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Red herring?

Red herring?. Susan Limb, MD June 16, 2006 Allergy Grand Rounds. History of the red herring. 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

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Red herring?

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  1. Red herring? Susan Limb, MD June 16, 2006 Allergy Grand Rounds

  2. History of the red herring • 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

  3. Case history • 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

  4. Case history (cont.) • 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

  5. Family history • Recurrent sinusitis • Multiple sclerosis 6yo 9yo • No family history • autoimmune disease • fertility problems • situs inversus

  6. Physical exam • 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

  7. Laboratory evaluation • 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)

  8. In a 6-year-old boy with intact humoral immune responses, is mannan-binding lectin (MBL) deficiency an explanation for recurrent sinusitis and otitis media?

  9. MBL part of collectin family (lung surfactants) • Important constituent of innate immune system

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

  11. MBL deficiency • 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

  12. MBL missense mutations in population of unselected Australian blood donors Worthley DL et al. Int Med J 35 (9), 548-555

  13. Clinical manifestations • 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

  14. Summerfield JA et al. BMJ. 1997 Apr 26;314(7089):1229-32 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

  15. Infections in 133 children heterozygotic for mutations in mannose binding protein gene

  16. Clinical details of children homozygotic for mutations in MBL gene

  17. 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)

  18. Koch A et al.JAMA 2001; 285: 1316–1321 • 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)

  19. Association between MBL genotypes and risk of acute respiratory tract infections (ARI) in 252 children from Sisimiut, Greenland

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

  21. Dahl M et al. J Exp Med 2004; 199: 1391–9 • 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

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

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

  24. Treatment options • 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

  25. In a 6-year-old boy with intact humoral immune responses, is mannan-binding lectin (MBL) deficiency an explanation for recurrent sinusitis and otitis media? 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

  26. Sometimes it’s good to catch a herring! Steve and Les holding their prize giant herring

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