Sudden unexpected death (SUDC) caused by infectious diseases

PIGS Training Course27 November 2010

Christoph AebiUniversitätsklinik für KinderheilkundeInstitut für InfektionskrankheitenUniversität Bernchristoph.aebi@insel.ch

Definition SUDC

The sudden death in a child older than 1 year of age, which remains unexplained after a thorough caseinvestigation, including review of the clinical historyand circumstances of death, and performance of a complete autopsy with appropriate ancillary tests

Krous HF et al. Pediatr Develop Pathol 2005;8:307

Background / Rationale

SUDC Forensic medicine

Lack of input frompediatric specialists

Background / Rationale

• specialists in forensic medicine have little knowledge in pediatrics, notably in infectious diseases and primaryimmunodeficiencies.

• The interpretation of microbiology data is often difficult, because there is little knowledge on the age-specificrelevance of a given pathogen/commensal.

• more and more infectious diseases are recognized as having a genetic background; genetic predisposition mayneed to be investigated and genetic counselling of theparents may be indicated.

• Collaboration is fruitful and motivating for both sides.

Causes of „apparent“ SUDC[50 cases]

Krous HF et al. Pediatr Develop Pathol 2005;8:307

Diagnosis No. of casesSUDC 39Accidental asphyxia 2Sepsis (S. pneumoniae x2) 2Lymphocytic myocarditis 1Eosinophilic myocarditis 1Fatty acid oxidation defect 1DIC after febrile infection (P. aeruginosa sepsis) 1Arrythmogenic congenital heart disease 1Brain stem encephalitis (etiology unknown) 1Suicidal salicylate intoxication 1

Etiology of bacteremia in children < 5 years (UK, 1992-2005)

Sharland M et al. J Antimicrob Chemother 2007;60;i15

Conclusions

• THE TOP 4 CAUSES OF SUDS IN DEVELOPED COUNTRIES* ARE- pneumococcal infections- gastroenteritis- myocarditis- invasive meningococcal disease

Byard BW . Cambridge University Press, 2004

*high coverage rate with Hib vaccine → epiglottitis ↓

Bacterial infections

• Neisseria meningitidis- deficiencies in complement components, e.g., C5-C9- lectin pathway deficiencies

Bulletin BAG 2008;4:48

*2007: 65 cases

Meningococcal infections in Switzerlandbetween 1995-2007

Invasive meningococcal disease (IMD)

Morphology- intracutaneous bleeding- bizarre margins- narrow, erythematous margins- disseminiert across the body- diameter of lesions > 2 mm

Invasive meningococcal disease (IMD)

Davila S et al. Nat Genet 2010;42;772

Invasive meningococcal disease (IMD)

• IMD is associated with SNP polymorphisms in the genes for

- Complement factor H (CFH)- Complement factor H related protein 3 (CFHR3)- Complement factor H related protein 1 (CFHR1)

• Nm expresses fHbp, which prevents binding of C3 to factorH, CFHR3 and CFHR1, and protects Nm from direct lysisand opsonization.

Davila S et al. Nat Genet 2010;42;772

Bacterial infections

• Neisseria meningitidis

• Streptococcus pneumoniae- fulminant invasive pneumococcal disease in asplenia- pneumococcal infections in genetically susceptible patients

BAG Bulletin 206, December 4; 977

Genetic susceptibility for severepneumococcal (and S. aureus) infections

Bustamante J et al Curr Opin Immunol 2008;20:39

• mutations in NF-κB pathwayleading to susceptibility for severepneumococcal infections:

• NEMO (X-linked recessive)• IκBα (autosomal dominant)• IRAK4 (autosomal recessive)• MyD88 (autosomal recessive)

Bacterial infections

• Neisseria meningitidis

• Streptococcus pneumoniae- fulminant invasive pneumococcal disease in asplenia- pneumococcal infections in genetically susceptible patients

• Late-late onset GBS sepsis/meningitis

• S. aureus

Fulminant tracheitis

CNS infectionENT infectionLymphadenitisBacterial tracheitisPneumoniaInfections of the heartSkeletal infectionsSkin and soft tissue infection

Hopkins A et al. Pediatrics 2006;118:1419

• often begins as a viral croup• typically older than children with

uncomplicated viral croup• S. aureus most common organism• severe complications care common

(ARDS, TSS)

Fulminant S. aureus infections

CNS infectionENT infectionLymphadenitisBacterial tracheitisPneumoniaInfections of the heartSkeletal infectionsSkin and soft tissue infection

• Toxic shock syndrome (TSS)• PVL-associated disease

Toxin-mediated diseaseCatheter-related infections

Staphylococcal toxic-shock syndrome(STSS)

Major S. aureus superantigensToxic Shock Syndrome Toxin (TSST-1)Staphylococcal enterotoxin B (SEB)Staphylococcal enterotoxin C (SEC)

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 30-60

day of staphTSS

Fever, myalgia, pharyngitis

Watery diarrhea

Erythroderma, red mucosae

Desquamation

Hypotension, oliguria

Somnolence, confusion, etc.

Clinical course of STSSFactors needed for initiation of staphTSS

(1) Infection/colonization with TSST-1 producing S. aureus.→ provides source of superantigen

(2) Absence of neutralizing anti-TSST-1serum antibody.

(3) Local milieu favoring expression of TSST-1 (pH > 6.0; elevatedpO2; source of protein).

(4) Individual TCR Vβ subunit repertoire→ defines proportion of T cells to be stimulated by

superantigen

Age-specific seropositivity for anti-TSST1

020406080

100120

0 10 20 30 40 50 60 70 80

Age (years)

anti-

TSST

-1 T

iter>

1:1

00

Stolz JM et al. J Infect Dis 1983;148:692

Clinical manifestations

CNS infectionENT infectionLymphadenitisBacterial tracheitisPneumoniaInfections of the heartSkeletal infectionsSkin and soft tissue infection

• Toxic shock syndrome (TSS)• PVL-associated disease

Toxin-mediated diseaseCatheter-related infections

PVL-associated disease[e.g. staphylococcal purpura fulminans]

Kravitz GR et al. Clin Infect Dis 2005;40:941

Panton-Valentine Leukocidin (PVL)

Panton-Valentine Leukocidin (PVL)

Gillet Y et al. Lancet 2002;359:753; Dohin B et al. Pediatr Infect Dis J 2007;26:1042

• mainly expressed bycommunity-acquired MSSA and MRSA.

• associated with severenecrotizing pneumonia in children.

• associated with severesepsis related to focalS.aureus infections, e.g. osteomyelitis.

• associated with S. aureuspurpura fulminans.

PVL-mediated necrosis ?

Boyle-Vavra S et al. Lab Invest 2007;87:3 Dohin B et al. Pediatr Infect Dis J 2007;26:1042

ca S. aureus bone/joint infectionPVL positive (n=14) PVL negative (n=17)

Age (y) 10.5 6.8Septic shock (n)* 6 0CRP (median)* 203 83Duration of fever (d)* 29 3Duration of IV Abx (d)* 48 11Duration of hosp (d) 45 13Subperiosteal abscess (n)* 11 1Abscess/myositis/fasciitis (n)* 8 0Visceral abscess* 11 0CA-MRSA 2 0* P < 0.05

Virulence factor PVL: Clinical evidence ?

• empiric antimicrobial therapy withceftriaxone iv.

• blood culture grows P. aeruginosa.

• aminoglycoside (once daily) added.

Sepsis in a 4-month-old[case] Admission + 24 h

Meningococcemia

Sepsis in a 4-month-old

Median age 6 monthsMedian duration of symptoms 4 daysFever 100%Diarrhea 72%Skin lesions (ecthyma, pustules, furuncles) 25%Leukopenia < 5.0 G/L 57%Thrombocytopenia < 100 G/L 34%Inappropriate empiric antimicrobial therapy 90% of fatal cases

24% of nonfatal casesCase fatality rate 30%

Huang Y et al Pediatr Infect Dis J 2002:21:1049

Community-acquired P. aeruginosasepsis in children

Bacterial infections

• Neisseria meningitidis

• Streptococcus pneumoniae- fulminant invasive pneumococcal disease in asplenia- pneumococcal infections in genetically susceptible patients

• Late-late onset GBS sepsis and menigitis

• S. aureus

• S. pyogenes (strepTSS; necrotizing fasciitis)

• fulminant enterobacteriaceal sepsis (UTI, VAPP)

