Dr Hermann Salmhofer | Minimising the Damage Caused by Systemic Viral Infections

The mechanisms via which viral diseases infect and progress within the human body have become the subject of intense scrutiny since the emergence of the serious respiratory condition COVID-19, although many other viruses remain woefully under-researched. Recently, Dr Hermann Salmhofer and colleagues at the Paracelsus Medical University in Salzburg, Austria, have described the successful treatment of a harmful systemic virus affecting the kidneys, and suggest a possible new treatment target to mitigate the progression of the disease and prevent the development of permanent organ damage. Their findings, combined with broader research on viral infections, highlight the critical importance of both preventive measures and targeted treatments in managing viral diseases.

Understanding the Mechanisms Underpinning Viral Progression

The recent COVID-19 pandemic forced scientists to refocus on the potential causes of organ damage induced by systemic viral infections. The serious complications associated with such diseases are frequently fatal, and rapid diagnosis and treatment are key to increasing the chances of survival. Usually, the presence of a virus triggers a tightly controlled immune response to fight the infection, which activates the innate and adaptive immune responses. Derangement may occur at early or late stages of disease course, which may involve the largely underrecognised innate immune system. Yet, as we have learned from the corona crisis, comprehension and optimisation of innate immunity is essential in global pandemic management. The innate immune system serves as first and earliest mechanism of defense against pathogens. For immediate action, it must remain unspecific and limit disease progression at earliest moment, until specific adaptive immunity, comprising T-cells, B-cells and antibody production, may arise. Finally, upon elimination of the pathogen, the immune response must be terminated to prevent autoimmunity and chronic inflammation. Derangements of this delicately regulated system may lead to severe and progressive disease.

The case demonstrated here reveals a massive dysregulation of innate immunity, namely activation of the complement system, that causes severe damage to endothelial cells, which constitute a smooth inner lining of blood vessels. As soon as the integrity of this protective surface layer is injured, the complement system attacks capillaries (tiny blood vessels, that supply organs with oxygen and nutrients), inducing micro-clotting and precarious organ damage. In severe COVID-19, this complement attack was caused by the viral spike protein and typically occurred in the vasculature of the lungs, inevitably leading to respiratory failure and death.

A comprehensive understanding of viral infections requires consideration of both early preventive measures and late-stage interventions. Research has shown that optimising the immune system through adequate vitamin D levels can significantly impact disease outcomes, while targeted treatments such as complement inhibitors may be crucial in managing severe cases. To this end, Dr. Hermann Salmhofer and the team at the Paracelsus Medical University in Salzburg, Austria, along with colleagues in Vienna and Budapest, have investigated the effects of a systemic virus called Hanta virus, which has shown increasing prevalence in recent years. Originating in rodents, the virus affects the kidneys, but sometimes may also attack endothelial cells, leading to micro-clotting and further deterioration. Among Hanta virus subtypes, this is more common in American and South-East Asian variants and may cause fatal outcomes.

A Fascinating Case Study

Dr. Salmhofer and colleagues encountered a patient who had initially been admitted to the emergency department with acute diarrhoea, visual disturbances and general malaise. At first, a gut-type manifestation of COVID-19 without respiratory symptoms was assumed, since the SARS-CoV2 PCR test was positive. Surprisingly acute kidney injury associated with destruction of red blood cells and massive consumption of blood platelets (summed up as thrombotic microangiopathy) were found in lab analysis. At that time point, COVID-19 was suspected the trigger of this acute complement dysregulation. The spike protein of SARS-CoV2 virus had earlier been identified as culprit of endothelial damage in COVID-19, thus causing the complement attack. Given the severity of events in this patient, immediate action had to be taken.

A Surprising Response to Treatment and a Definitive Diagnosis

To stop this detrimental disease course, eculizumab, a terminal complement inhibitor, which blocks formation of the membrane attack complex, was administered. Upon a single dose, complement activity and haemolysis were immediately stopped. While blood parameters rapidly turned normal, kidney damage persisted. Since renal function did not improve in parallel to normalisation of blood parameters, a kidney biopsy was performed. It showed acute damage and inflammation of kidney tubules, yet no sign of thrombotic microangiopathy. Since the type of lesion found was typical for Hanta virus disease, additional tests were performed and confirmed Hanta virus infection of the kidneys. The patient may have acquired the virus while cleaning a henhouse, where dust will have contained virus-contaminated rodent excrements.

