At the Amsterdam institute for Immunology and Infectious diseases (AI&I), we are committed to advancing research in three key areas: Post-Acute Infection Syndrome (PAIS), Immunomonitoring, and Vaccination. Each quarter, we highlight one of these areas through a dedicated series of articles. This quarter (Q4 2025), our spotlight is on PAIS. In this article, we focus on the recent advances, ongoing challenges, and future directions in research on Post-Acute Infection Syndromes (PAIS).
PAIS refer to persistent symptoms that remain after an infection with any type of pathogen. Remarkably, different PAIS share many hallmark symptoms, such as post-exertional malaise (PEM), brain fog, and POTS (Postural Orthostatic Tachycardia Syndrome). The importance of PAIS research is highlighted by its prevalence: over 400 million people worldwide are affected by post-COVID alone, with an annual economic burden exceeding 1 trillion dollars. When including other PAIS, such as Post-Treatment Lyme Disease Syndrome (PTLDS) and Q fever fatigue syndrome, the impact is even greater.
Recent advances in PAIS research
One of the most significant advancements in recent years is the emergence of several hypotheses that could explain the underlying mechanisms of PAIS, including viral persistence, autoimmunity, and metabolic dysfunction. For the first time, researchers have identified biomedical abnormalities in PAIS patients, such as altered metabolism in
skeletal muscles.
Dr. den Dunnen: ‘Our own research has contributed to this progress by testing the autoimmunity hypothesis in post-COVID. By transferring antibodies from the blood of post-COVID patients to mice, we observed that the mice developed severe symptoms, unlike those injected with control antibodies. This finding suggests that autoantibodies may play a causal role in post-COVID, at least for a subset of patients’
Another important insight is that post-COVID is not a new phenomenon. Historical records show that post-infection syndromes have been described for centuries, often following outbreaks of diseases like Lyme, Dengue, Chikungunya, Ebola, SARS, and even influenza.
Current challenges in PAIS research
Despite these advances, major challenges remain. Dr. den Dunnen explains: ‘There are still no reliable biomarkers, making diagnosis difficult. Treatment options are also limited, while some therapies exist for POTS symptoms, most PAIS patients have no effective treatments available yet.’
He also highlights concerns about the long-term consequences: ‘Autoimmunity rates have increased in the population after the pandemic compared to pre-pandemic levels, and recent findings suggest similar patterns for other infectious diseases. There is also growing concern about a potential rise in neurodegenerative diseases in the post-pandemic era. While these issues may not be immediately apparent, they could pose major challenges in the long run.’
Ethical and social considerations
As research progresses, ethical questions arise, especially regarding the cost of treatment and the use of genetic testing. The heterogeneity of PAIS poses additional challenges. Dr. den Dunnen: ‘Imagine if a biomarker is found that identifies only a subset of patients, what does this mean for those who do not test positive? Will they be excluded from clinical trials or support systems?’ These are important issues to address as the field moves forward. Ensuring that new diagnostics or treatments are accessible to all patient groups, especially given the diversity within PAIS, is a complex challenge. Dr. den Dunnen emphasizes that clear communication is crucial: a negative biomarker test does not mean a patient is not ill.
Looking ahead: goals and game changers
The main goals for PAIS research in the next 5 to 10 years are clear according to Dr. den Dunnen:
- Develop reliable diagnostics and clear inclusion criteria: currently these are vague and subjective. This is reflected in the difference between studies, in one center results look promising while this cannot be reproduced in another center.
- Unravel the underlying pathophysiology: right now it is unclear if PAIS are an immunological, neurological, or metabolic disease, or a combination of these.
- Test and develop new treatments: starting with drug repurposing and moving toward targeted therapies based on the results of the studies into underlying pathophysiology.
Technological innovations could also be game changers. Dr. den Dunnen: ‘Reverse engineering could provide a leap in our understanding of PAIS: by testing repurposed drugs we could hit something that works, which in turn will teach us a lot about the underlying mechanism. This has worked before for e.g. anti-IL-17 therapy for rheumatological conditions’.
Until now, omics analyses have not advanced knowledge on PAIS pathophysiology. Dr. den Dunnen: ‘Previously, we have focused these analyses on blood. We might improve these analyses by looking at other compartments, such as the intestine, bone marrow, lymph nodes, and skeletal muscle. Furthermore, when combined with AI and machine learning, we could identify patterns across different patient groups. At the same time, ‘old-school’ hypothesis-driven research remains essential for understanding disease mechanisms’.
research has been the active involvement of patients
Personal perspective
One of the most inspiring developments in PAIS research for Dr. den Dunnen has been the active involvement of patients. Regular contact with patients not only provides valuable feedback and inspiration, but also highlights the real-world impact of research for him. Dr. den Dunnen: ‘As a fundamental scientist, I previously studied diseases without ever seeing a patient. Since I’m doing post-COVID and ME/CFS research, I am in touch with patients almost every week, where I tell them about my research, and they continuously update me on recently published papers and preprint. This connection with patients provides additional inspiration and meaning to what I do as a basic scientist.’
The fact that post-COVID is not something ‘new’ has shifted Dr. den Dunnen’s perspective: ‘While post-COVID may seem new, PAIS have likely existed for centuries, affecting people after a wide range of infections. The lack of biomarkers not only hampers research and treatment, but also contributes to the misconception that these diseases are not “real”, a challenge that ME/CFS and fibromyalgia patients have faced for decades’.
Dr. den Dunnen: ‘With continued collaboration between researchers and patients, the future of PAIS research holds promise for better understanding, diagnosis, and treatment.’
Discover more articles in this series:
Stay tuned for the next article in this PAIS series, where we will delve into the real-world impact of research projects.
Text: Jeroen den Dunnen and Esmée Vesseur