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).

Read the rest of this article HERE.

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)

Onset Patterns of Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: A Mixed Method Approach

Abstract:

The onset of Chronic fatigue syndrome (CFS) and Myalgic Encephalomyelitis (ME) is considered a key area of inquiry. Case criteria for ME and CFS and much of the academic literature suggest that patients typically experience one of two possible onset patterns: sudden or gradual. The current study provided an in-depth investigation of ME and CFS onset in order to provide insight into early symptoms, onset duration, and the progression of functional disability. We collected qualitative descriptive data to gain a rich description of illness onset from the patients’ point of view.

Overall, qualitative findings revealed detailed descriptions of ME and CFS onset experiences. Major themes that emerged from the data included: onset/illness progression patterns, illness causes, methods of adapting and coping, hardworking and active lives prior to onset, healthy lives prior to onset, prior health problems, comorbid health conditions, emotional responses to onset, exertional effects, the illness as life limiting, stress, traumatic experiences, lack of support, support, and treatment limitations. A closer examination of the onset/illness progression patterns that emerged from the data provided evidence that individuals with ME and CFS experience complex onset patterns.

Furthermore, the study findings suggest that the method of categorizing individuals into sudden versus gradual onset groups fails to capture the more nuanced and varied onset experiences. Prospective research studies that capture the onset period as it is developing could lead to improvements in the way we define and assess ME and CFS onset, and may also lead to methods for early detection, prevention, and individualized treatment approaches.

Source: Meredyth Anne Evans & Leonard A. Jason. Onset Patterns of Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: A Mixed Method Approach. Res Chron Dis (2018) 2(1), 001–0030 (Full article)

Chronic fatigue syndrome versus sudden onset myalgic encephalomyelitis

Abstract:

A revised sudden onset case definition for Myalgic Encephalomyelitis (ME) has been developed (Jason, Damrongvachiraphan, et al., 2012 ) based on past case definitions. In a prior study, Jason, Brown, and colleagues ( 2012 ) compared patients recruited using the 1994 case definition of chronic fatigue syndrome (CFS) to contrast those meeting criteria for the revised ME criteria.

They found that this revised ME case definition identified patients with more functional impairments and physical, mental, and cognitive problems than those meeting the CFS criteria. The study by Jason, Brown, et al. ( 2012 ) only selected individuals who first met the CFS criteria, and it only relied on one Chicago-based data set. The current study replicated this comparison with two distinct data sets with different case ascertainment methods. Results indicate that the ME criteria identified a group of patients with more functional disabilities as well as more severe post-exertional malaise symptoms.

 

Source: Jason LA, Evans M, Brown A, Sunnquist M, Newton JL. Chronic fatigue syndrome versus sudden onset myalgic encephalomyelitis. J Prev Interv Community. 2015;43(1):62-77. doi: 10.1080/10852352.2014.973233. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295655/ (Full article)

 

Search for Borna disease virus in Danish fibromyalgia patients

Abstract:

OBJECTIVE: The purpose of this study was to look for Borna disease virus (BDV) in 18 patients with acute onset of fibromyalgia (FMS) following a “flu-like” episode. BDV is a neurotropic RNA virus affecting horses and sheep. Infections in animals have been reported to cause immune mediated disease characterized by abnormalities in behavior. A possible link between BDV and neuropsychiatric diseases in man has been described, and lately a connection to chronic fatigue syndrome (CFS) has been suggested.

METHODS: A BDV-specific nested PCR (RT-PCR) was performed on serum and spinal fluid.

RESULTS: The BDV genome was not detected in any of the FMS cases.

CONCLUSION: Although BDV was not demonstrated in spinal fluid or serum from the tested patients with FMS, we believe that it is important to report our results, since FMS can exhibit many manifestations in common with CFS. Possible reasons for the discrepant findings are discussed.

 

Source: Wittrup IH, Christensen LS, Jensen B, Danneskiold-Samsee B, Bliddal H, Wiik A. Search for Borna disease virus in Danish fibromyalgia patients. Scand J Rheumatol. 2000;29(6):387-90. http://www.ncbi.nlm.nih.gov/pubmed/11132208

 

Longitudinal analysis of symptoms reported by patients with chronic fatigue syndrome

Abstract:

PURPOSE: To determine the effect of chronic fatigue syndrome (CFS) illness duration and onset type on the likelihood of reporting a symptom during successive follow-up periods.

