Primary immunodeficiency for the primary care provider

Abstract

Primary immunodeficiencies are a group of heterogeneous disorders resulting from defects affecting the function of ≥1 parts of the immune system. Current estimates of the prevalence of primary immunodeficiency disease are one in 1200 patients. In Ontario, where the average general practitioner follows 1300 to 2000 patients, an estimated two patients will have primary immunodeficiency. With new primary immunodeficiencies being described at an exponential rate, and those previously described becoming better understood, it is challenging for health care providers to stay up to date. Knowledge gaps delay diagnosis and treatment, leading to increased morbidity and mortality. The present review aims to provide the primary care provider with the tools necessary to recognize primary immunodeficiency and assist in establishing diagnoses.

Primary immunodeficiency disease was once believed to be rare, with a reported incidence rate of one to two per 50,000 for primary antibody deficiency in 1989 (1). Since Bruton (2) described agammaglobulinemia in 1952, our understanding of the immune system has grown exponentially, as has our understanding of primary immunodeficiency. Currently, >250 individual gene defects have been described resulting in immunodeficiencies (3). A telephone survey of 10,000 United States (US) households estimated the prevalence of primary immunodeficiency to be one in 1200 patients (4). Data from administrative health care databases in the US suggest an increase in the prevalence of primary immunodeficiency diseases from 38.9 to 50.5 per 100,000 and 29.1 to 41.1 per 100,000 among privately and publicly insured persons, respectively, between 2001 and 2007 (5). Immunoglobulin (Ig)A deficiency is often not included in prevalence estimates because many patients are asymptomatic; however, it has an estimated incidence in the US of one in 223 to one in 1000 (6). This increase may be partially explained by improved awareness among primary health care providers, increased knowledge of molecular pathways leading to immunodeficiency, the resultant advances in diagnostic capabilities, newborn screening for severe combined immunodeficiency (SCID) and improved medical care for sick patients who may not have survived in the past.

In 2013, a Canadian study reported incidence rates for one form of primary immunodeficiency, SCID, of 1.2 per 100,000 in the Canadian population (7). Less is known about the prevalence of other primary immunodeficiencies in Canada. A recent Canadian initiative, Canadian Primary Immunodeficiency Evaluation Study (C-PRIMES), aims to determine the prevalence, clinical presentation, diagnosis and management of primary immunodeficiencies in Canada (8–11).

With remarkable improvements in medical care and reductions in infectious disease through advances in public sanitation, antimicrobial treatment, vaccination and herd immunity, patients who may have previously succumbed to these illnesses are now surviving. In patients with severe, unusual or recurrent infection, we must ask: why did this patient get so sick? When are these illnesses more than just bad luck? To address these questions, it is helpful to regard the immune system’s role in preventing or mitigating potentially severe illness as well as in health maintenance.

EVIDENCE FOR REVIEW

PubMed was searched for relevant articles using MeSH search terms “primary immunodeficiency”, along with “primary care” and “primary immunodeficiency”. Individual diseases were searched independently.

INNATE AND ADAPTIVE IMMUNITY

The immune system is broadly divided into two arms: innate and adaptive (Figure 1).

Figure 1).

The immune system can be broadly divided into two arms: innate and adaptive. Innate components include barrier defences (such as epithelial cells), complement, neutrophils and macrophages. Adaptive immunity is composed of B cells, the antibodies they produce, as well as helper and cytotoxic T cells. Immunodeficiency impacts one or more of these components. NK Natural killer; TLR Toll-like receptor

The innate system targets pathogens on first encounter through recognition of pathogen-specific patterns and tissue damage-related molecules. Innate immunity includes anatomical barriers, such as skin and mucosa, and sentinel cells, such as dendritic cells, which continually sample the environment. When pathogens are encountered, pattern-recognition receptors are activated, leading to the release of cytokines and chemokines. These trigger inflammation, attracting cells, such as neutrophils and macrophages, to the area. The complement cascade of proteins may be activated through one of several mechanisms: antigen-antibody complexes (classical pathway), activation of complement protein 3 on pathogen membrane (alternative pathway) or though mannose residues characterizing bacterial pathogens (lectin pathway). Together, these activities aim to contain and eliminate the pathogen from the body. Defects in innate immunity often result in rapidly progressing infection with organisms such as Staphylococcus aureus. Innate immunodeficiencies can present with a range of pathogens including other bacteria, viruses and fungi (12).

