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INTRODUCTION

Primary immunodeficiency (PID) encompasses a heterogeneous group of several hundred defects of immunity that result in poor or absent function of one or more immune system components.¹ Individuals with PID experience increased frequency and severity of infection, and potential complications such as autoimmunity, inflammation, and malignancy.^1,2 While some forms of PID are mostly fatal without treatment, appropriate management with immune globulin replacement, antibiotic prophylaxis, and immunization can help many patients achieve near normal life expectancy.^3,4 This offering provides an overview of common forms of PID, their recommended management, and considerations for pharmacist intervention and patient counseling to optimize care of patients with PID.

DISEASE BACKGROUND

Epidemiology

Although the various forms of PID are rare individually, the overall prevalence as a group is approximately 1 in 10,000 live births.⁵ Estimates based on data from 2001 through 2007 suggest that 6 million people worldwide may be living with PID, though far fewer than this number have been recorded in national registers.⁶ In the US, the estimated prevalence of PID ranges from 29.1 to 50.5 per 100,000 persons, and is approximately two-fold greater in White compared with Black or Hispanic persons.⁷ An analysis of US claims data found that persons with versus without PID were approximately twice as likely to be hospitalized, and experienced significantly longer hospital stays. This analysis also found an increase in prevalence throughout the study period, which may indicate trends in improved survival, increased awareness, or improvements in diagnosis and screening of PID.

Pathophysiology and Classification

Primary immunodeficiency is associated with genetic defects of immune system function.¹ This differs from secondary immunodeficiency, which is attributable to other causes such as HIV infection, malnutrition, hematologic malignancy, or some medications.⁸ Classification of PID considers whether the immune deficiency affects innate or adaptive immunity.^1,9 Innate immunity represents the first line of defense against pathogens, and involves mounting an inflammatory response with phagocytes (neutrophils and macrophages) and complement proteins. Adaptive immunity involves antibody production, with B cells producing antibodies and T cells mediating immune responses through killing of infected host cells and activation of other immune cells.

Disease Classification

The number of unique forms of PID exceeds 300, but several of these are more commonly encountered and thus will be the focus of this review.^6,10 These include agammaglobulinemia, hypogammaglobulinemia (including common variable immune deficiency [CVID]), severe combined immunodeficiency (SCID), selective IgA deficiency (SIGAD), Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD). These may be broadly categorized as B-cell disorders of antibody deficiency (agammaglobulinemia, hypogammaglobulinemia, and SIGAD), combined immunodeficiencies (WAS, SCID), and innate immunodeficiencies (CGD).¹ Forms of PID affecting B cells are most common, accounting for approximately 60% to 70% of all PID diagnoses.⁹ The most common forms of PID are described in more detail below.

Presentation

The hallmark manifestation of PID is frequent infection.⁴ However, the specific nature of infection and affected organ systems vary by the specific form of PID. Nonetheless, all forms share some features of presentation, typically related to infection. A list of 10 warning signs of PID in children and adults has been prepared to encourage early identification and diagnosis (TABLE 1).^1,11 Patients with 2 or more of any signs for their age group should be considered for referral to an allergist/immunologist.¹¹

Agammaglobulinemia

Agammaglobulinemia is a rare X-linked disease of adaptive immunity, with an estimated prevalence of 1 in 350,000 to 700,000.^1,12 Agammaglobulinemia is due to a mutation in the Bruton’s tyrosine kinase gene, which aids in production and maturation of B cells.¹ Because B cells differentiate into antibody-secreting plasma cells, which in turn produce immune globulins, agammaglobulinemia is characterized by reduced levels of B cells and their downstream products of immune globulins IgA, IgG, and IgM.