• fulminant P. aeruginosa sepsis

Hidalgo-Carballal A et al. Am J Forensic Med Pathol 2006;27:93

Acute infantile hemorrhagic edema(Sedlmayer‘s or Finkelstein‘s disease)

[Differential diagnosis] Bacterial infections

• rapidly fatal hemolytic-uremic syndrome (HUS)[Manton N et al. Am J Forensic Med Pathol 2000;21:90]

- brain hemorrhage- fulminant sepsis from transmural sepsis

• fulminant Lemierre syndrome

Gilbert JD et al. J Forensic Legal Med 2009;16:478

Viral infections

• viral myocarditis

Viral infections – acute myocarditis

• Annual 1: 100‘000 in USA in chidren < 15 years

• Most commonly of viral origin:- Coxsackie B- Adenovirus- EBV- Influenza A (novel H1N1?) and B- HHV-6- CMV- Parvovirus B19

Levine MC et al. Curr Opin Pediatr 2010;22:278

Viral infections – acute myocarditis

• Cause of death- dysrythmia- acute cardiac failure

• Most dangerous- subacute phase- day 7-14- influx of cytotoxicT lymphocytes

Levine MC et al. Curr Opin Pediatr 2010;22:278

Viral infections

• viral myocarditis

• Varicella

DIC following transient antibody productiondirected against protein S and CJosephson C et al. Pediatr Res 2001;50:345

Purpura fulminans post varicella[Varicella gangraenosa]

Purpura fulminans post varicella[Varicella gangraenosa]

Purpura fulminans post varicella[Varicella gangraenosa]

Viral infections

• viral myocarditis

• Varicella

• Acute encephalitis- TBE (sudden brain edema)- fulminant influenza-associated necrotizing encephalopathy- Herpes simplex encephalitis

Herpes simplex encephalitis (HSE)

Bustamante J et al Curr Opin Immunol 2008;20:39

• genetic basis for HSE.

• autosomal-recessive UNC93B deficiency.

• autosomal dominant TLR3 deficiency.

• mutations are associated withimpaired antiviral interferon-α, -βand –γ responses.

Viral infections

• viral myocarditis

• Varicella

• Acute encephalitis- TBE (sudden brain edema)- fulminant influenza-associated necrotizing encephalopathy- Herpes simplex encephalitis- brain stem encephalitis (enteroviruses; L. monocytogenes

etc.)

Viral infections

• viral myocarditis

• Varicella

• Acute encephalitis- TBE (sudden brain edema)- fulminant influenza-associated necrotizing encephalopathy- Herpes simplex encephalitis- brain stem encephalitis (enterovirus; L. monocytogenes

etc.)

• Acute gastroenteritis with severe dehydration and hypovolemic shock [rotavirus]

• brain abscess

• tuberculoma

• cytotoxic brain edema associated, e.g. with viralmeningitis/meningoencephalitis

Cerebral mass lesion[slow progression, herniation]

Infant brain abscess

Parasitic infestations

• Myocarditis in Chagas disease (Trypanosoma cruzi)

• Echinococcus cyst in myocardium (E. granulosus)

• etc.

Parasitic infestations

• acute rupture of a right ventricular hydatid cyst.

• 10-year-old previouslyhealthy child.

• sudden death.

Demirci S et al. Am J Forensic Med Pathol 2008;29:346

Conclusions / 1

• THE TOP 4 CAUSES OF SUDS IN DEVELOPED COUNTRIES*- pneumococcal infections- gastroenteritis- myocarditis- invasive meningococcal disease

Byard BW . Cambridge University Press, 2004

*high coverage rate with Hib vaccine → epiglottitis ↓

Conclusions / 1

• THE TOP 4 CAUSES OF SUDS IN DEVELOPED COUNTRIES*- pneumococcal infections (effect of PCV 13?) - gastroenteritis (effect of rotavirus immunization program?)- myocarditis- invasive meningococcal disease (effect of group B vaccine?)

Byard BW . Cambridge University Press, 2004

*high coverage rate with Hib vaccine → epiglottitis ↓

Conclusions / 2

• incidence of SUDS ~ 1: 100‘000 < 15-Jährige.

• socio-economic and logistic factors likely of relevance.

• new vaccines likely to change the epidemiology.

• collaboration with forensics specialists should bepromoted.

• consider neglect [„pseudo sudden“]

Byard BW . Cambridge University Press, 2004