IDCases 26 (2021) e01330

Contents lists available at ScienceDirect

IDCasesjournal homepage: www.elsevier.com/locate/idcases

Case report

Hiccups as a specific neurological manifestation in males with COVID-19⁎

Aya Nakaya , Eiji Ogura, Yuki Katayama, Masami Yoshii, Eiko Yoshino, Kazuya Hozumi,
Saori Tago, Yuko Teranishi, Yuki Minamibashi, Makiko Harada, Mami Yoshioka, Yuri Kawano,
Yuka Arai, Keno Yoshida, Shozo Shimizu, Kazuma Ogura, Katsuaki Iwashita, BOH
Covid-19 Team]]]]]]]]]]

Biwako Ohashi Hospital, Japana r t i cl e i nfo

a bstr ac t

Article history:
Received 24 September 2021
Received in revised form 3 November 2021
Accepted 4 November 2021
Available online xxxx

Several clinical manifestations of COVID-19 have been reported in the literature since then. In addition toupper respiratory symptoms, dysgeusia and anosmia are relatively common neurological manifestations
with COVID-19. We had five cases of hiccups in succession; therefore, we assume that hiccups might be aspecific symptom of COVID-19. We retrospectively analyzed 46 patients with COVID-19 diagnosed fromFebruary 2021 to May 2021. Among the 46 patients, 5 developed hiccups (11%). All patients were male. The
median age of was 56 years. None of the patients were smokers. Further, all patients exhibited pneumonia
without dysgeusia or anosmia. The median onset of hiccups was 5 days after diagnosis, with a median
duration of 2 days. All patients recovered from hiccups and COVID-19. Hiccups might be a specificneurological symptom in male patients with COVID-19.
© 2021 The Author(s). Published by Elsevier Ltd.
CC_BY_NC_ND_4.0

Keywords:
COVID-19
Hiccups
Pneumonia
Neurological symptom
MaleIntroduction
Currently, it has been more than a year since the start of theCOVID-19 pandemic. Several clinical manifestations of COVID-19
have been reported in the literature since then. In addition to upper
respiratory symptoms, dysgeusia and anosmia are relatively
common neurological manifestations with COVID-19 [1].
We formed the COVID-19 treatment team in February 2021. We
have mainly treated patients with mild and moderate disease
without any pulmonary dysfunction. We noticed that there werequite a few patients who developed hiccups. To date, 10 short cases
have been reported on this topic [2–11]. We witnessed five cases insuccession; therefore, we assume that hiccups might be a specificsymptom of COVID-19. We investigated the characteristics andoutcomes of the patients and reviewed the literature.
Methods
There were 46 patients admitted to our hospital from February
2021 to May 2021. We retrospectively analyzed the prevalence ofhiccups, concomitant symptoms and outcomes. This study was⁎Correspondence to: Internal Medicine, Biwako Ohashi Hospital, 5-1-29 Mano,
Otsu city, Shiga 520-0232, Japan.
E-mail address: nakaya1016@yahoo.co.jp (A. Nakaya).
https://doi.org/10.1016/j.idcr.2021.e01330
2214-2509/© 2021 The Author(s). Published by Elsevier Ltd.
CC_BY_NC_ND_4.0

conducted as per the ethical principles of the Declaration of Helsinki
and was approved by the institutional review board of Biwako
Ohashi Hospital. Written informed consent was obtained from thepatients for the publication of this report.
Results
Five out of the 46 patients had hiccups (11%). Patient characteristics are summarized in Table 1. All patients were male, and their
median age was 56 years (range: 34–87 years). None of the patientswere smokers. All the patients had pneumonia and three of themhad cough. However, none of the patients had dysgeusia or anosmia.
Three of the patients were treated with remdesivir and two withfavipiravir. The median onset of hiccups was 5 days after diagnosis,
and the median duration of the hiccups was 2 days. Two of the fivepatients were treated with chlorpromazine, two of the five weretreated with clonazepam and timepidium bromide, respectively.
One patient was not treated with any hiccup specific medication. All
the patients recovered from hiccups and COVID-19.
Discussion
Hiccups are defined as an involuntary, spasmodic contraction of
the diaphragm and intercostal muscles [11]. This contraction causes
an active closure of the glottis and results in a characteristic soundA. Nakaya, E. Ogura, Y. Katayama et al.

