Non-hospitalised COVID-19 patients have more frequent long COVID-19 symptoms

Abstract

BACKGROUND: Long COVID-19 syndrome refers to the persistence of symptoms for more than 12 weeks after the start of acute symptoms. The pathophysiology of this syndrome is not yet clear. OBJECTIVE : To assess long COVID-19 symptoms in hospitalised and non-hospitalised patients. METHODS : A cross-sectional survey was used. The study included 262 patients who were divided into two groups based on their hospital admission history: 167 (63.7%) were not hospitalised, while 95 (36.3%) were hospitalised. RESULT S : Long-COVID was reported in 157 out of 262 patients (59.9%), and was significantly more frequent in non-hospitalised patients (68.3% vs. 45.3%; P , 0.001). During the acute phase, hospitalised patients had more respiratory symptoms (95.9% vs. 85.6%), while non-hospitalised patients had more neuropsychiatric symptoms (84.4% vs. 69.5%; P , 0.05). Constitutional and neuropsychiatric symptoms were the most frequently reported persistent symptoms in both groups, but all persistent symptoms were more frequent in the non-hospitalised group (P , 0.005). CONCLUS ION: Long COVID-19 symptoms affect both hospitalised and non-hospitalised patients. Neuropsychiatric manifestations were the most common persistent COVID-19 symptoms. Rehabilitation and psychotherapy could be advised for all recovered COVID-19 patients. Non-hospitalised COVID-19 patients should be counselled to contact healthcare providers whenever needed. © 2021 International Union against Tubercul. and Lung Dis.. All rights reserved.

Full text

INT J TUBERC LUNG DIS 25(9):000–000
Q
2021 The Union
http://dx.doi.org/10.5588/ijtld.21.0135
Non-hospitalised COVID-19 patients have more frequent long
COVID-19 symptoms
A. A. R. Mohamed-Hussein,
1
M. T. Amin,
2
H. A. Makhlouf,
1
N. A. Makhlouf,
3
I. Galal,
4
H. K. Abd-Elaal,
5
D. Abdeltawab,
3
K. M. S. Kholief,
2
M. K. Hashem
1
1
Chest Department,
2
Department of Public Health and Community Medicine, and
3
Department of Tropical
Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut,
4
Chest Department, Aswan Faculty
of Medicine, Aswan,
5
Faculty of Nursing, Assiut University, Egypt
SUMMARY
BACKGROUND: Long COVID-19 syndrome refers to
the persistence of symptoms for more than 12 weeks
after the start of acute symptoms. The pathophysiology
of this syndrome is not yet clear.
OBJECTIVE: To assess long COVID-19 symptoms in
hospitalised and non-hospitalised patients.
METHODS: A cross-sectional survey was used. The study
included 262 patients who were divided into two groups
based on their hospital admission history: 167 (63.7%)
were not hospitalised, while 95 (36.3%) were hospitalised.
RESULTS: Long-COVID was reported in 157 out of 262
patients (59.9%), and was significantly more frequent in
non-hospitalised patients (68.3% vs. 45.3%; P
,
0.001). During the acute phase, hospitalised patients
had more respiratory symptoms (95.9% vs. 85.6%),
while non-hospitalised patients had more neuropsychi-
atric symptoms (84.4% vs. 69.5%; P
,
0.05). Consti-
tutional and neuropsychiatric symptoms were the most
frequently reported persistent symptoms in both groups,
but all persistent symptoms were more frequent in the
non-hospitalised group (P
,
0.005).
CONCLUSION: Long COVID-19 symptoms affect both
hospitalised and non-hospitalised patients. Neuropsychi-
atric manifestations were the most common persistent
COVID-19 symptoms. Rehabilitation and psychotherapy
could be advised for all recovered COVID-19 patients.
Non-hospitalised COVID-19 patients should be coun-
selled to contact healthcare providers whenever needed.
KEY WORDS: long COVID-19; post-COVID-19; hos-
pitalised; non-hospitalised
In December 2019, the coronavirus disease 2019
(COVID-19) was first discovered in Wuhan, China.
