Another 2 year old with fever and a rash

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Another 2 year old with fever and a rash

• Kathryn Patchett and Glenn ReevesDepartment of
  Immunology and Infectious DiseasesHunter Area
  Pathology Service

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Presentation

• 2y 3mths boy
• 7-10 day history of fever and rash abdominal,
  spread to back and arms
• Non itchy
• 2/7 prior to admission developed facial rash and
  was started on Cephalexin by his GP

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PMHx

• Eczema and ? Mild asthma
• No previous admissions
• Missed 12 month vaccination
• NKDA

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FHx
Eczema
12months- well
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Examination

• Miserable
• Febrile
• PR 124
• RR32 O2 sats 99 R/A
• CVS/RESP/Abdo/Neuro exam NAD

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Summary

• Fever
• Morbilliform- erythematous maculopapular rash

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DDx?
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Differential Diagnosis
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Morbilliform Rashes

• 52 no laboratory diagnosis
• 48 (93/195 UK children lt16y) - (17) Parvo B19
  (erythema infectiosum/slap cheek)- (15) group A
  strep- (6) HHV-6 (Roseola Infantum)- (5)
  Enteroviral (ECHO, Coxsackie, entero, polio)-
  (4) Adenovirus- (3) group C Strep

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Other Maculopapular rashes

• Measles
• Rubella
• Early meningococcal
• Kawasakis disease
• ?Allergy
• ??drugs

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Progress

• Admitted and treated with IV ceftriaxone 4
  doses
• Rehydrated
• Investigations- bloods,blood urine and faecal
  cultures, throat swab
• Echocardiogram

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Investigations
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Investigations 2
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Progress 2

• Discharged day 7- Primary Diagnosis Morbilliform
  rash 2 to measles- Microcytic anaemia
  ?secondary to cows milk
• HOWEVER

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Admission 2

• Readmitted 4 days later- ongoing fever up to
  38.8C- worsening rash
• Examination essentially unchanged- no mouth
  ulcers- conjunctivae normal- no peeling of
  palms or soles- reluctant to walk
• Dermatology registrar noted - Facial lilac
  erythema- erythema of hands

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Immunology/Virology
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Outstanding results reviewed

• Enteroviral PCR of serum and faeces positive
• Coxsackie and ECHO CFT neg
• U/S abdomen - unremarkable

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Mi-2 show an undefined homogeneous/ fine
speckled nuclear pattern, which generally spares
nucleoli and metaphase chromosomes.
No cytoplasmic staining is visible
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A diagnostic procedure had been performed!
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Neurology Review

• Waddling gait
• Slow to stand from crouch
• Unable to roll in bed
• Head Lag

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Another diagnostic procedure was performed
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Summary of Histology

• SKIN Features of hyperkeratosis, dermal
  fibrosis and a degree of extracellular mucinosis
• Relative absence of inflammation in biopsy over
  MCP joint
• Perivascular and periadnexal chronic inflammation
  with focal changes suggestive of lymphocytic
  vasculitis
• Could be consistent with CT disease

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Histology 2 Muscle

• MUSCLE - myositis
• Inflammatory infiltrate (predominately
  lymphocytes)
• Break up of syncytial muscle fibres and and focal
  pallor of myocytes consistent with muscle
  necrosis

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Treatment and progress

• 1 month post onset of illness given IVIG
• Discharged 6/7 later with F/U- Dermatology-
  Neurology- Immunology (on ward with next course
  of IVIG)

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Resolution of Fever
IVIG given
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Juvenile Dermatomyositis

• Systemic vasculopathy
• Primary disease expression in skin and muscle
• Illness characterised by- rash periorbital
  heliotrope, alligator skin- proximal muscle
  weakness
• Time between symptom onset and diagnosis
  generally approximately 3/12 (can be gt 12 mths in
  subacute forms)

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Juvenile Dermatomyositis
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Other clinical features

• Soft tissue calcifications in up to 40
• Myopathy can be focal especially early in disease
  MRI to detect involved areas
• Also get- GI- Cardiac- Pulmonary (assoc with
  Jo-1 antibodies)- Ophthalmic changes- thrombosis
  and oedema

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Immunology

• ANA usually speckled in 60
• 10 children with JDM have myositis specific
  antibodies esp anti-M2
• vWF may be increased

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Juvenile Dermatomyositis

• Rare
• Gender ratio varies between countries
• Mean age onset 6.9 years possibly bimodal
  distribution with peaks lt 5y and at 12-15y
• Strong link with HLA B8/DR3 DQA10501
• Pathogenesis - ? Infectious trigger (60 had
  symptoms of infection within 3 months of
  recognition of definite symptoms of JDM)Pachman
  et al Arthritis and RheumVol 53, No.2
  pp166-172)

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A role for enterovirus?

