Tag: covid symptoms

Predictive Factors and ACE-2 Gene Polymorphisms in Susceptibility to Long COVID-19 Syndrome

Abstract:

Long COVID-19 syndrome is present in 5–10% of patients infected with SARS-CoV-2, and there is still little information on the predisposing factors that lead to its development. The purpose of the study was to evaluate the predictive factors in early symptoms, clinical features and the role of Angiotensin-Converting Enzyme-2 (ACE-2) c.513-1451G>A (rs2106806) and c.15643279T>C (rs6629110) polymorphisms in the susceptibility to developing Long COVID-19 syndrome subsequent to COVID-19 infection.
A total of 29 patients who suffered COVID-19 were recruited in a descriptive longitudinal study of two groups: Long COVID-19 (n = 16) and non-Long COVID-19 (n = 13). Early symptoms and clinical features during COVID-19 were classified by a medical service. ACE-2 polymorphisms were genotyped by using a Single Nucleotide Primer Extension (SNPE). Of the early symptoms, fatigue, myalgia and headache showed a high risk of increasing Long COVID-19 susceptibility. Clinical features such as emergency care, SARS-CoV-2 reinfection, previous diseases, respiratory disease and brain fog also had a high risk of increasing Long COVID-19 susceptibility.
The A allele in the rs2106806 variant was associated with an odds ratio (OR) of 4.214 (95% CI 2.521–8.853; p < 0.001), and the T allele in the rs6629110 variant was associated with an OR of 3.754 (95% CI 1.785–6.105; p = 0.002) of increasing Long COVID-19 susceptibility. This study shows the risk of ACE-2 polymorphisms, different early symptoms and clinical features during SARS-CoV-2 infection in susceptibility to Long COVID-19.
Source: Varillas-Delgado D, Jimenez-Antona C, Lizcano-Alvarez A, Cano-de-la-Cuerda R, Molero-Sanchez A, Laguarta-Val S. Predictive Factors and ACE-2 Gene Polymorphisms in Susceptibility to Long COVID-19 Syndrome. International Journal of Molecular Sciences. 2023; 24(23):16717. https://doi.org/10.3390/ijms242316717 https://www.mdpi.com/1422-0067/24/23/16717 (Full text)

The relevance of headache as an onset symptom in COVID-19: a network analysis of data from the LONG-COVID-EXP-CM multicentre study

To the Editor,

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus primary affects the respiratory system; however, a multiorganic affection is evident. Neurological symptoms are frequent at the acute- and post-acute phases after infection [1]. Headache is a neurological symptom experienced as a COVID-19-onset symptom associated with a more benign course of the disease [2]; however, it has been also associated with a higher prevalence of post-COVID headache [3].

During the acute COVID-19 phase, headache often co-exists with other neurological symptoms, e.g., anosmia or ageusia [4]. The presence of anosmia as an onset symptom is also associated with lower mortality rate and a less severe disease, although it seems that patients with anosmia and ageusia represent a different group than those with headache [5]. In this letter, we applied a network analysis to determine the relevance of COVID-19-onset symptoms, including headache, as well as pre-existing medical co-morbidities in a sample of previously hospitalised COVID-19 patients.

The LONG-COVID-EXP-CM is a multicentre cohort study including individuals with a diagnosis of SARS-CoV-2 infection by RT-PCR technique and/or radiological findings hospitalised during the first wave of the pandemic in five hospitals of Madrid (Spain). Among all patients hospitalised during the first wave, a sample of 400 from each hospital was randomly selected. The Ethics Committee of all the hospitals approved the study (HCSC20/495E, HSO25112020, HUFA20/126, HUIL/092-20, HUF/EC1517). Verbal informed consent was obtained from participants for the use of their data in this analysis. Demographic data, pre-existing medical comorbidities, COVID-19 symptoms at hospital admission, days at hospital, and intensive care unit (ICU) admission were collected from hospital records.

The network included 28 nodes linked by edges weighted by partial correlation coefficients. The dataset as well as the related two vectors specifying the type (“g” for Gaussian, “p” for Poisson, “c” for categorical) and the number of levels (or categories) for each variable is provided. The mgm was estimated for order = 2 to only take pairwise interactions into account, using least absolute shrinkage and selection operator (LASSO, ℓ1-regularisation) that seeks to maximise specificity (to include as few false positives as possible) with rule = “AND” (which specifies whether the two estimates for an edge are combined with an “AND” or an “OR” rule). Since not all nodes in a network are equally important, centrality was assessed by calculating strength centrality (defined as the sum of weights of edges), betweenness centrality (defined as the total number of shortest paths that pass through the target node, moderated by the total number of shortest paths existing between any couple of nodes in the graph) and closeness centrality (defined as the inverse sum of the distances of shortest of the target node from all other nodes in the network).