1
Since then, COVID-19 has taken on new forms, and
as more patients recover from acute COVID-19
infection, more evidence and awareness about chron-
ic sequelae and post-COVID-19 symptoms have
emerged.
Long COVID-19 syndrome describes the persis-
tence of symptoms for more than 12 weeks in some
individuals after the start of acute symptoms.
2
Fatigue, muscle ache, sleeplessness, anxiety and
depression were reported in patients after 6 months
of acute infection.
3
Persistent COVID-19 symptoms
have been reported in 40–80% of patients after the
convalescent stage.
4–6
The pathophysiology of long COVID development
is not yet clear. Many theories were discussed,
including prolonged inflammatory response, organ
damage, the effect of chronic health conditions, social
isolation or post-traumatic effects of the hospital or
intensive care admission.
7
Serious medical conditions
necessitate management in the intensive care unit
(ICU), and may lead to long-term consequences such
as physical, mental, psychological and respiratory
abnormalities.
8,9
These complaints are stated as post-
intensive care syndrome (PICS), which can even have
a persistent effect on patient life quality.
10
Moreover,
many patients with mild COVID-19 who were
isolated at home without conventional testing or
treatment due to the limited resources,
11
showed
recurrent symptoms many months after the acute
infection.
12
This work aims to assess long COVID-19 symp-
toms in hospitalised and non-hospitalised patients
after 12 weeks of infection.
PATIENTS AND METHODS
The current cross-sectional survey was performed
from 1 July to 9 October 2020. Patients were
included in the study if they had COVID-19
confirmed in the registry (positive or indeterminate
COVID-19 polymerase chain reaction [PCR] test) or
if clinical, laboratory and radiological criteria sug-
Correspondence to: Maiada K Hashem, Chest Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
email: maiada.hashem@aun.edu.eg; Maiada.hashem@gmail.com
Article submitted 3 March 2021. Final version accepted 13 May 2021.
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gested that they had COVID-19. They were inter-
viewed in the follow-up clinics or by phone and were
asked to fill out paper or online forms. Medical
students, residents and volunteers evaluated the
patient’s symptoms and revised the submitted forms
for missing data.
The study was approved by the ethical committee
of Aswan Faculty of Medicine, Aswan, Egypt
(Clinicaltrial.gov: NCT04479293).
The sample size was calculated using Epi Infoe
Statistical Package v7 (Centers for Disease Control and
Prevention, Atlanta, GA, USA). Based on previous
studies and literature review, the expected frequency of
persistent symptoms was 60% with a 6% margin of
error, and at 95% confidence interval (CI), the
minimum required sample size was 257 patients.
4,13
The following data were collected: 1) patient
demographics, including age, sex, body mass index
(BMI), smoking status, history of comorbid disor-
ders, history of seasonal influenza vaccination, the
mean duration since the onset of the symptoms,
history of the need for oxygen therapy, hospital or
ICU admission, and treatment taken during the acute
attack; 2) symptoms during the acute attack of
COVID-19; and 3) symptoms after the recovery from
the acute attack of COVID-19 and its duration.
Symptoms reported by participants were categorised
as constitutional (fever, myalgia, arthralgia, restriction
of daily activity, tachycardia, headache, dizziness and
excessive sweating), respiratory (cough, sputum,
dyspnoea, chest pain, sore throat and rhinorrhoea),
gastrointestinal (GIT) (gastritis, anorexia, diarrhoea,
abdominal pain and dysphagia) and neuropsychiatric
(sleeping problems, tinnitus, anosmia and/or ageusia,
memory loss, loss of concentration, anxiety and/or
depression and peripheral neuropathy). A patient who
experienced at least one of the previously mentioned
symptoms for 12 weeks was considered to have long
post COVID-19 symptoms.
Statistical analysis
Statistical analyses were performed using IBM SPSS
Statistics v20 (IBM Corp, Armonk, NY, USA).
Categorical data were presented as numbers and
percentages and compared using v
2
test. In contrast,
continuous data were reported as means 6standard
deviation (SD) and/or median (min-max) and tested
for normality using the Shapiro–Wilkes test. The t-
test was used when the quantitative data were
normally distributed, and the Mann–Whitney test
was used when the data were not normally distrib-
uted. In all statistical tests, P,0.05 was considered
statistically significant.
