Headache Medicine 2021, 12(2) p-ISSN 2178-7468, e-ISSN 2763-6178

105

ASAA

DOI: 10.48208/HeadacheMed.2021.20

Headache Medicine

Review

Most prevalent symptoms associated with headache in COVID-19

patients in the acute phase: a systematic review

Vitória Rodrigues Salomão

, Anna Júlia Romão Baccarin

, Thaís Yayoi Okido

Pontifícia Universidade Católica do Paraná, Campus Londrina (PUC-PR), Londrina, Brazil.

Abstract

Introduction

Considering the frequency of headache among the neurological symptoms of COVID-19,

there is a need to understand other manifestations associated with this complaint.

Objective

To review the literature regarding the most prevalent symptoms associated with headache in

patients diagnosed with COVID-19.

Method

A systematic literature review was carried out on studies that evaluated published articles

about clinical characteristics and headache associated symptoms in patients diagnosed with

COVID-19.

Results

Among the 1,190 patients in the analyzed studies, the following signs and symptoms were

associated with headache: fever, hyposmia, anosmia, ageusia, phonophobia, dehydration,

prostration and symptoms of the gastrointestinal tract.

Conclusion

Headache was the main neurological symptom of COVID-19, among the main associated

symptoms are fever, hyposmia or anosmia, ageusia and phonophobia.

Vitória Rodrigues Salomão

Rua Anu Branco, 366,

Jardim Portal das Flores, CEP:

86701-530Arapongas, PR, Brasil

vitoria_salomao@hotmail.com

Edited by:

Marcelo Moraes Valença

Keywords:

Headache

COVID-19

Coronavirus

Nervous system diseases

Anosmia

Ageusia

Received: September 1

, 2021

Accepted: September 29, 2021

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Salomão VR, Baccarin AJR, Okido TY

Most prevalent symptoms associated with headache in COVID-19 patients in the acute phase: a systematic review

Introduction

n December 2019, in Wuhan, Hubei province, China,

a new disease caused by the coronavirus was identi-

ed, named COVID-19, referring to “Coronavirus disease

2019”. With its high transmissibility, the WHO announced

COVID-19 as a pandemic in March 2020. The virus respon-

sible for severe acute respiratory syndrome 2 (SARS-CoV-2)

has a single RNA envelope and strand structure and belongs

to the ß-Coronaviruse Family.

The highly contagious disease has the horseshoe bat

(

Rhinolophus

) as its reservoir and the transmission is

through droplets that contain viral load, mainly airway

secretions such as coughing, sneezing and saliva, and/

or contaminated surfaces and subsequent contact with

mucous membranes.

According to Pan American Health Organization,

107,423,526 cases of COVID-19 and 2,360,280 deaths

have been conrmed worldwide up to February 12, 2021.

In Brazil, there were 10,195,160 conrmed cases and

555,460 deaths registered.

Among the most prevalent symptoms of COVID-19 are

fever, fatigue and dry cough. However, the patient may

be asymptomatic or even present myalgia, dyspnea,

rhinorrhea, headache, pharyngitis, diarrhea, hyporexia,

hyposmia, ageusia, among other symptoms that progress

progressively.

3-4

As it is a complex pathogen, it can lead to complications

such as kidney or heart damage, secondary infections and

even shock. In addition, mortality rates are directly related

to age group, especially elderly people over 80 years

old, and the presence of comorbidities such as chronic

respiratory diseases, diabetes, heart disease and cancer.

1,6

Although respiratory symptoms are the most commonly

associated with COVID-19, headache represents the

highest prevalence among neurological manifestations

related to the infection, which may or may not be associated

with the presence of fever

, often occurring in association

with other symptoms such as anosmia, diarrhea, among

others.

Headache presents in approximately 11% to 34%

of hospitalized patients due to COVID-19 and is reported

by approximately 6% to 10% of symptomatic patients who

did not require hospitalization during the period of disease

activity.

Regarding the characteristics of headache resulting from

COVID-19, it is believed that it can have a rapid or

insidious onset, being generally unresponsive to simple

analgesics. In addition, it presents as a pulsatile pain, of

moderate intensity, bilateral and in the temporoparietal,

frontal or periorbital region.

However, as the clinical picture of the disease is varied,

headache can occur as an isolated symptom of COVID-19

and, being a common occurrence in everyday life, it ends

up being ignored by some patients, but in most cases, it

occurs in association with other symptoms.

Among them

are hyposmia/anosmia and with hypogeusia/ageusia,

and patients who reported olfactory and/or taste symptoms

had a higher frequency of headache than patients without

these symptoms.

Another study carried out in Zhejiang Province, China,

showed that patients with nausea, vomiting or diarrhea

experienced headache more frequently than patients

without gastrointestinal symptoms.

In addition, headache is also related to a better prognosis

for patients, as it has been shown that there is a decrease

in the duration of the disease in these individuals, in

addition to the serum levels of interleukin-6 (IL-6), a pro-

inammatory cytokine. smaller and more stable during

hospitalization.