In addition to frequent infection in agammaglobulinemia, some of the more common signs identified in a US registry included otitis, pneumonia, sinusitis, diarrhea, conjunctivitis, and pyoderma and/or cellulitis.¹³ Physical findings may also reveal absent or diminished tonsils and adenoids.¹ Agammaglobulinemia is typically diagnosed at age 2.6 years in boys with a family history, and at age 5.4 years in those without a family history. The cornerstone of treatment is immune globulin replacement therapy, and most patients can lead a normal life without greatly reduced life expectancy.¹²

Hypogammaglobulinemia/Common Variable Immunodeficiency

Hypogammaglobulinemia is a nonspecific diagnosis of low antibody levels.⁹ The specific diagnosis of CVID represents an immune deficiency of 1 or more immune globulin isotypes, although a consensus definition does not exist.^4,9 Levels of B cells in patients with CVID are variable; approximately half of patients have normal levels.^9,14 CVID affects approximately 1 in 20,000 persons, and although it is predominantly recognized in adults at approximately 30 years of age, diagnosis may occur at any age.^9,15 Recurrent sinopulmonary infections are common in CVID; bronchiectasis is a common presentation, and may lead to chronic morbidity and mortality.¹ Patients with CVID may also experience complications that are autoimmune (20%), granulomatous (8%-22%), and gastrointestinal (GI, 20%-25%) in nature.⁴ Therapy of CVID involves immune globulin replacement therapy, and most patients can have near normal life expectancy, particularly with early diagnosis and treatment.¹⁰

Selective IgA Deficiency

SIGAD is a defect of adaptive immunity characterized by isolated deficiency of IgA with normal levels of IgG and IgM.⁹ Diagnosis is definitive in patients 4 years of age or older with a serum IgA concentration <7 mg/dL and normal levels of IgG and IgM. Selective IgA deficiency is one of the more common PIDs, affecting approximately 1 in every 300 to 700 White persons in the US.^4,9 It is also one of the less severe PIDs, as many patients may remain asymptomatic. When symptoms are present, these may include atopy, autoimmune disease, celiac disease, and malignancy. Sinopulmonary infection remains common in SIGAD as with other PIDs, but invasive infections are rare. While SIGAD is heritable, a thorough medication use history should be taken to rule out medication-induced causes (TABLE 2).^4,16-18 Cessation of the offending drug may reverse SIGAD. Management of SIGAD involves antimicrobial therapy and/or prophylaxis. Immune globulin replacement therapy in SIGAD is controversial, as most patients will exhibit no or little response. Patients with recurrent infection despite antimicrobial prophylaxis may benefit from immune globulin. Should IgG be used, the available formulation with the lowest IgA content should be selected to avoid anaphylaxis that may result from the presence of anti-IgA antibodies that complex with IgA in the preparation.⁴

Severe Combined Immunodeficiency

SCID is characterized by impaired or absent T-cell function with or without impaired function of B cells and natural killer cells.⁹ This functional absence of specific immunity places patients with SCID at extreme risk of infection. Suspicion of SCID constitutes a medical emergency because severe infection can occur at any time, and without treatment, often leads to death.^1,4,19 The incidence of SCID is estimated at 1 in 50,000 live births and is more common in males.¹⁹ The disease usually manifests within the first year of life, accompanied by chronic diarrhea, failure to thrive, and severe opportunistic infections (eg, Candida, Pneumocystis, and cytomegalovirus).⁹ Initial treatment of SCID involves immune globulin replacement and continuous prophylactic antibiotic therapy, but only hematopoietic stem cell transplantation (HSCT) may be curative. When human leukocyte antigen (HLA)-identical HSCT is performed early, long-term survival of patients with SCID may exceed 90%.²⁰

Wiskott-Aldrich Syndrome

WAS is a combined immune deficiency characterized by reduced T-cell number and function, and diminished natural killer cell activity.^4,9 The incidence of WAS in North America has been estimated at 1 in 250,000 males.^21,22 WAS is caused by a mutation in the WAS gene on the X chromosome that results in deficient production of the WAS protein, which is involved in cytoskeletal structure. Because of the X-linked nature, WAS almost exclusively affects males. The WAS protein is expressed in hematopoietic cells and its dysfunction causes altered structure and function of T cells, B cells, and natural killer cells. Presentation of WAS is often in the early months to years of life, but diagnosis may be delayed into adulthood.⁴ Common presentations involve thrombocytopenia, low platelet volume, bleeding, bruising, eczema, autoimmune disease, and malignancy.⁴ Replacement immune globulin therapy is indicated in patients with WAS, though only HSCT is potentially curative, with an 80% survival rate.^4,21,22 Without treatment, WAS may result in death due to overwhelming infection or hemorrhage, and the prognosis is especially poor when malignancy is present.²²