RESULTS
The survey included 732 patients, 262 (35.8%) of
whom experienced the acute phase of COVID-19
infection at least 12 weeks before data collection
(Figure 1). The 262 patients included were then
divided according to the history of hospital admission
into two groups: 167 (63.7%) were not hospitalised,
while 95 (36.3%) were hospitalised. Both groups
were comparable regarding sex, BMI and smoking
history, while hospitalised patients had significantly
higher age, more comorbid conditions and increased
need for oxygen therapy (Table 1).
Long-COVID-19 symptoms were reported by 157/
262 patients (59.9%), and it was substantially more
common in non-hospitalised patients than in hospi-
talised group (68.3% vs. 45.3%; P,0.001) (Figure
2). Table 2 shows the treatment provided to both
groups. Hospitalised patients received 4.3 61.0 types
of medications vs. 2.9 61.4 in non-hospitalised
group (P,0.001).
As regard symptoms during the acute phase, the
respiratory symptoms were more frequent in the
hospitalised group than in the non-hospitalised group
(95.9% vs. 85.6%; P,0.05), while non-hospitalised
patients had more neuropsychiatric symptoms
(84.4% vs. 69.5%; P,0.05). Constitutional and
GIT symptoms were comparable in both groups. The
median number of symptoms in the non-hospitalised
group was 16 vs. 11 in the hospitalised groups (P¼
0.02; Table 3).
Analysis of long-COVID symptoms revealed that
constitutional and neuropsychiatric symptoms were
the most frequently reported persistent symptoms in
both groups, but generally, all symptoms were more
common in the non-hospitalised group (P¼0.005;
Table 4).
DISCUSSION
Long COVID-19 symptoms are now an increasing
concern for both physicians and patients. Many
recent publications have tried to define and describe
post/long COVID-19 syndrome.
2,3,7
In the current
study, surveillance data for long COVID-19 symp-
toms in hospitalised and non-hospitalised COVID-19
patients after 12 weeks of acute infection were
analysed. It was surprising to note that the incidence
of prolonged symptoms was significantly higher in
the non-hospitalised group (68.3% vs. 45.3%, P,
0.001). Non-hospitalised patients had more persis-
tent symptoms and a higher total number of
symptoms.
Consistent with previous literature,
4,14,15
the most
common long COVID-19 symptoms were persistent
constitutional symptoms, reported in 44.2% of
hospitalised patients and 64.1% of non-hospitalised
patients, and neuropsychiatric symptoms. Neuropsy-
chiatric symptoms included sleeping problems, tinni-
tus, anosmia and/or ageusia, memory loss, loss of
concentration, anxiety and/or depression and periph-
eral neuropathy, which were reported in 45.3% of
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2The International Journal of Tuberculosis and Lung Disease

hospitalised patients and 65.9% of non-hospitalised
patients after 12 weeks of infection.
Numerous neurotropic respiratory viruses, such as
influenza viruses, herpes simplex one virus and
coronaviruses, have been linked to chronic neuropsy-
chiatric conditions, including emerging cognitive
dysfunction and dementia, motor disorders and
psychotic illness.
16
On the other hand, new-onset
cognitive impairment was found in up to 25.4% of
post-COVID-19 patients.
17
COVID-19-induced cog-
nitive impairment may result from direct viral
pathogenicity, as COVID-19 attacks angiotensin-
converting enzyme receptors in the central nervous
system, and respiratory and gastrointestinal systems,
leading to cell invasion, viral replication and dysreg-
ulated inflammatory response.
18,19
Figure 1 Flow chart of all COVID-19 patients included in the study. *Fever, myalgia, arthralgia,
restriction of daily activity, tachycardia, headache, dizziness and excessive sweating.
†
Cough,
sputum, dyspnoea, chest pain, sore throat and rhinorrhoea.
‡
Gastritis, anorexia, diarrhoea,
abdominal pain and dysphagia.
§
Sleeping problems, tinnitus, anosmia and/or ageusia, memory
loss, loss of concentration, anxiety and/or depression and peripheral neuropathy. GIT ¼
gastrointestinal.
