Immune testing and treatment: still an open debate

Sir, We read with interest the recent publications from Moffett and Shreeve (2015) and Sacks (2015) on a topic that generates considerable interest for our patients and confusion among physicians. We have all witnessed an increasing demand for ‘immune treatments’ from our patients. Some colleagues have sympathetically introduced these treatments into clinical practice, either based on the simplistic explanation presented by Moffett and Shreeve, or because of patients' desperate demands to try ‘something different’, or, as proposed by Sacks (2015), because as doctors we are trying to offer patients every possible way to achieve a successful pregnancy. However, we must acknowledge that clinical practice cannot be driven by patients' (or doctors') desperation and frustration. We agree that, on a daily basis, clinicians are faced with frustrated patients armed with information from the Internet. The great problem with information from the Internet is that it has not been critically assessed by experts. We also acknowledge that not all the protocols used to investigate infertile couples are evidence based; examples include tests for thrombophilia, sperm DNA fragmentation, hysteroscopy, and endometrial receptivity. In relation to the debate on ‘immune treatments’, we would like to clarify some issues: In Sacks' view, Natural Killer (NK) cells from the peripheral blood (pbNK) and uterus (uNK) are merged together with the simple marker ‘NK cells’ as the ‘main immune cells at the maternal–fetal interface’. This is a mistake as pbNK cells and uNK are completely different types of immune cell. PbNK cells are cytotoxic and represent the first line of defense against viruses, tumors and damaged cells. In contrast, uNK acquire their functional properties in utero and seem to play an important role in controlling trophoblast invasion and the development of a healthy placenta. Using ‘NK cells’ to describe these two contrasting subsets of NK cells as a unique marker in women with infertility or disorders of pregnancy will only continue to contribute to the confusion in this field. Sacks (2015) also states that ‘women with recurrent miscarriage do appear to have higher numbers of the more cytotoxic CD56dim subtype (and less of the CD56superbright cells) even if overall numbers are unchanged’. This is very confusing for clinicians as the number of pbNK and uNK cells shows great variability depending on the patient's clinical condition, day of the menstrual cycle, treatment condition (ovarian stimulation), stress, time of day, exercise, etc. None of the studies quoted by Sacks (2015) has taken these variables into consideration. All the previous studies suffer from very heterogeneous patient populations and a lack of information regarding the source of oocytes (own oocytes or donated oocytes), natural cycles, extent of hormonal replacement treatment, or presence of other pathologic conditions such as infections, tumors or autoimmune disorders. None of those previous studies included other immune tests such as maternal KIR and fetal HLA-C genotypes (Alecsandru et al., 2014). Our view is that the main reason that immune treatments have failed so far and immune tests (pbNK or uNK cell testing) have shown very weak or no predictive value is due to poor study design and great patient heterogeneity. These tests and treatments should only be used in research settings at present. Immunosuppression of patients for no valid reason, without proper evidence-based studies, is a real problem. Too many pseudo-immune treatments have been ‘cooked’ around IVF with a complete lack of real evidence, exploiting patients' hopes and resources. We must remember that infertile patients are extremely vulnerable, and we cannot be driven by their frustration. We need better, far better, studies with basic scientists collaborating with clinical researchers to study the immune system in reproduction. As suggested by our scientific societies, we need to stop offering empirical treatments, focus on basic research, and then, after efficacy has been proven, intervene correctly and safely.