IDCases 26 (2021) e01330

Table 1
Patients’ characteristics.
PatientAge (years)

Sex

Smoking
habit

Treatment forCOVID-19

Pneumonia

Loss oftaste

Loss ofsmell

CoughDay of
hiccup onset(from Dx)

Duration of
hiccups(days)

Treatment for
hiccupOutcome of
COVID-19123456534568745M
M
M
M
M

−−−−−

Favipiravir
Remdesivir
Remdesivir
Favipiravir
Remdesivir+++++−−−−−−−−−−++−−+Day 5
Day 5Day 9Day 4Day 10

31232

Clonazepam–
Chlorpromazine
Chlorpromazine
Timepidium
bromideRecoveryRecoveryRecoveryRecoveryRecovery

M: male[12]. Intractable hiccups lasting for < 48 h are called acute hiccups,
whereas those lasting for > 48 h are called persistent hiccups. Whereas
hiccups of short duration are often benign in etiology, Prolonged
hiccups may be attributed to a severe underlying pathology [13].
Although the precise mechanism of hiccups is not completelyunderstood, hiccups result from the stimulation of the central orperipheral components of the hiccup reflex arc.
Regarding the central nervous system, Giancarlos et al. reported
that SARS-CoV-2 shows selective neurotropism to areas of the brain
controlling respiration [14]. Such a mechanism may also contributeto hiccups. Irritation of this neural network can be a possible
mechanism for the development of hiccups.
With respect to the phrenic nerve, it has been reported thatpneumonia has an influence on hiccups. Inflammatory pneumonia
induced irritation of the phrenic nerve and its pericardial branch
may stimulate the diaphragm and lead to the development of hiccups [15]. All of our patients and those in the literature were afflictedwith pneumonia (Table 2). Therefore, we assume that there is acausal relationship between pneumonia and hiccups.
Ten cases of hiccups with COVID-19 have been reported to date
(Table 2). All patients were male and were afflicted with pneumonia,
which is consistent with our patients. All the patients exhibited
hiccups for > 3 days. All patients recovered from COVID-19, although
one patient was lost to follow up.
Hiccups were reported as adverse event with favipiravir (< 0.1%)[16]. There is no report of remdesivir as causing hiccups. Some reports suggested that relation between steroids and hiccups [17].
However, we don’t think that the treatments would induce hiccups
because four in the reported cases were without treatment andothers were used various treatments (Table 2). Therefore, it isdifficult to prove the involvement of specific treatment.

The most interesting finding of our study is that all the patientswere male. In the literature, all reported cases are of males. It isunlikely that this is a mere coincidence. We believe that hiccups
might be a specific symptom of COVID-19 in males. Lee et al. reported that hiccups were seen more frequently in males. They assumed that male susceptibility to developing hiccups could
potentially be attributed to lower synaptic threshold and easier excitability of afferent or efferent nerves in the hiccup reflex arc among
males [18]. This may contribute to the predominance of hiccups inmales. Regardless of COVID-19, hiccups are more common in males.
The median day when the patients developed hiccups was 5 days
from COVID-19 diagnosis. This indicates that hiccups are not an early
symptom. It may occur after the disease condition has progressed toa certain extent. Three patients developed cough that disappeared
before the hiccups developed. Other typical neurological symptoms
such as dysgeusia and anosmia did not coexist. In the literature, only
one patient showed the coexistence of dysgeusia. We assume thatthese symptoms rarely overlap with hiccups or are simply lesscommon in variant types. The reason for this finding remains
unclear.
Fortunately, all patients recovered from COVID-19. In the literature, all but one patient who was lost to follow-up showed goodoutcomes. Therefore, hiccups might not have a correlation with poor
prognosis.
Our study has several limitations. First, this study was conductedin one facility with a small number of patients. Second, we only
treated patients with mild and moderate disease; therefore, we do
not know whether the findings are applicable to patients with severe
disease. Third, we administered anti-hiccup medications immediately after the hiccups developed; therefore, we do not know
the natural course of the hiccups. Despite these limitations, weTable 2
Review of the literature.
ReferenceAge (years)