Table 1 Demographic and basic characteristics of non-
hospitalised vs. hospitalised COVID-19 participants (n¼262)
Non-hospitalised
(n¼167)
n(%)
Hospitalised
(n¼95)
n(%) P-value*
Age, years
40 11 (66.5 ) 40 (42.1) ,0.001
†
.40 56 (33.5 ) 55 (57.9)
Mean 6SD 38.7 613.1 47.1 615.8 ,0.001
†
Median (min–max) 36 (21–80) 44 (21–80)
Sex 0.772
Male 69 (41.3 ) 41 (43.2)
Female 98 (58.7 ) 54 (56.8)
Body mass index
Underweight 12 (7.3 ) 9 (9.5) 0.595
Normal 40 (24.2 ) 18 (18.9)
Overweight 51 (30.9 ) 35 (36.8)
Obese 62 (37.6 ) 33 (34.7)
Mean 6SD 27.2 67.8 26.4 610.4 0.522
Median (min–max) 28 (10–47) 27.8 (11–61)
Smoking 0.303
Non-smoker 140 (83.8 ) 74 (77.9)
Current smoker 8 (4.8 ) 9 (9.5)
Ex-smoker 19 (11.4 ) 12 (12.6)
Previous influenza vaccine 0.829
Yes 23 (13.8 ) 14 (14.7)
No 144 (86.2 ) 81 (85.3)
Need of oxygen therapy ,0.001
†
Yes 14 (8.4 ) 60 (63.2)
No 153 (91.6 ) 35 (36.8)
Chronic illness ,0.001
†
Yes 35 (21.0 ) 47 (49.5)
No 132 (79.0 ) 48 (50.5)
* Student’s t-test, Mann-Whitney and v
2
tests.
†
Statistically significant.
SD ¼standard deviation.
Figure 2 Long COVID-19 symptoms among non-hospitalised
vs. hospitalised COVID-19 participants (n¼262).
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Non-hospitalised patients and long COVID-19 3

Insomnia, hypersomnia, nightmares and misuse of
sleep medications are various patterns of sleep
disorders described by post-COVID-19 patients.
COVID-somnia is a term for sleep disorders that
occur during the pandemic.
20
The depression and
anxiety caused by the pandemic or the changes in
sleep schedule, bedtime and excess use of electronic
devices contribute to the sleep disturbance.
21
The
systemic inflammation caused by the infection
directly affects sleep pathophysiology.
Post-COVID fatigue was described as decondition-
ing in mental and physical performance, resulting
from central, psychological and/or peripheral chang-
es due to COVID-19 infection.
22
More than half of
recovered patients reported persistent fatigue 10
weeks after initial symptoms regardless of the severity
of COVID-19 acute infection.
23
In contrast with Halpin et al.’s findings, our study
results indicate that respiratory symptoms (i.e., dry or
productive cough, dyspnoea and chest pain) were the
least prevalent in hospitalised and non-hospitalised
patients.
4
Many theories may explain it: 1) only
36.3% of included patients in this study were
hospitalised, and those were supposed to have more
severe disease with more frequent respiratory symp-
toms, 2) the treatment protocols in the study area
focused more on respiratory manifestations,
24
and 3)
the absence of an objective tool to estimate dyspnoea,
which could be referred as ’fatigue’ by the patients
themselves in the current study.
Although hospitalisation, ICU admission, and the
need for oxygen therapy and/or mechanical ventila-
tion raises the likelihood of post-traumatic stress
disorder and prolonged post-discharge symptoms in
various medical and surgical conditions, hospitalised
patients reported fewer long COVID-19 symptoms in
the current study. Furthermore, in a previous study
examining risk factors for long COVID hospitalisa-
tion, it was discovered to be a protective factor.
17
According to a major study based on an online survey,
it has been found that non-hospitalised COVID-19
patients with mild disease had more frequent post-
COVID-19 symptoms after 3 months of acute
infection.
12
Even after 6 months of infection, a recent
study noticed persistent symptoms in more than a
third of both outpatients (32.7%) and hospitalised
patients (31.3%).
