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ARTICLE
Investigation and management of primary immunodeficiency in South African children
B Eley,1 MB ChB, FCPaed, BSc (Hons); M Esser,2 MB ChB, MMed Paed (Cert Rheum)
1 Paediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital and Department of Paediatrics and Child Health,
University of Cape Town, South Africa
2 Immunology Unit, National Health Laboratory Service, Tygerberg, and Department of Pathology, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa
The primary immunodeficiency diseases (PIDs) are inherited, non-communicable diseases that cause immunological dysfunction. PIDs are seldom reported in South Africa (SA). Based on a mid-2013 population estimate of 52.98 million and assuming that the prevalence of PIDs is similar to that in well-resourced settings, the total number of individuals with PIDs in our country should range between 2 850 and 45 723. However, fewer than 500 cases of PID have been reported in SA. Between five and 15 new, fully characterised PIDs are reported annually. Our understanding of the physiology of the immune system has been substantially enhanced by these discoveries, and consequently the international classification of PIDs has been updated.
S Afr Med J 2014;104(11):793.
DOI:10.7196/SAMJ.8946
The primary immunodeficiency diseases (PIDs) are inherited,
non-communicable diseases that cause immunological dysfunction.
They primarily manifest with a wide range of infections. The
pattern, frequency and severity of infection depend on the
underlying immunological defect (Table 1), and geographical and
social determinants. For example, in high tuberculosis (TB)
prevalence settings chronic granulomatous disease (CGD) may
manifest with recurrent TB.
In well-resourced countries, estimates of the prevalence of PIDs vary widely from 5.38/100 000 in France to 86.3/100 000 in the USA.1 , 2 There is very little reporting of PIDs from Africa, including South Africa (SA). In the latest Jeffrey Modell Foundation (JMF) global survey, 1 463 patients with PIDs out of a global total of 77 193 were from Africa.3 This low reporting prevalence of 1.9% contrasts with Africa’s contribution of approximately 15% to the global population. Recent speculation suggests that as many as 902 000 PID cases should be reported from Africa.1 In SA, based on a mid-2013 population estimate of 52.98 million and assuming that the prevalence of PIDs is similar to that in well-resourced settings, the total number of people with PIDs should range between 2 850 and 45 723. However, fewer than 500 PID cases have been reported in SA.4 , 5
The almost 300 patients in the SA
National PID Registry reflect deficiencies similar to those in
European and US data, with the majority due to antibody
deficiencies. Respiratory infections are the most common
presenting symptom and a positive family history is recorded in
30%. Paediatricians outside of tertiary care centres contribute
a significant third of registry entries. Of special concern is
the under-reporting of PIDs from disadvantaged communities. As
infections are common in childhood, a high level of awareness is
needed to investigate those that may be caused by an immune
deficit.
Classification of PIDs
Between five and 15 new, fully characterised PIDs are reported
annually. Our understanding of the physiology of the immune
system has been substantially enhanced by these discoveries, and
consequently the international classification of PIDs has been
updated. It now includes nearly 250 different PIDs spanning nine
categories, including a new category, phenocopies of PIDs, which
contains conditions caused by somatic mutations and
autoantibody-mediated PIDs (Table 2).6 Given the complexity of the
human immune system, the rate at which new PIDs are being
discovered will most likely continue for the foreseeable future,
necessitating further revision to the international
classification.
Investigation
The medical history, clinical presentation and causative organism guide the laboratory investigation of PIDs.
Red flag signs in the medical history include severe, persistent, unusual and recurrent (SPUR) infections and, very importantly, a history of previous infant death due to infections or a known family history of PID. The frequency of infection commonly indicates the need for further investigations. Six or more upper respiratory infections per year are acceptable in the average toddler.7 Increased frequency is seen with overcrowding and poor sanitation. Aggravating factors for recurrent infections such as allergy or daycare have to be evaluated. Secondary immunodeficiencies such as HIV infection are far more common and have to be excluded initially. Repeated infections at the same site indicate a possible anatomical cause.
The clinical presentation of PIDs may include features of autoimmunity or inflammation, apart from those of infections. The JMF warning signs (Table 3) provide a useful guide to the need for investigation, but in the SA context have to include bacillus Calmette-Guérin (BCG) dissemination, recurrent meningococcal infections and awareness of infections with atypical mycobacteria. The following warning signs were found to be most predictive of PID in children: a family history of PID, use of intravenous antibiotics to treat sepsis and failure to thrive in T-lymphocyte PID.8
The causative organisms may be defined as virulent, opportunistic, hospital or community acquired and assist in determining the relevant immunodeficiency to be investigated: deficiency for intracellular (e.g. TB) versus extracellular bacterial targeted immune responses. Infections with encapsulated organisms may point to a deficient immune response specific to Streptococcus pneumoniae, with antibody responses being crucial. T-cell PIDs, although commonly manifesting with intracellular infections, generally also involve B-cell-dependent (humoral) immune responses and hence result in bacterial infections. T-cell-related immune deficit manifests early in life, sometimes in the first months, whereas B-cell PIDs tend to present with symptoms at the time of loss of maternal passive antibodies in the infant, especially >6 months of age.
