Uncovering the Contrasts and Connections in PASC: Viral Load and Cytokine Signatures in Acute COVID-19 versus Post-Acute Sequelae of SARS-CoV-2 (PASC)
Abstract
:1. Introduction
2. Materials and Methods
3. Viral Loads
3.1. Viral Loads during Acute COVID-19
3.2. Relation between Acute-Phase Viral Dynamics and PASC Phase
4. Cytokines and Chemokines
4.1. Cytokines and Chemokines during Acute COVID-19
4.2. Relationship between Viral Load and Cyto- and Chemokine Markers across COVID-19 Disease Subsets
4.3. Differences and Similarities in Cytokine Profiles in Acute and PASC
5. In Vitro Models and Preclinical Animal Models to Study Acute COVID-19 and PASC
Animal | Susceptibility | Severity | Acute Phase | PASC | Ref. |
---|---|---|---|---|---|
Transgenic Mice |
|
| K18-hACE2 mice:
|
| [113,114] |
Syrian Hamsters |
|
|
|
| [112,115,116,117,118] |
Ferrets |
|
|
|
| [107,108,118,119] |
6. Concluding Remarks and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Term | Description |
---|---|
PASC or Long COVID | WHO definition of PASC is adopted for this review. This defines PASC as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. |
Acute phases spectrum | The phases, asymptomatic, mild, moderate, severe and critical are most often used. However, in this review, the spectrum includes asymptomatic, mild/moderate and severe phase. Rationale for this deviation is that is the review focuses on the differences and progression from non-severe phases (asymptomatic, mild/moderate) to the severe phases. |
Asymptomatic | Individuals positive for COVID-19 in absence of infection related symptoms. |
Mild/Moderate | Individuals who display mild symptoms including fever, muscle pain and anosmia and moderate symptoms including tachypnea and mild pneumonia without the need for hospitalization. |
Severe | Hospitalized patients with clinical signs of pneumonia, severe tachypnea, severe dyspnea and critical symptoms including respiratory and organ failure and coma. |
Cytokine storm | State of deregulated immune system, characterized by an excessive production and release of cytokines and chemokines. Release may cause damage to various tissues including lung. Cytokine storm may subsequently trigger acute respiratory stress syndrome leading to organ failure or even death. |
Viral load | Commonly quantitatively expressed as concentration in viral copies/mL in plasma. Here, viral load magnitude is defined by the copy number or Ct value determined via (RT-q)PCR. This definition is widely used in the papers cited in this review and is therefore adopted here. |
Viremia | Classically defined as the presence of (non-) infectious whole virus or immune neutralized whole virus in serum. Publications referred to here do not use viral culture or staining to determine presence of virus in serum. In turn, the majority uses (RT-q)PCR and adopt the Ct value or quantified copy number as a benchmark for viremia. Therefore, in case the review refers to viremia or viral load, remember that these are Ct values representing RNA copy numbers. |
Ct value | Cycle threshold (Ct) value in PCR is the number of cycles needed to indicate that a sample contains the target RNA or DNA. The Ct value negatively correlates with the initial amount of target RNA or DNA, i.e., in this review a low Ct value indicates a high viral load. |
Persistent infection | Prolonged presence of SARS-CoV-2 (non-)infectious virus or RNA remnants that is detected for an extended period beyond acute infection. Persistence could be associated with display of symptoms or in absence of symptoms. |
URT & LRT | Upper respiratory tract (URT) that includes nasal cavity, pharynx and larynx. Lower respiratory tract (LRT) that includes trachea and lungs. |
RNA Load | Copy number of SARS-CoV-2 RNA, detected by (RT-q)PCR on samples from various origin including serum, BAL, nasopharyngeal swabs. |
