Systemic Ozone Therapy by Rectal Insufflation for IgA Deficiency: A Randomised Controlled Trial

Background: IgA deficiency and why ozone was investigated

Selective IgA deficiency is the most common primary immunodeficiency, and unlike some other antibody defects it has no replacement therapy. Because IgA is the dominant antibody in mucosal secretions - lining the gut and the respiratory tract - people with the deficiency are prone to recurrent bacterial respiratory infections, gastrointestinal parasitic infections such as giardiasis, and a high rate of allergic and autoimmune conditions. Management is otherwise limited to treating infections as they arise.

The researchers noted that recurrent infection and chronic inflammation tip the balance between free radical production and antioxidant defence towards oxidation, and that this pro-oxidant state itself worsens immune function. Ozone therapy acts as a hormetic stressor - a controlled, low-dose oxidative challenge that upregulates the body's own antioxidant systems - so they set out to test whether it could shift that balance in this patient group.

Study design: 40 patients, randomised, phase 2, open-label

This was a monocentric randomised controlled phase 2 clinical trial, registered as RPCEC 00000236 and approved by the ethics committee of the Roberto Rodriguez Fernandez Provincial General Teaching Hospital in Moron, Ciego de Avila Province, Cuba. Patients were recruited through the hospital's Immunology Service between January 2010 and September 2016.

Forty patients aged 5 to 50 years with complete or partial IgA deficiency were assigned by systematic random sampling to two groups of 20. There were no withdrawals. Both groups continued to receive specific treatment for any allergic or autoimmune condition they had.

The ozone group received two cycles of rectal insufflation, each cycle consisting of 20 sessions at five sessions per week, with a three-month interval between cycles - 40 doses in total. Doses were adjusted for age, ranging from 1.25 mg for the youngest children up to 8 mg for adults. Ozone was produced by an OZOMED plus generator.

The control group received Hebertrans transfer factor, one unit per square metre of body surface area given subcutaneously once weekly for 12 weeks. This is the standard treatment used for IgA deficiency in Cuba, chosen so that the comparison group received the best available product rather than a placebo.

Serum immunoglobulins, a panel of pro-oxidant and antioxidant biomarkers, and the frequency and severity of clinical symptoms were recorded at the start of treatment and one month after completion. Therapeutic response was classified in advance as complete, partial, stable disease or progressive disease.

Findings: immunoglobulins and redox balance

The two groups were comparable at baseline. Most patients were aged 5 to 10 years; 82.5% had a history of recurrent bacterial respiratory infections and 42.5% had giardiasis.

After two cycles of ozone therapy, the difference between groups was statistically significant for IgG (p = 0.000) and IgM (p = 0.033).

Both groups showed a pro-oxidant state at the outset, with advanced oxidation protein products (AOPP) and malondialdehyde (MDA) elevated above normal reference values. In the ozone group, AOPP fell (p = 0.003) and MDA fell (p = 0.001), reduced glutathione normalised (p = 0.032), and three antioxidant defence markers rose significantly: superoxide dismutase (p = 0.001), glutathione peroxidase (p = 0.012) and the ferric reducing ability of plasma (p = 0.001). Total peroxide levels did not change. None of these shifts were observed in the control group.

Complete therapeutic response was recorded in 85% of the ozone group (17 of 20) with the remaining 15% partial. In the control group, 45% (9 of 20) had a complete response, 35% partial, and 20% stable disease.

Safety and tolerability

Adverse events in the ozone group were mild and transient: bloating immediately after insufflation in two patients, and abdominal pain in one. In the control group, eight patients (40%) reported pain and redness at the injection site.

What the authors concluded

The authors conclude that rectal ozone insufflation is a suitable therapeutic option in the treatment of IgA deficiency because it produces antioxidant and immunomodulatory effects and is feasible, safe and minimally invasive.

Limitations of this study

The authors identify the single-centre design as a limitation, since it prevents the findings being generalised as guidance for other hospitals. Several further caveats are worth stating plainly.

The trial was open-label - neither patients nor assessors were blinded to which treatment they received - which leaves room for expectation to influence the reported clinical outcomes, although the biomarker results are less susceptible to this. The sample of 40 was small, and recruitment ran over more than six years at one hospital.

Importantly, the deficiency itself was not corrected. IgA levels were not reported to have normalised; the significant changes were in IgG, IgM and redox markers. The trial should be read as evidence about immune and antioxidant modulation, not as evidence that ozone resolves IgA deficiency.

The comparison was against an active treatment rather than a placebo, so the trial does not separate the effect of ozone from the effect of receiving 40 supervised sessions of any kind. There has been no independent replication outside Cuba.

This treatment was administered in a hospital immunology service under medical supervision, including in children, with doses calculated by age. IgA deficiency is a diagnosed primary immunodeficiency requiring specialist care, and any decision about complementary treatment should be made with the treating clinician.

Published in MEDICC Review under the Creative Commons Attribution (CC BY 4.0) licence.