Chronic Granulomatous Disease

CGD is a PID of innate immunity caused by defects in phagocytosis.⁹ These genetic defects lead to loss or functional inactivation of the nicotinamide adenine dinucleotide phosphate (NADP) oxidase complex that produces microbicidal reactive oxygen species. Thus, neutrophils, monocytes, and macrophages lose their ability to destroy certain microorganisms, particularly bacteria and fungi that produce the catalase enzyme that inactivates hydrogen peroxide.^1,4 The incidence of CGD is approximately 1 in 200,000 births in the US. Males are most often affected because the X-linked form accounts for 70% of cases.⁴

CGD typically presents in infancy with granulomatous abscesses in the lungs, lymph nodes, skin, liver, and bones; GI symptoms may also be frequent. Common pathogens include Staphylococcus and Aspergillus; therefore, management of CGD involves lifelong antibacterial and antifungal prophylaxis and aggressive treatment of infection, generally with trimethoprim/sulfamethoxazole (TMP/SMX) and itraconazole.^23,24 Interferon gamma-1b may also be utilized in some centers and is approved by the FDA to reduce frequency and severity of infections in CGD.^23,25 Immune globulin replacement is not typically used in CGD. When possible, HSCT should be considered as a potentially curative therapy in CGD.^4,23 Untreated, annual mortality in CGD ranges from 2% to 5%, but patients may live to adulthood.²⁶

IMMUNE GLOBULIN THERAPY

The cornerstone of management for many patients with PID involves immune globulin replacement and prophylactic antimicrobial therapy.^3,27 Characteristics of immune globulin products differ in various ways related to their formulation and manufacturing processes, which should be considered when selecting the most appropriate product (TABLE 3).²⁸ Similarly, no consensus recommendations exist for antimicrobial prophylaxis in PID; thus, patient characteristics should be considered when determining an optimal regimen.

Manufacturing

Immune globulin is pooled serum immune globulin that is used to replace deficient antibodies in patients with PID.^28,29 Immune globulin products are prepared from donor plasma from approximately 3,000 to 10,000 healthy individuals. Their manufacturing processes are intended to purify IgG while maximizing product safety. The first step involves fractionation, which isolates IgG and reduces or eliminates IgA. Subsequent steps assist in removing impurities and inactivating viral contaminants, and include ion exchange chromatography, ultrafiltration, enzymatic digestion, incubation at low pH, and pasteurization. Despite these steps to mitigate risk of infection, all products contain warnings regarding viral infection and Creutzfeldt-Jakob disease.^30-47 Each aspect of manufacturing influences the characteristics of immune globulin products and their potential adverse effects, as described below.²⁸

Concentration and Volume

Immune globulin products may differ in concentration and require administration of different volume loads to provide the desired dose of IgG.²⁸ Thus, lower-concentration products may require delivery of higher volumes, which may be problematic in patients at risk of fluid overload (eg, heart failure, renal dysfunction). The overall volume administered is greater with intravenous immune globulin (IVIG) than with subcutaneous immune globulin (SCIG) as well, and SCIG may be preferred in volume-sensitive patients.⁴⁸ In addition, the required administration volume may influence the infusion time for IVIG products and the number of administrations for SCIG products.²⁸

Osmolarity

Immune globulin products range in osmolarity from approximately physiologic (280-296 mOsm/kg) to greater than 1000 mOsm/kg.^28,30-47 Administration of hyperosmolar preparations may cause fluid shifts, hemodynamic changes, and thromboembolism.⁴⁹ Sodium content contributes to osmolality, and therefore should also be present in lower amounts in patients at risk of thromboembolism.^28,49