Two thousand (n = 2000) patients were randomly selected and invited to participate. A total of 1969 (age:61 ± 16 years, 46.4% women) were included. The most common symptoms at hospital admission were fever (74.6%), dyspnoea (31.5%), myalgia (30.7%) and cough (27.9%). The network identified one group of variables grouping all COVID-19-onset symptoms at hospitalisation, and a second one grouping all pre-existing medical co-morbidities (Fig. 1). Multiple positive correlations between the variables in each group were found. The highest correlation (ρρ:5.87) in the medical co-morbidity group was between asthma (node 9) and rheumatological diseases (node 13). Within the COVID-19-onset symptoms group, headache (node 20) had several high correlations with fever (node 16, ρρ:5.981), dyspnoea (node 17, ρρ:5.617), anosmia (node 22, ρρ:5.2276 and ageusia (node 23, ρρ:4.660). No correlations between both groups of variables were seen. In the group of COVID-19-onset symptoms, headache was the node showing the highest strength centrality, highest betweenness centrality and highest closeness centrality (node 20, Fig. 2).

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Source: Fernández-de-las-Peñas, C., Varol, U., Gómez-Mayordomo, V. et al. The relevance of headache as an onset symptom in COVID-19: a network analysis of data from the LONG-COVID-EXP-CM multicentre study. Acta Neurol Belg (2022). https://doi.org/10.1007/s13760-022-01998-x  https://link.springer.com/article/10.1007/s13760-022-01998-x (Full text)

Small fiber neuropathy underlying dysautonomia in COVID-19 and in post-SARS-CoV-2 vaccination and long-COVID syndromes

Letter:

We eagerly read the excellent editorial by Gemignani and the corresponding original article by Abrams et al. about the suspected involvement of small fibers (small fiber neuropathy [SFN]) in acute severe, acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and in long-coronavirus disease (COVID) syndrome.1, 2 It was speculated that at least some of the clinical manifestations of long-COVID syndrome could be attributed to involvement of small nerve fibers by the viral infection. The authors believe that studies are needed that investigate the role of autonomic dysfunction in long-COVID syndrome and the prevalence of SFN by means of the 13-item SFN symptom inventory questionnaire. The papers are appealing but raise some concerns that require discussion.

I do not agree with the notion that long-COVID syndrome is the same as post-COVID syndrome.1 Acute COVID-19 usually lasts one to 4 wk. Subacute COVID-19 lasts 5 to 12 wk. When clinical manifestations of COVID-19 persist beyond 12 wk, the condition is termed post-COVID syndrome. Both subacute COVID-19 and post-COVID syndrome are included under the overarching term long-COVID-syndrome. Differentiating long-COVID syndrome from post-COVID-syndrome is crucial for their management and for assessing long-term outcomes.

An issue not addressed in the paper is Guillain-Barre syndrome (GBS) due to an infection with SARS-CoV-2.3 There is ample evidence that the immune response to the virus can trigger autoimmune reactions, including those that are involved in the development of GBS. There is evidence accumulating that mRNA- and vector-based anti-SARS-CoV-2 vaccines can trigger the development of GBS.4 GBS can affect not only motor and sensory fibers, but also peripheral autonomic fibers, particularly in the GBS subtype of acute motor and sensory axonal neuropathy (AMSAN). There is a subtype of GBS that may exclusively affect autonomic fibers and present with pure dysautonomia.5 Because GBS may be mild, it can go unrecognized; because patients often have a long recovery time, autonomic manifestations in long COVID syndrome could be explained by incomplete recovery from autonomic involvement in abortive GBS.

Not addressed in the articles is the involvement of the central autonomic nervous system (ANS). There are several reports demonstrating that a SARS-CoV-2 infection can be complicated by hypophysitis.6 Furthermore, patients with a pre-existing pituitary micro- or macro-adenoma have an increased risk of pituitary apoplexy during SARS-CoV-2 infection.7 Accordingly, the hypophysial-pituitary-adrenergic axis can be impaired,8 thus leading to autonomic dysfunction.

