ASCENIV utilization in a primary immunodeficiency patient with recurrent viral infections

Abstract Primary immunodeficiency (PI) patients may still experience persistent viral and bacterial respiratory infections with ongoing treatments. We report a challenging case of a PI patient who experienced recurrent viral respiratory infections despite receiving standard immunoglobulin replacement therapy. The patient was subsequently managed with immune globulin intravenous, human-slra (ASCENIV™) that contains elevated antibodies against multiple respiratory pathogens. The patient demonstrated significant clinical improvement with a resolution of persistent and debilitating viral respiratory infections and associated sequela.


Report
Primary immunodeficiencies (PI) are a broad set of genetic disorders that result in deficits in cellular and/or humoral immune response. PI patients may experience recurrent severe bacterial and viral respiratory infections despite regular treatment with immunoglobulin replacement therapy with or without anti-infectives. PI patients are at high risk for development of pneumonia and acute hypoxemic respiratory failure [1].
We report a case of an 86-year-old male with a PI diagnosis of late-onset combined immune deficiency (LOCID) due to hypogammaglobulinemia in combination with impaired cellular immunity [2]. The patient's past medical history included multiple uncontrolled recurrent bacterial and viral respiratory tract infections, life-long allergies (e.g. allergic rhinitis, conjunctivitis, bilateral otitis, and pharyngitis), nummular eczema, contact dermatitis, moderate persistent allergic asthma, bronchiectasis, and a 40 pack-year former smoking history.
The patient presented for an allergy evaluation. Upon further assessment, an immune evaluation was conducted due to his history of recurrent infections. Analysis revealed normal total immunoglobulin G (IgG) at 824 mg/dL and normal isotype levels (IgG, IgM, IgA), but IgG2 & IgG3 subclass levels were below the reference range. Other humoral markers were also normal. Tetanus and diphtheria antibody titers were high, but the patient had protective titers for only 11 of 23 pneumococcal serotypes despite previous vaccination suggesting specific antibody deficiency. Markers of cellular immunity were also impaired as indicated by an absence of T-cell activation in response to all antigens by both a lymphocyte proliferation assay and T-cell function test (T Cell Fx TM -Complete, Eurofins Viracor). Mast cell markers for tryptase were normal, but histamine levels were elevated. IgE levels were also elevated and his skin test was positive for multiple allergens. Clinically, the patient had experienced approximately 7-8 recurrent upper respiratory infections (URIs) per year. Most previous URIs had resulted in bronchitis and, when untreated, progressed to pneumonia. Recurrent infections were of both bacterial and viral origin, including methicillin-sensitive and -resistant Staphylococcus aureus, Streptococcus pneumoniae, Serratia marcescens, Enterobacter sp., influenza Aand B, human metapneumovirus (hMPV), and human rhinovirus. The patient had required antibiotics, antivirals, and/or prednisone at least every other month and had developed a myopathy secondary to prolonged corticosteroid use. A timeline of the patient's clinical course beginning with his first consultation at our practice is illustrated in Figure 1. The patient was started on subcutaneous immunoglobulin replacement therapy (SCIG) at a dose of 229 mg/kg every two weeks and achieved desired IgG trough levels of approximately 1300 mg/dL. The patient reported some clinical improvement and there was no evidence of bacterial infections during the initial six months on SCIG.
At six months of treatment, the patient experienced both a cold and subsequent influenza infection that resulted in a three-day hospitalization during which he was treated with oseltamivir and prednisone. Pulmonary function recovery was slow and the patient continued on prolonged treatment for viral bronchitis. Further, the patient continued to experience intermittent exacerbations of asthma. A new trough IgG goal of 1400 mg/dL was set and the SCIG dose was increased to 286 mg/kg every two weeks. Over the next three months, despite the IG dose increase, the patient continued to experience breakthrough viral URIs and respiratory complications with evidence of continued bronchitis requiring treatment. Procalcitonin levels remained undetectable, suggesting the infectious cause was not bacterial. A new trough IgG goal of 1600 mg/dL was set and the SCIG dose was increased to 343 mg/kg every two weeks, consistent with requirements for bronchiectasis.
The patient's clinical status improved slightly on high dose SCIG with a decrease in URIs. The patient initiated strict self-quarantine and social distancing to reduce the risk of SARS-CoV-2 infection in early 2020 with continued high dose Ig replacement therapy and oseltamivir as needed for any symptoms of viral respiratory infection. The patient maintained an IgG trough >1600 mg/dL. In August 2020, he experienced a productive cough and fever with right lung pneumonia and was admitted to the hospital for presumed SARS-CoV-2 positive pneumonia where he was treated with remdesivir, dexamethasone, and SARS-CoV-2 hypergammaglobulin through a clinical research study. A subsequent SARS-CoV-2 test conducted two days after initial positive result was negative and he was released. Subsequent diagnostic and antibody testing for SARS-CoV-2 was negative although inconclusive given his PI.
High dose immunoglobulin (IG) supplementation diminished recurrent bacterial infections but did not provide sufficient protection against viral infections. The patient did well on oseltamivir as needed, but our practice was notified that the patient utilized a one-year supply within a few months and was unable to obtain further refills. As an alternative, amantadine was initiated for daily prophylaxis but the patient experienced a severe allergic reaction within days prompting discontinuation. Due to the limited antiviral treatment options, recurrent URIs and viral pneumonia, along with frequent asthma exacerbations, the patient was transitioned from SCIG to ASCENIV TM 10% 571 mg/kg IV every four weeks. ASCENIV TM (ADMA Biologics, Boca Raton, FL) is a commercially available immunoglobulin product that contains high neutralizing antibody titers against respiratory syncytial virus (RSV). Plasma donors are screened using a proprietary microneutralization assay that quantitatively measures anti-RSV neutralizing antibodies. This selection process results in high titer anti-RSV plasma which is then pooled with normal source plasma. An association has been demonstrated between this process and significantly elevated IgG titers against other common circulating respiratory viruses including influenza A and B, human metapneumovirus, parainfluenza, and seasonal coronaviruses [3]. ASCENIV TM is U.S. Food and Drug Administration (FDA)-approved for the treatment of PI in adults and adolescents, but both pre-clinical and clinical data exists supporting the prevention and treatment of infections from respiratory pathogens [4][5][6][7][8][9].
Following the initiation of ASCENIV TM , the patient demonstrated significant clinical improvement. The patient reported that persistent and disabling viral URIs have resolved with no further infections. The patient reports that his asthma is much better controlled, and he no longer requires systemic corticosteroids, nebulizer therapies, metered dose inhalers, or symptomatic treatment to control mucus or cough. These symptoms were probably triggered by the patient's persistent respiratory viral infections and resolved with successful management. ASCENIV TM has been well tolerated during approximately 2 years of follow-up.
Herein, we describe a patient who continued to suffer from chronic and persistent infections while receiving conventional IG replacement therapy and anti-infective therapies who was successfully treated and continues to be effectively managed with ASCENIV TM . This product may provide a substantial benefit in immunodeficient patients who continue to experience breakthrough infections despite standard IG replacement therapies or those highrisk patients that possess both humoral and cellular immunity defects.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
Gene Wetzstein is Head of Medical Affairs and Scientific Engagement at ADMA Biologics. The editorial assistance of Benjamin Greener was supported by funding from ADMA Biologics.