Although Hanta virus primarily affects the kidneys and COVID-19 primarily affects the airways and, possibly, the lungs, the two viruses, that each may induce diarrhoea, share a common infection modality: Both may, sometimes, target endothelial cells and activate an immune response via the same mechanism. In the case presented here, the COVID-19 and Hanta virus infections likely occurred in parallel. Yet by infecting separate organs, they could evolve independently and may only have overlapped at the final step of complement activation. Possibly this may have accounted for the severity of disease.

Understanding the Dual Nature of Immune Response

This case highlighted a critical aspect of viral infections: while a robust immune response is essential for fighting infection, excessive activation of immune pathways can lead to tissue damage. This dual nature is particularly evident in the complement system, which can be both protective and destructive, depending on the context. Early intervention through vitamin D supplementation can help maintain balanced immune responses, while in severe cases, targeted inhibition of specific immune pathways, such as complement activation, may be necessary. The timing of interventions proved crucial, with preventive measures being most effective before severe symptom onset.

The Role of Preventive Measures in Viral Defence

Recent research has highlighted the critical importance of maintaining optimal vitamin D levels in preventing severe viral infections. Vitamin D deficiency affects up to 90% of populations at higher latitudes and has crucial impacts on the immune system. This largely explains the winter surplus of mortality, the so-called flu-deaths. Vitamin D deficiency negatively affects early innate immunity, limitation of inflammatory response, T-cell function and finally, termination of inflammation. At early stages of infection, vitamin D deficiency impairs the production of interferons (antiviral, protective proteins) and cathelicidin (an anti-microbial peptide), thus allowing for dissemination of the infection. Even more, in vitamin D deficiency, an excessive inflammatory response via the NFkB signal pathway may occur, leading to a pro-inflammatory “cytokine storm” and hyperinflammation, which is regarded as crucial event towards fatal disease.

Bridging Prevention and Treatment: A Comprehensive Approach

The research findings point to a comprehensive approach to viral infections that encompasses both preventive and therapeutic strategies. At the preventive level, maintaining adequate vitamin D levels with a target of 30–50 ng/ml and supporting innate immunity through micronutrient sufficiency have emerged as crucial factors. Early intervention at the first signs of infection can significantly impact disease progression. Recently, a novel option of immediate vitamin D repletion has emerged, since a partially activated vitamin D derivative, calcifediol, has become available for therapeutic interventions, as drug and as nutritional supplement. Due to its excellent bioavailability, this allows for rapid vitamin D repletion within a few hours, which might be life-saving for patients, who already show symptoms of infection. These “host factors” to optimise immunity have been severely underrecognised in individual patient care, management of risk populations and public health considerations.  Several efforts to mitigate ongoing hyperinflammation in progressive viral disease (such as anti-IL1, anti-IL6 or JAK-STAT pathway inhibition, e.g. in COVID-19), have been made, yet with equivocal results. Targeted complement inhibition may – in select cases, that reveal thrombotic microangiopathy – show promise in preventing irreversible organ damage and fatal disease outcomes. Remarkably, in this case, whilst kidney damage was not reversed immediately, kidney function was restored within 4 months after receiving treatment. This recovery timeline suggests, that even severe organ dysfunction may be reversible, if the underlying immune disorder related to dysregulation is effectively addressed.

A Model for Future Pandemic Preparedness

The increasing prevalence of both Hanta virus and emerging respiratory viruses highlights the urgent need for a dual approach to virus diseases. Population wide preventive measures such as vitamin D supplementation and earliest calcifediol treatment could substantially reduce the burden of severe cases and prevent the winter overload of public health care systems. Awareness of novel pathophysiological mechanisms, such as thrombotic microangiopathy, in viral disease allows for development of new treatments tailored to individual demands.

Furthermore, advanced therapeutic options, such as complement inhibitors, should be readily available for select, severe cases. Understanding the timing and interaction of immune responses has proven crucial for optimal treatment outcomes. This important research has highlighted the potential mechanisms of Hanta virus infection and progression within the human body, regarding COVID-19 as a comparator. Furthermore, Dr. Salmhofer and associates have identified a treatment to effectively and rapidly stop the immune response, which appeared to be fuelling the symptoms observed. A comprehensive approach, combining preventive and early measures, that are rapid, simple, safe and inexpensive, with targeted treatments aligned to individual patients´ needs in severe cases, could significantly improve outcomes in systemic viral infections. Further studies are warranted to verify whether components of the immune response are a feasible therapeutic target for certain patients with life-threatening viral infections. New tailored treatments could be developed, potentially transforming the lives of countless patients and their families by avoiding severe organ damage and improving overall survival rates.