Page 539 - Clinical Immunology_ Principles and Practice ( PDFDrive )

518 ParT fOur Immunological Deficiencies

patients having had Pneumocystis pneumonia and CMC. Finally, disease, resulting in the deaths of 20 of the 49 known patients,
some patients presented with recurrent diarrhea and/or colitis. all of whom died before the age of 8 years. Eleven of these patients
Thus a diagnosis of IκBα deficiency should be considered in died from invasive pneumococcal disease. There is an overall
children with EDA and CID with impaired T-cell immunity. A trend toward improvement with age, as shown by the seven adult
preventive treatment, including antibiotic prophylaxis with patients doing well with no treatment at ages of 18 to 37 years.
trimethoprim–sulfamethoxazole and/or penicillin V, should be Patients with IRAK-4 deficiency should also be immunized
proposed and IgG substitution should be carried out in patients with S. pneumonia, H. influenzae, N. meningitidis conjugated
with IκBα deficiency. The recommendations for febrile patients vaccine (and also nonconjugated vaccine when available). A
with NEMO deficiency should also be applied to patients with preventive treatment, including antibiotic prophylaxis with
IκBα deficiency. HSCT has been reported in four patients with cotrimoxazole plus penicillin V, should be administered through-
severe IκBα deficiency causing CID. 45,46 out the life of the patient. Given the severity of bacterial infection
during childhood and the defective antibody production found
IL-1 Receptor–Associated Kinase-4 Deficiency in some patients with IRAK-4 deficiency, we also recommend
Inherited IRAK-4 deficiency (OMIM 607676) is an AR disorder the administration of empiric IgG replacement until the patient
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first described in 2003. In total, 49 patients have since been is at least 10 years old. This prophylaxis seems to decrease the
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identified, from 32 kindreds. 13,16 The blood cells of the patients incidence of invasive bacterial infections. It is important to
fail to produce the proinflammatory cytokines IL-1β and IL-18 initiate empiric parenteral antibiotic treatment against S. pneu-
upon stimulation with all known TLR agonists (with the exception moniae, S. aureus, and P. aeruginosa as soon as an infection is
of TLR3 agonists). Patients with IRAK-4 deficiency seem to have suspected or if the patient develops a moderate fever, without
normal antigen-specific T- and B-cell responses, as shown in taking inflammatory parameters into account because patients
routine immunological investigations, with two notable excep- may die of rapid invasive bacterial infection despite appropriate
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tions. First, the glycan-specific IgG and IgM antibody responses prophylaxis. A diagnosis of IRAK-4 deficiency should be con-
to pneumococcal and AB glycans (allohemagglutinins of the sidered in children presenting with recurrent pyogenic infection
ABO system) are impaired in up to one-third of the cases and poor inflammatory responses.
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explored. Second, serum IgE and IgG4 concentrations are high
in up to two-thirds and one-third, respectively, of patients tested. 13 MYD88 Deficiency
MyD88 deficiency is an AR disorder recently described in 22
THEraPEuTIC PrINCIPLES patients (OMIM 612260). 12,13,16 Patients with MyD88 deficiency
Patients with Inherited Disorders of Toll and IL-1 display a lack of production of IL-6 by whole blood and no
CD62L shedding from granulocytes following activation with
Receptor (TIR)-Mediated Immunity most of the TLR and IL-1R agonists tested, with the exception
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• Patients should receive conjugated and nonconjugated vaccines against of TLR3, which signals through a MyD88-independent pathway.
encapsulated bacteria (Pneumococcus, H. influenzae, Thus there seems to be no overt defect of leukocyte development
Meningococcus). in patients with MyD88 deficiency, and antigen-specific T- and
• A preventive treatment, including antibiotic prophylaxis with cotri- B-cell responses appear to be normal, as shown by routine
moxazole plus penicillin V, should be administered throughout the life immunological analyses, in most cases. Serum IgE and IgG4
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of the patient. concentrations were high in up to one-half and one-third,
• Monthly prophylactic administrations of intravenous or subcutaneous 13
immunoglobulins should be considered in selected patients. respectively, of the patients tested. Some of the modest, subclini-
• Empiric parenteral antibiotic treatment against Streptococcus pneu- cal abnormalities of B-cell responses observed, such as the
moniae, Staphylococcus aureus, and Pseudomonas aeruginosa should production of low levels of antibodies against carbohydrates in
be initiated as soon as an infection is suspected or if the patient some patients, may thus reflect impaired TACI responses, rather
develops a moderate fever, without taking inflammatory parameters than impaired TLR and IL-1R responses. MyD88 deficiency, like
into account. IRAK-4 deficiency, confers a predisposition to severe bacterial
• Hemopoietic stem cell transplantation (HSCT) should be considered infection, with impairment of the ability to increase plasma
in selected patients with NEMO and IκBαα deficiency.
C-reactive protein (CRP) concentrations and to mount fever at
the beginning of infection. However, pus formation has been
IRAK-4–deficient patients suffer from recurrent infections observed at various sites of infection.
caused by pyogenic bacteria, mostly S. pneumoniae, S. aureus, Patients with MyD88 deficiency present a narrow susceptibility
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and P. aeruginosa, with little or no fever or inflammatory to invasive pyogenic bacterial infections. S. pneumoniae was
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response. The leading pathogen responsible for infections in involved in 41% of the documented invasive episodes in patients
these patients is S. pneumoniae, which was found in half the with MyD88 deficiency, whereas S. aureus and P. aeruginosa
cases of documented invasive infection (septicemia, meningitis, were found in 20% and 16% of such episodes, respectively.
abscesses, or arthritis), whereas S. aureus and P. aeruginosa were Most patients with MyD88 deficiency suffered from their first
found in 14% and 19% of such episodes, respectively. Patients bacterial infection before the age of 2 years. Nine patients died
with IRAK-4 deficiency also suffer from noninvasive pyogenic from invasive bacterial infections, all before the age of 4 years,
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bacterial infections, mostly affecting skin and upper respiratory and most before the age of 1 year. Seven of these patients died
tract, with necrotizing infections particularly common. The from invasive pneumococcal disease. However, MyD88 deficiency
principal bacterial strains isolated during noninvasive infections seems to improve with age, and none of the patients has presented
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in patients with IRAK-4 deficiency are S. aureus in 43% of invasive bacterial infection after adolescence. MyD88 deficiency
episodes, P. aeruginosa in 22% of episodes, and S. pneumonia in also confers a predisposition to noninvasive pyogenic bacterial
16% of episodes. All reported sudden invasive infections occurred infections, mostly affecting skin and the upper respiratory tract.
before the age of 14 years. IRAK-4 deficiency is a life-threatening The principal bacterial strains found during noninvasive infections