Stabilizers

Most immune globulin preparations contain stabilizers to prevent aggregation of IgG molecules.²⁸ In previously available formulations, sugars accomplished this task, but these have largely been phased out because of reports of acute renal failure with sucrose-containing IVIG products.³ Currently available IVIG formulations have largely substituted amino acids for sugars. However, rare cases of hemolysis have been reported with use of amino acid–stabilized immune globulin products.⁵⁰ Additionally, some products still contain maltose, which may cause falsely elevated blood glucose readings by glucometers.³ All IVIG products contain a boxed warning regarding the risk of renal dysfunction and acute renal failure.^30-42

IgA Content

All immune globulin products contain variable amounts of IgA, even if in trace amounts.²⁸ The presence of IgA is particularly concerning in patients with SIGAD because they may develop anaphylaxis due to existing antibodies against IgA.⁴ Therefore, use of preparations low in IgA are recommended to reduce the risk of anaphylaxis in patients with SIGAD.

Preparation

Some immune globulin products are available in ready-to-use liquid preparations, while others are available in lyophilized form.^3,30-47 The latter require considerable time for reconstitution and sterile preparation, which may be a disadvantage from the perspective of a pharmacy department. Ready-to-use preparations also contribute to less waste when administrations are canceled or missed, whereas lyophilized products typically are prepared prior to patient arrival at a clinic and may need to be discarded. These considerations are particularly important in times of drug shortage and settings of medication stewardship.

Pharmacokinetics

The pharmacokinetic properties of immune globulin products differ most markedly between IV and subcutaneous (SC) preparations. The bioavailability of SCIG is approximately 65% to 70% that of IVIG, requiring a dose conversion for patients who transition to SCIG.⁵¹ Generally, dosage conversions involve multiplying the prior IVIG dose in grams by the conversion factor (typically between 1.3 to 1.4) and dividing by the number of weeks between IVIG doses to obtain the new weekly SCIG dose.^43-47

With IVIG, an initial high peak concentration occurs shortly after infusion.⁵¹ In contrast, SCIG must exit the SC space and enter the lymphatic system; thereafter, it is gradually released into the bloodstream. Thus, SCIG results in IgG concentrations that increase more gradually and demonstrate lower peaks. This translates to a potentially lower rate of adverse events with SCIG, which are often related to peak IgG concentration.⁵¹ Additionally, the less frequent administration of IVIG results in a greater degree of IgG metabolism between infusions and greater peak-to-trough variation. The more frequent dosing of SCIG provides more predictable and less variable steady-state concentrations.⁴⁹ Studies of SCIG measured steady-state serum IgG levels ranging from 900 to 1200 mg/dL, similar to normal physiologic concentrations (typically from 600-1500 mg/dL in healthy adults).^27,52 Results of a survey of patients with PID showed 68% of respondents reported either usually or sometimes experiencing “wearing off” of effects of IVIG before their next dose was due.⁵³ Overall, the more frequent dosing and reduced variability in serum IgG levels with SCIG may address some shortcomings of IVIG in appropriately selected patients.

Adverse Effects

Immune globulin therapy may cause a variety of adverse events that may be broadly categorized as immediate or delayed.^3,54 Immediate adverse effects may be mild (eg, flu-like syndrome, flushing, headache, chills), moderate (eg, vomiting, chest pain, severe headache), or severe (eg, hypertension, anaphylaxis, bronchospasm). These systemic adverse effects are more common with IVIG than with SCIG. Delayed adverse effects of immune globulin are rare but may be severe. These include thromboembolism, neurologic disorders (eg, aseptic meningitis, seizure), renal impairment, hematologic disorders (eg, hemolysis, neutropenia), and electrolyte disturbances.^3,54

Adverse reactions to immune globulin can be mitigated through several strategies.⁵⁴ Prior to infusion, premedication with antihistamines, corticosteroids, and/or acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful in patients with previous skin reactions or other mild-to-moderate immediate adverse reactions.⁴⁹ Mild analgesics can also be used to treat postinfusion headaches, which typically occur within 24 hours.⁵⁵ Prehydration with normal saline may also be utilized to minimize risk of renal impairment and thrombotic events. Management of immediate adverse effects may also require decreases in IV infusion rate or discontinuation.

