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 Clinical Microbiology and Infection 29 (2023) 570e577

Contents lists available at ScienceDirect

Clinical Microbiology and Infection

journal homepage: www.clinicalmicrobiologyandinfection.com

Systematic review

A systematic review of trials currently investigating therapeutic

modalities for post-acute COVID-19 syndrome and registered on WHO
International Clinical Trials Platform
Nader A. Fawzy 1, y, Bader Abou Shaar 1, y, Rand M. Taha 1, z, Tarek Z. Arabi 1, z,
Belal N. Sabbah 1, z, Mohamad S. Alkodaymi 2, Osama A. Omrani 3, Tariq Makhzoum 1,
Najwa E. Almahfoudh 4, Qasem A. Al-Hammad 5, Wed Hejazi 1, Yasin Obeidat 6,
Naden Osman 1, Khaled M. Al-Kattan 1, Elie F. Berbari 7, Imad M. Tleyjeh 1, 7, 8, 9, *
1)
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
2)
Department of Family and Community Medicine, Alfaisal University, Riyadh, Saudi Arabia
3)
University College Hospital, London, United Kingdom
4)
College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
5)
College of Medicine, King Faisal University, Al Ahsa, Saudi Arabia
6)
UMass Chan Medical School, Baystate, MA, United States
7)
Division of Public Health, Infectious Diseases and Occupational Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
8)
Infectious Diseases Section, Department of Medical Specialties, King Fahad Medical City, Riyadh, Saudi Arabia
9)
Division of Epidemiology, Mayo Clinic College of Medicine and Science, Rochester, MN, United States

a r t i c l e i n f o a b s t r a c t

Article history:
Background: Post-acute COVID-19 syndrome (PACS) is a well-recognized, complex, systemic disease
Received 26 October 2022
which is associated with substantial morbidity. There is a paucity of established interventions for the
Received in revised form
1 January 2023 treatment of patients with this syndrome.
Accepted 5 January 2023 Objectives: To systematically review registered trials currently investigating therapeutic modalities for
Available online 13 January 2023 PACS.
Data sources: A search was conducted up to the 16 September, 2022, using the COVID-19 section of the
Editor: L Leibovici WHO Internal Clinical Trials Registry Platform.
Study eligibility criteria, participants, and interventions: Interventional clinical trials of any sample size
Keywords: examining any therapeutic modality targeting persistent symptoms among individuals after diagnosis
Coronavirus with COVID-19.
COVID-19
Methods: Data on trial characteristics and intervention characteristics were collected and summarized.
Long COVID
Results: After screening 17 125 trials, 388 trials, from 42 countries, were eligible. In total, we had 406
Post-acute COVID-19 syndrome
SARS-CoV-2 interventions, of which 368 were mono-therapeutic strategies, whereas 38 were intervention combi-
nations. Among 824 primary outcomes identified, there were >300 different outcomes. Rehabilitation
was the most employed class of intervention in 169 trials. We encountered 76 trials examining the
pharmacological agents of various classes, with the most common agent being colchicine. Comple-
mentary and alternative medicine encompassed 64 trials exploring traditional Chinese medicine, Ay-
urveda, homeopathic medications, naturopathic medications, vitamins, dietary supplements, and
botanicals. Psychotherapeutic and educational interventions were also employed in 12 and 4 trials,
respectively. Other interventions, including transcranial direct current stimulation, transcutaneous
auricular vagus nerve stimulation, general electrical stimulation, cranial electrotherapy stimulation,
various stem cell interventions, and oxygen therapy interventions, were also employed.
Conclusion: We identified 388 registered trials, with a high degree of heterogeneity, exploring 144
unique mono-therapeutic interventions for PACS. Most studies target general alleviation of symptoms.
There is a need for further high-quality and methodologically robust PACS treatment trials to be

* Corresponding author. Imad M. Tleyjeh, Section of Infectious Diseases, King Fahd Medical City, PO Box 59046, Riyadh 11525, Saudi Arabia.
E-mail address: Tleyjeh.Imad@mayo.edu (I.M. Tleyjeh).
y
These 2 authors contributed equally as first authors.
z
These 3 authors contributed equally as second authors.

https://doi.org/10.1016/j.cmi.2023.01.007
1198-743X/© 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577 571

conducted with standardization of outcomes while following WHO's recommendation for uniform
evaluation and treatment. Nader A. Fawzy, Clin Microbiol Infect 2023;29:570
© 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All
rights reserved.