Autonomic dysfunction may not always be recognized by those involved in the management of COVID-19 patients. Thus, patients with SARS-CoV-2 infection are often not investigated sufficiently for their symptoms of autonomic dysfunction, such as insomnia, fatigue, cognitive impairment, hypersensitivity to light, blurred vision, dry eyes or mouth, drooling, palpitations, syncope, orthostatic dizziness, hot flashes, dysphagia, bowel or bladder dysfunction, sexual dysfunction, changes in skin, hair, and nails, or abnormalities of sweating. Studies that may be performed to assess ANS involvement are a contrast-enhanced magnetic resonance imaging (MRI) of the pituitary gland, determination of releasing factors, pituitary stimulating hormones, and hormones of peripheral endocrine organs, and diagnostic testing for involvement of the peripheral ANS. Several of the latter tests are not widely available and their sensitivity and specificity may be low if portions of the peripheral ANS are tested that are not affected.

Not addressed was the role of anti-COVID-19 drugs in the development of SFN. There is increasing evidence that some of the compounds administered to infected patients are neurotoxic and can be responsible for polyneuropathy. Some of these compounds, such as lopinavir, ritonavir, daptomycin, and linezolid, may also damage autonomic fibers.

I agree that there is a need to investigate the involvement of the central and peripheral ANS in some patients with acute SARS-CoV-2 infections or long-COVID syndrome. Such patients should be investigated not only by use of questionnaires and the Quantitative Sudomotor Axon Reflex Test (QSART) but particularly by quantitative sensory testing (QST), micro-neurography of C-fibers of the superficial peroneal nerve, sensory stimulation tests, the deep breathing test, the Valsalva maneuver, tilt testing, cerebral blood flow velocity measurements, pain-related evoked potentials (PREP), laser speckle contact analysis (LASCA), laser Doppler flowmetry, laser Doppler imaging, contact heat-evoked potentials (CHEP), corneal confocal microscopy (CCM), and proximal or distal skin biopsy stained with protein gene product (PGP) 9.5. Furthermore, hormone levels should be determined and autopsy of COVID-19 patients should include histological investigations of central and peripheral autonomic pathways.

Source: Finsterer J. Small fiber neuropathy underlying dysautonomia in COVID-19 and in post-SARS-CoV-2 vaccination and long-COVID syndromes. Muscle Nerve. 2022 Apr 6. doi: 10.1002/mus.27554. Epub ahead of print. PMID: 35385125.  https://onlinelibrary.wiley.com/doi/10.1002/mus.27554 (Full text)

Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients

Abstract:

Objectives: Post–COVID-19 symptoms experienced by many survivors have a further devastating effect. This study aimed to analyze the risk factors associated with long COVID-19 in a prospective cohort of hospitalized patients including those requiring intensive care unit (ICU) transfer, taking into account objective measures of COVID-19 severity.

Methods: Hospitalized patients with confirmed COVID-19 were enrolled. A structured follow-up visit was performed 4 months after hospital admission. Multivariable adjusted regression models were used to analyse the association between parameters at the acute phase and persistent symptoms.

Results: A follow-up visit was performed in 316 patients including 115 (36.4%) discharged from the ICU. Mean age was 64.1 years, and 201 patients (58.3%) were men. Female sex (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.17-3.22; P =.01), hypertension (OR, 2.01; 95% CI, 1.22-3.31; P <.01), and the number of initial symptoms (NIS) (OR, 1.35; 95% CI, 1.17-1.54; P <.001) were significantly associated with long COVID-19. Number of persistent symptoms was significantly associated with NIS (adjusted incidence rate ratio [aIRR], 1.16; 95% CI, 1.11-1.22; P <.001), female sex (aIRR, 1.56; 95% CI 1.29-1.87; P <.001), hypertension (aIRR, 1.23; 95% CI, 1.02-1.50; P =.03), and length of stay in hospital (aIRR, 1.01; 95% CI, 1.005-1.017; P <.001).

Conclusion: Our study suggested that female sex, hypertension, and NIS had a significant impact on persistent symptoms in hospitalized patients in contrast to severity of acute COVID-19 infection.

Source: Adrien CSK, Alexandre C, Marie M, Cédric J, Schmit JL, Jean-Philippe L, Claire A. Number of initial symptoms is more related to long COVID-19 than acute severity of infection: a prospective cohort of hospitalized patients. Int J Infect Dis. 2022 Mar 4;118:220–3. doi: 10.1016/j.ijid.2022.03.006. Epub ahead of print. PMID: 35257903; PMCID: PMC8896858. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8896858/ (Full text)