SCIG is accepted to have lower risk of systemic adverse effects than IVIG; therefore, patients experiencing adverse effects with IVIG may be candidates for conversion.^3,48,56 Notably, premedication is generally not required with SCIG treatment. Nonetheless, SCIG is associated with local infusion site reactions in a majority of patients, though these are usually transient, mild or moderate in severity, and can be managed with warm/cold compress and NSAIDs.

SCIG may also have benefits in patients experiencing adverse effects on quality of life with IVIG.⁴⁸ For example, SCIG may be preferred in patients with difficulty accessing infusion sites, such as those who travel frequently or who reside in a remote location. Additionally, patients who desire more independence or greater portability of treatment, such as younger patients, may be candidates for SCIG. In addition to therapeutic goals, patients’ values and preferences should be discussed when selecting an appropriate route and setting of immune globulin administration.

Dosing and Monitoring

Starting doses of immune globulin for management of PID typically range from 400 to 600 mg/kg every 3 to 4 weeks for IV formulations and from 100 to 150 mg/kg every week for SC formulations.⁵⁷ However, individual package inserts should be consulted, as labeled dosage ranges differ. For example, some SCIG products may be administered as infrequently as every 3 to 4 weeks.⁴⁶

There is significant interpatient variability in the pharmacokinetics of IgG; thus, monitoring and dose titration are needed to achieve optimal response.^4,56,57 An initial target trough IgG level is typically above 500 mg/dL, which has been associated with lower infection risk and improved outcomes. However, some recommendations suggest targets above 800 mg/dL, and some clinicians target a serum IgG level that is 300 mg/dL above a patient’s pretreatment level.^3,56 Meta-analyses have demonstrated that increased trough levels correlate with decreased risk of infection, particularly pneumonia.^58-60 However, there is no single target IgG concentration that is guaranteed to be effective in all patients, highlighting the concept of a “biologic” trough specific to each patient’s needs based on the overall clinical picture.⁶¹

Typical intervals for monitoring trough IgG concentrations range between every 3 to 6 months in growing patients and every 6 to 12 months in adults.^4,56,57 Monitoring should also occur when clinically indicated, such as upon infection, with changes in body mass, and when clinical response is not optimal.

Weight-Based Dosing in Obesity

Much controversy exists regarding the optimal dosing weight for IVIG in obesity.⁶² Its low volume of distribution suggests that IVIG may undergo minimal distribution into adipose tissue. Therefore, patients who are overweight or obese may still experience benefit when IVIG is dosed based on ideal body weight (IBW) or adjusted body weight (AdjBW) rather than total body weight (TBW). Nonetheless, there remains no consensus on the optimal dosing weight. Studies have found no significant differences in clinical outcomes of infection rate with IBW- or AdjBW-based methods compared with TBW, despite one study finding that IBW-based dosing resulted in the best correlation between serum IgG concentration changes and IVIG dose.⁶³

Although there is no definitive evidence that clinical outcomes differ with use of different IgG dosing weights, this body of evidence does indicate the potential for cost savings.⁶² Stewardship efforts have documented reductions in IVIG usage and expenditures with IBW-based compared with TBW-based dosing.^64,65 Furthermore, some have proposed that obesity may be a risk factor for thrombosis in patients treated with IVIG; thus, receipt of lower IBW- or AdjBW-based doses may reduce the risk of this adverse event.⁶⁶ Regardless of the chosen dosing weight, therapeutic monitoring and dose modifications should still occur, which should ultimately lead to the desired serum IgG concentration and response for each patient.