Inoculum | The virus quantity or concentration introduced at the time of host infection. |
Study Population Characteristics | Acute-Phase Viral Load Correlation or Association with PASC Phase | Ref. |
---|---|---|
Hospitalized (n = 47) Vaccinated Strain variant unknown | Plasma of PASC patients tested positive more frequently (55% vs. 29%) and had higher average viral loads compared to previously infected persons without PASC. In PASC-positive patients, plasma viral load remained unchanged or increased, while in PASC-negative individuals, it decreased or became undetectable over time. | [40] |
Mix of mild-to-critical patients. Exact numbers unknown. Unvaccinated * Wuhan-Hu-1 strain | Detectable plasma viral load was associated with memory-related issues, whereas there were no associations with anosmia or fatigue. | [41] |
Hospitalized (n = 129) Severe/Critical (≥90% pneumonia) | Viremia at time of hospitalization resulted in a higher chance of PASC symptom development as compared to hospital-admitted patients without viremia. | [42] |
Mild/moderate (n = 119) Severe/Critical (n = 8) Unvaccinated * Wuhan-Hu-1 strain ** | Patients with detectable plasma viral load at enrollment were more likely to report PASC symptoms one month after confirmed infection as compared to individuals without detectable plasma viral loads (83% vs. 41%). | [43] |
Mild/moderate (n = 70) Severe/Critical (n = 6) Vaccination status *** Strain variant unknown | Viral URT loads correlated with an increased number of experienced PASC symptoms. | [44] |
Study Population Characteristics * | Viral Load | Cytokine | Ref. | |
---|---|---|---|---|
Origin | Origin | Correlation with *** | ||
Non-stratified ** Mild/Moderate (n = 26) Severe/critical (n = 11) | URT | Plasma | IL-6, IL-10 | [76] |
TNF-α, INF-γ | ||||
Non-stratified ** Asymptomatic (n = 6) Mild/Moderate (n = 17) Severe/critical (n = 8) | URT | Plasma | CCL-2 | [77] |
IFN-α, IFN-γ, TNF-α, IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A | ||||
Non-stratified ** Asymptomatic (n = 4) Mild/Moderate (n = 58) Severe/critical (n = 8) | URT | Plasma | CCL-2, VEGF, G-CSF | [82] |
IL-1β, IL-1ra, IL-2, IL-2Rα, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, IL-17, IL-18, IFN-α2, IFN-γ, TNF-α Whole list; see reference | ||||
Hospitalized Severe/critical (n = 88) | Plasma | Plasma | IL-6, IL-8, IP10, CCL-2 | [32] |
IFN-γ, IL-1RA | ||||
URT | Plasma | IL-6, IL-8, IP10, CCL-2, IFN-γ | ||
IL-1RA | ||||
LRT | Plasma | IL-6 | ||
IL-8, IP10, CCL-2, IFN-γ, IL-1RA | ||||
Non-stratified ** Mild/moderate (n = 15) Severe/critical (n = 34) | Plasma | Plasma | IL-6, CCL-2, CCL-19 | [74] |
IFN-α2 | ||||
URT | URT | IFN-γ, IL-33 | ||
IL-10 |
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Compeer, B.; Neijzen, T.R.; van Lelyveld, S.F.L.; Martina, B.E.E.; Russell, C.A.; Goeijenbier, M. Uncovering the Contrasts and Connections in PASC: Viral Load and Cytokine Signatures in Acute COVID-19 versus Post-Acute Sequelae of SARS-CoV-2 (PASC). Biomedicines 2024, 12, 1941. https://doi.org/10.3390/biomedicines12091941
Compeer B, Neijzen TR, van Lelyveld SFL, Martina BEE, Russell CA, Goeijenbier M. Uncovering the Contrasts and Connections in PASC: Viral Load and Cytokine Signatures in Acute COVID-19 versus Post-Acute Sequelae of SARS-CoV-2 (PASC). Biomedicines. 2024; 12(9):1941. https://doi.org/10.3390/biomedicines12091941
Chicago/Turabian StyleCompeer, Brandon, Tobias R. Neijzen, Steven F. L. van Lelyveld, Byron E. E. Martina, Colin A. Russell, and Marco Goeijenbier. 2024. "Uncovering the Contrasts and Connections in PASC: Viral Load and Cytokine Signatures in Acute COVID-19 versus Post-Acute Sequelae of SARS-CoV-2 (PASC)" Biomedicines 12, no. 9: 1941. https://doi.org/10.3390/biomedicines12091941