Fifteen-minute consultation: the infant with frequent infections
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* Penelope A Bryant
* Mike South

## Abstract

Children with frequent or recurrent infections commonly present to medical practitioners in both primary and secondary care. Here we provide a structured approach to the consultation of the infant under 2 years of age with frequent infections. The key is a focused history and examination to elicit red flags to an underlying diagnosis, while at the same time seeking benign explanations for the frequency of infections, which account for the majority of children, thereby avoiding unnecessary investigations.

*   Infectious Diseases
*   Immunology
*   Respiratory
*   Allergy

## BACKGROUND

An 18-month-old infant presents with a history of eight infections since birth. His parents are concerned that ‘there must be something wrong with his immune system’. Is there?

Children under the age of 2 years presenting with frequent infections can be broadly divided into those with 

*   an underlying problem with the immune system

*   an underlying problem with another system, and

*   no underlying problem.

This last category accounts for the large majority of children. The key to this consultation is recognising the red flags suggestive of an underlying problem, and having the confidence to diagnose a child as normal without unnecessary investigations.

## What are the important features of the history?

In the history, you are trying to elicit benign explanations for frequent infections and pick up on features that may indicate a more serious cause.

### Number of infections

Upper respiratory tract infections (colds, otitis media, tonsillitis) are by far the most common type of infection in infants. Two birth cohort studies published in the last 5 years quantified the number of respiratory infections in infancy and found a mean of 3–6 respiratory infections per year in infants under 2 years old, with the 95th percentile being 12 infections per year.1 ,2 Therefore, an average of one respiratory infection a month (more frequent in winter and balanced by fewer in the summer months) in the first 2 years of life can be considered within the range of normal. However, this assumes that the infections are predominantly in the upper respiratory tract and viral in origin. It is also important to ascertain that all episodes are indeed infections, as rhinitis, wheeze and cough may be due to allergy and this should lead you down a different management pathway.3

### Site of infections

The site of infection is important because frequent infections in sterile sites are more suggestive of an underlying disorder than in non-sterile sites.

#### Upper respiratory

Frequent otitis media is usually viral,4 but recurrent suppurative otitis media with otorrhoea is more commonly bacterial and occasionally may be due to an immune defect such as an immunoglobulin deficiency or HIV. Differential diagnoses for a chronically draining ear include a foreign body or a cholesteatoma. Recurrent bacterial tonsillitis is less common than viral tonsillitis in this age group, and is not usually associated with an immune defect.

#### Lower respiratory

Both cohort studies discussed above included wheeze as a symptom, so lower respiratory tract involvement is not necessarily indicative of an underlying abnormality. However, a second episode of pneumonia, particularly requiring intravenous antibiotics, or responding poorly to antibiotics, should alert you to a possible underlying disorder, the most serious in young infants being severe combined immunodeficiency (SCID) which affects humoral (B cell) and adaptive (T cell) immunity.5 While some organisms particularly predispose to lung abscesses, recurrent lung abscesses should prompt investigation for a neutrophil defect such as chronic granulomatous disease (CGD).6 ,7 If infection is always in the same lobe, a structural abnormality, for example, lobar sequestration or a foreign body, should be considered. Other suppurative lung diseases, such as cystic fibrosis or bronchiectasis, can also predispose to frequent lower respiratory tract infections because of the inability to clear bacteria effectively.8

#### Skin

Recurrent skin infections and abscesses can occur in immunocompetent individuals due to virulent strains of *Staphylococcus aureus*. However, these are uncommon presentations in infancy, so they should prompt investigation of defects in B cells, such as X-linked agammaglobulinaemia and, particularly, neutrophil function such as CGD, respectively.7 ,9

#### Gastrointestinal

Gastroenteritis in infants is usually due to viruses (eg, rotavirus, adenovirus) and parasites (eg, giardia), and as such, frequent episodes are most commonly due to exposure. However, red flags are recurrent bacterial gastroenteritis that may point to a specific IgA (immunoglobulin) deficiency, or certain bacteria, such as recurrent salmonella infections, which are associated with T cell defects (eg, SCID).

#### Urinary tract

Frequent urinary tract infections are unlikely to be due to immunodeficiency. In most children, there is no serious underlying abnormality, but anatomical abnormalities in the urinary tract, such as obstruction, or functional abnormalities, such as significant vesicoureteric reflux or elimination disorders, should be considered.

#### Septicaemia and meningitis

Infections of these sterile sites are relatively unusual and a second episode should prompt consideration of immunodeficiency, for example, SCID, agammaglobulinaemia and complement deficiency.10 Recurrent meningitis also raises the question of an anatomical connection to the cerebrospinal fluid through which organisms can enter.

### Type of organism

Frequent infections with a specific type of organism can point to a defect in a specific arm of the immune system (table 1). For example, the immune response to encapsulated organisms requires both an intact complement pathway and the ability to produce immunoglobulins. Recurrent infections with this type of organism (eg, *Streptococcus pneumoniae* and *Haemophilus influenzae*) should prompt investigation for immune defects. Likewise, recurrent infections with intracellular bacteria (eg, mycobacteria, salmonella) point to a defect in T cell function, and recurrent meningococcal infection to a terminal complement defect. With all these organisms, one infection can be normal, so it is only with recurrences that further investigation is usually required.

View this table:
[Table 1](http://ep.bmj.com/content/99/1/8/T1)

Table 1 
The association between immune defects and clinical infections

Some infections, such as *Pneumocystis jiroveci* pneumonia and candida oesophagitis, are so unusual that even a single episode should raise a red flag. There is likely to be an immune defect, and children with these infections should be investigated after the first episode.

Infections caused by viruses are generally considered relatively benign, but recurrent herpes virus infections (eg, varicella zoster, Epstein-Barr virus) in particular can be due to an underlying defect in T cell function, such as HIV.11 A child experiencing a single episode of herpes zoster (shingles) is most likely to be immunocompetent, but multiple recurrences are more suspicious, and should be further investigated.

### Associated symptoms

Failure to thrive is associated with some of the more severe underlying causes of frequent infections, including SCID, HIV and cystic fibrosis.12 Although an underlying cause cannot be excluded in its absence, a thriving child with frequent upper respiratory tract infections is of less concern than one who is not growing.

Rash is a common symptom in infancy, and atopic dermatitis may point to allergy being the underlying cause of respiratory symptoms rather than infection. Eczematous rashes may also be associated with immunodeficiency, such as Wiskott–Aldrich syndrome and hyper IgE syndrome.13 ,14 A graft-versus-host rash may occur in SCID.

Chronic diarrhoea is common in infants with severe immunodeficiencies with or without infection and may also occur in cystic fibrosis.

Developmental delay is associated with some syndromes in which immunodeficiency is also a feature, such as DiGeorge syndrome.15 However, mild delay can occur in otherwise normal children with frequent infections, such as speech delay with recurrent otitis media, and children may even temporarily developmentally regress during infections.

### Immunisation history

There are three pieces of information to be gleaned from this part of the history: coverage, response and side effects. If a child is not fully immunised this can be a cause of frequent infections, particularly ones that may be prevalent in the community, such as pertussis or rotavirus.16 Even if a child is fully immunised, there is a small failure rate of vaccines, but if multiple vaccines have failed or if boosters do not elicit an antibody response, then a defect in the humoral arm of the immune system may underlie this. If a child has adverse side effects to live vaccines, for example, diarrhoea post-rotavirus vaccine, disseminated lymphadenopathy post-BCG vaccine, or more than a few vesicles post-varicella vaccine, then a T cell defect should be considered.

### Exposure history

In the birth cohort studies, frequent respiratory infections were associated with attendance at child care and having older siblings, particularly of preschool age.1 ,2 ,4 Parental smoking is associated with more frequent respiratory infections and otitis media.4 ,17 Other air environmental exposure, such as air pollution and home dampness may also increase susceptibility to respiratory infections. Specific questioning about the home environment depending on the type of infection is also important: for example in recurrent giardia infection, does the family have a potentially contaminated water supply, or in recurrent tinea, is there a chronically infected pet?