Introduction Intervention/Comparator: Any intervention/comparator related

to the treatment (not prevention) of PACS symptoms;
Post-acute infection syndromes are commonly under-diagnosed Outcomes: Any outcome;
and represent a burden on health care worldwide [1]. As the global Study type: Interventional clinical trials.
COVID-19 pandemic comes to an end, a sizeable sub-set of recov- No restrictions were made on language, country, randomiza-
ering patients will continue to experience symptoms lasting weeks tion, blinding, trial arms, or the trials' population characteristics.
to months beyond the acute phase, as reported by several sys- We excluded withdrawn or terminated trials, trials with unknown
tematic reviews [2e10]. This conglomeration of symptoms has recruitment status, observational trials, COVID-19 diagnostic
been denoted by different terms: ‘long COVID’, ‘long-haul COVID’, studies, non-clinical studies, and trials investigating the treat-
‘chronic COVID’, ‘post-acute sequelae of SARS-CoV-2 infection’ or ment of acute symptoms of COVID-19. For trial registry entries
PASC, and ‘post-acute COVID-19 syndrome’ or PACS. The United which were deemed eligible, data were extracted simultaneously
Kingdom National Institute for Health and Care Excellence (NICE) by 12 reviewers (BAS, BNS, MSA, NAF, NEA, OAO, QAA, RMT, TM,
has also further sub-categorized PACS into a sub-acute phase, TZA, WH, and YO) in duplicate into a shared Excel sheet. Any
defined as the persistence of symptoms 4e12 weeks after the onset discrepancy was resolved in consultation with a senior reviewer
of illness (on-going symptomatic COVID-19), and a chronic phase, (IMT). This review was conducted according to the Preferred
in which symptoms persist for 12 weeks after the onset of the Reporting Items for Systematic Reviews and Meta-Analyses
disease, with no alternative underlying disease (post-COVID-19 guidelines [18].
syndrome) [11]. On the other hand, the WHO has defined it as a
condition characterized by symptoms that interfere with daily life Data extraction and management
and occur 3 months from the onset of acute symptoms of COVID-19,
lasting for at least 2 months and cannot be explained by an alter- Data on registry source, recruitment country, recruitment sta-
native diagnosis [12]. tus, site description, allocation status, phase, masking, intervention
More than 100 persistent symptoms have been associated with model, estimated enrolment, inclusion criteria, primary out-
COVID-19 [13]. Fatigue, followed by dyspnoea, was the most re- come(s), publication status, and intervention details were extracted
ported symptom according to multiple systematic reviews [2,10,14]. as reported in the trial registries. The trial registry source was taken
To date, there have been no published systematic reviews exam- as linked in the ICTRP sheet. If not stated explicitly, we used the
ining registered interventional clinical trial entries evaluating addresses of the facilities organizing the trial to identify recruit-
different treatment modalities for PACS. In addition, there is a ment countries. Trials with multiple recruitment countries were
paucity of published studies on potential treatment options for combined into ‘multiple countries’. Similarly, trials with phases 1 or
PACS. Thus, we aimed to conduct a systematic review of registered 2 and 2 or 3 were combined into one category.
interventional clinical trial entries examining therapeutic treat- Two reviewers (BAS and NAF) merged overlapping primary
ments for PACS. The purpose of this study is to provide an overview outcomes and grouped them into appropriate outcome domains.
of therapies for PACS which are currently being investigated as well None of the protocols reported composite primary outcomes. A
as the key limitations of current trials and gaps to guide future consensus was achieved with the merging and organization of the
research. primary outcomes. The taxonomy of outcome domains was based
on the Williamson/Clarke revised version of the Cochrane Database
Methods of Systematic Reviews and the Core Outcome Measures in Effec-
tiveness Trials database of core outcome sets, which is a taxonomy
Registry search with 38 outcome domains in five core areas [19].
We explored the trials' inclusion criteria by noting their defi-
Trial registry entries were identified on September 16, 2022, nition of PACS: mentioned a time reference of 4 weeks from acute
using the COVID-19 section of the WHO Internal Clinical Trials COVID-19 infection or PCR (consistent with the NICE definition of
Registry Platform (ICTRP), which includes trial entries from 17 PACS); mentioned a time reference of 12 weeks from acute
different trial registries [15]. The WHO ICTRP necessitates that COVID-19, with symptoms persisting for 8 weeks (consistent with
these registered trials meet specific criteria for content, quality, the WHO definition of PACS); explicitly mentioned as patients with
validity, accessibility, unambiguous identification, technical ca- PACS (or its equivalent) without the definition of a time reference;
pacity, administration, governance, and requirements of the Inter- or neither explicitly mentioned PACS (or its equivalent) nor defined
national Committee of Medical Journal Editors [16]. a time reference but used the PACS term (or its equivalent) in the
title or study description. In addition, the patients' hospitalization
Trial selection status during the acute COVID-19 phase was recorded. Further-
more, we determined whether the trials reported symptoms before
Eligibility criteria were assembled using the Patient Intervention COVID-19. Using each trial's scientific title and trial identification, a
Comparison Outcomes Study type framework [17]. The inclusion web search was performed to determine whether the trials' results
criteria were as follows: were published.
Population: Any sample size of patients of any age diagnosed with The experimental arm(s) for each trial were used to identify all
COVID-19 who present with symptoms 4 weeks from the time of interventions under investigation for PACS. Each arm was recorded
diagnosis or specifically mentioning PACS (or its equivalent); separately in the summary figure for trials with multiple
572 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577

