child with recurrent infections

ما ل إ ا ن ل م ل ع ل ك ن حا ب س لوا قام ـ ي ل ع ل ا ت ـ ن أ ك ـ ن إ ا ـ ن ت م ل ع

م ـ كي ح ل االبقرةسورة

Dr.Osama Arafa Abd EL HameedM. B.,B.CH - M.Sc Pediatrics - Ph. D.

Consultant

Pediatrician & Neonatologist Head of Pediatrics Department - Port-

Fouad Hospital

By

Child with Recurrent Infection

Normal pattern of infections in childhood :

•Healthy children experience 6–8 upper respiratory tract infections per year in the first few

years of life.

•The high frequency of infections results from immunologic immaturity and frequent exposure to

respiratory pathogens.

•Attendance in child care and exposure to secondhand smoke may increase the number of

infections.

Recurrent infections may be a sign of an underlying, possibly immunologic, disorder. •This is much less common than "normal" childhood infections.•Early identification of these children is critical.•Prompt intervention can decrease morbidity and mortality.

Port said Pediatrics conference 2015

Table 2: General guidelines for determining if a patient may be experiencing too many infections


Differentiating the child with recurrent infection due to a primary

immunodeficiency (PID) from the "normal child"

•It is important to differentiate the child with a primary immunodeficiency (PID) from the "normal child" who has more than the average number of viral infections or from the child who has an underlying disease that mimics infection, predisposes the child to certain types of infections, and/or results in secondary immune system dysfunction. Most often these categories can be determined from the history, physical examination, and screening investigations.

•In children with normal underlying immune system, growth and development is unaffected. They respond quickly to appropriate treatment, recover completely, and appear healthy between infections. The physical examination and laboratory tests are normal.

•Risk factors include day-care attendance, school-aged siblings, and second-hand smoke.5 Children with atopic disease seem more likely to develop recurrent and persistent upper respiratory infections. This may be due to enhanced adherence of pathogens to inflamed respiratory epithelium.6


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377046/?report=classic

Theses children can be grouped into 4 categories:

The “normal” child

The child with atopic disease

The child with another chronic condition

The child with immunodeficiency


There are four general reasons why children have recurrent infections. Those reasons include:

1. Exposure to others

2. Physical reasons related to the anatomy or structure of the

child

3. Problems with the immune system such as:

• An overactive immune system, which results in the classic

allergy

• An underactive immune system, which can be defined as

immune deficiency

4. Other, which includes recurrent infections that are never

totally cured


I) Exposure to others

•Exposure to other people is the most common reason for recurrent

infections in children.

pinpointed factors that are associated with recurrent infections.

Those factors include the age of the patient, the size of the family, the

season and school exposure.


Some physical reasons for recurrent infections include:

1. Circulation issues, such as those caused by sickle cell disease, diabetes, kidney ailments and heart disease.

2. Obstruction issues, as caused by Eustachian tube blockage in the ear, cystic fibrosis or stenosis, which is the abnormal narrowing of a passageway in the body.

3. Foreign bodies, such as shunts, catheters, valves or aspirated foreign bodies.4. Broken barriers when a protective system (like the skin) of the body is

compromised, such as eczema, burns.

5. Irritants that are not part of the physical body. Irritants such as cigarette smoke or strong smells can increase the risk of respiratory tract illness.

II) Physical factors


III) Deficient immune system

This deficiency may occur in two major areas:A)An overactive immune system, which may result in the classic allergy.

B) An underactive immune system, which may indicate a deficient immune system.A) Allergic Conditions

•Allergic conditions may lead to infection. Those illnesses include allergic rhinitis), atopic dermatitis (an itchy skin disorder) and asthma.

•Allergic rhinit is may be associated with as many as one-third of cases of serous chronic fluid in the ears. Infectious complications of allergic rhinitis may also include chronic sinusitis (nasal inflammation).

•Those with atopic dermatit is who are constantly scratching and breaking down the skin barrier may suffer from recurrent skin infections.

•Recurrent pneumonia, a serious lower respiratory tract infection, may actually be asthma.


III) Deficient immune system

B) Immunodeficiency disease:

•Immunodeficiency disease, IDD:

results from a genetic or developmental defect or acquired factors in

the immune system, and is a syndrome mostly characterized by

infection in clinic.

Classification:

•Primary immunodeficiency diseases (PIDD) 、

•Secondary immunodeficiency diseases (SIDD) (specific and nonspecific).