### Family history

Arguably, the most important clue to immunodeficiency is a history of a family member dying young, potentially without a diagnosis, or males in the family having similar symptoms. The genetic aetiology of many immunodeficiencies has been elucidated and may be X-linked (eg, agammaglobulinaemia, SCID, CGD) or autosomal recessive (eg, SCID), so a history of consanguinity is important. However, lack of a family history does not exclude an immune defect, which may be caused by a de novo mutation. A family history of atopy may also suggest allergy as the underlying cause of symptoms.

### Other specific questions

Gestation: prematurity is associated with increased respiratory infections.

Duration of attachment of the umbilical cord: delayed separation over 3 weeks is associated with leucocyte adhesion deficiency.7 However, this is neither a very sensitive (some patients with leucocyte adhesion deficiency have no delay) nor specific (separation can occur in normal infants up to 6 weeks after delivery) clinical feature of the disease, so should be taken in the context of recurrent localised bacterial infections or persistent oral thrush.

A recent study investigated the clinical usefulness of ‘The 10 Warning Signs of a Primary Immunodeficiency’, a list based on expert opinion and promoted by patient support groups as a general screening tool.18 The study found that in patients referred to a tertiary centre, strong identifiers of a defined primary immune deficiency were family history, failure to thrive, use of intravenous antibiotics, persistent thrush and over 2 months of oral antibiotics without effect. Having two or more deep-seated infections, two or more episodes of pneumonia and deep abscesses were not useful overall. Further, recurrent acute otitis media and having two or more sinus infections were significantly more common in patients with no immune deficiency.

## What is the focus of the examination?

General appearance and growth parameters give an indication about the child's overall health. There are specific signs that should alert you to an underlying aetiological diagnosis.

### Dysmorphic features

Some immunodeficiencies are associated with syndromes, for example, Di George and hyper IgE syndromes.

### Skin

Eczema may suggest allergy, and is also associated with several immunodeficiencies (see above). A petechial rash may be seen in Wiskott–Aldrich syndrome due to low platelets. Widespread molluscum contagiosum is associated with defects in T cells and innate immunity.

### Mouth

Oral thrush is common in newborns, but candidal infection beyond 3 months of age that is persistent or hard to treat, particularly without a concomitant source of reinfection from infected nipples, should be considered abnormal. Underlying immunodeficiencies include T cell defects, such as in SCID, HIV and chronic mucocutaneous candidiasis. Mouth ulcers may be associated with immunodeficiency, such as IgA deficiency or HIV, but periodic fever syndromes, such as PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) and cyclical neutropenia should also be considered in this age group.19

### Cardiovascular

Congenital heart disease may predispose to recurrent respiratory infections. There are also syndromes of associated congenital heart disease and immunodeficiency (eg, DiGeorge syndrome).

### Respiratory

Signs of persistent lung infection should be sought, but many of the physical indicators of underlying respiratory disease such as nasal polyps in cystic fibrosis or clubbing in suppurative lung disease will not be present in this age group.

### Gastrointestinal

Hepatosplenomegaly may occur in CGD and HIV infection.

## When should you investigate and how far?

Most children need no investigations at all. In a study of preschool children with recurrent respiratory infections, 13% had an immune defect but all were mild (eg, IgG subclass deficiency, transient hypogammaglobulinaemia).3 If there are any red flags, then the most basic level of investigations should include a full blood count, most importantly for the lymphocyte number, and immunoglobulin (IgG, IgM, IgA) levels.9 IgG subclasses rarely add useful information at screening level.20 Further immune investigations should be guided by clinical features (table 1). The European Society for Immunodeficiencies has published a step-wise approach to investigating for primary immunodeficiency to take into account different clinical features and to ensure cost effectiveness.21 Other investigations for non-immunological chronic diseases (eg, a sweat test in recurrent pneumonia) should be guided by clinical suspicion.

So, an 18-month-old infant presenting with a history of eight infections since birth is well within the acceptable range. This is especially the case if the child has exposure risk factors, such as child care and older siblings, is thriving, and has none of the red flags described. There is unlikely to be a sinister underlying cause, and you can be reassuring to his parents without the need for an extensive immunological work-up.

## Footnotes

*   Contributors PB drafted the manuscript and approved the final manuscript. MS reviewed, provided suggestions and approved the final manuscript.

*   Competing interests None.

*   Provenance and peer review Commissioned; internally peer reviewed.

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