Keywords
COVID-19 - long haulers - postacute COVID-19 - persistent COVID-19 Symptoms - post-COVID-19
manifestations - post-COVID-19 syndrome
Introduction
The coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus
2 was detected dates back in December 2019 in Wuhan, China. Due to the high infectivity
rate, it had a tremendous spread throughout the globe within a very short period of
time.[1] It has caused millions of deaths worldwide with a variable clinical manifestation.[2] Apart from the usual clinical manifestation, COVID-19 has been recently known for
its long term or persistent effect in many patients after recovery from the acute
phase.[3] Till date there is no consistent term to describe this slow and progressing sequelae
of COVID-19. Different authorities and literatures have explained this with terms
such as, “Post-acute COVID-19,” “Long-COVID-19,” “Long Haulers,” “Persistent COVID-19
Symptoms,” “Post COVID-19 manifestations,” “Long-term COVID-19 effects,” and “Post
COVID-19 syndrome.”
Literatures are increasing with time, reporting various long-term symptoms and syndromes.[4]
[5] The pattern and characteristics are still not well understood on probable account
of the geographical variability, clinical course, medication, and the presence of
comorbidities. However, it has been accepted that COVID-19 is a multisystem disorder.[6] The probable natural history of the disease has been recently proposed based on
the present understanding and available evidence.[3]
The National Institute for Health and Care Excellence (NICE)[7] has categorized the COVID-19 spectrum into three groups: (1) Acute phase of COVID-19, which includes sign and symptoms up to 4 weeks, (2) Ongoing symptomatic COVID-19, which includes sign and symptoms from 4 to 12 weeks beyond the acute phase, and
(3) Post-COVID-19 syndrome, where any sequelae persisting or developed after an infection, consistent with COVID-19,
continuing for more than 12 weeks and not attributable to alternative diagnoses. The
last two categories, that is, “Ongoing symptomatic COVID-19” and “Post-COVID-19 syndrome”
could be termed as “long COVID.”
In regard to the clinical spectrum, several studies have reported fatigue and dyspnea
as the most frequent symptoms after acute COVID-19.[4]
[8]
[9] Other symptoms such as joint pain, chest pain, cough, anosmia, rhinitis, red eyes,
dysgeusia, headache, sputum, lack of appetite, sore throat, vertigo, myalgia, and
diarrhea were also reported.[3]
[9] In addition to these general symptoms, specific organs dysfunctions have also been
observed, particularly in the heart, lungs, and brain. The other spectrum of the disease
could manifest as a hyperimmune response in the postacute phase or 2 to 5 weeks after
the onset of COVID-19 infection. The manifestation includes prominent cardiovascular,
gastrointestinal as well as mucocutaneous affection.[10] The pathogenesis is termed as multisystem inflammatory syndrome (MIS) in adults (MIS-A) and in children (MIS-C).[11] The clinicopathological understanding of MIS-C is well characterized,[10] whereas the MIS-A is not clearly distinct[12] and awaiting further investigation. This might be due to more severe and complex
clinical course in adults compared with the children where distinct separation of
inflammatory response from the usual clinical spectrum is difficult.
Due to the paramount importance to understand and manage such aftermaths, National
Institutes of Health (NIH) has included a separate emerging section in their COVID-19
guidebook (https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/). NICE has also created a workforce to provide evidence-based understanding and guidance
on postacute consequences.[7] However, no proper study has been published till date describing the postacute phase
of COVID-19 in Indian population.
Sanjiban Hospital is the referral tertiary care center treating COVID-19 patients
since the beginning of the outbreak in India. A special taskforce was also deployed
to follow up the patients after the discharge from hospital. However, on having fragmentary
reports of various symptoms persisting weeks even months after recovery, a structured
post-COVID assessment was necessitated. We conducted this preliminary study to characterize
the symptomatic array and prevalence of persistent symptoms after COVID-19 in patients
discharged from this hospital, and to look into the feasibility further study. Also,
based on the results, obtained from this study, and expert consensus, we intent to
develop an assessment form for further large-scale study and clinical assessment of
post-COVID patients.