25
This was explained by overesti-
mating symptom burden due to data collection bias
(via social media), and the larger number of female
respondents expressing symptoms than males. How-
ever, there was no statistical difference between the
sexes in both non-hospitalised and hospitalised
patients who were older and had significant comor-
bid diseases in the current study. In agreement with a
previous study, the present results suggest that many
non-hospitalised patients did not recover well after 3
months of infection, possibly due to less medical
guidance, than hospitalised ones.
12
Azithromycin was one of the main lines of
treatment in early management protocols in our
region as it was easily obtained without a prescrip-
tion, explaining the overuse of antibiotics by non-
hospitalised patients in the current study. The
adherence of in-home isolated patients to all treat-
ments, whether dosing or timing, is not guaranteed,
leading to an increased occurrence of long COVID
symptoms. Furthermore, self-treated patients’ failure
Table 2 Received treatments during acute illness among non-
hospitalised vs. hospitalised COVID-19 participants (n¼262)
Non-hospitalised
(n¼167)
n(%)
Hospitalised
(n¼95)
n(%) P-value*
Antibiotics 147 (88.0) 90 (94.7) 0.075
Anticoagulants 77 (46.1) 79 (83.2) ,0.001
†
Corticosteroids 74 (44.3) 75 (78.9) ,0.001
†
Hydroxychloroquine 32 (19.2) 48 (50.5) ,0.001
†
Antiviral 16 (9.6) 18 (18.9) 0.030
Biological (anti-IL6) 2 (1.2) 4 (4.2) 0.117
Vitamins and zinc 142 (85.0) 91 (95.8) 0.008
†
Number of drugs ,0.001
†
Mean 6SD 2.9 61.4 4.3 61.0
Median (min–max) 3 (1–6) 4 (1–6)
*v
2
and student’s t-tests.
†
Statistically significant.
IL ¼interleukin; SD ¼standard deviation.
Table 3 Differences in acute stage symptoms among non-
hospitalised vs. hospitalised COVID-19 participants (n¼262)
Non-hospitalised
(n¼167)
n(%)
Hospitalised
(n¼95)
n(%) P-value*
Reported symptoms
Constitutional 161 (96.4) 93 (97.9) 0.501
Respiratory 143 (85.6) 91 (95.8) 0.010
†
Gastrointestinal 139 (83.2) 71 (74.7) 0.097
Neuropsychiatric 141 (84.4) 66 (69.5) 0.004
†
Number of symptoms 0.020
†
Mean 6SD 15.0 67.4 12.6 67.2
Median (min–max) 16 (0–27) 11 (2–27)
* Mann-Whitney test and v
2
test.
†
Statistically significant.
SD ¼standard deviation.
Table 4 Differences in post-COVID stage symptoms among
non-hospitalised vs. hospitalised COVID-19 participants (n¼
262)
Non-hospitalised
(n¼167)
n(%)
Hospitalised
(n¼95)
n(%) P-value*
Reported symptoms
Constitutional 107(64.1) 42 (44.2) 0.002
†
Respiratory 88 (52.7) 31 (32.6) 0.002
†
Gastrointestinal 88 (52.7) 35 (36.8) 0.013
†
Neuropsychiatric 110 (65.9) 43 (45.3) 0.001
†
Number of symptoms 0.005
†
Mean 6SD 8.1 67.5 5.7 67.7
Median (min–max) 8 (0–26) 0 (0–25)
* Mann-Whitney test was used.
†
Statistically significant.
SD ¼standard deviation.
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4The International Journal of Tuberculosis and Lung Disease

to take certain drugs, resulting in some side effects,
may play a role in the persistence of symptoms.
Finally, social isolation and lack of psychological
support for home-isolated patients might add to the
risks for prolonged post-COVID-19 symptoms.
Restrictions on daily activities, social isolation
and vulnerability in non-hospitalised patients may
also lead to more severe long COVID symptoms.
Various mental health consequences were reported
in previous quarantines among isolated persons,
such as depression, stress, irritability or insomnia.
Moreover, regarding physical health, restriction of
social activities leads to worse dynamic balance and
muscle strength, poor lung function, higher dis-
abilities and chronic inflammation.