experimental arms. For each intervention under investigation, we Only 78 trials (20.1%) had completed recruitment at the time of
recorded the number of trials, total patients enrolled, countries, analysis (17 September, 2022). In the majority of the trials (238
and specific clinical use as stated by the trial source. Because the trials, 61.3%), only one primary outcome was identified. Among 824
trial registries did not record interventions in a standardized primary outcomes identified, there were >300 different outcomes.
format, we organized all interventions into different classes and The trial characteristics, including patient populations, in-
sorted them into seven different organ systems, as highlighted by terventions, and outcome core areas, are detailed in Table 1. The top
our previous systematic review and meta-analysis of the preva- 20 primary outcomes identified according to their frequency are
lence of PACS symptoms [10]. The organ systems included the detailed in Table 2. All primary outcomes identified, arranged ac-
nervous, mental, gastrointestinal, pulmonary, cardiovascular, cording to Core Outcome Measures in Effectiveness Trials core
musculoskeletal, and other systems. Interventions targeting fa- outcome sets, can be found in Table S1.
tigue, hair loss, or other general indications (post-COVID-19
symptom relief, quality of life, etc.) were labelled as ‘other’. Characteristics of trials' inclusion criteria
WHO's definition of rehabilitation was used to organize the
interventions under the rehabilitation class [20]. We utilized the There were 239 trials (61.6%) that did not mention the hospi-
WHO's Anatomical Therapeutic Chemical Classification System to talization status of the included population resulting from the acute
classify drugs into intervention classes [21]. We used product in- COVID-19 phase. Only 72 trials (18.6%) collected symptoms prior to
formation from the European Medicines Agency [22], U.S. Food and COVID-19. Among the included trials, only 95 (24.5%) and 87 trials
Drug Administration [23], or companies' websites to characterize (22.4%) had their inclusion criteria consistent with the NICE and
some drugs which were not part of WHO's Anatomical Therapeutic WHO definitions, respectively.
Chemical algorithms. The mechanisms of action and approved
clinical uses of drugs were extracted from the Food and Drug Sample size
Administration or European Medicines Agency, where applicable.
We also checked the Traditional Herbal Medicines Registration The included trials had a median (interquartile range) enrol-
Scheme [24,25] to determine whether any of the herbal in- ment of 60 participants (40e101.5), and the total number of par-
terventions acquired a Traditional Herbal Registration certification ticipants planned for enrolment for all the included trials was
mark and the National Institute of Health National Center for 58 340. The smallest trial included only five patients. Of the four
Complementary and Integrative Health “Herbs at a Glance” [26] to international multi-regional trials, one (NCT05002530) had the
determine whether any were mentioned; however, none were largest planned enrolment, with 10 000 participants.
mentioned. Trials of Ayurveda, a natural system of medicine which
originated in India; traditional Chinese medicine; traditional Therapies being investigated
Korean medicine; herbals; homeopathy; and dietary supplement
interventions were categorized under ‘complementary and alter- Out of the 406 interventions explored, 368 (n ¼ 40 834) tested
native medicine’ [27]. mono-therapeutic strategies, whereas 38 (n ¼ 17 506) included a
combination of interventions. There were 144 unique mono-ther-
Analysis apeutic interventions in total. Among the trials indicated for non-
system-specific symptoms, 108 targeted fatigue and 70 had broad
Descriptive statistics using Excel was used to analyse the indications (relief of PACS symptoms, improved quality of life,
extracted data. Using percentages, the trial characteristics were etc.). Out of the trials which tested mono-therapeutic in-
summarized. terventions, 169 trials were on rehabilitation strategies, 76 trials
were on pharmacotherapy, 64 trials were on complementary and
Results alternative medicine, 12 trials were on psychotherapy, four trials
were on education, and the rest were uncategorized.
Trial search results
Rehabilitation
Of 17 125 trials identified, 10 688 registered trials were manually
screened, and 388 trials, with 406 experimental arms, were Trials on rehabilitation most commonly employed exercises that
included in our final analysis after de-duplication (Fig. 1). During included aerobic exercises, strength exercises, bicycling, swim-
the manual screening process, the most common reason for ming, etc. Various forms of rehabilitation, including tele-
exclusion was trials investigating treatment strategies for acute rehabilitation, cognitive rehabilitation, virtual reality rehabilita-
COVID-19 infection (n ¼ 4635). From the 388 trials, 48 trials (12.4%) tion, yoga rehabilitation, and even rehabilitation robots, were uti-
were found to be published at the time of writing. lized. Inspiratory and/or expiratory muscle training as well as
breathing exercises were also commonly used. Various applications
General characteristics of the clinical trials and custom-made programmes, such as Akili Interactive; Breath-
ing, Rest/recovery, Education, Activity management, Thinking/
From the 17 WHO ICTRP record registries, 223 included trials cognition, Healthy voice strategies, and Eating/nutrition pro-
(57.5%) were registered on ClinicalTrials.gov. The results indicate that gramme; long COVID optimal health programme; etc., were
on-going research on PACS treatment originated from 42 countries, designed to help ameliorate PACS symptoms.
with the United States (n ¼ 60) and India (n ¼ 57) harbouring the
greatest number of trials. The most common recruitment regions for Pharmacotherapy
our included trials consisted of 114 trials (29.4%, n ¼ 22 711) based in
Europe, 98 trials (25.3%, n ¼ 9492) in Asia, and 73 trials (18.8%, There were 61 unique pharmacological interventions tested for
n ¼ 6672) in North America (Table 1). There were four international PACS. The most commonly used agents were colchicine, nintedanib,
multi-regional trials (NCT05002530, NCT05494424, NCT04652518, pirfenidone, ivermectin, methylprednisolone, mometasone, mon-
ACTRN12621000637842). telukast, prednisolone, and treamid.
 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577 573