Methods
Study Setting
The study was conducted at Sanjiban Hospital, Howrah, India, which was the tertiary
referral center during COVID-19 since April 2020. This is one of the largest tertiary
care hospitals in West Bengal, having 600 beds and multispecialty facilities. Up to
January 2021, it has served more than 4,500 COVID-19 patients referred from other
hospitals. Patients treated here were contacted regularly to evaluate their general
health status after discharge. In December 2021, a team of specialists was deployed
to interview the discharged patients for any post-COVID sequel. The study was performed
in the “Office of Medical Research &Data Management (OMRDM)” at the Hospital.
Interview Structure Development
A team was formed to prepare the interview structure consisted experts from various
specialities such as pulmonology, neurology, general medicine, anesthesiology, surgery,
psychology, research methodology, and statistics. The list of probable symptoms was
prepared by consensus between all the members of the team. The assessment included
present symptoms and its corroboration with the acute phase, or any newly appeared
symptoms. Additionally, open-ended questions were also asked to find out any complaints
beyond the list. All the records were maintained in a standardized proforma and imputed
in a specially designed excel sheet.
Study Participants
A telephonic interview was conducted among the hospitalized patients discharged between
June 2020 and August 2020. Upon agreeing to participate in the study, a structured
interview was performed for each participant at different time points after discharge.
The surveyed population was divided into two groups according to the duration, that
is, 3 to 12 weeks and >12 weeks post-discharge. The symptoms comparison between intensive
care unit (ICU) and non-ICU patients were also done.
Analysis Plan
We analyzed all the data using SPSS. The baseline information was analyzed and reported
either as n (%) for categorical data or mean (µ) ± standard deviation (SD) for continuous data.
Number (%) for symptoms prevalence were calculated in respect to the belonging group.
All the detailed descriptions and symptoms not contained in the list were interpreted
and modified into simpler version. Word cloud analysis was also done at different
intervals to visualize the frequency of presenting symptoms.
Consent
All potential participants were provided information details of the study at the very
beginning. In accordance with ethical standards, telephonic consents were collected
prior to the interview. We assured all the participants about the deidentification
and anonymous handling of all the data.
Results
Total 100 patients discharged before 3 weeks or more were identified randomly from
the electronic patient record. Of these, 94 could be contacted and approached, and
82 consented to participate in the study. Of nonconsenters, two patients died after
few days of discharge and 10 patients refused to take part in the interview (4—unwilling
to participate, 5—communication problem, and 1—unknown reason) ([Fig. 1]).
Fig. 1 Participant flow.
The baseline age, age groups, and gender were comparable between groups in both the
clusters, that is, general ward versus ICU and 3 to 12 weeks versus >12 weeks postdischarge.