Switching Between Immune Globulin Products

While immune globulin products are generally considered therapeutically equivalent from an efficacy standpoint, this is not necessarily the case with adverse events.⁵⁷ Therefore, adverse events may warrant product switches, as may restrictions on formulary agents, shortages, and patient preference. Clinicians should remain vigilant during product switches, as adverse reactions have been reported in approximately 15% to 18% of patients switching IVIG products.³

Switches from IVIG to SCIG should be guided by package inserts.^43-47 While SCIG is generally initiated 1 week after the previous receipt of IgG, there are product-specific differences in initial dosing. Some SCIG products may have different dose conversions based on previous IVIG dosages, while others may require an initial “ramp-up” period before reaching a target dose.⁴⁶ Prescribing information for the chosen product should always be consulted.

Before a product switch, serum IgG trough levels should always be measured.^43-47 Subsequently, differences between measured and target trough levels (or between trough levels during IVIG vs SCIG treatment) can be used to determine appropriate dose modifications, as delineated in SCIG package inserts. Although most studies of SCIG involved transitions from IVIG to SCIG, efficacy is believed to be similar when SCIG is initiated in patients naïve to immune globulin therapy.³

ANTIMICROBIAL PROPHYLAXIS

In addition to immune globulin therapy, patients with PID who experience recurrent infection may require prophylactic antibiotic therapy to reduce the frequency and severity of infection.^1,61 More frequent infection (>3 annually), severe breakthrough infection, or declining lung function in patients treated with immune globulin may warrant prophylaxis. Those with milder phenotypes or SIGAD with upper respiratory infection may be candidates for antibiotic prophylaxis alone.⁶¹ Patients with particular disorders may additionally benefit from antiviral and antifungal prophylaxis, such as patients with SCID who may receive prophylaxis against Pneumocystis jirovecii and fungal and viral pathogens. Although a survey of US immunologists who treat PID reported that 75% provide prophylactic antibiotics for at least some patients, there is no standardized approach.⁶⁷ Specific agents and dosages vary; thus, example first-line and alternative prophylactic agents are presented in TABLE 4.^4,61,68

IMMUNIZATIONS

Immunization is also important in patients with PID, but consideration should be given to whether the vaccine is safe for a particular patient and whether they will mount a sufficient response.⁶⁹ Killed, inactivated, or subcomponent vaccines may be given to patients with PID because their risk is no greater than in immunocompetent patients. In general, these vaccines should be given per routine schedules except in cases such as severe antibody deficiency or combined immunodeficiency with concomitant immunosuppressive therapy.⁴

The safety of live vaccines depends on the degree of immunodeficiency.⁶⁹ Live vaccines may result in disseminated disease and are contraindicated in many types of PID. Some examples of live vaccines include the live attenuated influenza vaccine (LAIV); measles, mumps, rubella (MMR); rotavirus; and varicella vaccines. All live vaccines are contraindicated in severe immunodeficiencies (eg, SCID) and partial combined immunodeficiencies (eg, WAS).⁶⁹ Patients with CGD can receive inactivated and most live vaccines, though live bacterial vaccines (eg, salmonella) should be avoided. Household contacts of immunodeficient patients should also receive inactivated vaccines, and most live vaccines (except for LAIV and oral polio) according to routine schedules. Overall, the variety of vaccines and forms of PID complicate the decision regarding safety and appropriateness of any given vaccine, and decisions on immunization should occur in consultation with a specialist.⁶⁹

Patients with PID treated with immune globulin should be adequately protected against organisms covered by most common vaccines received by the general population.^57,69 Therefore, most inactivated vaccines are unnecessary or ineffective in the setting of concomitant immune globulin therapy. An exception is inactivated influenza because of antigenic drift and the low likelihood that immune globulin preparations contain antibodies to circulating strains. Patients treated with immune globulin may also have neutralizing antibodies that may inactivate live vaccines including measles, rubella, and varicella.^57,69

HSCT AND GENE THERAPY

Immune reconstitution with HSCT and gene therapy may be curative options depending on the form of PID. Among the forms discussed here, HSCT is required in patients with SCID, and may be indicated in those with WAS and CGD.⁶⁸ It is often not indicated in agammaglobulinemia or CVID, as the risks of HSCT may outweigh the benefits in these forms. Patients who undergo HSCT should be monitored vigilantly for complications such as graft-versus-host disease, organ dysfunction, endocrinopathy, and secondary malignancy.²⁶

