Pediatric Severe Combined Immunodeficiency Treatment & Management

Drug therapy is not a major part of treatment of the primary disease. Surgical intervention is customarily not indicated for severe combined immunodeficiency (SCID) and also is not part of the primary treatment.

Conventional care for any patient with SCID includes isolation to avoid infection and meticulous skin and mucosal hygienic care while the patient is awaiting stem cell reconstitution. Parenteral nutrition is customarily provided to children with diarrhea and failure to thrive. Blood product transfusions must be lymphocyte-depleted and irradiated to prevent transfusion-associated graft-versus-host disease (GVHD).

Signs of sepsis and pulmonary infections may be subtle; fever mandates a detailed search for infectious agents. Empiric broad-spectrum antibiotics should be administered parenterally during the wait for the results of cultures and body fluid analysis. Consider prophylactic treatment with nystatin to prevent mucocutaneous candidiasis.

SCID is a pediatric emergency and must be addressed expeditiously. Intravenous immunoglobulin (IVIg) should be administered promptly, and evaluation for bone marrow transplantation (BMT) should be started. Patients with SCID who are treated with BMT before age 3.5 months have better survival rates. BMT is the primary treatment of choice for most types of SCID when an appropriate donor is found. Pretreatment with ablative chemotherapy is controversial. If B cells do not engraft, monthly IVIg replacement therapy may be required.

Administration of nonirradiated blood products or live-virus vaccines (especially polio or bacille Calmette-Guérin [BCG]) to a patient suspected of having SCID or undergoing a workup for SCID is an error that may prove dangerous if the patient turns out to have SCID. These children can develop disease from attenuated viruses and may even die after exposure to these vaccines.

Because T cells are absent, dysfunctional, or both, administer P jiroveci (carinii) pneumonia (PCP) prophylaxis to all patients until T-cell function is restored by means of BMT or other therapy. Trimethoprim-sulfamethoxazole is the drug of choice and can be administered in a patient who is older than 2 months or in whom neonatal jaundice is no longer a concern.

In individual cases, prophylaxis with antiviral agents (eg, acyclovir) or antibiotics also may be appropriate. After exposure to varicella zoster virus (VZV), prophylaxis with varicella zoster immune globulin (VZIG) should be administered within 48 hours, if possible; VZIG may be efficacious up to 96 hours after exposure. Beyond that interval, acyclovir has been administered and may prevent or modify the severity of VZV infection.

The consensus among clinical immunologists is that an IVIg dose of 400-600 mg/kg each month or a dose that maintains trough serum immunoglobulin (Ig) G levels above 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia and meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy.

Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 weeks) of smaller doses may maintain the serum level in the reference range.

The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

Numerous IVIg preparations are available. ^{[38, 39, 40, 41]} For replacement therapy in patients with primary immune deficiency, all brands of IVIg are probably equivalent, though viral inactivation processes differ (eg, solvent detergent vs pasteurization and ready-to-use liquid vs lyophilized powder requiring reconstitution). Additional knowledge of IgA content of a particular brand may be necessary depending on the particular patient. The choice of brands may be dependent on the hospital or home care formulary and the local availability and cost. The Immune Deficiency Foundation provides a useful resource that describes the characteristics of immunoglobulin products.

Monitoring liver and renal function test results periodically (approximately 3-4 times a year) is also recommended. The US Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, those older than 65 years) and those who use nephrotoxic drugs, the recommended doses should not be exceeded and the infusion rates and concentrations should be at the minimum practicable levels.

Initial IVIg treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions at this point is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may have to be reduced and the dose halved (ie, 200-300 mg/kg), with the remainder of the dose given the next day. Treatment should not be discontinued. Once normal serum IgG levels are reached, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIg products, adverse effects are greatly reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with profound immunodeficiency or patients with active infections have more severe reactions.

Anticomplementary activity of IgG aggregates in the IVIg and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause.

Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg orally every 6-8 hours), acetaminophen (15 mg/kg/dose orally), diphenhydramine (1 mg/kg/dose orally), or hydrocortisone (6 mg/kg/dose, not to exceed 100 mg) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIg treatment. Reports suggest that IVIg products using sucrose as a stabilizer may be associated with a greater risk of this complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIg should not exceed 3 mg sucrose/kg/min.

Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring blood urea nitrogen (BUN) and creatinine levels before starting the treatment and before each infusion is necessary. If renal function deteriorates, the product should be discontinued.

IgE antibodies to IgA have been reported to cause severe transfusion reactions in IgA-deficient patients. A few reports exist of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. In actual experience, however, this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency.