Sex

Smoking
habit

Treatment for Covid-19

Pneumonia

Loss oftaste

Loss of
smell

Cough

Duration of
hiccupTreatment for
hiccupOutcome of
COVID-192362
48

M
M−
NA

Hydroxychloroquine−++−−−−−−>4 days
>4 days−
Metoclopramide434M−+−−−>7 days

Baclofen

5560
68

M
M−−++−−−−−−>3 days
>3 days

662

M

NA

Hydroxychloroquine/
Oseltamivir
Favipiravir
Favipiravir/
Hydroxychloroquine−

Recovery
Lost tofollow-up
Recovery++−+>3 days

789106172
6564MMMM+NA−−

Dexamethasone
Oseltamivir/Favipiravir−−++++−
−
−
−

−
−
−
−

−
−
−
−

>3 days>5 days>7 days>3 days

Chlorpromazine
Metoclopramide/
Chlorpromazine
Metoclopramide/
Lidocaine/
Clonazepam/
Haloperidol
Metoclopramide
Baclofen
Baclofen−

M: maleNA: not available

2

RecoveryRecoveryRecoveryRecoveryRecoveryRecoveryA. Nakaya, E. Ogura, Y. Katayama et al.

IDCases 26 (2021) e01330

believe that our findings are worth reporting to demonstrate thepractical manifestations of COVID-19.
Our findings showed the characteristics of patients with hiccups:
all males, afflicted with Mild or Moderate COVID-19 pneumonia,
non-smokers, and with a lack of other symptoms.
Further investigation and accumulation of cases to determine theclinical significance of hiccups in COVID-19 are warranted.