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram.

Complementary and alternative medicine intervention, medical psycho-educational talks, and pain and self-
management education.
This category encompassed 25 trials on traditional Chinese
medicine, which included multiple Chinese herbal products (de- Other interventions
coctions, capsules, granules, etc.), Tai Chi, and different forms of
acupuncture (needle, laser, or electro-acupuncture). There were 24 Electrical therapy was commonly employed, with nine trials on
trials of Ayurvedic therapies, which mainly included herbal medi- transcranial direct current stimulation, four trials on transcutaneous
cines such as ashwagandha. Other trials used homeopathic medi- auricular vagus nerve stimulation, two trials on general electrical
cations, naturopathic medications, vitamins, dietary supplements, stimulation, and one trial on cranial electrotherapy stimulation.
and botanicals. Various stem cell interventions were used such as allogenic culture-
expanded adipose-derived mesenchymal stem cells and allogenic
Psychotherapy marrow stromal cells. Oxygen therapy interventions, such as hy-
perbaric oxygen, a hydrogen-oxygen generator using a nebulizer, and
Different therapeutic approaches fell under this category, a portable oxygen concentrator, were also used.
including cognitive behavioural therapy, amygdala and insula Each mono-therapeutic intervention, with its target organ sys-
retraining programmes, mind-body syndrome therapy, etc. tem, can be found in Fig. 2, whereas the combinations of in-
terventions are detailed in Table S2. For full details, unique
Education interventions under investigation, the number of registered clinical
trials, estimated enrolment of all trials, countries, clinical use in the
Only four educational interventions were encountered, which trial, mechanism of action, and approved clinical use can be found
included cognitive psycho-education, education and strategies in Tables S3eS9.
574 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577

Table 1 Table 1 (continued )