Differentiating the child with recurrent infection due to a primary immunodeficiency (PID) from the "normal child"

Table 1 Features suspicious of an underlying primary or secondary immunodeficiency:


50% of children with recurrent infections The average child has (+/-) 4-8 respiratory

infections per year The mean duration of viral respiratory symptoms is

8 days (however can extend beyond two weeks) Normal growth and development Respond quickly to treatment, with complete

recovery Appear healthy between infections Physical examination and lab tests are normal


Account for 30% of children with recurrent infection

Increased susceptibility to URTI

Usually develop coughing and wheezing following respiratory infections (reactive airway disease/asthma)


Respond well to allergy or asthma medications

Growth and development are usually normal

Characteristic physical findings

Elevated serum IgE


10% of children with recurrent infection

Cystic fibrosis, GERD, CHD, chronic aspiration, cerebral palsy

Increased susceptibilty to infection:◦ Inadequate clearance of secretions◦ Increased pulmonary blood flow◦ FB – artificial cardiac valve, VP shunt, indwelling catheter


Account for 10% of children with recurrent infection

PID usually affect B cells

Secondary immune deficiency usually affects T cells ( malnutrition, drugs…..)


Approach to diagnosis of a child with recurrent infection

I) History

• A complete history should be obtained for all children being evaluated for recurrent infections.

• Document characteristics of previous infections :- Types of pathogens and infections.- Duration of illnesses.- Need for hospitalization• Detailed family history is important.

Many of the primary immunodeficiencies are hereditary.• History of risk factors for HIV &hepatities infection- Personal for adolescents- Parental when congenital transmission is a possibility

i.Drug useii.Blood-product transfusioniii.History of sexually transmitted infection


•Obtain a complete review of systems.

-Pay attention to known associated features of immunodeficiency syndromes.

i. Failure to thrive

ii. Intractable diarrhea and malabsorption

iii. Rheumatologic conditions

iv. Hepatosplenomegaly

v. Lymphadenopathy

vi. Absence of lymph tissue

vii. Thrombocytopenia

viii.Eczema

ix. Oculocutaneous albinism.


Approach to diagnosis of a child with recurrent infection

•Immunization history Failure to make protective antibodies in response to immunizations can be indicative of immunodeficiency.

•Infections associated with an underlying immune disorder may present in various ways.

•Increased frequency of common infections•Repeated serious bacterial infections

•Immunodeficiency may cause a common infection to: •Have increased severity•Have prolonged duration•Fail to respond to appropriate treatment

Immunodeficiency may cause a common infection to present at an uncommon age. Thrush or candidal diaper dermatitis in children >1 year suggests a defect in T-cell immunity.

Immunodeficiency may produce an infection with an opportunistic pathogen. - Pneumocystis carinii - Cryptococcus neoformans

Immunodeficiency may become apparent as an infection after the administration of a live virus vaccine (rare).


II) Physical Examination

•A complete physical examination should be performed.•Children with immunodeficiency appear chronically ill.•Growth parameters should be obtained to determine the presence of failure to thrive.

- Height- Weight-Head circumference

•Physical signs that may indicate underlying immunodeficiency - Absence of tonsils- Presence of generalized lymphadenopathy and hepatosplenomegaly- Skin lesions

•Eczema •Abscesses•Seborrhea

•Look for evidence of ongoing infection.-Thrush

•Note any specific or abnormal signs that may be associated with a particular immunodeficiency syndrome.

- Oculocutaneous albinism in Chédiak-Higashi syndrome.


•Signs associated with primary immunodeficiencies - Intractable diarrhea and malabsorption

•Severe combined immunodeficiency (SCID), X-linked agammaglobulinemia (XLA), common variable immunodeficiency

- Rheumatologic conditions Common variable immunodeficiency, IgA deficiency, XLA

- Hepatosplenomegaly, lymphadenopathy Hyper-IgM syndrome

- Absence of lymph tissue XLA

- Thrombocytopenia Wiskott-Aldrich syndrome

EczemaWiskott-Aldrich syndrome, chronic granulomatous disease, hyper-IgE syndrome (Job syndrome)

- Oculocutaneous albinism Chédiak-Higashi syndrome


III) Laboratory Evaluation

•Laboratory evaluation should be guided by the type of infections the child is experiencing.•Initial screening tests usually include:

Complete blood count and differentialSerum Ig levels (IgG, IgA, and IgM)HIV serology, as indicated by the history and physical findings

•Tests of humoral immunityB-cell countIgG subclass determinationsAntibody titers against protein (diphtheria, tetanus toxoid) and polysaccharide (Pneumococcus, Haemophilus) antigens

•Antibody levels must be interpreted with respect to age-appropriate values.•High or low levels can be significant.

•Tests of cellular immunity Delayed-type hypersensitivity skin test (skin testing may not be reliable < 1 year of age)Lymphocyte count

•Total lymphocyte count is obtained by multiplying the total leukocyte count by the percentage of lymphocytes.•A value < 1500 cells/µL is considered lymphopenia.


III) Laboratory Evaluation

•Phagocytic (macrophage or neutrophil)

Complete blood count Neutrophil count may be abnormal.

IgE level Elevated in hyper-IgE syndrome (Job syndrome)

Nitroblue tetrazolium test

Flow cytometric respiratory burst assay

•ComplementCH50 assayScreening assay for components of classic complement pathway.


IV) Imaging

•Radiologic studies are used primarily in the diagnosis or management of associated infections.

•The absence of a thymic shadow can be indicative of DiGeorge syndrome or SCID.


Treatment Approach

•Rational approach to diagnosis and management of a child with recurrent infections is needed, or else the child is subjected to unnecessary investigations and multiple drugs.

•Prompt recognition of infection and aggressive treatment are essential to avoid to life-threatening complications and improve prognosis.

•Initiation of early empiric coverage for suspected pathogens after obtaining appropriate cultures. •Antibiotics should be judiciously chosen depending on age, socioeconomic status, severity of infection and the type of organism expected and always given in adequate doses and proper duration.

•Children at highest risk for developing resistant bacteria are those who have failed previous treatments, have had numerous previous antibiotic prescriptions, or received low doses of antibiotics over a prolonged period.

•Physician opinion varies as to the best timing for these antibiotics. They may be given for a consistent three- to six-month period following the last acute episode.

•Some physicians may prescribe them only in winter and spring when the risk for respiratory infections is high. Port said Pediatrics conference 2015

Treatment Approach

•Patients with B cell immunodeficiencies who continue to experience recurrent infections despite intravenous immunoglobulin replacement treatment also should be considered for concomittant antibiotic therapy to avoid complications, such as chronic lung disease and bronchiectasis.

•Recurrent infections may predispose children to poor weight gain and growth; therefore, monitoring of the height and weight should be performed frequently and appropriate nutritional interventions initiated early if problems arise.

•Recent approaches have included the encouragement of breastfeeding, and respiratory syncytical virus immune globulin, as well as methods of stimulating immunity, such as ribosomal immunotherapy.


When to Refer

Referral to an immunologist or infectious disease specialist should be considered in the following cases:

1. Recurrent serious bacterial infections 1. Sepsis2. Pneumonia3. Meningitis2. Serious bacterial infection in the context of failure to thrive3. Infection with an opportunistic pathogen - Pneumocystis - Cryptococcus 4. Vaccine-associated infection5. Unusual age for infection- Zoster- Thrush6. Unusual severity or chronicity for a given infection7. Family history of immunodeficiency


When to Admit

1. All patients with severe infections, infections with an unusual organism, or infections requiring intravenous antibiotics

2. Patients suspected of having severe immunodeficiencies, such as SCID or Wiskott-Aldrich syndrome


Nutrients and their role in host resistance to infection

•Almost all nutrients in the diet play a crucial role in maintaining an “optimal” immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens.

• Iron and vitamin A deficiencies and protein-energy malnutrition are highly prevalent worldwide and are important to the public health in terms of immunocompetence.

• There are also nutrients (i.e., glutamine, arginine, fatty acids, vitamin E) that provide additional benefits to immunocompromised persons or patients who suffer from various infections.

•These nutrients specifically modulate host defense to infectious pathogens (long-chain polyunsaturated n-3 fatty acids, vitamin E, vitamin C, selenium, and nucleotides).

•Long-chain polyunsaturated n-3 fatty acids has great effect on host defense as an example of how the disciplines of nutrition and immunology have been combined to identify key mechanisms and propose nutrient-directed management of immune-related syndromes.


Role of Vaccination

•Children who are susceptible to recurrent infections should probably be given vaccinations against influenza viruses and pneumococci.

•The influenza vaccine must be given to protect against the current year's specific flu strain.

•The pneumococcal vaccine, which is used against Streptococcus pneumoniae, provides protection for many years, and some experts now recommend if for children with recurrent infections who are over two years. While most of young, healthy children has been found to be immunogenic in pneumococcal vaccine, a significant percentage of children with recurrent sinopulmonary infections fail to produce adequate serotype specific antibodies following pneumococcal immunization.

• Additionally, immunotherapy has been proposed as a means of preventing these recurrent infections by providing children with small doses of inactive bacterial antigens liable to trigger specific and protective immune responses. Among such drugs, ribosomal preparations appear to be not only well tolerated, but also ideally targeted to induce mucosal responses.


Types of Most common infection

I)Respiratory infection:

a)Upper respiratory tract infections:

•Upper respiratory tract infections (URTI) including nasopharyngitis, pharyngitis, tonsillitis and otitis media constitute 87.5% of the total episodes of respiratory infections. Recurrent throat problems in children are common and have an impact on the family. Time off school, or parental time off work was significantly associated with parental worry and disruption.

b) Lower respiratory tract infections:

•Children presenting in early infancy with persistent or recurrent bronchiolitis should be considered to have SCID.

•Prolonged interstitial pneumonia because of either viral infection such as parainfluenza virus or cytomegalovirus or Pneumocystis jerovici is suggestive of human immunodeficiency virus (HIV) infection, SCID, CD40 ligand deficiency or other combined immunodeficiency.

•Recurrent sinobacterial infection, particularly occurring after 6 months of age, is more suggestive of a humoral immunodeficiency.



•The finding of staphylococcal lung infection leading to pneumatocele formation, particularly when associated with eczema, should raise the suspicion of the hyper-IgE syndrome.

•Fungal pneumonias are uncommon and CGD should be considered, particularly in the case of fulminant pneumonitis .

•Common variable immunodeficiency is uncommon in children, but may present with recurrent sinopulmonary infection later in childhood.

•Complement deficiency may present with sinopulmonary infection later in childhood. Children with neutrophil defects such as cyclical neutropenia may also present with recurrent respiratory infection.


Causes of recurrent respiratory tract infections:

•Gastro-esophageal reflux.

•Cystic fibrosis.

•Tracheobronchial foreign bodies.

•Asthma

•Immunodeficiency disorders.



II) Gastrointestinal infection:

•Failure to thrive and malabsorption associated with infection-related diarrhoea.

•Infection is often persistent with failure to clear virus and there may be an associated malnutrition because of malabsorption. Persistent non-infective diarrhoea in boys who require parental nutrition, with associated eczema and recurrent respiratory infection, should raise the suspicion of immunodysregulation, polyendocrinopathy, enteropathy or X-linked (IPEX) syndrome.


III) Dermatological infection:

•In a boy with recurrent sinopulmonary infection with associated eczema and petechiae, Wiskott–Aldrich syndrome is likely.

•Eczema in association with staphylococcal pneumatoceles is suggestive of hyper-IgE syndrome and an eczematous rash associated with thoracic or abdominal abscesses suggests Chronic granulomatous disease CGD.

•Persistent mucosal candida infection may be suggestive of SCID, chronic mucocutaneous candidiasis or hyper-IgE syndrome.

•Mucocutaneous albinism may be associated with disorders of cell-mediated killing, such as Griscelli syndrome or Chediak–Higashi syndrome.

•Midline ulceration may be seen in major histocaompatibility complex class I deficiency, although ulceration in other areas may also be seen.

•Systemic lupus erythematosus (SLE) is a feature of deficiencies of the complement proteins and may also be seen in carriers of X-linked CGD.

•Telangiectasia or photosensitivity with recurrent infection are suggestive of a DNA repair disorder such as ataxia telangiectasia .



IV) Neurological infection:•Enteroviral meningo-encephalitis should raise the suspicion of humoral immune deficiency, particularly X-linked agammaglobulinaemia.

V) Haematological infection:•The finding of lymphopenia in a child with recurrent or persistent infection should prompt reinvestigation: lymphopenia present on two or more occasions, particularly in an infant, is highly suggestive of SCID and warrants further investigation. However, a normal lymphocyte count does not preclude the diagnosis of SCID.

•Recurrent episodes of erythrophagocytosis are highly suggestive of an underlying PID.

•Neutropenia occurring every 3–4 weeks, often with an associated fever, infection or mouth ulcers, is suggestive of cyclical neutropenia. Some cases are associated with elastase 2 gene defects also found in SCN. These patients present with bacterial sepsis, skin abscesses or cellulitis, mucosal infections (gingivitis, stomatitis, apthous ulcers, periodontitis) and respiratory infection.

•Wiskott–Aldrich syndrome should be excluded in boys with thrombocytopenia − a small mean platelet volume (< 5fl) is pathognomic. •Patients with DiGeorge syndrome may present with autoimmune cytopenia or other autoimmune features. The finding of myelodysplasia should raise the suspicion of XLP, or a DNA repair defect such as Nijmegen breakage syndrome.


