Headache as a COVID-19 onset symptom or Post-COVID symptom according to the SARS-CoV-2 Variant.

INTRODUCTION: COVID19 associated headaches are highly common and there is currently an unmet need to better understand their association with SARSCoV2 variants. Headaches are a prevalent symptom in the acute phase of COVID19 and are associated with a better prognosis and better immune response. They are also a relevant post-COVID symptom. AREAS COVERED: This article analyses the differences in the prevalence of headache as an onset symptom and in post-COVID headache among the different SARS-CoV-2 variants: the historical strain, Alpha, Delta and Omicron. The different pathophysiological mechanisms by which SARS-CoV-2 infection may cause headache are also discussed. EXPERT OPINION: The presence of headache at the acute phase is a risk factor for post-COVID headache, whereas a history of primary headache does not appear to be associated with post-COVID headache. The prevalence of headache as an onset symptom appears to be variable for the different SARS-CoV-2 variants, but current data are inconclusive. However, the current evidence also suggests that headache represents a prevalent symptom in the acute and post-infection COVID-19 phase, regardless of SARS-CoV-2 variant.

Headache as a COVID-19 onset symptom and post-COVID-19 symptom in hospitalized COVID-19 survivors infected with the Wuhan, Alpha, or Delta SARS-CoV-2 variants.

OBJECTIVE: This study looked at differences in the presence of headache as an onset symptom of coronavirus disease 2019 (COVID-19) and as a post-COVID-19 symptom in individuals previously hospitalized owing to infection with the Wuhan, Alpha, or Delta variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). BACKGROUND: Headache can be present in up to 50% of individuals during the acute phase of SARS-CoV-2 infection and in 10% of subjects during the post-COVID-19 phase. There are no data on differences in the occurrence of headache in the acute- and post-COVID-19 phase according to the SARS-CoV-2 variants. METHODS: A cross-sectional cohort study was conducted. Unvaccinated subjects previously hospitalized for COVID-19 caused by the Wuhan (n = 201), Alpha (n = 211), or Delta (n = 202) SARS-CoV-2 variants were scheduled for a telephone interview 6 months after hospital discharge. Hospitalization data were collected from hospital medical records. RESULTS: The presence of headache as a COVID-19 onset symptom at hospitalization was higher in subjects with the Delta variant (66/202, 32.7%) than in those infected with the Wuhan (42/201, 20.9%; odds ratio [OR] 1.83, 95% confidence interval [CI] 1.17-2.88) or Alpha (25/211, 11.8%; OR 3.61, 95% CI, 2.16-6.01) variants. The prevalence of post-COVID-19 headache 6 months after hospital discharge was higher in individuals infected with the Delta variant (26/202, 12.9%) than in those infected with the Wuhan (11/201, 5.5%; OR 2.52, 95% CI 1.22-5.31) or Alpha (eight of 211, 3.8%; OR 3.74, 95% CI 1.65-8.49) variants. The presence of headache as a COVID-19 onset symptom was associated with post-COVID-19 headache in subjects infected with the Wuhan (OR 7.75, 95% CI 2.15-27.93) and Delta variants (OR 2.78, 95% CI 1.20-6.42) but not with the Alpha variant (OR 2.60, 95% CI 0.49-13.69). CONCLUSION: Headache was a common symptom in both the acute- and post-COVID-19 phase in subjects infected with the Wuhan, Alpha, and Delta variants but mostly in those infected with the Delta variant.

Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study.

This multicenter cohort study investigated the differences between coronavirus disease 2019 (COVID-19) related symptoms and post-COVID symptoms between male and female COVID-19 survivors. Clinical and hospitalization data were collected from hospital medical records in a sample of individuals recovered from COVID-19 at five public hospitals in Spain. A predefined list of post-COVID symptoms was systematically assessed, but patients were free to report any symptom. Anxiety/depressive levels and sleep quality were also assessed. Adjusted multivariate logistic regressions were used to identify the association of sex with post-COVID related-symptoms. A total of 1969 individuals (age: 61, SD: 16 years, 46.4% women) were assessed 8.4 months after discharge. No overall significant sex differences in COVID-19 onset symptoms at hospital admission were found. Post-COVID symptoms were present in up to 60% of hospitalized COVID-19 survivors eight months after the infection. The number of post-COVID symptoms was 2.25 for females and 1.5 for males. After adjusting by all variables, female sex was associated with ≥3 post-COVID symptoms (adj OR 2.54, 95%CI 1.671-3.865, p < 0.001), the presence of post-COVID fatigue (adj OR 1.514, 95%CI 1.040-2.205), dyspnea (rest: adj OR 1.428, 95%CI 1.081-1.886, exertion: adj OR 1.409, 95%CI 1.109-1.791), pain (adj OR 1.349, 95%CI 1.059-1.720), hair loss (adj OR 4.529, 95%CI 2.784-7.368), ocular problems (adj OR 1.981, 95%CI 1.185-3.312), depressive levels (adj OR 1.606, 95%CI 1.002-2.572) and worse sleep quality (adj OR 1.634, 95%CI 1.097-2.434). Female sex was a risk factor for the development of some long-term post-COVID symptoms including mood disorders. Healthcare systems should consider sex differences in the management of long haulers.