• Agents associated include influenza,
  parainfluenza, hep B, RNA picornaviruses,
  parvovirus, parasites including Toxoplasma
• Genus enterovirus belongs to the picornavirus
  family, ss RNA viruses

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Enteroviral PCR

• RT- PCR rapid, sensitive and specific
• In house methods no commercial kit available
• Amplify highly conserved 5 region detect most
  enteroviruses
• Most experience CSF specimens(Aseptic
  meningitis PCR detects EV RNA in 66-86 cf viral
  isolation 30)

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Treatment Issues

• Is there any significance in the negative
  enteroviral serology?
• What is the role of immunosuppressive therapy in
  paediatric DM?
• How about antiviral therapy?

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Enteroviral serology

• Convalescent serology was also negative
• Complement fixation test
• Serotype specific mostly useful in outbreak
  situations

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Immunosuppressive therapy

• Corticosteroids have been the mainstay of therapy
  (PO or IV if more severe)
• Hydroxychlorquine (Plaquenil) if prominent skin
  rash sunscreen
• Cytotoxic therapy- if bad prognostic features eg
  myocarditis, dysphagia, dyspnoea- as steroid
  sparing agents

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IVIG

• Case report data
• 2gm/kg/month
• Recent use of IVIG for serious enteroviral
  infections

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Antiviral therapy

• Pleconaril antiviral drug that interfers with
  EV attachment and uncoating
• Binds to the virus protein capsid
• Active against gt90 of the circulating serotypes
• Well absorbed with long t ½
• Preliminary studies 38-50 improvement in
  symptoms, ?duration symptoms
• Not currently available in Australia

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Prognosis

• Related to degree of vasculitis
• Course can be monocyclic, chronic polycyclic or
  chronic continuous
• Overall survival has improved with better use of
  steroids
• Residual disability is related mainly to
  calcification and flexion contractures
  importance of early muscle training exercises

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Antigen
Pattern Recognition Receptor
Normal Immune Response
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(2) Aberrant Antigen-Specific Responses

• Rheumatic Fever
• Aberrant cross-reactivity between streptococcal
  cell wall antigen myocardial protein (myosin)
• Guillain-Barre Syndrome
• Antibodies to Camplyobacter jejuni surface
  proteins produced which cross-react with neuronal
  gangliosides

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Autoreactivity Initiation(Within At-Risk
Genetic Substrate)

• Infectious Triggers
• Molecular mimicry
• Polyclonal activation
• Release of sequestered antigens
• Innate / Toll / Danger / Hygeine
• Non-infectious Triggers
• Interferon therapy
• Trauma / Ischaemia Post-MI cardiac antibodies
• Hormones Oestrogen
• Drugs TNF-blockade procainamide
• Complement Deficiency a/w ?removal dead cells,
  ICs
• Haptenic Penicillin binds RBC membrane ?
  antigenic
• Gluten in CD
• Loss of Regulatory Cells
• Mouse neonatal thymectomy ?thyroid,gastric,ovarian
  Abs
• CD4CD25 T cells TH3 cells (TGFbeta, IL10)

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Model

• At-risk genome
• Auto-reactive memory cells
• Viral infection damage cells, releasing
  sequestered antigens
• Secondary autoimmunity develops
• Progression despite infection resolving

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Novel ApproachesIntragam

• Controlled Trial Evidence of IVIG Efficacy
• Idiopathic Thrombocytopaenic Purpura
• Guillain-Barre
• CIDP and Multifocal Motor Neuropathy
• Myaesthenia Gravis
• Steroid-resistant dermatomyositis
• Kawasaki Disease
• Prevention of GVHD
• ANCA-Positive Vasculitis
• Autoimmune uveitis
• Multiple Sclerosis

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