The enigma of post-acute infection syndromes

In a recent review published in the journal Nature Medicine, researchers summarized known literature findings of the unexplained post-acute infection syndromes (PAISs).

Review article: Unexplained post-acute infection syndromes. ​​​​​​​Image Credit: Donkeyworx / Shutterstock

Overview and clinical presentation of PAISs

Unfortunately, the chronic sequelae of acute infections often go undiagnosed due to the non-specific symptoms and lack of objective diagnostic features. Such an illness characterizes PAISs, in which patients are not able to recover entirely from the acute infections, the cause of which is unexplainable, and the causative pathogen remains unidentifiable by routine diagnostic methods.

Q fever fatigue syndrome is a well-established PAIS that is caused by the Coxiella burnetiid bacterium and is a very debilitating condition. Another PAIS with an established causative pathogen is the post-dengue fatigue syndrome, caused by the mosquito-borne dengue virus.

Other PAIS include the post-Ebola syndrome (PES), post-polio syndrome (PPS), and Post-chikungunya chronic inflammatory rheumatism (pCHIK-CIR), the causative pathogens of which are the Ebola virus, poliovirus, and chikungunya virus, respectively.

However, several pathogens such as the Epstein Barr virus (EBV), West Nile virus, Ross River virus, Coxsackie Ba virus, H1N1/09 influenza virus, Varicella Zoster virus (VZV) virus have been reported to cause unexplained and unnamed PAISs. Further, Post-Polio syndrome can manifest even after 15 to 40 years after a poliomyelitis infection.

PAIS by neurotropic organisms such as the West Nile virus has been reported to cause persistent changes similar to those observed in post-polio syndrome. Likewise, the symptomatology of Ross River virus-induced PAIS and chikungunya virus infection are known to be similar.

H1N1/09 influenza A virus, VZV, and coxsackie B have been associated with an increased risk of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), underpinning the development of chronic sequelae on exposure to certain pathogens.

The core symptoms of PISs are centered on fatigue, exertion intolerance, sensory and neurocognitive impairments, flu-like symptoms, irritability, poor sleep, sweating, arthralgia, and myalgia, with a wide spectrum of non-specific and varied symptoms.

The neurocognitive symptoms include loss of concentration, brain fog, and memory loss. The symptoms are recurrent or chronic in nature. Other symptoms are disease-specific, such as eye disorders in Ebola virus-induced PAISs and anosmia and/or ageusia in long coronavirus disease (COVID).

Long COVID       

Long COVID or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC) is a term that encompasses several chronic effects observed among SARS-CoV-2-positive patients post the acute infection. PASC has been identified in mild, moderate, and severe COVID 2019 (COVID-19) patients. The symptoms last for several months and cannot be explained by another diagnosis.

Common PASC symptoms include cough, dyspnea, chest pain, anosmia, cognitive impairments, and fatigue. The symptoms also affect the performance of daily activities and may relapse or fluctuate. Long COVID patients present with variable symptoms that last for different time durations.

PASC patients recovering from severe SARS-CoV-2 infections may either present with pulmonary damage subsequent to acute respiratory distress syndrome (ARDS) or pneumonia or may exhibit persistent post-intensive care unit (ICU) syndrome symptomatology. Most of the PASC individuals have been reported to be elderly males with severe COVID-19.

PASC patients recovering from asymptomatic or mild to moderate COVID-19 may present with fever, arthralgia, myalgia, sensory disturbances, and intolerance to exertion, similar to those observed among ME/CFS patients. Such PASC presentations have been predominantly found in women.

Researchers have postulated that SARS-CoV-2 infections may trigger or unmask medical conditions such as diabetes, postural orthostatic tachycardia syndrome (POTS), Guillain–Barré syndrome, and thrombotic disorders.

Pathogenesis of PAISs

All types of pathogenic organisms such as bacteria, fungi, viruses, and parasites have been implicated in the pathogenesis of PAISs.

The long-term presence of pathogens (bacteria/virus/fungi/parasite) presenting as persistent infections or persistent unviable pathogen remnants leads to chronic stimulation of the host immune system. Subsequently, T lymphocytes and B lymphocytes are activated, which enables the interaction of the persistent pathogen with the pathogen-associated molecular patterns (PAMPs) of the host. Subsequently, the pathogenic ribonucleic acid (RNA) binds to the pattern recognition receptors (PRR) of the host cell. The pathogen-PRR binding stimulates innate immunity.

An alternative mode of activation of the immune system involves the impairment of regulatory T (Treg) lymphocytes by the persistent pathogen, as a result of which, autoreactive lymphocytes target antigens of the host (self) and induce antibodies causing autoimmune impairment of the host immune systems.

Persistent and chronic infections could also occur due to microbiome dysbiosis or dysregulation of the microbiota-gut-brain axis due to reactivation of latent pathogenic organisms and activation of microglia by afferents of the vagus nerve. Either of the mechanisms could result in organ damage such as brain atrophy, lung fibrosis, cardiovascular damage, renal dysfunction, vasculature damage, and villous atrophy.

To conclude, PAISs represent an enigmatic spectrum of medical diseases. Further biomedical research is required to elucidate their underlying molecular mechanisms and develop objective markers for prompt diagnosis and effective treatment.

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