The age of the participants was between 21 and 81 years. Fifty-three (64.6%) patients
were male participants, 26 (31.7%) were discharged from ICU, and 56 patients (68.3%)
from general ward. Most common comorbidities were hypertension, diabetes mellitus,
ischemic heart diseases, and chronic obstructive pulmonary diseases. Baseline data
were statistically comparable ([Table 1]).
Table 1
Baseline information
Variables
|
Total (n = 82)
|
Ward admitted
|
Duration after discharge
|
General ward (n = 56)
|
ICU (n = 26)
|
p-Value
|
3–12 weeks (n = 40)
|
>12 weeks (n = 42)
|
p-Value
|
Gender
• Male
• Female
|
53 (64.6)
29 (35.4)
|
35 (66.03)
21 (72.41)
|
18 (33.97)
8 (27.59)
|
0.352 (ns)
|
25 (47.17)
15 (51.72)
|
28 (52.83)
14 (48.28)
|
0.156 (ns)
|
Age, µ ± SD
|
56.48 ± 11.97
|
54.79 ± 13.1
|
60.14 ± 8.16
|
0.027 (ns)
|
54.73 ± 11.15
|
58.15 ± 12.61
|
0.219 (ns)
|
Age groups
|
|
|
|
0.182 (ns)
|
|
|
0.112 (ns)
|
• 21.0–40.0
|
11 (13.41)
|
10 (90.91)
|
1 (9.09)
|
6 (54.55)
|
5 (45.45)
|
• 41.0–60.0
|
46 (56.10)
|
31 (67.39)
|
15 (32.61)
|
28 (60.87)
|
18 (39.13)
|
• 61.0–81.0
|
25 (30.49)
|
15 (60.00)
|
10 (40.00)
|
6 (24.00)
|
19 (76.00)
|
Comorbidities
|
71 (86.59)
|
45 (63.38)
|
26 (36.61)
|
|
34 (47.89)
|
37 (52.11)
|
|
• Hypertension
|
42 (59.15)
|
21 (50)
|
21 (50)
|
0.292 (ns)
|
23 (53.49)
|
19 (44.18)
|
0.157(ns)
|
• Diabetes
|
31 (43.66)
|
14 (45.16)
|
17 (54.84)
|
21 (67.74)
|
10 (32.26)
|
• COPD
|
18 (25.35)
|
6 (33.33)
|
12 (66.67)
|
14 (77.78)
|
4 (22.22)
|
• IHD
|
23 (32.39)
|
4 (17.39)
|
19 (82.61)
|
9 (39.13)
|
14 (60.87)
|
• Chronic kidney diseases
|
15 (21.13)
|
6 (40)
|
9 (60)
|
10 (66.67)
|
5 (33.33)
|
• Cerebrovascular diseases
|
17 (23.94)
|
6 (35.29)
|
11 (64.71)
|
7 (41.18)
|
10 (58.82)
|
• Hypothyroidism
|
19 (26.76)
|
7 (36.84)
|
12 (63.16)
|
11 (57.89)
|
8 (42.11)
|
• Other
|
9 (12.68)
|
5 (55.56)
|
4 (44.44)
|
4 (44.44)
|
5 (55.56)
|
Abbreviations: µ, mean; COPD, chronic obstructive pulmonary disease; ICU, intensive
care unit; IHD, ischemic heart diseases; ns, nonsignificant; SD, standard deviation.
Twenty-one (25.61%) patients could not identify any residual or newly appeared symptoms.
Among 61 participants with persistent symptoms, fatigue was the most common (46.67%
of total symptomatic patients). Other frequently appeared symptoms were cough, shortness
of breath, loss of appetite, and constipation. In total, 47 different symptoms were
reported in which, 32 were physical and 15 were mental symptoms ([Table 2]). In addition to that, insomnia, depression, loss of memory, irritability, and traumatic
stress were most commonly reported mental symptoms. Prevalence of symptoms in respect
to the total included patients is visualized in [Fig. 2]. Cluster of symptoms in physical and mental domain were visualized as “word cloud”
in [Figs. 3] and [4], respectively.
Fig. 2 Bar diagram showing the prevalence of symptoms.
Fig. 3 Word cloud of physical symptoms.
Fig. 4 Word cloud of mental symptoms.
Table 2
Persistent symptoms in the postacute phase of COVID-19 among the hospital-discharged
patients
Symptom status
|
Total
|
ICU
|
General ward
|
3–12 Weeks
|
>12 weeks
|
Asymptomatic, n (%)
|
21 (25.9)
|
4 (19.1)
|
17 (80.9)
|
8 (38.1)
|
13 (61.9)
|
Symptomatic,
n (%)
|
61 (74.4)
|
22 (36.1)
|
39 (63.9)
|
32 (52.5)
|
29 (47.5)
|
A. Physical symptoms, n (%)
|
|
|
|
|
|
Fatigue
|
28 (45.9)
|
18 (81.8)
|
10 (25.6)
|