The adaptive immune system requires several days to generate a directed specific response against pathogens and results in immunological memory. On subsequent exposures, the adaptive response is able to rapidly target and remove pathogens it has previously encountered. The primary components of adaptive immunity are the lymphocytes: B cells and T cells. B cells produce antibodies, and are most effective at achieving this with T cell stimulation.

Primary immunodeficiency affects one or both systems resulting in different clinical phenotypes.

HUMORAL/ANTIBODY DEFECTS

Humoral (antibody) defects are the most common primary immunodeficiency (13). Humoral defects include IgA deficiency, common variable immune deficiency (CVID), x-linked agammaglobulinemia and specific antibody deficiency. Classically, these patients present with recurrent sino-oto-pulmonary infections, with bacteria such as Streptococcus pneumoniae and Haemophilus influenza. Other manifestations include autoimmune diseases, particularly cytopenias (14), and sensorineural hearing loss (15). Defects of humoral origin are managed with replacement Ig and timely treatment of infectious complications. Long-term prognosis depends on complications arising from delays in treatment, including bronchiectasis and chronic lung disease, and on the degree of impairment of other parts of the immune response that may increase the possibility of malignancy and autoimmunity.

The spectrum of T cell impairment varies from milder forms defined as combined immunodeficiency syndromes to SCID. Classically, these patients present with Gram-negative, mycobacterial, parasitic viral or fungal infections. Additionally, auto-immune phenomena may result from T cell dysregulation.

Case 1: Innate defects

A nine-year-old boy presented to the emergency department on multiple occasions with recurrent abdominal pain. Although initially diagnosed with gastroenteritis, his symptoms persisted for three weeks and an abdominal ultrasound revealed a liver abscess. Immunology was consulted. He had abnormal phagocytic cell activity, which prompted genetic testing, revealing a mutation in the NADPH oxidase complex and established the diagnosis of chronic granulomatous disease (CGD).

Innate deficiencies include phagocyte defects, such as CGD, defects affecting the complement system and pattern-recognition receptors and natural killer (NK) cell defects. These present in a variety of ways, including pyogenic infections, with cold abscess formation, and impaired wound healing. The innate immune system is responsible for the typical signs of infection clinicians rely on to assess a patient’s clinical condition such as fever, malaise, pain and elevated acute phase reactants. Patients with innate defects may not mount the expected inflammatory responses to infection and may fail to generate fever, delaying diagnosis of infection and worsening clinical outcomes. Complement defects are rare among primary immunodeficiencies, accounting for <1% of identified cases. Complement defects should be considered in patients with severe or recurrent infections with encapsulated organisms such as Neisseria (16). Patients with innate defects must be managed cautiously because severe infections can present with minimal clinical signs (17).

Case 2: Combined immunodeficiency

A 13-day-old girl was admitted to hospital with bronchiolitis. Her paediatrician noted that she was lymphopenic with an absolute lymphocyte count (ALC) of 1.2, and requested an immunology consultation. Further examination of lymphocytes revealed absent T, B and NK cells, and that the few existing lymphocytes were unable to respond appropriately to stimuli, suggestive of a diagnosis of SCID. Further work-up established the diagnosis of adenosine deaminase deficiency and the patient underwent a hematopoietic stem cell transplantation (HSCT) from a matched sibling donor.

Normal ALC values vary with age; what would represent a normal value in an older child may be severe lymphopenia in an infant. Lymphopenia can be a result of bone marrow suppression from an infection, related to medication, such as steroids, primary bone marrow failure or infiltrative disease. Low lymphocyte counts are an important warning sign of primary immunodeficiency, and should be reassessed in periods of wellness. Age-adjusted values for lymphocytes and subsets have been previously reported by Comans-Bitter et al (18).

Infants with SCID classically, although not always, present before their first birthday with failure to thrive, chronic diarrhea, respiratory infections, and/or Candida species infections in the oral cavity or of the skin (19). Live viral vaccines, including measles, mumps, rubella varicella and the rotavirus vaccine, are contraindicated in patients with SCID. Rotavirus vaccine is the first live viral vaccine given in many cases, typically at two and four months of age. SCID is a medical emergency and requires immediate treatment with antimicrobials, protective isolation, replacement Ig, and immune system reconstitution involving HSCT or gene therapy. Early identification and intervention in patients with SCID reduces morbidity and mortality (20).