Characteristics of the clinical trials registered for the treatment of post-acute COVID-
19 syndrome (n ¼ 388) Trial characteristics Total number of
trials (n ¼ 388), n (%)
Trial characteristics Total number of
Estimated enrolment
trials (n ¼ 388), n (%)
Median (IQR) 60 (40e101.5)
Trial registry source 50 139 (35.8)
ClinicalTrials.gov 223 (57.5) 51e100 152 (39.2)
CTRI 54 (13.9) >100 97 (25.0)
ReBEC 23 (5.9) Primary outcomes core areasa
ChiCTR 23 (5.9) Mortality/survival 3 (0.8)
IRCT 20 (5.2) Physiological/clinical 522 (134.6)
ISRCTN 14 (3.6) Functioning 282 (72.7)
German Clinical Trials Register 14 (3.6) Resource use 4 (1.0)
Others 17 (4.4) Adverse events/effects 13 (3.4)
Recruitment region Organ system targeteda
Europe 114 (29.4) Pulmonary system 133 (34.3)
Asia 98 (25.3) Nervous system 70 (18)
North America 73 (18.8) Mental health 47 (12.1)
Middle East 55 (14.2) Cardiovascular system 26 (6.7)
South America 40 (10.3) Musculoskeletal system 21 (5.4)
Australia 3 (0.8) Gastrointestinal system 5 (1.3)
Africa 1 (0.3) Non-system specific 178 (45.9)
Multiple regions 4 (1.0) Intervention typea
Site description Rehabilitation 168 (43.3)
Single centre 325 (83.8) Pharmacotherapy 77 (19.8)
Multi-centre 63 (16.2) Complementary and alternative medicine 64 (16.5)
Recruitment status Psychotherapy 12 (3.1)
Recruiting 165 (42.5) Education 4 (1.0)
Not yet recruiting 120 (30.9) Others 43 (11.1)
Completed 78 (20.1) Intervention combinations 38 (9.8)
Active, not yet recruiting 14 (3.6)
ChiCTR, Chinese Clinical Trial Registry; CTRI, Clinical Trials Registry e India; IQR,
Enrolling by invitation 10 (2.6)
interquartile range; IRCT, Iranian Registry of Clinical Trials; ISRCTN, International
N/A 1 (0.3)
Standard Randomised Controlled Trial Number; N/A, not available; NICE, National
Allocation
Institute for Health and Care Excellence; PACS, post-acute COVID-19 syndrome;
Randomized 310 (79.9)
ReBEC, Brazilian Clinical Trials Registry.
Not randomized 25 (6.4) a
Total percentages may exceed 100% because several trials had multiple primary
N/A 53 (13.7)
outcomes, organ systems targeted or experimental interventions.
Phase
Phase 0 12 (3.1)
Phase 1 9 (2.3) Discussion
Phase 2 48 (12.4)
Phase 3 27 (7.0) Findings
Phase 4 19 (4.9)
Multiple phases 26 (6.7)
N/A 247 (63.7)
COVID-19 has caused mortality and morbidity at an unprece-
Trial arm dented scale globally, affecting >616 million people worldwide, of
Multi-arm 332 (85.6) whom 10%e20% are thought to have PACS according to the WHO
Single arm 56 (14.4)
Masking Table 2
Open-label 139 (35.8) The top 20 primary outcome measures in terms of frequency (N)
Single blind 76 (19.6)
Double blind 83 (21.4) Rank Primary outcome measures N
Triple blind 29 (7.5)
1 6-minute walk test 58
Quadruple blind 28 (7.2)
2 Pulmonary function testing 43
Not stated 33 (8.5)
3 Changes in symptoms of PACS 24
Trials' inclusion criteria for PACS definition
4 36-Item Short-Form Survey 23
Mentioned a time reference of 4 weeks from acute 95 (24.5)
5 Cardiopulmonary exercise test/peak oxygen 20
COVID-19 infection or PCR (consistent with the
consumption (VO2 max)
NICE definition of PACS)
6 European Quality of Life 5 Dimensions 5 Level Version 19
Mentioned a time reference of 12 weeks from 87 (22.4)
7 Visual Analogue Scale 17
acute COVID-19, with symptoms persisting for
8 Fatigue Severity Scale 16
8 weeks (consistent with WHO definition of
9 Post-COVID-19 Functional Status Scale 12
PACS)
10 Sniffin’ Sticks Test 12
Explicitly mentioned as patients with PACS (or its 140 (36.1)
11 Modified Medical Research Council Dyspnea Scale 10
equivalent) without the definition of a time
12 Chalder Fatigue Scale (CFQ-11) 9
reference
13 Fibrosis in high-resolution computed tomography of the lung 9
Neither explicitly mentioned PACS (or its 66 (17.0)
14 Incidence of treatment-emergent adverse effects 9
equivalent) nor defined a time reference but has
15 Inspiratory muscle strength or maximal inspiratory pressure 9
been stated in the title or study description
16 Borg Dyspnea Scale 8
Hospitalization status during acute COVID-19 phase
17 Changes in blood oxygenation 8
Hospitalized 66 (17.0)
18 Fatigue Assessment Scale 8
Non-hospitalized 61 (15.7)
19 Handgrip strength dynamometer 8
Mixed (hospitalized and non-hospitalized) 22 (5.7)
20 Routine blood test 7
Not stated 239 (61.6)
20 SGRQ 7
Collected symptoms prior to COVID-19
Yes 72 (18.6) PACS, post-acute COVID-19 syndrome; SGRQ, St. George's Respiratory
No 316 (81.4) Questionnaire.
 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577 575