17 (53.1)
|
11 (37.9)
|
Myalgia
|
5 (8.1)
|
2 (9)
|
3 (7.6)
|
3 (9.3)
|
2 (6.8)
|
Loss of appetite
|
6 (9.8)
|
4 (18.1)
|
2 (5.1)
|
2 (6.2)
|
4 (13.7)
|
Loss of taste
|
1 (1.6)
|
–
|
1 (2.5)
|
1 (3.1)
|
–
|
Constipation
|
6 (9.8)
|
3 (13.6)
|
3 (7.6)
|
4 (12.5)
|
2 (6.8)
|
Aversion to fruits
|
1 (1.6)
|
–
|
1 (2.5)
|
1 (3.1)
|
–
|
Cough
|
19 (31.1)
|
14 (63.6)
|
5 (12.8)
|
9 (28.1)
|
10 (34.4)
|
Weight loss
|
2 (3.2)
|
–
|
2 (5.1)
|
1 (3.1)
|
1 (3.4)
|
Chest pain
|
4 (6.5)
|
3 (13.6)
|
1 (2.5)
|
2 (6.2)
|
2 (6.8)
|
Shortness of breath
|
11 (18)
|
9 (40.9)
|
2 (5.1)
|
3 (9.3)
|
8 (27.5)
|
Exertional dyspnea
|
5 (8.1)
|
4 (18.1)
|
1 (2.5)
|
3 (9.3)
|
2 (6.8)
|
Globus hystericus
|
4 (6.5)
|
3 (13.6)
|
1 (2.5)
|
1 (3.1)
|
3 (10.3)
|
Vomiting
|
1 (1.6)
|
–
|
1 (2.5)
|
–
|
1 (3.4)
|
Numbness
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Gingivitis
|
2 (3.2)
|
1 (4.5)
|
1 (2.5)
|
1 (3.1)
|
1 (3.4)
|
Diarrhea
|
2 (3.2)
|
1 (4.5)
|
1 (2.5)
|
1 (3.1)
|
1 (3.4)
|
Dysgeusia
|
2 (3.2)
|
2 (9)
|
–
|
2 (6.2)
|
–
|
Menorrhagia
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Chilliness
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Change of taste
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Chest tightness
|
2 (3.2)
|
1 (4.5)
|
1 (2.5)
|
–
|
2 (6.8)
|
Dyspepsia
|
3 (4.9)
|
3 (13.6)
|
–
|
1 (3.1)
|
2 (6.8)
|
Trembling
|
2 (3.2)
|
2 (9)
|
–
|
–
|
2 (6.8)
|
Fever
|
1 (1.6)
|
1 (4.5)
|
–
|
–
|
1 (3.4)
|
Skin rash
|
1 (1.6)
|
1 (4.5)
|
–
|
–
|
1 (3.4)
|
Vertigo
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Anemia
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Perspiration
|
3 (4.9)
|
2 (9)
|
1 (2.5)
|
2 (6.2)
|
1 (3.4)
|
Greying of hair
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Burning urine
|
1 (1.6)
|
1 (4.5)
|
–
|
–
|
1 (3.4)
|
Cough with expectoration
|
1 (1.6)
|
1 (4.5)
|
–
|
–
|
1 (3.4)
|
Nausea
|
2 (3.2)
|
–
|
2 (5.1)
|
1 (3.1)
|
1 (3.4)
|
B. Mental symptoms, n (%)
|
|
|
|
|
|
Insomnia
|
13 (21.3)
|
9 (40.9)
|
4 (10.2)
|
7 (21.8)
|
6 (20.6)
|
Depression
|
9 (14.7)
|
5 (22.7)
|
4 (10.2)
|
4 (12.5)
|
5 (17.2)
|
Memory loss
|
8 (13.1)
|
4 (18.1)
|
4 (10.2)
|
5 (15.6)
|
3 (10.3)
|
Irritability
|
8 (13.1)
|
6 (27.2)
|
2 (5.1)
|
5 (15.6)
|
3 (10.3)
|
Confusion
|
4 (6.5)
|
3 (13.6)
|
1 (2.5)
|
2 (6.2)
|
2 (6.8)
|
Anxiety
|
3 (4.9)
|
3 (13.6)
|
–
|
2 (6.2)
|
1 (3.4)
|
Incoherence
|
4 (6.5)
|
1 (4.5)
|
3 (7.6)
|
1 (3.1)
|
3 (10.3)
|
Suicidal ideation
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Religious mania
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Impatient
|
2 (3.2)
|
2 (9)
|
–
|
1 (3.1)
|
1 (3.4)
|
Fear of serious ailment
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Traumatic stress
|
7 (11.4)
|
5 (22.7)
|
2 (5.1)
|
3 (9.3)
|
4 (13.7)
|
Fear of falling
|
1 (1.6)
|
1 (4.5)
|
–
|
–
|
1 (3.4)
|
Rage
|
1 (1.6)
|
1 (4.5)
|
–
|
–
|
1 (3.4)
|
Sleepiness
|
1 (1.6)
|
1 (4.5)
|
–
|
1 (3.1)
|
–
|
Abbreviations: COVID-19, coronavirus disease 2019; ICU, intensive care unit.
General Ward versus ICU
Most of the commonly reported persistent complaints including fatigue, cough, insomnia,
shortness of breath, loss of appetite, constipation, chest pain, exertional dyspnea,
depression, irritability, and confusion were more prevalent among the patients discharged
from the ICU, compared with the patients admitted and discharged from general ward.