Basic laboratory screening (full blood count, differential count, immunoglobulins and complement) is readily available to identify the majority of significant defects. A more comprehensive four-step laboratory approach has been developed by the JMF and modified for use in SA.
Step 1. After exclusion of HIV and, where indicated on history, an assessment for atopy, the investigation starts with a full blood count and, importantly, differential count for neutrophil and lymphocyte numbers. A persistently low lymphocyte count for age, which should be >1/3 of leukocytes <3 years of age or >3.0 × 109/L, is an important indicator of possible severe combined immunodeficiency (SCID) or combined immunodeficiencies. A blood smear will assist, e.g. to identify small platelets as seen in Wiskott-Aldrich syndrome. Serum immunoglobulin (Ig) G, M, A and E, total complement activity and subsequent fractions as indicated by the absence of activity, cystic fibrosis screening and investigation for active TB where suspected on history and clinical examination complete step 1.
S tep 2. Vaccine antibody response to a range of antigens but more targeted to polysaccharide-specific antigens (pneumococcus) and protein antigens (tetanus) is indicated with recurrent bacterial infections, even in the presence of normal immunoglobulin levels. Patients have to be off immunoglobulin replacement therapy for 6 months. These responses should be repeated four weeks after vaccine boosting to determine an appropriate increase in IgG, of which there are four subclasses. These can be further investigated for deficiency of one or more, especially if total IgG levels are normal in the presence of recurrent infections. Both IgG subclass deficiency and deficient vaccine antibody response, especially to S. pneumoniae, should be investigated concurrent with symptomatic IgA deficiency (IgA <0.08 g/L), as these are common associations.
Lymphocyte subsets are enumerated by flow cytometry with cluster of differentiation (CD) markers to document B-cell numbers (CD19), which are absent in X-linked agammaglobulinaemia when all immunoglobulin isotypes are severely reduced. Total T cells (CD3) are measured with the sum of T-helper (CD4) and T-suppressor (CD8) cells, and natural killer cells are measured as CD16 and CD56.
Step 3. Lymphocyte enumeration does not provide information on function, which can be done at specialised laboratories on request. The response to mitogens, e.g. phytohaemagglutinin, or to antigens, e.g. Candida, can give information on specific immune deficit or suppression. Neutrophil function, particularly in suspected deficiency such as CGD, can be evaluated with the neutrophil burst activity. This test, done on the mother in X-linked CGD, can also guide on possible carrier status. Neutrophil studies for leukocyte adhesion, chemotaxis and phagocytosis, lymphocyte subset definitions of naïve and memory status are all requested after specialist consultation.
Stage 4. Cytokine studies, enzyme studies and genetic molecular investigations are not generally available and can only be selectively done.
While neonatal screening for SCIDs is becoming routine practice in North America and Europe by T-cell-receptor excision circle assay, this is costly and only available on request in SA. Dissemination of routinely applied neonatal BCG vaccine remains an important alerting sign outside HIV infection.9
Management
Most interventions for managing PIDs are available to a varying
degree in SA.
Immunisation practice
Immunisation with live viral or bacterial vaccines poses an infection risk to individuals with severe PIDs of T-cell, B-cell and phagocytic origin, requiring modification to routine immunisation practice of children with PIDs and changes to the immunisation of household contacts of patients with PIDs. For example, recent evidence suggests that 51% of infants with SCID experience BCG-related complications following neonatal immunisation, 34% develop BCGosis and 17% develop localised BCG complications.10 Oral polio and smallpox vaccines are contraindicated in children with severe antibody deficiencies. For children with combined B- and T-cell deficiencies, such as SCID, all live vaccines are contraindicated, and for those with phagocytic disorders live bacterial vaccines are contraindicated.11
Immunocompetent household contacts of PID patients should not receive smallpox or oral polio vaccine, because these vaccine virus strains may be transmitted to immunocompromised patients. Other vaccines may be administered to close contacts because they pose little risk of transmission to the PID patient.11
Antimicrobial prophylaxis
Several PIDs may benefit from antimicrobial prophylaxis. In milder antibody conditions, such as IgA deficiency or transient hypogammaglobulinaemia of infancy, recurrent infection may occasionally require short courses of prophylactic antibiotics. Antibiotic prophylaxis should be the first intervention for prevention in patients with specific antibody deficiency or IgG subclass deficiency and recurrent infection, before considering immunoglobulin replacement therapy (IRT). Antibiotic prophylaxis may be added in patients with severe antibody deficiency if IRT is unable to adequately prevent recurrent infections. Both antibacterial and antifungal prophylactic agents are required in children with severe phagocytic disorders. Prior to haematopoietic stem cell transplantation (HSCT), children with severe combined immunodeficiencies such as SCID require broad-spectrum antibacterial, antiviral and antifungal prophylaxis. Detailed prophylactic regimens have recently been published.12
Immunoglobulin replacement therapy
Many predominantly antibody deficiencies and combined immunodeficiencies in which quantitative and/or qualitative IgG deficiency occurs may benefit from IRT. Lifelong IRT is required for severe, genetically confirmed deficiencies in which arrest in early B-cell development is demonstrated, such as X-linked agammaglobulinaemia. Incompletely defined predominantly antibody deficiencies characterised by the presence of circulating B cells and subnormal IgG concentration may require a 12-month trial of IRT, while documenting the clinical response. If the response is favourable, treatment may be extended for 1 - 5 years, followed by periodic re-evaluation of serum immunoglobulin concentrations as hypogammaglobulinaemia may be transient and resolve spontaneously. Functional antibody responses should ideally not be checked until IRT has been discontinued for at least 6 months. If IgG deficiency persists, IRT should be restarted and may have to be continued indefinitely if the deficiency fails to resolve. Treatment with intravenous immunoglobulin is most widely used. Subcutaneous immunoglobulin administration is less frequently used but is equally effective. Intravenous immunoglobulin is administered at 3 - 4-week intervals at the usual starting dose of 400 mg/kg for patients without bronchiectasis and 600 mg/kg for those with bronchiectasis. After achieving steady state, an IgG trough concentration of >5 g/L reduces the infection rate and trough levels up to 10 g/L will progressively reduce the risk of pneumonia. Progressive adjustment of the total infusion dose is required to optimise the IgG trough concentration.13
Additional measures to control infection
General advice aimed at
reducing the risk of infection will benefit many
immunodeficient patients, including advice on personal, hand
and dental hygiene, avoidance of exposure to individuals with
active infections and annual influenza immunisation for
household contacts. Antimicrobial prophylaxis is often
administered with other interventions to reduce the risk of
infection. In SCID, prior to an HSCT, the infant should
ideally be managed in a laminar flow facility, with full
contact precautions, and receive sterile feeds. In the
immediate post-HSCT period, similar management interventions
apply. In CGD, life-long interferon-γ is recommended in
combination with co-trimoxazole and itraconazole prophylaxis.
However, the high cost precludes its routine use in SA. In Job
syndrome, which causes a markedly elevated IgE concentration,
the risk of colonisation and infection with Staphylococcus aureus may be reduced by regular bleach
or chlorhexidine soaks and intermittent mupirocin
applications.
Haematopoietic stem cell transplantation
This is the treatment of choice for many severe PIDs, including SCID. In SA, there is limited access to HSCT in the public sector. However, three children with SCID have been successfully transplanted, permitting the development of guidelines for the pre-HSCT management of children with SCID, including the tissue typing procedure and identification of suitable donors.14
Other therapies
Other therapeutic modalities include cytokine therapy, such as myeloid haematopoietic growth factors for congenital and cyclical neutropenia, enzyme replacement for adenosine deaminase deficiency and C1-inhibitor deficiency, colchicine in familial Mediterranean fever (FMF), and interleukin 1-blocking agents in autoinflammatory disorders including patients with colchicine-resistant FMF. Gene therapy offers hope as a potential treatment and cure for PIDs in the future.15
Conclusion
PIDs worldwide are more common than is generally believed.1 In SA, diagnosis may be masked by a high background prevalence of infectious diseases. It is hoped that this article increases awareness of PIDs among general practitioners and paediatricians.
References
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14. Eley B, Hendricks M, Davidson A, Lochan H, Schlaphoff T, Maart S. Primary immunodeficiency diseases (PIDs): Diagnostic and treatment considerations for patients managed at Red Cross War Memorial Children’s Hospital (RCWMCH), August 2014. http://www.paediatrics.uct.ac.za/sites/default/files/image_tool/images/38/1.5.10%20PIDs-diagnostic%20%20treatment%20considerations.pdf (accessed 20 August 2014).
15. Zhang L, Thrasher AJ, Gaspar HB. Current progress on gene therapy for primary immunodeficiencies. Gene Ther 2013;20(10):963-969. [http://dx.doi.org/10.1038/gt.2013.21]
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Useful information sources
- • African Society for Immunodeficiency Diseases
(ASID): http://www.asid.ma
- • Immune Deficiency Foundation (IDF):
http://www.primaryimmune.org
- • International Patient Organization for Primary
Immunodeficiency (IPOPI): http://www.ipopi.org
- • Primary Immunodeficiency Network South Africa
(PiNSA): http://www.pinsa.org
- • Primary Immunodeficiency Resource Center:
http://www.info4pi.org
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