Therefore, due to the variety of possible symptoms of this

disease and the impact of headache on these patients,

this study will carry out a systematic review with the aim

of evaluating the clinical characteristics and symptoms

associated with headache in the acute phase of infection

by COVID-19.

Methodology

A systematic literature review was performed based on

the identication of published articles on the clinical

characteristics and symptoms associated with headache

in patients diagnosed with acute infection by COVID-19.

The search for the materials was carried out from February

to August 2021, through a systematic review using the

databases PubMed, Biomed Central, Biblioteca Virtual em

Saúde (BVS), LILACS e Cochrane.

The keywords used in the search for the articles were

“COVID-19” AND “headache”. The selected publications

were read in full, and systematized based on their main

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Salomão VR, Baccarin AJR, Okido TY

Most prevalent symptoms associated with headache in COVID-19 patients in the acute phase: a systematic review

characteristics.

Were included articles reporting the presentation of

headache and the acute symptoms associated with it in

patients diagnosed with COVID-19 during the period

from December 2019 to August 2021. Articles reporting

changes in headache patterns in post-infection patients by

coronavirus, or articles that reported only epidemiological

characteristics or therapeutic approach, as well as articles

that were published before December 2019 or case series

with less than 10 patients were exclude.

Thus, 14 articles were analyzed, of which 7 were selected

and briey described in Table 1. A tabulation of the data

found was formulated. Thus, the items were described: title,

authors; year; description of the sample and synthesis of

the results. From this, a descriptive and qualitative analysis

of the bibliographic sample was performed, following the

critical discussion of the content

Results

Data and results are in table 1

Discussion

After the appearance of several cases of atypical pneumonia

in China at the end of 2019, and from clinical and laboratory

investigations, it was discovered that the viral etiology of

the new disease called COVID-19 would be due to acute

respiratory coronavirus syndrome 2 (SARS-CoV-2), which is

responsible for the current pandemic.

The pathology in question has a high potential for contagion

through mucous secretions and contaminated fomites, presents

with a wide range of clinical manifestations, which may involve

not only the respiratory system, but also the gastrointestinal,

hepatic and neurological systems.

Considering the frequency of headache as a symptom

reported in patients infected with SARS-CoV-2, there was a

need to understand other manifestations associated with this

complaint. Thus, the studies shown in Table 1 corroborate the

association of these symptoms.

The cross-sectional study of Madgy et al.

showed that

headache in the studied patients was characterized by diffuse

pressure pain (52.9%), with moderate intensity and frequency

of 7 days a week. It also suggested that the frequency of

this symptom was related to a previous history of headache,

severity of the infection (mild or moderate), dehydration and

comorbidity, with relevant statistical signicance (p<0.05). In

the female sex, the presence of fever and dehydration were

associated with predictors of pain intensity.

The cross-sectional study by Membrilla et al.

demonstrates

that among patients seen in the emergency room, with a

conrmed diagnosis of COVID-19 and who complained

of headache, 38.9% also had anosmia. Headache was

characterized as moderate intensity, bilateral, frontal or

holocranial. Also in this study, fever was identied as a

predictor in 39.4% of those patients who had headache and

a propensity for prostration, photophobia and phonophobia.

Other factors that showed statistical signicance (p<0.05)

associated with the presence of headache were a history of

migraine, odynophagia, myalgia, anosmia and comorbidities

such as systemic arterial hypertension, dyslipidemia and liver

disease.

The case study by Toptan et al.

had thirteen participants,

who had headache as the main complaint and who were

later diagnosed with COVID-19. The headache was mostly

described as holocranial with focus on the frontal and lateral

areas bilaterally, throbbing/pulsating and/or with moderate

to severe pressure sensation, more frequently associated with

photophobia and/or phonophobia in nine of the patients,

two of them had anosmia associated. Headache was also

accompanied by gastrointestinal tract symptoms in ve

participants. And only one had osmophobia associated with

the disease.

The cross-sectional study by Rocha-Filho and Magalhães

showed that 64.4% of the participants had headache, the

most common presentation being bilateral (94%), with severe

intensity (53%). Patients with previous migraine had a migraine

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Salomão VR, Baccarin AJR, Okido TY

Most prevalent symptoms associated with headache in COVID-19 patients in the acute phase: a systematic review

phenotype more often (p<0.05). Headache was associated

with ageusia in 39.7% and with anosmia in 38.4% of cases.

Patients with hyposmia/anosmia and/or hypoageusia/

ageusia were approximately ve times more likely to have

headache than those who did not present these symptoms

(p=0.024). And when comparing the group with headache

with anosmia and ageusia and the group with headache

without these symptoms, it was shown that the association with

phonophobia was greater in the group with anosmia and

ageusia (p< 0.05).

The prospective study by Caronna et al.

described a

comparative analysis between the group of patients who

experienced headache during the infecction and those who did

not. Of the total group, 74.6% had headache, in comparison

these patients had more anosmia/ageusia (p<0.0001), had

a lower clinical course of disease (p =0.028), as well as had

lower levels of interleukin-6 in the emergency room (p=0.036)

and were more stable during hospitalization.

