Consider increasing Ig therapy for breakthrough infections

For many people with primary immunodeficiency (PI), immunoglobulin (Ig) replacement therapy is the standard treatment. Ig replacement provides patients with the working antibodies they can’t produce. But what happens when a patient receives the Ig replacement therapy and continues to have breakthrough infections or debilitating fatigue? It may be time to discuss increasing the dose of Ig replacement therapy to achieve better health.

Ig replacement therapy is not a one-size-fits-all when it comes to dosage, administration, and Ig brand. Every person is unique, based on diagnosis and symptoms, and therefore, the amount of Ig required for one person with PI won’t necessarily work for another person with PI.

In order to learn how to proceed with Ig replacement therapy, clinicians run tests to help determine how the PI is affecting a patient. They test patient Ig, or antibody, levels, and how well their B cells function, because B cells make the Ig. Thus, clinicians are exploring both quantitative and qualitative aspects of the immune system. Some patients have low Ig and chronic infections, and others have what are considered “normal” levels of Ig, with chronic infections. Still other patients have low Ig levels but no infections.

“Before the administration begins, there is the decision as to whether or not Ig is right for them in the first place,” said Dr. Laura Youngblood, Immune Deficiency Foundation (IDF) Nurse Advisory Committee (NAC) member and lead nurse practitioner in immune dysregulation and bone marrow transplant at Children’s Healthcare of Atlanta (CHOA).

An average starting dose of Ig therapy is between 400 and 600 mg/kg of body weight. Once the treatment starts, clinicians measure a patient’s IgG trough level to help them determine if the dose needs to be adjusted. A trough level is the lowest amount of IgG in a person’s body at the end of their monthly intravenous immunoglobulin (IVIG) treatment or at the end of their weekly or bi-weekly treatment with subcutaneous immunoglobulin (SCIG).

Youngblood said each patient’s trough level is individual, with most patients remaining healthy with at least a 600 mg/dL trough level. However, others may require a trough level of between 800 and 1,000 mg/dL if they are about to undergo a bone marrow transplant or they are struggling with lung disease, for example.

“It varies a lot depending on the circumstances,” said Youngblood. “For the PI population, I think over 600 mg/dL at a minimum makes more sense for infection prevention. Yes, you want to treat the low IgG and get caught up to help stop current infections, but you also want to prevent future breakthrough infections as much as possible.

“I would love for the guideline to be 700 to 1,000 mg/dL. I think that we would see a lot fewer breakthrough infections and, from my perspective, as a pediatric nurse, if they are age 3 or 4 and they are having recurrent breakthrough pneumonias, that’s a big deal because you could be looking at bronchiectasis later in life.”

One-off infections like ear infections and colds aren’t unusual while on Ig replacement therapy, but when patients have a lingering cough and congestion, then an increase in Ig therapy should be considered, said Youngblood.

“That’s one thing that tells me, OK, we’re not treating this well enough. If you have this chronic wet cough or this chronic sinus drainage, then we need to do better,” said Youngblood.

“Most people, if they are in the right spot, feel really good after their infusions. And so that’s what I’m always going for. We might not get it perfect, but if you’re coming back every month saying I’m still stuffy—and sometimes they don’t even complain—but I hear that wet cough, I feel like we’re not quite there yet. You should feel good. You should have energy.”

Studies support that an increase in Ig dosage leads to better health outcomes for PI patients.

According to a 2024 journal article that reviews dosing strategies for Ig replacement therapy, while a trough level of 500 mg/dL provides benefits to patients with PI, higher trough levels can be particularly important for those with additional chronic health issues.

“In recent years, clinical monitoring of patients with PIDs has shown that IgG trough levels of 7–10 g/l (or 700 to 1,0000 mg/dL) are more effective in the prevention of infections, particularly pneumonia, and thus targeting this higher threshold should be considered in patients with comorbidities such as chronic lung diseases,” reports the article.

“As the protective threshold varies between individual patients, treatment should be individualized to allow for appropriate dosing and infusion intervals to achieve optimal IgG trough levels.”

One meta-analysis of studies focused on PI diagnoses associated with low levels of antibodies, such as common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA), found that pneumonia incidence decreased by 27% with each increase of 100 mg/dL in trough IgG. Furthermore, patients with a trough maintenance of 500 mg/dL had a five-fold increase in pneumonia as compared to those with a trough maintenance of 1,000 mg/dL.

A 2025 study examined the correlation of IgG levels and frequency of infections in 75 antibody-deficient patients, most of whom had PIs, including CVID, XLA, STAT-1 gain-of-function (GOF) mutation, autoimmune lymphoproliferative syndrome (ALPS), and specific antibody deficiency (SAD). All were treated with Ig therapy. The patients with steady-state IgG levels in the range of 800 to 900 mg/dL had an average of three to four infections a year, whereas patients with steady-state IgG levels between 606 and 635 mg/dL had six infections per year.

“These results indicate the optimal IgG level for treatment should change based on diagnosis, but likely begins at least 800 mg/dL,” concluded the study.

Youngblood encourages patients and/or caretakers to keep a health journal to provide long-term overviews of their breakthrough infections and their frequency. Patients may also record fatigue levels throughout each month, another indicator that the Ig may need to be increased.

“I think it’s good for them to know their own limits because everybody is going to be different, and it’s not going to be something that we can predict necessarily. It’s a fluid process and things can change over the years. For example, a person might get a particularly bad infection, and subsequently need their dosing or baseline trough level Ig bumped up to a higher level to maintain health,” said Youngblood.

“Patients don’t need to endure ongoing symptoms. By keeping track of their levels, dosing, and response, they can self-advocate and present this to their physician to discuss if an increase in Ig therapy is appropriate.”

Though research shows that an increase in Ig replacement therapy has benefits for patients, simply obtaining the treatment to start with can be difficult. Accessing Ig replacement therapy is becoming more challenging, said Youngblood, because most health insurance companies require additional documentation before they approve the treatment.

“These days, in many of the cases where patients require Ig, we need to write letters of medical necessity. With private insurance, we frequently get denials and must provide more paperwork in medical support,” explained Youngblood.

If the letters of medical necessity are not successful, though, doctors will discuss the issue with a representative from the health insurance company in a peer-to-peer meeting.

“The longer that treatment is delayed, however, the more likely that insurance companies may end up paying for a hospitalization or additional treatments, which can be much more expensive in the long run, so it’s counterintuitive," said Youngblood.