Child with recurrent infections

‫ما‬َ ‫ل‬ّ ‫إ‬ِ ‫نا‬َ ‫ل‬َ ‫م‬َ ‫ل‬ْ ‫ع‬ِ ‫ل‬ ‫ك‬َ ‫ن‬َ ‫حا‬َ ‫ب‬ْ ‫س‬ُ ‫لوا‬ُ ‫قا‬َ
‫م‬ُ ‫ليـ‬ِ ‫ع‬َ ‫ل‬ْ ‫ا‬ ‫ت‬َ ‫ـ‬ْ ‫أن‬َ ‫ك‬َ ‫ـ‬ّ ‫إن‬ِ ‫نـا‬َ ‫ت‬َ ‫م‬ْ ‫ل‬ّ ‫ع‬َ
‫م‬ُ ‫كيـ‬ِ ‫ح‬َ ‫ل‬ْ ‫ا‬
‫سورة‬‫البقرة‬

Dr.Osama Arafa Abd EL Hameed
M. 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

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 rhinitis 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 dermatitis 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 use
ii.Blood-product transfusion
iii.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.
Port said Pediatrics conference
2015

•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
Eczema
Wiskott-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 differential
Serum Ig levels (IgG, IgA, and IgM)
HIV serology, as indicated by the history and physical findings
•Tests of humoral immunity
B-cell count
IgG subclass determinations
Antibody 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
•Complement
CH50 assay
Screening 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.

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. Sepsis
2. Pneumonia
3. Meningitis
2. Serious bacterial infection in the context of failure to thrive
3. Infection with an opportunistic pathogen
- Pneumocystis
- Cryptococcus
4. Vaccine-associated infection
5. Unusual age for infection
- Zoster
- Thrush
6. Unusual severity or chronicity for a given infection
7. 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.
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respiratory infections in the first 12 yr among children from a birth
cohort. Pediatr Allergy Immunol.;19:505–12.
•American Academy of Pediatrics Committee on
Environmental Health (1997): Environmental tobacco
smoke: a hazard to children. Pediatrics;99:639–42.
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•AlKhater S.A. (2009): Approach to the child with recureent
infections. J Family Community Med.; 16(3): 77–82.
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Slatter MA and Gennery AR. (2008): Clinical immunology
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REFRENCES
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presenting with recurrent infections and low immunoglobulins: characteristics and analysis of
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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, Nadiminti H, et al. (2007): Causes of death in hyper-IgE syndrome. J
Allergy Clin Immunol. ;119:1234–40.
•Grimbacher B, Holland SM, Gallin 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, Hilligoss DM, et al. (2007): Fulminant mulch pneumonitis: an
emergency presentation of chronic granulomatous disease. Clin Infect Dis. ;45:673–81.
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Child with recurrent infections

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