The advent of T cell receptor excision circle (TREC) to newborn screening assists early detection of many forms of SCID. Infants diagnosed through newborn screening have survival rates of 90% after HSCT compared with 40% in infants who presented later in life, often with infection (21). Newborn screening in California (USA) established the incidence of some forms of SCID, SCID variants and non-SCID immunodeficiency to be one in 66,250 live births (21), demonstrating both the effectiveness of screening in diagnosis and that SCID is more common than initially believed (22). TREC newborn screening is now available in Ontario and is in development in other Canadian provinces. Following a positive screen, diagnostic follow-up with a clinical immunologist is indicated to confirm the diagnosis of SCID or another T cell lymphopenia. Not all forms of SCID will be detected by newborn screening, such as ZAP70 deficiency (23) and, thus, a high index of suspicion for SCID remains an important facet of early diagnosis.

Combined immunodeficiencies usually present beyond infancy with immune dysregulation, in the form of infection, autoimmunity or malignancy. They are often a result of hypomorphic mutations in SCID-associated genes or partial defects in T cell development (24). Dysregulation of immunity may lead to increased infection rates, infections with atypical organisms and/or severe infections.

Certain genetic syndromes can be associated with various immunodeficiency states. Some of the more commonly encountered syndromes associated with primary immunodeficiency include 22q11 deletion (DiGeorge syndrome), CHARGE syndrome, ataxia telangectasia and trisomy 21.

WARNING SIGNS OF PRIMARY IMMUNODEFICIENCY

To assist primary care physicians in identifying patients at risk for primary immunodeficiency, the Jeffrey Modell Foundation has published “10 warning signs of primary immunodeficiency” (Figure 2). Patients with ≥2 warning signs should be evaluated. Positive family history, use of intravenous antibiotics for sepsis, and failure to thrive have been identified as the strongest predictive factors (25). While these criteria serve as a good starting point, they will not identify all patients, particularly those with subtle but important innate and combined defects. In one study, 20% of patients presented with autoimmune phenomena and would not have been diagnosed using the Modell criteria.

Figure 2).

The Jeffrey Modell Foundation has developed 10 warning signs of primary immunodeficiency to help physicians and health care workers identify patients who may have underlying primary immunodeficiency

There is considerable delay in establishing diagnosis of primary immunodeficiency. The national registry in the United Kingdom (UK) reported a median diagnostic lag of five years between onset of symptoms and diagnosis for patients with CVID (26). For patients with SCID, the mean age at diagnosis was 97 days, which is beyond the optimal age for HSCT (<90 days) (27,28). Between onset of symptoms and initiation of treatment, the patient remains susceptible to infections with consequent irreversible end organ damage.

Primary immunodeficiency diseases present in a variety of ways and at any age; from IgA deficiency, in which patients are often asymptomatic (6), to SCID, to fatal without prompt medical intervention. Infections with common pathogens may be the only sign of an underlying primary immunodeficiency. Patients may also, however, present with malignancy, particularly lymphoproliferative diseases and lymphomas, or with autoimmunity. Clinicians must maintain a strong index of suspicion for primary immunodeficiency in any patient with recurrent, difficult to treat or unusual infections, autoimmunity and malignancy.

INVESTIGATIONS

The primary care provider plays a key role in establishing the diagnosis of primary immunodeficiency in several ways. Radiographic and/or microbiological documentation of infections are important to confirm clinically suspected infection. Direct pathogen detection using culture or polymerase chain reaction (PCR) is necessary in patients with primary immunodeficiency because some individuals are unable to mount an appropriate antibody response.

Immunologists use quantitative and qualitative tests to examine different aspects of the immune system. Valuable information about immune function can be garnered from tests that are available at most centres. First-line tests in the evaluation of a patient with suspected immunodeficiency include complete blood count (CBC), measurement of immunoglobulin levels (IgG, IgA, IgM and IgE), and response to vaccines such as tetanus, diphtheria and pneumococcus. Urinalysis, serum albumin and total protein are also important investigations in assessing for secondary immunodeficiency that could present with hypogammaglobulinemia. Abnormalities in blood count including neutropenia, lymphopenia or cytopenias involving other cell lines could be signs of underlying immunodeficiency. Low immunoglobulin levels or poor vaccine response may be observed in humoral or B cell defects. Given the major role that T cells play in the activation of B cells, hypogammaglobulinemia and impaired vaccine response are often detected in T cell defects.