[2] Prince G, Sergel M. Persistent hiccups as an atypical presenting complaint ofCOVID-19. Am J Emerg Med 2020;38(7):1546.e5–6. https://doi.org/10.1016/j.
ajem.2020.04.045. Epub 2020 Apr 18. PMID: 32345563; PMCID: PMC7165082.
[3] Alvarez-Cisneros T, Lara-Reyes A, Sansón-Tinoco S. Hiccups and psychosis: twoatypical presentations of COVID-19. Int J Emerg Med 2021;14(1):8. https://doi.
org/10.1186/s12245-021-00333-0. PMID: 33472577; PMCID: PMC7816133.
[4] Bakheet N, Fouad R, Kassem AM, Hussin W, El-Shazly M. Persistent hiccup: a rare
presentation of COVID-19. Respir Investig 2021;59(2):263–5. https://doi.org/10.
1016/j.resinv.2020.11.003. Epub 2020 Nov 30. PMID: 33309013; PMCID:PMC7703547.
[5] Ikitimur H, Borku Uysal B, Ikitimur B, Umihanic S, Smajic J, Jahic R, et al. Case
report: two cases of persistent hiccups complicating COVID-19. Am J Trop MedHyg 2021;104(5):1713. https://doi.org/10.4269/ajtmh.21-0190. Epub ahead ofprint. PMID: 33793414; PMCID: PMC8103448.
[6] Totomoch-Serra A, Ibarra-Miramon CB, Manterola C. Persistent hiccups as main
COVID-19 symptom. Am J Med Sci 2021;9629(21):00001–:S0002. https://doi.
org/10.1016/j.amjms.2021.01.001. Epub ahead of print. PMID: 33563571; PMCID:PMC7832614.
[7] Atiyat R, Veeraballi S, Al-Atiyat N, Chan KH, Slim J. A rare case report of persistenthiccups as an atypical presentation of COVID-19. Cureus 2021;13(3):e13625https://doi.org/10.7759/cureus.13625. PMID: 33816024; PMCID: PMC8011285.
[8] Sangamesh S, Gosavi S, Shastry S, Johny SM. Hiccups and hyponatremia: unusual
co-presentation in COVID-19. J Fam Med Prim Care 2021;10(2):1040–3. https://doi.org/10.4103/jfmpc.jfmpc_1582_20. Epub 2021 Feb 27.PMID: 34041119;
PMCID: PMC8138369.
[9] Ali SK, Muturi D, Sharma K. Be wary of hiccups: an unusual case of COVID-19.
Cureus2021;13(1):e12974https://doi.org/10.7759/cureus.12974.
PMID:33654635; PMCID: PMC7914000.
[10] Zahran M. Persistent Hiccups as atypical presentation of COVID-19: A Case
Report, Jun 12 2020, Preprint (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-34617/v1].
[11] Federspil PA, Zenk J. Singultus [hiccup]. HNO 1999 Oct;47(10):867. Federspil PA,Zenk J. Singultus. HNO 1999;47(10):867–875. doi:10.1007/s001060050527.
PMID: 10550370.
[12] Kolodzik PW, Eilers MA. Hiccups (singultus): review and approach to management. Ann Emerg Med 1991;20(5):565–73. https://doi.org/10.1016/s01960644(05)81620-8. PMID: 2024799:.
[13] Smith HS, Busracamwongs A. Management of hiccups in the palliative care population. Am J Hosp Palliat Care 2003;20(2):149–54. https://doi.org/10.1177/104990910302000214. PMID: 12693648:.
[14] Conde Cardona G, Quintana Pájaro LD, Quintero Marzola ID, Ramos Villegas Y,Moscote Salazar LR. Neurotropism of SARS-CoV 2: mechanisms and manifestations. J Neurol Sci 2020;412:116824https://doi.org/10.1016/j.jns.2020.116824.
Epub 2020 Apr 8. PMID: 32299010; PMCID: PMC7141641.
[15] Burdette SD, Marinella MA. Pneumonia presenting as singultus. South Med J
2004;97(9):915. https://doi.org/10.1097/01.SMJ.0000125174.62424.C6[16] 〈https://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_favip_210419_eng.pdf〉 (accessed 4 November 2021).
[17] Sugandhavesa N, Sawaddiruk P, Bunmaprasert T, Pattanakuhar S, Chattipakorn
SC, Chattipakorn N. Persistent severe hiccups after dexamethasone intravenous
administration. Am J Case Rep 2019;20:628–30. https://doi.org/10.12659/AJCR.
915282. PMID: 31036799; PMCID: PMC6509965.
[18] Lee GW, Kim RB, Go SI, Cho HS, Lee SJ, Hui D, et al. Gender differences in hiccup
patients: analysis of published case reports and case-control studies. J Pain
Symptom Manag 2016;51(2):278–83. https://doi.org/10.1016/j.jpainsymman.
2015.09.013. Epub 2015 Nov 17. PMID: 26596880.

Author statement
Study design: A.N., E.O., data collections: Y.K., M.Y., E.Y., K.H., S.T.,
Y.T., Y.M., M.H., M.Y., Y.K., Y.A., K.Y., S.S., K.O., K.I., data analysis: A.N.,
writing: A.N., E.O.
Ethical approval
This study was conducted as per the ethical principles of theDeclaration of Helsinki and was approved by the institutional review
board of Biwako Ohashi Hospital.
ConsentWritten informed consent was obtained from the patients for thepublication of this report.
Conflicts of interest
The authors declare no conflicts of interest associated with thismanuscript.
AcknowledgmentsThe authors would like to thank patients who agreed to provide
information. We also thank Yuu Tochitani, Rika Umeda, ShizukaMorita, Yohei Takano, Masanori Fujie, Tsutomu Ito, Yuko Hirai, Ayako
Igosaki, and Satomi Ozawa for their assistance.
References[1] da Rosa Mesquita R, Francelino Silva Junior LC, Santos Santana FM, Farias deOliveira T, Campos Alcântara R, Monteiro Arnozo G, et al. Clinical manifestationsof COVID-19 in the general population: systematic review. Wien Klin Woche
2021;133(7–8):377–82. https://doi.org/10.1007/s00508-020-01760-4. Epub 2020
Nov 26. PMID: 33242148; PMCID: PMC7689634.

3