Caution should be exercised in those patients with IgA deficiency (< 7 mg/dL) who need IVIg because of IgG subclass deficiencies. IVIg preparations with very low concentrations of contaminating IgA are advised.

Although treatment of the acute infectious process is critical, the only cure for almost all forms of SCID is bone marrow transplantation or other stem cell reconstitution. ^{[42, 43]} This approach is successful if the disease is diagnosed within the first 3 months of life. Early transplantation before 3.5 months is associated with better overall survival. ^[44] With early transplantation and aggressive monitoring and treatment of infections, survival rates may be as high as 97%. No live vaccines should be administered before BMT.

The optimal bone marrow donor is a human leukocyte antigen (HLA)–matched sibling or parent if consanguinity is present. Haploidentical parent donors, HLA-matched unrelated donors, and HLA 5/6 allele–matched unrelated donors have also been successful; however, the risk for graft failure, GVHD, and inadequate B-cell function is higher. Neither pretransplant chemoablation nor GVHD prophylaxis is required for successful engraftment with an identical donor; however, the former is necessary with nonidentical HLA-matched donors.

Pretransplant evaluation routinely includes testing of the recipient and the donor for infectious agents, such as cytomegalovirus (CMV), HIV, and hepatitis viruses. After BMT, medication therapy to prevent GVHD must be maintained. ^[45] All blood products must receive 25-Gy irradiation to prevent fatal GVHD.

BMT is the primary therapy for purine nucleotide phosphorylase (PNP) deficiency and bare lymphocyte syndrome when an appropriate donor is available. It is also the primary treatment for Omenn syndrome; however, pretreatment ablative chemotherapy is necessary because of maternal cell engraftment.

In the largest series of patients with SCID, BMT was successful in 80% of patients. T-cell function has been adequate in approximately 90% of patients who survive 6 months after transplantation, and B-cell function has been adequate in 70% of these patients. Workup includes major histocompatibility complex (MHC) typing to identify a fully matched sibling, or, in the case of consanguinity, possibly a parent.

In utero BMT into the fetal peritoneal cavity is successful, with reconstitution of T-cells in X-linked SCID (XL-SCID) and in 1 case of due to interleukin (IL)-7 receptor α chain deficiency. Cord blood stem cell transplantation from related or unrelated donors is an option.

Enzyme replacement

The primary treatment for adenosine deaminase (ADA) deficiency is ongoing polyethylene glycol–conjugated ADA (PEG-ADA) replacement therapy. Patients need to have their immune function monitored and prophylaxis provided, depending on their immune status. Enzyme replacement therapy typically yields improvement in patients with ADA-deficient SCID, but not complete reconstitution of immune function.

The bovine-derived ADA replacement enzyme pegademase (Adagen) was approved by the FDA in 1990. However, pegademase was discontinued in 2019 from the market owing to a permanent shortage of the active ingredient. In October 2018, the FDA approved elapegademase (Revcovi), a recombinant adenosine deaminase based on bovine amino acid sequence, for treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in adults and children. Enzyme replacement helps prevent potentially serious, life-threatening infections in this patient population.

Interleukin replacement

Intravenous IL-2 replacement is the primary therapy, and a BMT is an alternative if an appropriate donor is available.

Cyclosporine and interferon

Specific therapy for dermatitis and eosinophilia in severe combined immunodeficiency is immunosuppression with cyclosporine and possible addition of interferon (IFN)-γ. These modalities have been used to treat Omenn syndrome but theoretically should be effective in treating maternal or transfusion-induced GVHD.

Gene therapy is a viable option for patients with XL-SCID or ADA-deficient SCID who have no HLA-identical sibling. Treatment is optimally provided early enough to reduce the risks of failed gene transduction and leukemia. Murine studies suggest that gene therapy may work for JAK3 and RAG2 mutations as well. Several gene therapy clinical trials have been utilized, including a CD34+ cells transduced with retroviral vector-based gene therapy (Strimvelis; Orchard Therapeutics) that was approved in Europe in 2016 and is currently in phase 3 trials in the US for ADA-SCID. ^{[46, 47, 48, 49]}

An investigational ex vivo autologous gene therapy, simoladagene autotemcel (OTL-101; Orchard Therapeutics), is in phase 3 clinical trials as of May 2020 for ADA-SCID in the US. ^[50]   

A clinical trial of gene therapy for XL-SCID found that in cases of successful gene insertion, functional T cells developed within 18 weeks and were detectable as long as 5 years later. ^[51] Adverse events have included failure of gene insertion and acute lymphoblastic leukemia due to aberrant insertion within the LMO-2 gene, both of which occurred in older patients. Other studies have confirmed the risk for leukemia in patients who underwent gene therapy and attempts are underway to minimize it.