Fig. 2. Mono-therapeutic interventions were organized by treatment category with their target organ system (n ¼ 368). BREATHE, Breathing, Rest/recovery, Education, Activity
management, Thinking/cognition, Healthy voice strategies, and Eating/nutrition; DiRECT, Diabetes Remission Clinical Trial; ENO, English National Opera; Hb-adMSC, Hope Bio-
sciences adipose-derived mesenchymal stem cell; HUS, Helsinki University Hospital; LISTEN, Long COVID PersonalIsed Self-managemenT support EvaluatioN; PACS, post-acute
COVID-19 syndrome; PEEP, positive end-expiratory pressure; REMM-HIIT, REmotely Monitored, Mhealth supported High Intensity Interval Training; TCM, traditional Chinese
medicine; tSVF, tissue stromal vascular fraction.

COVID-19 Dashboard [28]. The health-care demands of patients considerable heterogeneity was exhibited. Moreover, no trial had a
with PACS will continue to rise in the near future. Still, there are reference time of zero. Furthermore, 66 trials mentioning patients
several deficiencies in the current work towards therapeutic mo- with PACS, with no time reference in their inclusion criteria, most
dalities for PACS, and we believe that it does not match the sub- simply referred to their patients as having a positive COVID-19 test
stantial needs and burden caused by PACS worldwide. With only result and then a negative test result. This raises the question of
four international multi-centre trials, there is a definitive need for whether these patients recovered from COVID-19 and are now
more trials addressing PACS on a larger scale. exhibiting PACS symptoms. Remarkably, in terms of the inclusion
Fatigue and dyspnoea were the two most reported symptoms criteria of the four international multi-centre trials, 2 trials neither
by patients with PACS according to multiple systematic reviews explicitly mentioned PACS (or its equivalent) nor defined a time
[10,14,29]. This was concordant with the symptoms targeted by reference, and one trial explicitly mentioned patients with PACS (or
the experimental trials, with 108 trials specifically targeting fa- its equivalent) without defining a time reference.
tigue and 133 trials targeting the pulmonary system. The ma-
jority of interventions targeting a single organ system were non- Implications
system specfic, with 70 trials using a holistic approach to target
and alleviate PACS symptoms. This brings into question the The data presented are only as good as the data acquired from
reproducibility of such trials and the difficulty in measuring the registries; the ICTRP gathers records from 17 different trial
possible benefits later in the clinical setting. registries, collecting information from all around the world. Despite
Although there was a good number of trials investigating PACS its importance, there are still chances to improve the consistency
treatment, most of the therapies investigated were re-purposed and quality of the data provided [30e32]. Trials' protocols provide
from similar conditions; for example, many of the rehabilitation much more information and details on the methodology and pri-
interventions are currently used in the treatment of cancer- mary outcome. We reviewed the trials' protocols whenever they
associated fatigue syndrome. In addition, most of the in- were available; nonetheless, we had to rely on trial registry entries
terventions were used to target multiple PACS symptoms concur- and not trial protocols for many of the trials.
rently. Although we encountered new interventional agents With three-fourths of the trials enrolling 100 participants and
developed specifically for PACS (RSLV-132, AXA1125, etc.), they more than one-third being open-label, the numerous interventions
were very limited. In many instances, multiple trials proposed the reported are likely to yield only preliminary evidence concerning
same intervention for different symptoms. safety and effectiveness against PACS. Additionally, with the bulk of
It was not possible to classify interventions according to pa- the trials utilizing subjective and patient-reported scales, there is a
tients' clinical categories (such as being admitted to the intensive high risk of outcome assessment biases [33]. The reported primary
care unit or managed as out-patients or in-patients) because >60% outcomes were highly heterogeneous among the included trials.
did not indicate the hospitalization status of patients who were Considering the wide range of symptoms and the absence of
recruited for the trial in their inclusion and exclusion criteria. conclusive diagnostic tests, it is challenging to identify patients
Regarding the definition of PACS employed by the included trials, with PACS consistently and systematically while assembling an
576 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577