26
Thus, both
mental and physical disturbances caused by social
deprivation in home-isolated patients may have
contributed to the pathogenesis of long COVID-19
symptoms.
As COVID-19 has progressed and concerns about
the long-term effects of COVID-19, especially on
functional disabilities, increased, cardiopulmonary
exercise testing was implemented. COVID-19 pa-
tients were found to have persistent breathing
problems, decreased physical fitness and muscle
weakness, implying that a tailored rehabilitation
intervention is needed.
27
Significant improvement
was found after pulmonary rehabilitation.
28
Hence,
the Stanford Hall consensus has recently recommend-
ed a multidisciplinary rehabilitation statement for
post-COVID-19 illness.
29
This study had some limitations. It was carried out
as a patient-dependent subjective analysis concerning
the patient quality of life with no use of objective
parameters such as pulmonary function tests, radio-
logical or laboratory testing. The study’s cross-
sectional design prevented longitudinal follow-up of
either the included patients or those who did not
complete the 12 weeks following infection onset.
Moreover, multiple inpatient and outpatient treat-
ment protocols were used during the data collection
period due to the novelty of the disease.
CONCLUSIONS
Long COVID-19 is a growing medical challenge that
affects both hospitalised and non-hospitalised pa-
tients. Neuropsychiatric manifestations are one of the
most common persistent COVID-19 symptoms.
Rehabilitation and psychotherapy programmes could
be advised for all recovered COVID-19 patients, even
those with mild infection and home isolation. Non-
hospitalised patients should be counselled to contact
the medical hotline services or healthcare providers
whenever needed.
Conflict of interests: none declared.
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1159/000514387.
29 Barker-Davies RM, et al. The Stanford Hall consensus
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6The International Journal of Tuberculosis and Lung Disease

RE
´SUME
´
CONTEXTE : Le terme « COVID-long » se r´ef`ere `ala
persistance des sympt ˆomes de COVID-19 plus de 12
semaines apr `es l’apparition des sympt ˆomes aigus. La
physiopathologie de ce syndrome reste `ad´eterminer.
OBJECTIF : E
´valuer les sympt ˆomes de COVID-long
chez des patients hospitalis´es et non-hospitalis´es.
ME
´THODES : Une enquˆete transversale a ´et ´er´ealis´ee.
L’ ´etude a inclus 262 patients divis´es en deux groupes en
fonction de leurs ant ´ec ´edents d’admission `a l’h ˆopital :
167 (63,7%) n’ont pas ´et ´e hospitalis ´es, alors que 95
(36,3%) ont ´et´e hospitalis´es.
RE
´SULTATS : Un COVID-long a ´et´e rapport ´echez157
des 262 patients (59,9%), et ´etait significativement plus
fr´equent chez les patients non-hospitalis´es (68,3% vs.
45,3%; P
,
0,001). Pendant la phase aigu¨
e, les patients
hospitalis´es ont pr´esent ´e davantage de sympt ˆomes
respiratoires (95,9% vs. 85,6%), alors que les
patients non-hospitalis´es avaient davantage de
sympt ˆomes neuropsychiatriques (84,4% vs. 69,5%; P
,
0,05). Les sympt ˆomes constitutionnels et
neuropsychiatriques ´etaient les sympt ˆomes persistants
les plus fr´equemment rapport´es dans les deux groupes,
mais tous les sympt ˆomes persistants ´etaient plus
fr´equents dans le groupe de patients non-hospitalis´es
(P
,
0,005).
CONCLUSION : Les sympt ˆomes de COVID-long
touchent aussi bien les patients hospitalis´es que non-
hospitalis´es. Les manifestations neuropsychiatriques
´etaient les sympt ˆomes de COVID-19 persistants les
plus courants. Une r´e´education et une psychoth´erapie
pourraient ˆetre conseill´ees `a tous les patients r´etablis. Il
convient de conseiller aux patients atteints de COVID-
19 non-hospitalis´es de contacter un prestataire de soins
en cas de besoin.
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Non-hospitalised patients and long COVID-19 i

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