We found in this retrospective propensity-weighted cohort study of critically ill COVID-19 patients that IGAM treatment may confer beneficial effects in certain subgroups. In our cohort, patients not yet mechanically ventilated and those receiving ≥ 15 g daily for at least 3 days were most likely to benefit from an IGAM treatment, although we could not reach statistically significant differences compared to controls. Therefore, these findings must be tested for plausibility and causality in upcoming randomized trials.
The use of IVIGs in COVID-19 was initially reported by Cao et al.  who described a remarkable benefit in three deteriorating patients. Most of the studies published subsequently also reported a favourable clinical response, confirmed by the resolution of lung lesions with a normalization of oxygen saturation and global improvement in clinical status [18, 27, 28]. Gharebaghi et al.  in one of the first randomized placebo-controlled double-blind clinical trials confirmed the IVIGs were independently associated with a lower in-hospital mortality. Furthermore, a recent meta-analysis performed by Xiang and colleagues confirmed the clinical efficacy of IVIGs by showing a favourable impact on survival in critically ill COVID-19 patients . Nevertheless, the existing literature on IVIGs in COVID-19 is still controversial, which can be mainly explained by the high degree of heterogeneity in disease severity, different disease stages, small cohorts and a lack of standardized treatment regimens across the different studies [19, 29]. In this context, a large randomized controlled trial could not demonstrate any benefit on outcome, but even a trend towards an increased frequency of serious adverse events .
This problem might be solved by selecting the right patients, in the sense of personalized medicine. A recent large multicentre retrospective cohort study reported that treatment with IVIG for at least 5 days led to a significant decrease in 28-day mortality in critically ill COVID-19 patients . The study also elucidated that beneficial effects of an IVIG treatment were more pronounced in appreciation of the right timing, i.e. ≤ 7 days from ICU admission . Strikingly, further studies also found an association between treatment efficiency and a sufficient dosage and appropriate timing. Xie et al. , for example, reported the highest reduction in 28-day mortality in the case of IVIG administration within 48 h of ICU admission. This is consistent with our two results, indicating a trend towards relevant treatment effects in both patients who had not yet received mechanical ventilation, or those for whom IGAM treatment was not initiated until day 14 after the onset of first symptoms, respectively. This fact becomes particularly important because several other studies focused exclusively on patients already receiving mechanical ventilation at the start of IVIG treatment, thus focusing on later stages of the disease. In those studies, no clear evidence exists that IVIGs were effective in preventing disease progression or having a beneficial impact on survival [19, 20, 29]. In particular, a large randomized controlled trial from France showed no improved clinical outcome at day 28 by using IVIGs in patients already receiving mechanical ventilation . These findings are in line with our study results, as we could not demonstrate a beneficial effect for IGAMs in patients receiving mechanical ventilation at treatment initiation or being treated with IGAMs after day 14 (HR: 0.93; 95% CI: 0.58 to 1.52; p = 0.791). Therefore, it seems crucial to pay attention to a timely appropriate administration of IVIGs. Here, the recent studies and our results indicate that administration before mechanical ventilation is required, in order to achieve the most beneficial effects.
Furthermore, data on mortality among different studies are not conclusive, due to different IVIG dosing regimens, preparations and different IVIG treatment durations. The recommended dose of IgM-enriched preparations in patients with hyperinflammation is 0.25 g/kg per day for at least 3 days . However, the daily doses administered in our multicentric study differed between patients, ranging from 0.05 to 0.4 g/kg. In addition, the duration of the treatment also varied from 1 to 7 days. A subgroup analysis revealed that a dose of ≥ 15 g per day, equivalent to a daily dose of 0.2 to 0.3 g/kg, for at least 3 days may be superior to lower dose regimens, in line with previous studies in sepsis and COVID-19 [18, 31]. It is noteworthy that our results do not imply a definitive dosage or treatment recommendation. However, our results may indicate a dosage threshold at which favourable treatment possibly occur. Bearing these considerations in mind, a solidifying picture emerges supporting IGAM in certain subgroups of critically ill COVID-19 patients. However, this preliminary picture needs to be tested for causality in a prospective randomized controlled setting prior to implementation in clinical practice.
The clinical difficulties in treating this new disease also arise from the fact that we cannot reliably discriminate distinctive disease stages and different patients’ phenotypes, although it seems important to administer IGAM at the right time. Several clinical or biological markers, including ferritin, C-reactive protein, and pro-inflammatory interleukin-1 and interleukin-6, have currently been identified to help predict the course of COVID-19 and, therefore, can potentially help to guide IGAM usage . However, as shown in our subgroup analysis, alteration of these inflammatory markers does not appear as suitable or rather timely biomarkers in COVID-19 to indicate appropriate initiation of treatment with IGAM. In this context, we hypothesize that when our applied thresholds for inflammatory markers were reached, the inflammatory process was likely too advanced and the therapeutic window for a sufficient IGAM therapy was already closed. Thus, our data suggest that the decision regarding the initiation of IGAM treatment should currently be based on clinical parameters (i.e. not yet mechanically ventilated and/or within the first 14 days after the onset of symptoms) rather than on inflammatory biomarkers.