adequate control group for comparison. With many of the regis- using an objective measure of the severity and duration of symp-
tered trials designed expediently, the PACS trials inadequately toms. Furthermore, the primary outcomes assessed in trials are of
defined their inclusion criteria. They failed to indicate severity essence and should have a meaningful clinical use that is of
status of the acute phase of COVID-19 in their population, creating a importance to patients [46,47]. Moreover, a core outcome set
challenge to distinguish between, for example, PACS and post- developed by an international Delphi consensus study for PACS in
intensive care syndrome. Furthermore, only a small number of adults contained 12 outcomes and included survival, an outcome
trials reported acquiring history of symptoms prior to acute COVID- which was very scarcely reported among trials [48]. To facilitate
19, which may have resulted in the inclusion of patients without homogeneous outcome reporting and enhance the strength of ev-
PACS in these trials. The patients may have been experiencing idence in systematic reviews of upcoming trials, we recommend
symptoms because of other chronic conditions or infectious dis- adherence to the core outcome set [48].
eases. Post-acute infection syndromes, which have already been Although living mapping and living systematic review initia-
recognized, present as indistinguishable symptom profiles inde- tives are vitally important for different sections for pharmacolog-
pendent of the infectious pathogen [1,34,35]. ical, non-pharmacological, and preventative treatment, they should
Because clinical trials are costly and time consuming, interna- also aim to identify and differentiate PACS treatment and even PACS
tional collaborations are encouraged [36]. An example of such a prevention studies from acute COVID-19 studies and present them
partnership is the WHO COVID-19 Solidarity Therapeutics Trial, in separate sections.
which is evaluating three treatment arms: artesunate, infliximab,
and imatinib [37]. Additionally, the National Institute of Health Conclusion
created the REsearching COVID to Enhance Recovery initiative to
learn, prevent, and treat PACS [38]. We identified 388 trials with a high degree of heterogeneity
exploring 144 mono-therapeutic interventions for PACS. The defi-
Strengths and limitations nition of PACS illustrated by the trials was variable, and the primary
outcomes were often non-system specific and not standardized.
Our study is the first comprehensive systematic review of The data from these studies will guide future research and treat-
registered interventional clinical trial entries investigating thera- ment. Given that the health-care demands of patients with PACS
peutic interventions for PACS. In comparison with the extensive will keep increasing, there is a need for further high-quality and
living networks to capture COVID-19 studies which still lack a methodologically robust research on PACS treatment to be con-
dedicated section or filter for PACS treatment [39,40], we believe ducted with standardization of outcomes while following WHO's
that our overview of investigated interventions, and the quantifi- recommendations for uniform evaluation and treatment.
cation of several methodological parameters has merits which are
not provided elsewhere.
Even with double screening for inclusion as well as independent Author contribution
parallel screening and data extraction, several caveats are inherent
to the methodology and study design of the included trials. The NAF and BAS contributed equally as first authors. RMT, TZA, and
organization of interventions into different classes is, to some BNS contributed equally as second authors. IMT conceptualized the
extent, arbitrary, because some drugs fit into more than one cate- study. IMT, MSA, and OAO supervised the study. BAS and NAF were
gory. The trials in our review lacked uniform symptom terminology, involved in project administration. BAS and NAF performed formal
standardized recording methods, accurate population identifica- analysis. BAS, BNS, MSA, NAF, NEA, NO, OAO, QAA, RMT, TM, TZA,
tion, and grouping of multiple symptoms under umbrella terms. WH, and YO performed data curation. RMT performed visualiza-
This limited our ability to filter trials and divide interventions ac- tion. BAS, BNS, NAF, RMT, and TZA wrote the original draft. EFB,
cording to their target organ system. In addition, some trials KMA, MSA, and IMT reviewed and edited the manuscript.
included may subsequently be withdrawn, terminated, or unable to
reach the target enrolment. Transparency declaration

Future directions The authors declare that they have no conflicts of interest.