The above tests may be normal in affected patients; therefore, consultation with a clinical immunologist is appropriate if there is a suspicion of primary immunodeficiency. Other, more specialized tests that may be ordered include flow cytometry to evaluate lymphocyte subsets, T cell receptor diversity, lymphocyte proliferation studies to assess function, complement levels and function and neutrophil oxidative burst index. Genetic testing can identify underlying molecular defects and help direct treatment including gene therapy. Laboratory investigations and the number of known genetic defects are continually expanding, yet primary immunodeficiency remains underdiagnosed.

Although consultation with a clinical immunologist is not available in every centre, groups such as Immunodeficiency Canada (network@immunodeficiency.ca) and the Jeffrey Modell Foundation (www.info4pi.org) can assist in identifying resources to connect physicians appropriately.

MANAGEMENT

Management of primary immunodeficiency is individualized to patients’ underlying diagnosis and clinical conditions. Treatment options for primary immunodeficiency include supportive treatment (antimicrobial prophylaxis, immunization and replacement Igs) and curative treatment (HSCT and gene therapy). Antimicrobial prophylaxis is based on the underlying immune defect and predicted pathogen susceptibilities, as well as a patient’s history of infections. These may include antibiotics, antifungal or antiviral therapies. Vaccination plays an important role in protecting immunocompromised patients; however, live viral and bacterial vaccines are contra-indicated in primary immunodeficiency states associated with antibody and T cell defects (29). An immunologist can provide direction for vaccination of patients with particular immune defects.

Caution must also be exercised in using live vaccines for family members and close contacts of patients because viral shedding can occur in healthy hosts who may be dangerous for immunocompromised patients. Family members should be encouraged to receive other routine immunizations, including yearly influenza vaccines. Replacement Ig can be administered either intravenously or subcutaneously. Prompt HSCT is life-saving for children with SCID, combined immunodeficiency as well as specific innate defects. Gene therapy currently has limited clinical applications, but has significant potential for future use (30).

Patients with primary immunodeficiency are at risk for several comorbidities and require monitoring for respiratory complications, autoimmune disease and malignancy. Respiratory complications have been most common: in one cohort, 18.43% of patients had bronchiectasis and 6.9% had asthma (13). In patients with CVID, Chapel et al (26) reported complications such as auto-immune disease, including cytopenias, hypothyroidism and diabetes in a large cohort of patients. Furthermore, studies suggest an increased risk for malignancy, particularly lymphoma (13,26).

CONCLUSIONS

Primary immunodeficiencies can be subtle and vary in their presentation, involving recurrent or unusual infections, malignancies or autoimmune phenomena. Primary care providers are the first to assess and treat these patients. Documentation of infections through imaging and microbial evidence is essential in building an index of suspicion. When primary immunodeficiency is suspected, basic blood work (CBC, immunoglobulin levels and documenting response to vaccines) is often helpful. A clinical immunologist can advise on further diagnostic tests and management of these patients.

Ongoing research describing new primary immunodeficiencies and better characterizing those already described will optimize diagnosis and management of these conditions. Collaborative patient care among health care providers can save patient lives and improve long-term outcomes.

Table 1.

Key infections and investigations in primary immunodeficiencies

Category	Principle infectious presentations	Key investigations
Humoral (defects primarily in B cells and antibody production)	Encapsulated bacteria, sino-oto-pulmonary infections	IgG, A, M and E levels
		Antibody response to vaccines
Combined (defects in T and B cells)*	Opportunistic infections with bacteria, viruses and fungi	CBC (lymphopenia)
		lymphocyte subsets (flow cytometry)
		lymphocyte stimulation tests
		T cell receptor diversity
		Antibody response to vaccines
Innate (including defects in phagocytes, pattern recognition receptors and complement activation)	Pyogenic infections	Neutrophil oxidative burst index
	Absence or mild signs of inflammation	Assessing classical and alternative complement patheways
	Neiserria infections

^*B cells require interaction with T cells to generate a normal response. As such, defects in T cell function also result in humoral/antibody dysfunction. CBC Complete blood count; Ig Immunoglobulin