Of course, it is also necessary to discuss the question of the potential advantages of IGAM treatment compared to established immunotherapies. As inflammatory properties are considered the pathogenic basis for disease progression in critical COVID-19, most of the approved agents show anti-inflammatory properties . Although silencing the inflammation is currently the most favoured solution, there is growing evidence that profound anti-inflammatory patterns also prevail in critical COVID-19 . Therefore, it seems prudent when adjunctive therapies are also capable of tackling multiple immunologic perturbations in addition to inflammation. In more concrete terms, adjunctive therapies in COVID-19 should, firstly, control and resolve the prolonged inflammation, secondly, augment the restoration from immune dysregulation and, thirdly, should not harm, for example, due to the susceptibility of the host to secondary infections. In this sense, IVIGs may be capable of modulating the activity of the cytokine network, neutralizing autoantibodies, and regulating the proliferation and differentiation of immune cells . Therefore, especially IGAMs may represent promising candidates because they act on all three levels with synergistic mechanisms, helping to restore immune homeostasis .
Although the peaking inflammatory phase of COVID-19 progression is often imprecisely described as a “cytokine storm” , recent studies have shown that systemic levels of cytokines may not be as high as seen in ‘classical’ sepsis or acute respiratory distress syndrome [33, 36]. In this regard, we also detected, even on the day with the most critical medical condition, only moderately elevated concentrations of interleukin-6, serum ferritin and C-reactive protein. In line with a growing number of recently published studies describing this issue, the concentrations of inflammatory mediators measured do not fit into the classic picture of excessive hyperinflammation [33, 36]. By now, the immunological picture of severe COVID-19 has evolved to a moderate but persistent inflammation maintained by macrophages, which also helps to explain the efficacy of IGAM in COVID-19. The IgM via the protein AIM plays an especially vital role in macrophage activity and homeostasis [14, 37]. Given the important role of macrophages in SARS-CoV-2-induced immune responses, targeted reprogramming of macrophages via IgM substitution to stabilize anti-inflammatory M2 phenotypes by the scavenging of AIM may indicate a promising approach . Additionally, IGAMs also target several other important immunological pathways in COVID-19, such as inhibiting microvesicle-driven immunothrombosis . Thus, IGAM may have substantial advantages over classical IVIGs as an adjunctive treatment in critical COVID-19 [16, 39]. However, these mechanistical considerations need to be explored in future experimental studies.
Taken together, despite the huge clinical heterogeneity, we were able to reveal that an early and high-dose treatment may improve the prognosis of critically ill COVID-19 patients. However, neither the early use of IGAM (i.e. in not yet mechanically ventilated patients) nor a sustained high-dose (i.e. ≥ 15 g/d for at least 3 days) was associated with a markedly improved number of organ support-free days. Still, we see the possibility that IGAM can attenuate the burden of the critical COVID-19 disease and should be urgently evaluated for effectiveness in upcoming clinical trials.
All results are of an associative nature due to the retrospective design of our study. In addition, all subgroup analyses arose post hoc, and thus conclusions derived from these results must be interpreted carefully. Therefore, no direct treatment recommendations should be derived from our results, despite several strengths, such as the number of cases and the multicentric character. Secondly, the selection of the primary endpoint can also be critically discussed, as we did not assess long-term effects may occur from the chosen study design. However, IGAM treatment may not necessarily impact the underlying cause of death at later time points because patients with COVID-19 beyond day 30 also face multiple other risks. Thirdly, despite the greatest statistical effort to control confounders, we cannot entirely exclude an existing bias, even after confirming our results in different approaches to adjust for intergroup imbalance (i.e. SuperLearner, inverse probability of treatment weighting, Random-Forest and multivariate proportional hazards Cox regression; see Additional file 1). Nevertheless, residual confounding may exist, e.g. due to immortal time bias, which could limit the reproducibility of the data. Fourthly, our results may be affected by different patterns of physician’s treatment practice over time. Finally, we cannot entirely clarify to what extent the concurrent use of glucocorticoids or adjunctive drugs, such as Remdesivir, Tocilizumab or Anakinra, may impact the effect of IGAM treatment. Therefore, the need for a combined use of IGAM in future work should also be explored.