With the WHO describing the pandemic as causing more ‘mass Appendix A. Supplementary data
trauma’ than World War II, we must keep pace with the evolving
unmet needs of this pandemic. Although targeted re-purposing of Supplementary data to this article can be found online at
existing treatments is critical in the early phases of a threat, there https://doi.org/10.1016/j.cmi.2023.01.007.
needs to be a focus on targeted novel therapies addressing the
underlying pathophysiological mechanisms of PACS. Particularly,
References
trials investigating complementary and alternative medicine are
increasing in number but have low registration quality [41]. [1] Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection
Therefore, it is important to improve the quality of reporting syndromes. Nat Med 2022;28:911e23. https://doi.org/10.1038/s41591-022-
research protocols which are registered in strict accordance with 01810-6.
[2] Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al.
guidelines for conducting and reporting clinical trials [42,43]. In Post-acute COVID-19 syndrome. Nat Med 2021;27:601e15. https://doi.org/
addition, we support protocol sharing with trial registration to 10.1038/s41591-021-01283-z.
encourage routine public access for the benefit of patients and [3] SeyedAlinaghi SA, Afsahi AM, MohsseniPour M, Behnezhad F, Salehi MA,
Barzegary A, et al. Late complications of COVID-19; a systematic review of
other users of clinical trial evidence [44].
current evidence: Vol. 9. Archives of Academic Emergency Medicine.
Future trials should abide by the recommendations of Nasserie Shaheed Beheshti University of Medical Sciences and Health Services; 2020.
et al. [45] regarding areas for improvement in future research on p. e14.
PACS, whether in the conduct of studies or the reporting of various [4] de Oliveira Almeida K, Nogueira Alves IG, de Queiroz RS, de Castro MR,
Gomes VA, Santos Fontoura FC, et al. A systematic review on physical function,
characteristics of symptoms for such conditions, including the use activities of daily living and health-related quality of life in COVID-19 survi-
of a standardized definition for symptoms and time-zero, as well as vors. Chronic Illn 2022. https://doi.org/10.1177/17423953221089309.
 N.A. Fawzy et al. / Clinical Microbiology and Infection 29 (2023) 570e577 577

[5] Almas T, Malik J, Alsubai AK, Zaidi SM, Iqbal R, Khan K, et al. Post-acute COVID- [28] World Health Organization. WHO coronavirus (COVID-19) dashboard. 2022.
19 syndrome and its prolonged effects: an updated systematic review. Ann https://covid19.who.int/.
Med Surg 2022g;80:103995. https://doi.org/10.1016/j.amsu.2022.103995. [29] Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al.
[6] Long Q, Li J, Hu X, Bai Y, Zheng Y, Gao Z. Follow-ups on persistent symptoms Post-acute COVID-19 syndrome. Nat Med 2021;27:601e15. https://doi.org/
and pulmonary function among post-acute COVID-19 patients: a systematic 10.5281/zenodo.4669937.
review and meta-analysis. Front Med 2021;8:702635. https://doi.org/10.3389/ [30] Salholz-Hillel M, Grabitz P, Pugh-Jones M, Strech D, DeVito NJ. Results avail-
fmed.2021.702635. ability and timeliness of registered COVID-19 clinical trials: interim cross-
[7] Fugazzaro S, Contri A, Esseroukh O, Kaleci S, Croci S, Massari M, et al. Reha- sectional results from the DIRECCT study. BMJ Open 2021;11:e053096.
bilitation interventions for post-acute COVID-19 syndrome: a systematic re- https://doi.org/10.5281/zenodo.4669937.
view. Int J Environ Res Public Health 2022;19:5185. https://doi.org/10.3390/ [31] Speich B, Gloy VL, Klatte K, Gryaznov D, Heravi AT, Ghosh N, et al. Reliability of
ijerph19095185. trial information across registries for trials with multiple registrations. JAMA
[8] Cabrera Martimbianco AL, Pacheco RL, Bagattini AM, ^ Riera R. Frequency, signs Netw Open 2021;4:e2128898. https://doi.org/10.1001/jamanetworkopen.
and symptoms, and criteria adopted for long COVID-19: a systematic review. 2021.28898.
Int J Clin Pract 2021;75:e14357. https://doi.org/10.1111/ijcp.14357. [32] Tse T, Fain KM, Zarin DA. How to avoid common problems when using
[9] Malik P, Patel K, Pinto C, Jaiswal R, Tirupathi R, Pillai S, et al. Post-acute COVID- ClinicalTrials.gov in research: 10 issues to consider. BMJ 2018;361:k1452.
19 syndrome (PCS) and health-related quality of life (HRQoL)da systematic https://doi.org/10.1136/bmj.k1452.
review and meta-analysis. J Med Virol 2022;94:253e62. https://doi.org/ [33] Hro bjartsson A, