By 2024, more than 1.5 million people in Germany had been affected by long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Long COVID is recognized within postacute infection syndromes (PAIS).

At the 132nd Congress of the German Society for Internal Medicine in Wiesbaden, Germany, Christian Gogoll, MD, specialist in internal medicine and pulmonology and medical director of the outpatient services at the Evangelical Lung Clinic Berlin, and Carmen Scheibenbogen, MD, professor of clinical immunology and deputy head of the Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, both in Berlin, Germany, reviewed current evidence on diagnosis and management.

Three years after the COVID pandemic, clinicians continued to encounter a condition that remained diagnostically and therapeutically challenging. Key questions focused on whether long COVID is a psychosomatic illness and which strategies effectively address its broad symptom profile.

Core Features

Long COVID is a form of PAIS that is characterized by the following features:

• Multisystem symptoms involving multiple organs
• Onset after asymptomatic, mild, or severe primary infection
• Symptoms that persist for more than 3 months after the initial illness
• A disease course that may be continuous, fluctuating, or progressively worsening
• Symptoms not explained by another medical condition

Clinical Context

Standard diagnostic tests, including CT, pulmonary function testing, and laboratory assessments, are often unremarkable, even when individuals are severely affected by fatigue, cognitive dysfunction, and sleep disturbance. This “subjectively ill, objectively unremarkable” presentation complicates clinical evaluation and continues to raise questions about the underlying mechanisms, including whether long COVID is a psychosomatic condition.

Pathophysiology

Within a biopsychosocial framework, impairments may occur across multiple domains; however, current evidence supports a biologic basis. Researchers identified pathologic findings across several domains:

• Neurologic: Small fiber neuropathy detected by skin biopsy in individuals with pain or dysautonomia
• Cerebral: Neuroinflammation and hypoperfusion on PET and MRI, particularly during orthostatic stress
• Immunologic: Altered monocyte profiles and significantly increased inflammatory cytokines that correlated with fatigue severity
• Vascular: Microcirculatory disorders and endothelial damage

Viral infections, particularly SARS-CoV-2, lead to systemic vascular disease characterized by a self-amplifying cycle of cytokine storm-driven inflammation, severe oxidative stress, and endothelin-1 activity. This process damages the vascular lining, causing widespread endotheliopathy, which drives accelerated vascular aging, impaired organ perfusion, and subsequent multiorgan dysfunction.

Postexertional Malaise (PEM)

PEM is associated with autonomic dysregulation and is characterized by increased heart and respiratory rates during exertion. Abnormal blood distribution during physical activity reduces the oxygen supply to the skeletal muscle. Muscle samples collected after exertion showed mitochondrial dysfunction and muscle cell necrosis, which may explain the delayed or incomplete recovery.

Assessment Tools

Diagnostic procedures are often insufficient to characterize the clinical presentation. Gogoll recommended structured questionnaires, including the Fatigue Assessment Scale to assess fatigue severity, Canadian Consensus Criteria to evaluate ME/CFS, and Mini-Mental State Examination to assess cognitive impairment.

These tools enable the differentiation between fatigue alone and PEM. PEM is a central diagnostic criterion for ME/CFS and, according to Scheibenbogen, affects an estimated 10%-30% of individuals with long COVID.

Treatment strategies differ according to symptom patterns. In individuals with PEM, exercise intolerance requires strict pacing to maintain activity within individual energy limits. Exceeding these limits triggers symptom worsening, described as a “crash.” Recovery after a crash can take several weeks or may remain incomplete.

In individuals with fatigue but without PEM, structured exercise and breathing therapy can reduce persistent exhaustion.

Treatment Options

Treatment remains symptom-oriented and follows a biopsychosocial framework. The Federal Joint Committee has recommended several off-label options:

• Ivabradine for postural tachycardia syndrome, defined by an increase in heart rate exceeding 30 beats/min on standing without a drop in blood pressure
• Agomelatine for fatigue in the context of long COVID and ME/CFS
• Vortioxetine to improve cognitive function in individuals with long COVID
• Metformin to reduce risk for long COVID in individuals with BMI > 25

Key Takeaways

Gogoll concluded his presentation with the following key points:

• Long COVID does not have a primarily psychosomatic cause, according to the AWMF S1 guideline for Long/Post-COVID.
• Psychological comorbidities, including anxiety and depression, should be described as reactive consequences rather than causal factors.
• Treatment is symptom oriented and follows a biopsychosocial framework.
• Distinguishing PEM from fatigue is critical, with pacing maintained within individual energy limits to prevent symptom worsening.

Clinical Implications

Despite the increasing development of diagnostic questionnaires and therapeutic approaches, Gogoll and Scheibenbogen emphasized that one key issue remains underrecognized: the need to destigmatize long COVID. Because clinical findings are often unremarkable, symptoms are often attributed to psychological causes. Physicians were urged to take individuals seriously, ensure interdisciplinary care, and pursue further training in PAIS.

This story was translated from Coliquio, part of the Medscape Professional Network.