Prevalence and risk factors of musculoskeletal pain symptoms as long-term post-COVID sequelae in hospitalized COVID-19 survivors: a multicenter study.

ABSTRACT: This study investigated the prevalence of long-term musculoskeletal post-COVID pain and their risk factors in a large cohort of COVID-19 survivors. A multicenter cohort study including patients hospitalised because of COVID-19 in 5 hospitals of Madrid (Spain) during the first wave of the pandemic was conducted. Hospitalisation and clinical data were collected from medical records. Patients were scheduled for a telephone interview after hospital discharge for collecting data about the musculoskeletal post-COVID pain. Anxiety/depressive levels and sleep quality were likewise assessed. From 2000 patients recruited, a total of 1969 individuals (46.4% women, age: 61 years, SD: 16 years) were assessed on average at 8.4 (SD: 1.5) months after discharge. At the time of the study, 887 (45% women) reported musculoskeletal post-COVID pain. According to the presence of previous pain symptoms, the prevalence of "de novo" (new-onset) musculoskeletal post-COVID pain was 74.9%, whereas 25.1% experienced an increase in previous symptoms (exacerbated COVID-related pain). Female sex (odds ratio [OR]: 1.349, 95% confidence interval [CI]: 1.059-1.720), history of musculoskeletal pain (OR 1.553, 95% CI 1.271-1.898), presence of myalgia (OR 1.546, 95% CI 1.155-2.070) and headache (1.866, 95% CI 1.349-2.580) as COVID-19-associated onset symptoms, and days at hospital (OR 1.013, 95% CI 1.004-1.022) were risk factors associated with musculoskeletal post-COVID pain. In conclusion, musculoskeletal post-COVID pain is present in 45.1% of COVID-19 survivors at 8 months after hospital discharge with most patients developing de novo post-COVID pain. Female sex, history of musculoskeletal pain, presence of myalgia and headache as COVID-19 symptoms at the acute phase, and days at hospital were risk factors associated with musculoskeletal post-COVID pain.

Fatigue and Dyspnoea as Main Persistent Post-COVID-19 Symptoms in Previously Hospitalized Patients: Related Functional Limitations and Disability.

BACKGROUND: Multicentre studies focussing on specific long-term post-COVID-19 symptoms are scarce. OBJECTIVE: The aim of this study was to determine the levels of fatigue and dyspnoea, repercussions on daily life activities, and risk factors associated with fatigue or dyspnoea in COVID-19 survivors at long term after hospital discharge. METHODS: Age, gender, height, weight, symptoms at hospitalization, pre-existing medical comorbidity, intensive care unit admission, and the presence of cardio-respiratory symptoms developed after severe acute respiratory syndrome coronavirus 2 infection were collected from patients who recovered from COVID-19 at 4 hospitals in Madrid (Spain) from March 1 to May 31, 2020 (first COVID-19 wave). The Functional Impairment Checklist was used for evaluating fatigue/dyspnoea levels and functional limitations. RESULTS: A total of 1,142 patients (48% women, age: 61, standard deviation [SD]: 17 years) were assessed 7.0 months (SD 0.6) after hospitalization. Fatigue was present in 61% patients, dyspnoea with activity in 55%, and dyspnoea at rest in 23.5%. Only 355 (31.1%) patients did not exhibit fatigue and/or dyspnoea 7 months after hospitalization. Forty-five per cent reported functional limitations with daily living activities. Risk factors associated with fatigue and dyspnoea included female gender, number of pre-existing comorbidities, and number of symptoms at hospitalization. The number of days at hospital was a risk factor just for dyspnoea. CONCLUSIONS: Fatigue and/or dyspnoea were present in 70% of hospitalized COVID-19 survivors 7 months after discharge. In addition, 45% patients exhibited limitations on daily living activities. Being female, higher number of pre-existing medical comorbidities and number of symptoms at hospitalization were risk factors associated to fatigue/dyspnoea in COVID-19 survivors 7 months after hospitalization.