CONCLUSION

The majority of children who present with recurrent infections, have increased exposure, allergy, or an anatomic problem rather than an immunodeficiency

Primary immunodeficiency should be considered in children who have recurrent and/or complicated bacterial infections; persistent oral candidiasis; infection with opportunistic, unusual, or "signature" organisms; failure to thrive; or a family history of immunodeficiency


•B cell and combined B and T cell abnormalities account for nearly three-fourths of the primary immunodeficiencies and should be considered initially. Isolated T cell, phagocytic, and complement defects are rare.

RECOMMENDATIONS

1. A new interest should be directed towards the investigations of recurrent childhood infections as it

may be an indicator of a much serious event of immunodeficiency which can lead to greater co

morbidities if missed.

2. Greater concern should be directed towards potential early preventive strategies especially

nutrients role in enhancing the immune system of the child and the role of vaccination in facing

intercurrent childhood infections..

3. Efforts should be focused on implementing a Community wide program to pick out missed

childhood infections especially in the day care and educational institutes.



5.The early involvement of a clinical immunologist in cases of suspected immunodeficiency is crucial since early investigation and treatment of a child with an underlying primary immunodeficiency can prevent significant end-organ damage and

improve survival and long-term outlook.

4. Definitive diagnostic testing should be performed if the initial screening evaluation is abnormal, and should be done in consultation with a pediatric immunologist.

REFRENCES

•Esser M. (2008): APPROACH TO THE CHILD WITH RECURRENTINFECTIONS – PRESENTATION AND INVESTIGATION OF PRIMARY IMMUNODEFICIENCY.. Current Allergy & Clinical Immunology, Vol 21, No. 1; 8.•Gruber C, Keil T, Kulig M, et al. (2008): History of respiratory infections in the first 12 yr among children from a birth cohort. Pediatr Allergy Immunol.;19:505–12. •American Academy of Pediatr ics Committee on Environmental Health (1997): Environmental tobacco smoke: a hazard to children. Pediatrics;99:639–42.•Woroniecka M and Bal low M. (2000): Office evaluation of children with recurrent infection. Pediatr Clin North Am.;47:1211–24. •AlKhater S.A. (2009): Approach to the child with recureent infections. J Family Community Med.; 16(3): 77–82. •Bonil la FA, Bernstein IL, Khan DA, et al. (2005): Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. ;94:S1–S63. •Ballow M. (2008): Approach to the patient with recurrent infections. Clin Rev Allergy Immunol.;34:129–40. Slatter MA and Gennery AR. (2008): Clinical immunology review series: An approach to the patient with recurrent infections in childhood. Clin Exp Immunol. ;152:389–96.


REFRENCES

•Whelan MA, Hwan WH, Beausoleil J, Hauck WW and McGeady SJ. (2006): Infants presenting with recurrent infections and low immunoglobulins: characteristics and analysis of normalization. J Clin Immunol. ;26:7–11. •Dorsey MJ and Orange JS. (2006): Impaired specific antibody response and increased B-cell population in transient hypogammaglobulinemia of infancy. Ann Allergy Asthma Immunol. ;97:590–5. •Dalal I , Reid B, Nisbet-Brown E and Roifman CM. (1998): The outcome of patients with hypogammaglobulinemia in infancy and early childhood. J Pediatr. ;133:144–6. •Kornfeld SJ, Kratz J, Haire RN, Litman GW and Good RA. (1995): X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia of infancy. J Allergy Clin Immunol. ;95:915–17. •Wood PM, Mayne A, Joyce H, Smith CI, Granoff DM and Kumararatne DS. (2001): A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency. J Pediatr. ;139:148–51. •Ku CL, Picard C, Erdös M, et al. (2007): IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. ;44:16–23. •Freeman AF, Kleiner DE, Nadimint i H, et al. (2007): Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol. ;119:1234–40. •Grimbacher B, Hol land SM, Gall in JI, et al . (1999): Hyper-IgE syndrome with recurrent infections − an autosomal dominant multisystem disorder. N Engl J Med. ;340:692–702. •Siddiqui S, Anderson VL, Hil l igoss DM, et al. (2007): Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. Clin Infect Dis. ;45:673–81. •Ogershok PR, Hogan MB, Welch JE, Corder WT and Wilson NW. (2006): Spectrum of illness in pediatric common variable immunodeficiency. Ann Allergy Asthma Immunol. ;97:653–6.


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