METHODS: In 1997, a two-phase RDD survey in Wichita, Kansas, was conducted to estimate the prevalence of CFS. Phase I identified 56,154 respondents 18-69 years of age and screened for severe fatigue, extreme tiredness or exhaustion lasting for 1 month or longer. In phase II an equal number of fatigued (n = 7,176) and randomly selected non-fatigued subjects were asked about 8 CFS and 13 non-CFS symptoms, as well as the presence of specific medical and psychiatric conditions. Eligible respondents were clinically evaluated to establish CFS diagnosis. Phase II respondents were re-contacted at 12- (n = 4,331) and 24-months (n = 4,266) for additional follow-up and diagnosis. In this study we considered symptoms reported as being present most of the time during each successive observation period. Generalized estimating equations were used to model symptoms over time and to address study questions. Such a model accounts for correlations among repeated symptoms for each subject. We used an auto-regressive structure for the correlation matrix, assuming the correlations between each pair of repeated symptoms should decrease as the time between symptoms increased.

RESULTS: There were 74 CFS patients who had been ill for 1 to 20 years (median = 6.3 years). Among these, 46 reported gradual and 28 reported sudden onset. Symptoms fluctuated over the course of illness. However, only stomach pain (non-CFS symptom) was more likely to be reported as duration of illness increased (p < 0.05). There was no association between onset type and the likelihood of reporting a symptom during an interview, except that chills and severe headaches were more likely to be reported by sudden cases.

CONCLUSIONS: The likelihood of expressing CFS and non-CFS symptom “most of the time” is the same across years of illness. More analyses are warranted to consider expression of symptoms for >/=6 months and severe symptoms.

 

Source: Nisenbaum R, Jones A, Jones J, Reeves W. Longitudinal analysis of symptoms reported by patients with chronic fatigue syndrome. Ann Epidemiol. 2000 Oct 1;10(7):458. http://www.ncbi.nlm.nih.gov/pubmed/11018368

 

Idiopathic chronic fatigue and chronic fatigue syndrome: a comparison of two case-definitions

Abstract:

The aim of the study was to compare the signs and symptoms of individuals meeting two different definitions of chronic fatigue syndrome (CFS). Ninety-four patients fitting the eligibility criteria for idiopathic fatigue were enrolled into the study. Of the 94 patients, 48 met the 1988 definition of CFS, 20 the 1994 (but not the 1988) definition of CFS, and 26 met neither definition.

The 1994 defined cases were more likely than 1988 defined cases, and non-syndromal individuals to be male, married, and high school educated. The 1994 cases were less likely than 1988 cases to present acute onset, self reported sore throat, mild fever lymphadenopathy, pharyngitis.

In conclusion, the 1994 criteria increased the number of patients classified as CFS; however, those who fit only the 1994 criteria were less likely to have an acute symptomatic onset and signs and symptoms suggestive of an infectious process.

 

Source: Arpino C, Carrieri MP, Valesini G, Pizzigallo E, Rovere P, Tirelli U, Conti F, Dialmi P, Barberio A, Rusconi N, Bosco O, Lazzarin A, Saracco A, Moro ML,Vlahov D. Idiopathic chronic fatigue and chronic fatigue syndrome: a comparison of two case-definitions. Ann Ist Super Sanita. 1999;35(3):435-41. http://www.ncbi.nlm.nih.gov/pubmed/10721210

 

A 56-Year-Old Woman With Chronic Fatigue Syndrome, 1 Year Later

In June 1997, at the Medicine Grand Rounds, Dr Anthony Komaroff discussed Ms H, an educator unable to work because of debilitating symptoms associated with a 2-year history of chronic fatigue. Her ailment, which began shortly after a flu-like illness, was marked primarily by weakness, fatigue, chronic insomnia, and depression that she felt was in response to her symptoms. In recent years she had felt somewhat less depressed, and wondered also if the disease might be slowly diminishing in its severity.

