Some with PI explore off-label immunoglobulin uses

Immunoglobulin (Ig) replacement therapy administered via infusion is a common treatment for primary immunodeficiency (PI), but some people use Ig in a variety of other ways: in a nebulizer, as a nasal spray, eye drops, or mouthwash, or as oral medication.

The medical community considers these uses “off-label,” which means the Food and Drug Administration (FDA) has not approved Ig products to be administered in these ways. However, off-label use of medications is legal and, sometimes, medically necessary. Patients report, and studies show, that using Ig to treat or prevent infection in these different ways can be effective.

Seattle Children’s Hospital and Research Institute immunologist and Medical Advisory Committee (MAC) member Dr. Hans Ochs said the topic of using Ig off-label is under-researched. His personal experience is that PI patients take advantage of Ig in many ways to bolster their health, often sharing anecdotal success with each other.

“Many of my patients on self-infusion of IgG preparations use leftovers to prevent [or] treat conjunctivitis and sinusitis, and a few use it in a nebulizer to provide the upper airways with antibodies,” said Ochs. “A patient may be wanting to try it, and patients talk to each other about it.”

Ochs doesn’t write prescriptions to use Ig for these applications; he simply has discussions with his patients. “I’m not telling them to do it. I just tell them that some patients may put it in a nebulizer or spray it into their nose. They try it and many like it,” said Ochs.

The most-studied off-label uses of Ig include as a nebulizer for upper respiratory infections, taken orally for diarrhea control, and as a mouthwash to treat thrush.

Nebulizing Ig

Several studies have explored both the possibility and success of using Ig in a nebulizer to resolve an infection, and one company is actively developing a nebulizer product.

One study found that not only was it feasible to administer Ig into the lungs of primates and mice using a nebulized liquid formulation but that the Ig prevented acute respiratory infection.

Dr. Nicholas Brodszki, a Swedish pediatric immunologist and PI expert who specializes in PI treatment, published a paper describing how inhaled nebulized Ig reduced upper airway infections. Three brothers with antibody deficiency who were on traditional Ig replacement therapy and still had recurrent lung infections had a significant decrease in lung infections when they inhaled nebulized Ig twice a day.

CSL Behring is conducting Phase II clinical trials for a 10% IgG solution designed to be administered via a nebulizer to patients with bronchiectasis who have lung infections. According to their site, “Studies indicate this approach provides topically active IgG directly to the lungs, remains stable during nebulization, and shows potential to reduce respiratory morbidity.”

Ingesting Ig

Another common, off-label use of Ig is for the treatment of chronic diarrhea in patients who have compromised immune systems.

One study in 2015 found evidence that, “IgGs are less susceptible to digestion throughout the gastrointestinal tract and therefore may provide for a distinctive nutritional requirement unique to patients with intestinal disorders and diseases which other dietary proteins cannot provide.” A 2016 study observed that, “Oral Ig may emerge as an important ‘add-on’ therapy for a variety of gastrointestinal and nutritional problems during the next decade” for children.

Evidence for the use of oral Ig to treat chronic norovirus in common variable immune deficiency (CVID) patients includes 2017 case studies, a 2022 case study and a patient account.

In the 2017 case study of two patients, researchers used Ig to control chronic diarrhea in CVID patients. An 8-year-old boy with CVID who had been treated with IVIG since age 1, suffered from chronic diarrhea and severe malnutrition and when treated with oral Ig for two months, the diarrhea stopped. A 36-year-old woman who had experienced persistent daily diarrhea and weight loss over a period of two years took oral Ig and, within six months of treatment, her diarrhea resolved.

In the 2022 case study, researchers found that none of the several antiviral medications used to help clear norovirus in a CVID patient worked, but when they gave the patient Ig through a nasal tube into the stomach, the patient cleared the infection.

Another example of how oral Ig improved gastrointestinal distress is patient Irene Chen’s account of her experiences with the treatment. In 2022, Chen, diagnosed with CVID, spent a month in hospital battling symptoms caused by norovirus including nausea, vomiting, and diarrhea. She lost 30% or her body weight and weighed only 80 pounds. With the help of oral immunoglobulin, and other supportive care measures, Chen improved. Her symptoms stopped and she gained weight.

Finally, a 2020 retrospective study that looked at 19 immunocompromised pediatric patients who were hospitalized with both acute and chronic diarrhea and who were given oral immunoglobulin for one to five days found that 18 of them had a 50% reduction in stool output within one to nine days.

Although the studies look promising, Ochs said oral Ig for gastrointestinal issues may not always be successful. Doctors can identify gastrointestinal viruses and bacteria, but the Ig they are administering to patients may not contain antibodies to the specific pathogen.

“I know of cases where gamma globulin was given and didn’t help,” said Ochs.

Other ways to use Ig

Ig can also be used as a mouthwash to resolve thrush infections in PI patients, according to a 2018 study. Thrush is a fungal infection of the mouth caused by Candida albicans. In the study, two 8-year-old pediatric patients, one with IL-12Rβ1 deficiency and the other with STAT1 gain of function (GOF), had severe and persistent drug-resistant thrush since infancy. Using the Ig mouthwash three times a day over the course of two weeks reduced mouth infection by 98% and 70%, respectively. Both children had complete clearance after the addition of antifungal treatments.

While not related to PI specifically, the FDA has given clearance for clinical trials to begin on using Ig for the treatment of dry eye because of its anti-inflammatory and immunomodulatory properties.

Off-label Ig considerations

All Ig products contain 95-98% pure IgG and provide a broad spectrum of antibodies, regardless of their Ig concentrations. Choosing to use Ig off-label is a health decision that should be made with your healthcare provider. Ochs said about a third of his patients use Ig off-label, especially those who self-infuse.

“I tell them ‘You may need more in the winter and less in the summer,’ so they squirrel it away sometimes in the summer, so they have more in the winter,” said Ochs.

The possibility of Ig being approved for any type of off-label use is slim, said Ochs, because Ig is in short supply and industry may not find it profitable. For the foreseeable future, using Ig for purposes other than infusing will continue to be off-label.