Red herring? - PowerPoint PPT Presentation

Red herring?

Susan Limb, MD

June 16, 2006

Allergy Grand Rounds

• Curing process turns fish a red color and gives the fish a distinctive, pungent odor
• Dried fish tied to a string and trailed through the woods to train hunting dogs to follow a scent
• Later used by fugitives to confuse bloodhounds in pursuit

• CC: 6yo M with recurrent sinus infections
• HPI
• Born full term; no perinatal problems
• 10 ear infections during first year of life
• Tympanostomy tube placement at age 1 and 3
• Decreased frequency but still required extended courses of antibiotics
• No specific organisms cultured
• 2 hospitalizations for pneumonia at age 2 and 3
• Sinusitis starting at age 2
• Confirmed by CT scan
• Allergy skin testing negative
• Antibiotics ~6 months/year

• Past medical history
• Asthma diagnosed in infancy
• 3 courses of prednisone
• Occasional nocturnal and exertional cough
• No sputum production
• Medications
• Flovent 110mcg 2 puffs BID
• Albuterol PRN
• Singulair 5mg QD
• Rhinocort 2 sprays QD
• Immunizations
• All age-appropriate vaccinations
• Prevnar
• Pneumovax
• No antibody titers available

• Recurrent sinusitis
• Multiple sclerosis

6yo

9yo

• No family history
• autoimmune disease
• fertility problems
• situs inversus

• General: well-appearing 6 yo M
• Vitals: T 372 BP 84/50 HR 92 17kg 115cm
• HEENT:
• Nose –boggy turbinates, scant thick white mucus in nose, no polyps visualized
• Oropharynx –intact palate, 1-2+ tonsillar hypertrophy
• Ears –TM scarring, PE tubes
• No cervical LAD
• Cardiovascular –nl
• Lungs –nl
• Abd –nl, no hepatosplenomegaly
• No skin or nail abnormalities

• Normal CBC with differential
• Normal serum immunglobulin levels
• Normal sweat chloride testing
• Pneumococcal and H. influenzae antibody titers pending
• Mannan-binding lectin <50ng/ml (normal range >100)

• Important constituent of innate immune system

Table 1Some clinically relevant microorganisms recognized by mannose-binding lectin3,20,21

Some clinically relevant microorganisms recognized by MBL

• Commonly inherited missense mutations
• Additional polymorphisms in promoter and 5’-untranslated regions affect expression levels in serum
• Ethnic/racial variability
• Reduced levels in up to 40% Caucasians
• Very low levels in up to 8% Caucasians
• Very low levels in ~13% Africans
• Very low levels in ~3% Eskimos
• Additional variability with age

Worthley DL et al. Int Med J 35 (9), 548-555

• Clinically silent in most otherwise healthy individuals
• Manifests in individuals with immature or compromised adaptive immune systems
• Early infancy and childhood (range undefined)
• Cystic fibrosis
• Post chemotherapy
• Post-stem cell transplant
• Associations with other conditions
• Autoimmune disease
• Other inflammatory disorders
• Miscarriage
• Possibly beneficial in cases where increased opsonization and phagocytosis may promote intracellular pathogens such as mycobacteria

Objective: To determine the extent to which mutations in the mannose binding protein gene predispose to childhood infection

Design: Clinical details and genotype of mannose binding protein determined in consecutive children attending a paediatric department

Subjects: 617 children presenting to London inner city hospital between October 1993 and August 1995

Results:

• The prevalence of mutations in the mannose binding protein gene in children with infection (146/345) was ~2x that in children without infection (64/272) (P<0.0001)
• Increased susceptibility to infection was found in both heterozygotic and homozygotic children
• 13 out of 17 children homozygotic for variant alleles presented with strikingly severe infections, including 6 with septicaemia

Clinical details of children homozygotic for mutations in MBL gene

Prevalence of mutations was significantly greater in infected children under 6 months (P=0.05), between 6 and 18 months (P=0.03), and over 18 months (P=0.0001)

• Objective  To investigate the effect of MBL insufficiency on risk for acute respiratory tract infection (ARI) in unselected children younger than 2 years
• Design and Setting  Population-based, prospective, cohort study conducted in Sisimiut, Greenland
• Subjects  250 children (age <2yrs) followed weekly between August 1996 and August 1998 for morbidity surveillance
• Results 
• A 2.08-fold (95% CI, 1.41-3.06) increased relative risk (RR) in MBL-insufficient children (n = 13) compared with normals (n = 239; P<.001)
• Risk is stratified by age
• Age 6 to 17 months (RR, 2.92; 95% CI, 1.78-4.79)
• 0 to 5 months (RR, 1.47; 95% CI, 0.45-4.82) and
• No effect in 18 to 23 months (RR, 1.00; 95% CI, 0.42-2.37)

Interaction between age and MBL genotypes and risk of ARIs in 252 children from Sisimiut, Greenland

• Objective: Investigate associations between MBL-deficiency and infection, other common diseases, and death in an unselected adult population
• Study design: longitudinal cohort study (part of Copenhagen City Heart Study), evaluated at baseline and at 8 and 24-year-followup by questionnaire, interview, and chart review
• Subjects: 9245 adults age>20
• Results:
• No differences in infection or hospitalization rates between heterozygote/homozygote subjects and normals
• Increased risk associated with homozygosity in cardiac-related hospitalization
• Not confirmed by 2 subsequent case-control studies

Morbidity leading to hospitalization according to MBL deficiency genotype during 24 yr follow-up

Mortality according to MBL deficiency genotype during 8 yr follow-up

• Human and recombinant MBL therapy under development
• Anecdotal reports of successful replacement therapy
• Phase I trial (Valdimarsson H et al.Scand J Immunol 2004; 59: 97–102)
• 20 healthy, adult MBL-deficient subjects
• 6mg human MBL IV administered weekly x 3wks
• Infusions well tolerated
• Serum half-life 70h; twice to thrice weekly infusions may be needed to maintain stable, protective levels
• No antibodies to MBL detected up to 24 weeks after treatment
• Phase II trials underway

Yes and No

• May be explanation for early infections, setting up chronic inflammation and hypertrophy of mucosal tissues
• Follow-up post-vaccination antibody titers
• ENT evaluation
• Saline washes for sinuses
• Tonsillectomy/adenoidectomy scheduled
• Endotracheal aspirate for gram stain and culture

Sometimes it’s good to catch a herring!

Steve and Les holding their prize giant herring