You can read the rest of this article here: http://jama.jamanetwork.com/article.aspx?articleid=187800

 

Source: Thomas L. Delbanco, MD; Jennifer Daley, MD; Erin E. Hartman, MS. A 56-Year-Old Woman With Chronic Fatigue Syndrome, 1 Year Later. JAMA. 1998;280(4):372. doi:10.1001/jama.280.4.372. http://jama.jamanetwork.com/article.aspx?articleid=187800

Course and outcome of chronic fatigue in children and adolescents

Abstract:

PURPOSE: To describe the epidemiology, symptoms, and psychosocial characteristics of children and adolescents evaluated in a chronic fatigue program and determine the course and outcome of the syndrome in these patients.

METHODS: During the summer of 1994, chart review was performed for the 58 patients evaluated between 1990 and 1994 and a telephone follow-up was conducted with 42 of the 58 families. Patients were predominantly female (71%) and white (94%), with 50% between the ages of 7 and 14 years and 50% between the ages of 15 and 21 years (mean age 14.6 years).

RESULTS: At time of presentation, 50% of patients had been fatigued for 1 to 6 months and 50% had been fatigued for 7 to 36 months. Sixty percent indicated the fatigue had begun with an acute illness and 60% had a history of allergies. Most commonly reported symptoms were fatigue (100%), headache (74%), sore throat (59%), abdominal pain (48%), fever (36%), and difficulties with concentration and/or memory (33%). Most patients had a worsening of school performance and a decrease in social activities. On follow-up, there was significant improvement in many patients during the summer after the first visit, with continued improvement in most patients during the second and third years. At time of the follow-up telephone call, 43% of families considered their child “cured” and 52% considered their child “improved,” whereas only 5% considered their child to be “the same.” Statistical analyses demonstrated no demographic or clinical factors that distinguished between those who did or did not participate in the follow-up study, or between those who did or did not do well on follow-up.

CONCLUSIONS: These data demonstrate that children and adolescents with chronic fatigue have a syndrome that is similar to that described in adults, but that the syndrome differs in several ways, most specifically, presentation earlier in the course of the illness and a more optimistic outcome.

 

Source: Krilov LR, Fisher M, Friedman SB, Reitman D, Mandel FS. Course and outcome of chronic fatigue in children and adolescents. Pediatrics. 1998 Aug;102(2 Pt 1):360-6. http://www.ncbi.nlm.nih.gov/pubmed/9685439

 

Sudden vs gradual onset of chronic fatigue syndrome differentiates individuals on cognitive and psychiatric measures

Abstract:

To examine the influence of mode of illness onset on psychiatric status and neuropsychological performance, 36 patients with CFS were divided into two groups: sudden vs gradual onset of symptoms.

These two CFS subgroups were compared to each other and to sedentary healthy controls on standardized neuropsychological tests of attention/concentration, information processing efficiency, memory, and higher cortical functions. In addition, the distribution of comorbid Axis I psychiatric disease between the two CFS groups was examined.

The rate of concurrent psychiatric disease was significantly greater in the CFS-gradual group relative to the CFS-sudden group. While both CFS groups showed a significant reduction in information processing ability relative to controls, impairment in memory was more severe in the CFS-sudden group. Because of the significant heterogeneity of the CFS population, the need for subgroup analysis is discussed.

 

Source: DeLuca J, Johnson SK, Ellis SP, Natelson BH. Sudden vs gradual onset of chronic fatigue syndrome differentiates individuals on cognitive and psychiatric measures. J Psychiatr Res. 1997 Jan-Feb;31(1):83-90. http://www.ncbi.nlm.nih.gov/pubmed/9201650

 

Chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) has emerged as a public health concern over the past decade. A working case definition was created in 1988 and revised in 1994, and this has been used to establish prevalence estimates using physician-based surveillance and an a random digit dial telephone survey. Although CFS has some characteristics of an infectious disease, so far no infectious agent has been associated with the illness. Studies of immune function in CFS patients failed to detect differences between cases and healthy controls. However, when cases were subgrouped according to whether they had a sudden or gradual onset, differences in immunologic markers were detected between cases and their matched controls.

 

Source: Mawle AC. Chronic fatigue syndrome. Immunol Invest. 1997 Jan-Feb;26(1-2):269-73. http://www.ncbi.nlm.nih.gov/pubmed/9037629