A multicenter retrospective study, carried out in the hospitals:

Hospital Universitário Walter Cantído (HUWC), General

Hospital of Fortaleza (HGF), and Hospital São José for

Infectious Diseases (HSJ), with 108 patients diagnosed with

COVID-19, reports that 27.7% of these patients presented

headache, therefore it was the second most prevalent

neurological symptom. 58.3% of these patients had

symptoms associated with headache, including anosmia

(33%), irritability (16.6%), nausea, vertigo, allodynia and

concentration changes (8.3%) and vomiting, photophobia

and adynamia (4.1%). There was also an association with

a greater presence of fever in these patients (p=0.0028). The

majority (70.8%) reported worsening of the headache with

physical activity or coughing.

The retrospective cohort study carried out in Spain with

576 patients, showed that headache was more frequently

associated with anosmia, arthralgia, cough, dizziness and

myalgia.

Regarding the presence of this set of symptoms,

they found a lower probability of death due to premature

search for the emergency room compared to those patients

without headache.

Table 1. Description of studies with characteristics and symptoms associated with headache in patients in the acute phase of infection by COVID-19.

Authors Local Study period Sample size Results

Magdy et al.

Cairo e Beni-Suef

April to

June of

2020

172

52.9% had diffuse headache, with frequency and intensity

predictors of fever (69.8%), dehydration (64.5%) and

presence of comorbidities (19.8%).

Membrilla

Madrid

March to

April of

2020

145

68.3% of the patients reported headache. Among these, a

propensity to prostration (41.4%), photophobia (29.3%) and

phonophobia (27.3%) were identied. In addition, of 45

conrmed patients, 28 had anosmia. Fever was identied as a

precursor to headache in 39.4% of patients.

Caronna et al.

Barcelona (Hospital

Vall d’Hebro)

March to

April of

2020

130

74.6% had headache, and this group with headache suffered

more anosmia/ageusia (54.6% vs 18.2%) when compared

to the group without headache. And the headache group

still had a shorter presentation of the disease (23.9±11.6 vs.

31.2±12.0 days).

Rocha-Filho and

Magalhães

Pernambuco (Hospital

Universitário Oswaldo

Cruz)

May to June

of 2020

47 of these (64.4%) had headache, which was associated

with anosmia in 28 patients (38.4%) and with ageusia in 29

patients (39.7%). Individuals with hyposmia/anosmia and/

or hypoageusia/ageusia had more headache than those

without these symptoms (OR: 5.39; 95%CI: 1.66–17.45

logistic regression). Headache accompanied by photophobia

was more prevalent in patients with anosmia and ageusia

(p < 0.05)

Toptan et al.

Hospital Universitário

de Gazi, Ankara,

Turquia

April to

May of

2020

The most frequent associated symptoms were photophobia

and/or phonophobia.

Headache was associated with gastrointestinal tract symptoms

(diarrhea, loss of appetite, or weight loss) in ve patients, and

patients had anosmia associated with phonophobia and/or

photophobia.

Anjos de Paula

Hospital Universitário

Walter Cantído

(HUWC), Hospital

Geral de Fortaleza

(HGF), e Hospital

São José de Doenças

Infecciosas (HSJ)

May to July

of 2020

108

27.7% had headache, and most suffered from associated

symptoms (58.3%) including anosmia (33%), irritability

(16.6%), nausea, dizziness, allodynia and changes in

concentration (8.3%) and vomiting, photophobia and

adynamia (4.1%).

Trigo et al.

Valladolid, Espanha

March to

April of

2020

576

Main associated symptoms were anosmia (46.7%), arthralgia

(131%), cough (82.5%), dizziness (13.9%), myalgia (40.1%),

asthenia (51.1%), chest pain (24.1%) and fever (88.3%).

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Salomão VR, Baccarin AJR, Okido TY

Most prevalent symptoms associated with headache in COVID-19 patients in the acute phase: a systematic review

The main limitation found in this study was the heterogeneity of

the studies and the low methodological quality of the studies

published so far, also in part, because it is a recently discovered

disease and there are still unknowns about COVID-19.

Conclusion

The systematic review carried out demonstrates that the

headache manifested in COVID-19 is, in most cases,

holocranial, with a moderate to severe pain intensity.

Furthermore, it is suggestive that it is associated with signs and

symptoms such as fever, hyposmia or anosmia, ageusia and

phonophobia. In addition, some conditions are predictors of

more intense headache attacks, such as a previous diagnosis of

migraine, the intensity of the coronavirus infection, dehydration

and the presence of comorbidities.

Conflict of Interest: The authors declare no conict of interest.

Author contribution: The authors contributed equally to the

manuscript.

Vitória Rodrigues Salomão

https://orcid.org/0000-0002-8902-7378

Anna Júlia Romão Baccarin

https://orcid.org/0000-0002-6223-2929

Thaís Yayoi Okido

https://orcid.org/0000-0002-2507-575X

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