyama T.

Department of Pediatrics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, 113-8655, Japan.

 

ABSTRACT

Since 1992, many neonates from neonatal intensive care units in Japan developed fever and systemic exanthema. Immunological analyses of neonates with this condition revealed that the bacterial superantigen, toxic shock syndrome toxin-1 (TSST-1) was the cause. The name neonatal TSS-like exanthematous disease (NTED) has been applied to this condition. The most striking clinical finding was that none of the term neonates developed shock or died due to NTED. The timing of NTED epidemics coincided with the spread of emerging TSST-1-producing MRSA 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 they may actively suppress the immune response to NTED with IL-10. According to the T cell response in cases of infant or young children with diseases induced by TSST-1, the pathophysiology of TSST-1-related diseases could 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 with which to analyze the mechanism of neonatal immune tolerance and the age dependence of human immunity. This disease has not only become representative of diseases caused by superantigen but it has also yielded a considerable amount of evidence about human immune reactions against superantigens. © 2013 The Societies and Wiley Publishing Asia Pty Ltd.

KEYWORDS: clinical immunology, infection immunity, pathogenesis, toxin

PMID: 24033495

 

SUPPLEMENT:

We have reported a novel neonatal infectious disease induced by a superantigenic exotoxin, toxic shock syndrome toxin-1 (TSST-1) produced mainly by MRSA. Figure 1 shows the exanthema typical of a patient. TSST-1 is the major causative toxin of life-threatening infectious toxic shock syndrome (TSS). In contrast to TSS, most neonatal patients with the disease did not develop such severe symptoms and they usually spontaneously regressed in neonatal patients without active treatment. We proposed the name neonatal TSS-like exanthematous disease (NTED) to describe this disease and it has generally been accepted.

NTED1

The expression of T cell receptor (TCR) Vβ2 in T cells of infected neonates was far more than in controls and the expanded Vβ2+ T cells in neonates with NTED expressed high levels of an activation marker CD45RO. Double staining for Vβ2+ and CD45RO in peripheral blood T cells using flow cytometry is useful for a rapid and definitive diagnosis of NTED. Figure 2 shows representative flow cytometry finding. None of the term patients developed shock or died due to NTED. However, airway damage such as acquired tracheo-esophageal fistula due to necrotizing tracheobronchitis has been identified in patients with NTED. NTED also tends to be more severe in preterm infants than in term infants. NTED2

Nation-wide questionnaires revealed that neonates developed NTED in 25.7% and 85.6% of the 90 major NICUs in Japan surveyed in 1995 and 1998, respectively. NTED has reached epidemic proportions in Japan. A molecular epidemiological analysis showed that most of the MRSA isolates can be included in a single clone of coagulase type II, and the TSST-1 and SEC genes were retained. The timing of NTED epidemics coincided with the spread of an emerging novel MRSA clone in Japan. The number of patients with NTED has gradually decreased since 2000. A significant increase in the rate of methicillin-sensitive S. aureus (MSSA) isolation was observed among term neonates with NTED during 2005. NTED was not only a hospital-acquired infection in NICUs due to MRSA but it was also a health care-associated infection caused by MSSA. Of more than 200 pregnant Japanese women at 30 weeks of gestation, around 40% were negative for anti-TSST-1 Abs. The low frequency of pregnant women with positive anti-TSST-1 Ab titers could be one reason for the spread of NTED in Japan.

Anergy was specifically induced in T cells expanded by TSST-1 in NTED patients. Serum levels of the anti-inflammatory cytokine interleukin (IL)-10 are selectively elevated in patients with NTED (mean concentration >1200 pg/mL). Newborn infants might actively suppress the immune response induced by stimulation with the superantigen. T cells expanded after a stimulation with TSST-1 rapidly deleted from the peripheral blood of newborns with NTED. Literatures suggest that the pathophysiology of superantigen-related diseases might be age dependent. We hope that pediatricians around the world will become aware of this disease.

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