Few of the symptoms such as myalgia, weight loss, nausea, and incoherence were a bit
more reported in patients of later group ([Table 2]).
3–12 Weeks versus >12 Weeks Postdischarge
Symptoms such as fatigue, cough, insomnia, myalgia, and memory loss were more prominent
in the patients discharged within 3 to 12 weeks. However, shortness of breath, loss
of appetite, globus hystericus, chest tightness, trembling, depression, and incoherence
were more prevalent in the group of more than 12 weeks postdischarge ([Table 2]).
Discussion
Principal Finding
Our study found a vivid cluster of persistent symptoms after COVID-19 in patients
once admitted in the hospital. Total 49 types of symptoms were found in the participants
included in this study. Among physical symptoms, fatigue was the most common, followed
by cough, shortness of breath, constipation, loss of appetite, and myalgia, which
were commonly reported. In mental sphere, insomnia, depression, memory loss, and irritability
were most prevalent symptoms. We also observed some of the substantial differences
in the prevalence of symptoms between the groups of two clusters (general ward vs.
ICU and 3–12 weeks vs. >12 weeks postdischarge).
Comparison in Contrast to Other Studies
A qualitative study conducted on by Sudre et al[13] reported fatigue, headache, dyspnea, and anosmia as frequent persistent post-COVID
symptoms. It also showed the prevalence was more likely with increasing age and body
mass index and female sex. Another study by Logue et al[8] found fatigue and loss of smell or taste as the most prevalent symptoms at 6 months
after COVID-19. Fatigue, anxiety, dyspnea, cough, and joint pain were also reported
as the foremost symptoms in the other studies.[4]
[14]
[15] In contrast to these, our study revealed a little altered spectrum of symptoms particularly
from Indian population.
Strength of the Study
To our knowledge, this is the first study from India reporting on post-COVID-19 persistent
symptoms. We showed a vivid spectrum of symptoms that can arise after the acute illness
in this specified population. The study process was rigorous, an intrusive methodology
and predefined protocol was adopted before the initiation of the study. Trained personnel
and specialists handled every aspect of the study including, methodology, interview
structure, data collection, and analysis. The symptoms in physical and mental sphere
were also visualized through “word cluster” for better comprehension. Additionally,
a “Post-COVID-19 Quantitative Framework for Assessment” (pC-QFA ([Supplementary file-1], available online only)) proforma is also developed for screening of post-COVID
patients. The development of pC-QFA was based on the consensus between aforementioned
team of experts, available literature on the topic, and the findings on the present
study.
Limitation of the Study
One important caveat of this study is its generalizability. Being its preliminary
nature, the study findings lack proper implementation on the population. The sample
size could not be calculated beforehand due to the unavailability of similar study
on the defined population. Severity of the symptoms could not be quantified on account
of nonavailability of the quantitative assessment tool and uncertainty of their utility.
Owing to the telephonic nature of the interview, there are possibilities of noncapturing
any information, which might be relevant.
Further Recommendation
This preliminary pilot study can assist in many of the aspects of conducting a large-scale
similar survey in future. Future studies could be designed with proper sample size
based on these findings. Further studies can also look for specific symptoms' prevalence
and predictors for such persistence and development.
Implications
This study provides a boon to design the further large-scale studies in varied permutations
of methodology. The present findings point out the prevalence of varied symptoms in
the postacute phase of COVID-19 among hospital-discharged patients at different time-points.
Clinicians also can be used to screen and grade the postacute symptoms based on the
pC-QFA ([Supplementary file-1], available online only) according to their convenience. This proforma can also be
validated and altered in future in accordance with the need and nature of the utilization.
Conclusion
There are varied cluster of physical and mental symptoms that could be found after
COVID-19 in patients discharged from the hospital. Fatigue, cough, shortness of breath,
insomnia, depression, memory loss, irritability, and traumatic stress were the most
commonly reported symptoms. Some differences in the symptomatic prevalence could be
observed between different cohorts of patients. However, we recommend a large-scale
study to obtain a generalizable conclusion regarding prevalence and predictors of
postacute symptoms after COVID-19 infection. A framework for assessment was developed
using various sources that may be used for clinical assessment and in future studies
of similar nature.