Gene therapy may be an option for patients without a matched donor, in whom outcomes of HSCT are considerably worse.⁵ Gene therapy involves harvesting a patient’s HSCTs, introducing a functional copy of a defective gene into the cells, and reintroducing the genetically corrected cells through autologous transplantation. This eliminates risks for serious complications seen with HSCT, such as graft-versus-host disease. To date, gene therapy has been utilized in SCID, WAS, and CGD.⁷⁰ While promising, gene therapy is still in its infancy and not generally available.⁴

ROLE OF THE PHARMACIST

Pharmacists play an important role in optimizing care of patients with PID. Patients exhibiting signs and symptoms of PID can be identified by pharmacists and referred to appropriate care for more timely diagnosis and management. Upon initiation of immune globulin therapy, pharmacists should discuss with patients and prescribers the goals and characteristics of each patient to ensure selection of an appropriate product and site of infusion (inpatient, outpatient, community, or home-based settings).³ For patients initiating prophylactic antimicrobial therapy, pharmacists should obtain a thorough medical history, including drug allergies, to ensure selection of an optimal regimen and any appropriate dose adjustments.

Pharmacists should also counsel patients with PID who are treated with immune globulin product regarding the symptoms of characteristic adverse reactions.²⁷ These include IVIG-related symptoms of renal dysfunction (weight gain, edema), thrombosis (pain, swelling, warmth in extremities), meningitis (neck stiffness, photophobia), and hypersensitivity (hives, urticaria, wheezing), and SCIG-related infusion site reactions. Patients should also be advised that therapy with any immune globulin may interfere with the response to live virus vaccines, and to notify the immunizing provider of any recent immune globulin therapy.

Additional counseling points are necessary in patients who self-administer SCIG. First, patients should be confirmed to be appropriate candidates for self-administration, and demonstrate understanding of the importance of adherence, product preparation, and identification of adverse events. Patients should be given clear instruction on their dose schedule and encouraged to keep an infusion log documenting infusion site, location, time, dose, and any adverse reactions.^43-47 Some SCIG products include peel-off vial labels to facilitate recording this information. Additional symptoms of adverse events unique to SCIG should be monitored, including swelling and infusion-site reactions. Furthermore, SC administration may result in leakage of fluid at the infusion site with some products; in this case, longer needles may be used.⁴⁶ Infusion sites should be rotated (typically the abdomen, outer thigh, upper arm, and buttock), and the volume and rate of infusion per site should be directed by each product’s prescribing information.^3,46

Nonpharmacologic interventions should also be discussed with patients with PID.⁷¹ The importance of overall hygiene, particularly handwashing, should be reinforced. Additionally, patients should avoid contact with persons who are ill or not immunized. Other lifestyle modifications should be discussed as warranted, such as with travel to certain locations that may require drinking only bottled water, avoiding fresh produce, or avoiding undercooked food.⁶⁸

CASE STUDY 1

A provider at your clinic requests your assistance in the care of AC, a 4-year-old boy with suspected CGD.⁷² AC presents with fever, swollen joints of the lower extremity, GI complaints, and poorly healed superficial scrapes with abscess formation on his feet and ankles. Pending laboratory confirmation of CGD diagnosis, the provider requests your input on pharmacologic management.

What signs and symptoms suggest CGD?

AC is male, which is consistent with the predominantly X-linked nature of CGD. He also exhibits a characteristic sign of granulomatous abscess of the skin. His GI symptoms are also consistent with CGD.

What is appropriate pharmacotherapy to reduce AC’s risk for infection?