ADA deficiency was the first form of SCID for which gene therapy was attempted, and efficacy has been reported; it remains in the experimental phase. Although some long-term benefits of gene therapy have been reported for ADA-deficient patients with SCID, complications have arisen in some cases of gene therapy in patients with common γ chain deficiency.

The development of leukemia is a complication of gene therapy and appears to be related to the site of insertion of the transgene. Some suggest that better outcomes may occur with different vectors or more specific insertion sites. ^[52] A greater risk of cognitive abnormalities and emotional and behavioral problems has also been reported in patients with ADA-deficient SCID who received long-term enzyme replacement therapy. ^[53]

In general, no dietary limitations are necessary. However, the presence of chronic diarrhea and failure to thrive requires consultation with gastroenterology and nutrition.

Parenteral or enteral nutritional supplementation is often necessary to ensure adequate intake of calories, nutrients, and vitamins. Undernutrition decreases the success rate for stem cell reconstitution and increases the risk of opportunistic infections.

In general, activity is limited only by any infections that may develop secondary to the immune deficiency; the disease itself does not require limitation of physical activity.

Infants with any form of SCID are isolated to decrease the risk of common viral and bacterial infections. Avoidance of crowds in such places as stores, doctors’ offices, and hospitals is important, along with customary hygiene practices, like strict handwashing. The earlier practice of putting patients in reverse isolation (ie, in a “bubble”) with such precautions as special diets is no longer advocated.

SCID is under consideration for population-based newborn screening. ^[54] Screening tests do not prevent SCID but can identify infants early, before complications develop, thereby permitting earlier initiation of treatment. Diagnosis at birth may allow for better protection of babies with SCID from infection and improve transplantation outcome, significantly, improving the outcome in this otherwise potentially devastating condition. ^[55]

Newborn screening to identify SCID is currently performed in several American states using polymerase chain reaction (PCR) of DNA from universally collected, dried blood spots. ^[56]

Some states now screen all neonates for the most common forms of SCID by identifying T-cell receptor excision circles (TRECs). TRECs are a normal byproduct of T-cell receptor rearrangement. They can be detected in a newborn dried blood spot by using a unique molecular assay as a primary screen. In healthy neonates, they are made in large numbers, whereas in infants with SCID, they are barely detectable.

The pronounced deficiency of TRECs in patients with SCID makes identification of TRECs a reasonable screening test for the disease. Ideally, such screening will allow diagnosis and BMT before the infants become ill, thereby greatly increasing their chance of survival. ^{[57, 58]}

Microarray technology has also been proposed as a screening tool to detect the most common genetic defects leading to SCID. ^{[58, 52]} A combination of these therapies may be the eventual solution to the dilemma of screening for SCID.

Genetic counseling is necessary. If the family wishes to have other children, suggest that they obtain prenatal testing (eg, chorionic villus sampling) if the genetic defect is known.

Management of SCID required the participation of a number of different specialists, and coordinating their efforts can be challenging.

The need for excellent laboratory and radiology support mandates hospitalization in tertiary pediatric medical centers. Laboratory studies for stem cell reconstitution must be initiated promptly with the BMT team. In the meantime, gastroenterology and nutrition consultations provide important support.

As with any primary immunodeficiency disease, subtle signs of infection, morbidity/mortality from common infections, and the need to offer stem cell transplantation reinforces the importance of frequent monitoring and management by a clinical immunologist.

Consultation with an internal medicine specialist and an infectious disease specialist is important in the management and prevention of infection.

BMT should be coordinated between immunology/hematology and the BMT team. Admit the patient to an immunology/hematology clinic for IVIg therapy, IL-2 infusion, or PEG-ADA therapy, as necessary.

Ensure regular follow-up visits to monitor the immune system, with specialist physicians monitoring the SCID patient. Isolation to avoid transmission of infection is required. Usually, contacts are restricted to immediate family members and friends whose risks for infection can be monitored. Visits to doctors’ offices and hospitals must be orchestrated carefully to avoid exposure to infection.

Although allogeneic hematopoietic stem cell transplantation (HCST) is curative for SCID, the long-term outcome in a 90-patient cohort followed for 2-34 years showed that almost half experienced 1 or more significant clinical events, including persistent chronic GVHD, autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, and a requirement for nutritional support. ^[59] These late-onset complications suggest the need for prevention and careful follow-up.