Headache as an acute and post-COVID-19 symptom in COVID-19 survivors: A meta-analysis of the current literature.

BACKGROUND: Headache is identified as a common post-COVID sequela experienced by COVID-19 survivors. The aim of this pooled analysis was to synthesize the prevalence of post-COVID headache in hospitalized and non-hospitalized patients recovering from SARS-CoV-2 infection. METHODS: MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers, were searched up to 31 May 2021. Studies or preprints providing data on post-COVID headache were included. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. Random effects models were used for meta-analytical pooled prevalence of post-COVID headache. Data synthesis was categorized at hospital admission/symptoms' onset, and at 30, 60, 90, and ≥180 days afterwards. RESULTS: From 9573 studies identified, 28 peer-reviewed studies and 7 preprints were included. The sample was 28,438 COVID-19 survivors (12,307 females; mean age: 46.6, SD: 17.45 years). The methodological quality was high in 45% of the studies. The overall prevalence of post-COVID headache was 47.1% (95% CI 35.8-58.6) at onset or hospital admission, 10.2% (95% CI 5.4-18.5) at 30 days, 16.5% (95% CI 5.6-39.7) at 60 days, 10.6% (95% CI 4.7-22.3) at 90 days, and 8.4% (95% CI 4.6-14.8) at ≥180 days after onset/hospital discharge. Headache as a symptom at the acute phase was more prevalent in non-hospitalized (57.97%) than in hospitalized (31.11%) patients. Time trend analysis showed a decreased prevalence from the acute symptoms' onset to all post-COVID follow-up periods which was maintained afterwards. CONCLUSION: This meta-analysis found that the prevalence of post-COVID headache ranged from 8% to 15% during the first 6 months after SARS-CoV-2 infection.

Previous History of Migraine Is Associated With Fatigue, but Not Headache, as Long-Term Post-COVID Symptom After Severe Acute Respiratory SARS-CoV-2 Infection: A Case-Control Study.

OBJECTIVE: To investigate the association of pre-existing migraine in patients hospitalised and who recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the presence of post-coronavirus disease (COVID) symptoms. BACKGROUND: No study has investigated the role of migraine as a risk factor for development of post-COVID symptoms. METHODS: A case-control study including individuals hospitalised during the first wave of the pandemic (from February 20 to May 31, 2020) was conducted. Patients with confirmed previous diagnosis of migraine were considered cases. Two age- and sex-matched individuals without a history of headache per case were also recruited as controls. Hospitalisation/clinical data were collected from hospital medical records. Patients were scheduled for a telephone interview. A list of post-COVID symptoms was systematically evaluated, but participants were invited to freely report any symptom. The Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index were used to assess anxiety/depressive symptoms and sleep quality. Multivariable conditional logistic regression models were constructed. RESULTS: Overall, 57 patients with confirmed diagnosis of migraine and 144 non-migraine controls who had recovered from COVID-19 were assessed at 7.3 months (SD 0.6) after hospital discharge. The number of post-COVID symptoms in the migraine group was significantly greater (OR 1.70, 95% CI 1.29-2.25, P < 0.001) than in the non-migraine group. Fatigue was significantly more prevalent (OR 2.89, 95% CI 1.32-6.32, P = 0.008) in the migraine group. However, no between-groups difference in the prevalence of headache as a post-COVID symptom was detected. CONCLUSION: Patients with a history of migraine who recovered from COVID-19 exhibited more long-term fatigue as post-COVID sequelae than those without migraine. Some of the pathophysiological changes associated with migraine could predispose to the occurrence of post-COVID symptoms.

The presence of headache at onset in SARS-CoV-2 infection is associated with long-term post-COVID headache and fatigue: A case-control study.

OBJECTIVE: To investigate the association of headache during the acute phase of SARS-CoV-2 infection with long-term post-COVID headache and other post-COVID symptoms in hospitalised survivors. METHODS: A case-control study including patients hospitalised during the first wave of the pandemic in Spain was conducted. Patients reporting headache as a symptom during the acute phase and age- and sex-matched patients without headache during the acute phase participated. Hospitalisation and clinical data were collected from medical records. Patients were scheduled for a telephone interview 7 months after hospital discharge. Participants were asked about a list of post-COVID symptoms and were also invited to report any additional symptom they might have. Anxiety/depressive symptoms and sleep quality were assessed with the Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index. RESULTS: Overall, 205 patients reporting headache and 410 patients without headache at hospitalisation were assessed 7.3 months (Standard Deviation 0.6) after hospital discharge. Patients with headache at onset presented a higher number of post-COVID symptoms (Incident Rate Ratio: 1.16, 95% CI: 1.03-1.30). Headache at onset was associated with a previous history of migraine (Odd Ratio: 2.90, 95% Confidence Interval: 1.41-5.98) and with the development of persistent tension-type like headache as a new post-COVID symptom (Odd Ratio: 2.65, 95% CI: 1.66-4.24). Fatigue as a long-term symptom was also more prevalent in patients with headache at onset (Odd Ratio: 1.55, 95% CI: 1.07-2.24). No between-group differences in the prevalence of anxiety/depressive symptoms or sleep quality were seen. CONCLUSION: Headache in the acute phase of SARS-CoV-2 infection was associated with higher prevalence of headache and fatigue as long-term post-COVID symptoms. Monitoring headache during the acute phase could help to identify patients at risk of developing long-term post-COVID symptoms, including post-COVID headache.

Prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized COVID-19 survivors: A systematic review and meta-analysis.

BACKGROUND: Single studies support the presence of several post-COVID-19 symptoms; however, no meta-analysis differentiating hospitalized and non-hospitalized patients has been published to date. This meta-analysis analyses the prevalence of post-COVID-19 symptoms in hospitalized and non-hospitalized patients recovered from COVID-19 . METHODS: MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were searched up to March 15, 2021. Peer-reviewed studies or preprints reporting data on post-COVID-19 symptoms collected by personal, telephonic or electronic interview were included. Methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. We used a random-effects models for meta-analytical pooled prevalence of each post-COVID-19 symptom, and I² statistics for heterogeneity. Data synthesis was categorized at 30, 60, and ≥90 days after . RESULTS: From 15,577 studies identified, 29 peer-reviewed studies and 4 preprints met inclusion criteria. The sample included 15,244 hospitalized and 9011 non-hospitalized patients. The methodological quality of most studies was fair. The results showed that 63.2, 71.9 and 45.9% of the sample exhibited ≥one post-COVID-19 symptom at 30, 60, or ≥90days after onset/hospitalization. Fatigue and dyspnea were the most prevalent symptoms with a pooled prevalence ranging from 35 to 60% depending on the follow-up. Other post-COVID-19 symptoms included cough (20-25%), anosmia (10-20%), ageusia (15-20%) or joint pain (15-20%). Time trend analysis revealed a decreased prevalence 30days after with an increase after 60days . CONCLUSION: This meta-analysis shows that post-COVID-19 symptoms are present in more than 60% of patients infected by SARS-CoV­2. Fatigue and dyspnea were the most prevalent post-COVID-19 symptoms, particularly 60 and ≥90 days after.

Proposed integrative model for post-COVID symptoms.

BACKGROUND AND AIMS: To propose an integrative model for post-COVID symptoms by considering the absence/presence of previous symptomatology. METHODS: We searched different databases for original articles and reviews on post-COVID symptoms. RESULTS: The first consideration is to define which symptoms are of "new-onset" (symptoms never experienced by a patient before COVID-19 and experienced the first time after) and which symptoms are "exacerbated" (symptoms experienced by a patient prior to COVID-19 but aggravated later) after infection. The second consideration includes defining "persistent" (symptoms experienced at the acute phase and continuing after without remission period) and "delayed-onset" (symptoms not experienced at the acute phase of the infection but appearing after a "latency period"). This model integrates predisposing individual factors, biological factors associated to the severity of disease, hospitalization/treatment factors, and outbreak surrounding factors which may promote post-COVID. CONCLUSION: Since current literature on post-COVID is heterogeneous, this integrative model could help to a better characterization of long-COVID.

Defining Post-COVID Symptoms (Post-Acute COVID, Long COVID, Persistent Post-COVID): An Integrative Classification.

The pandemic of the coronavirus disease 2019 (COVID-19) has provoked a second pandemic, the "long-haulers", i.e., individuals presenting with post-COVID symptoms. We propose that to determine the presence of post-COVID symptoms, symptoms should appear after the diagnosis of SARS-CoV-2 infection; however, this situation has some problems due to the fact that not all people infected by SARS-CoV-2 receive such diagnosis. Based on relapsing/remitting nature of post-COVID symptoms, the following integrative classification is proposed: potentially infection related-symptoms (up to 4-5 weeks), acute post-COVID symptoms (from week 5 to week 12), long post-COVID symptoms (from week 12 to week 24), and persistent post-COVID symptoms (lasting more than 24 weeks). The most important topic is to establish the time reference points. The classification also integrates predisposing intrinsic and extrinsic factors and hospitalization data which could promote post-COVID symptoms. The plethora of symptoms affecting multiple systems exhibited by "long-haulers" suggests the presence of different underlying mechanisms.