Standard care for patients with CGD includes lifelong antibiotic and antifungal prophylaxis, typically with TMP/SMX and itraconazole. Barring any contraindications, these are appropriate options for AC. The potential for drug allergy should be investigated to rule out the risk for hypersensitivity and determine if alternative regimens are warranted. Additionally, any concomitant medications should be documented to identify potential interactions and direct any required dosage modifications. The use of interferon gamma-1b may be discussed as an option, but ultimately its use is varied, and this decision may depend on a risk-benefit determination that considers its adverse events and the degree of AC’s risk for recurrent infection. AC may receive most regularly scheduled vaccinations, except for live bacterial vaccines.⁶⁹

What counseling should be provided to AC and caregivers?

AC and his family should be counseled on the signs and symptoms of infection so that these may be rapidly identified and treated. Adverse effects of the chosen regimen should be discussed. These may include hematologic, GI, and dermatologic reactions with TMP/SMX; hepatic effects and drug interactions with itraconazole; and flu-like syndrome with interferon gamma-1b. Appropriate hygiene should be discussed to reduce risk of infection.

CASE STUDY 2

CH, a 31-year-old female, will begin immune globulin replacement therapy at your clinic. After several years of reliable follow-up for recurrent infection, she is diagnosed with CVID. Her past medical history includes obesity, type 2 diabetes (adequately managed with insulin), orthostatic hypotension, and history of venous thrombosis. CH’s physician requests your assistance in selecting an appropriate immune globulin product. Formulary options include Gammaplex, Octagam 5%, and Flebogamma 10% DIF.

What is an appropriate route of immune globulin administration?

CH is initiating therapy and does not yet have compelling reasons against IVIG. Moreover, given her reliable follow-up, there is no indication that CH lacks adequate access to care in a clinic setting. SCIG could be a reasonable initial product because its efficacy is not believed to differ when used as initial therapy versus when switching from IVIG; however, SCIG is not a preferred formulary option for CH. Additionally, CH has concomitant conditions that may increase risk of adverse events (eg, venous thrombosis) and may warrant ongoing monitoring during and after infusion. Therefore, an IVIG product may be most appropriate at this time.

What is an appropriate immune globulin product for CH?

CH has comorbidities that should be considered in selecting an IVIG product. First, the presence of type 2 diabetes and insulin therapy may warrant exclusion of products containing a maltose stabilizer, which could falsely elevate glucometer readings. Second, orthostatic hypotension may indicate the risk for hemodynamic changes due to fluid shifts; these might occur with products high in osmolality or sodium content. Likewise, high osmolality and sodium content may increase thromboembolism risk, and should be minimized due to CH’s history of venous thrombosis. IgA content is not a concern given CH does not have SIGAD. Among available products, Flebogamma 10% DIF offers the most physiologic osmolality, lowest sodium content, and no maltose, and therefore may be the most appropriate IVIG product.

What counseling should be provided to CH?

CH should be counseled on the typical adverse effects of IVIG therapy, including flu-like syndrome, chest pain, and headaches. She should be advised to report these during infusion to indicate a potential decrease in infusion rate or premedication with the next infusion, and she should also be counseled that acetaminophen or NSAIDs may help alleviate mild headache after this infusion. In addition, CH should be counseled regarding fluid intake to ensure adequate hydration prior to and after administration, particularly given her risk of orthostasis.

SUMMARY

Primary immunodeficiency may manifest in a variety of forms, which are most commonly encountered as agammaglobulinemia, hypogammaglobulinemia (CVID), SCID, SIGAD, WAS, and CGD. Most patients with PID experience increased frequency and severity of infection beginning at a young age, though some may be asymptomatic, and diagnosis may be delayed into adulthood. Many forms of PID may be managed with immune globulin replacement therapy, and some patients may additionally require antimicrobial prophylaxis. Immunization is also an important element to infection prevention using appropriate vaccines for the specific PID. Optimal management includes consideration of patient and product characteristics to determine an appropriate product, route, dose, and setting of immune globulin administration that minimizes infection and meets patients’ goals. Pharmacists are an integral part of the multidisciplinary care team in these decisions, and they can play an important role in counseling patients and monitoring immune globulin therapy, antimicrobial prophylaxis, and vaccination in patients with PID.

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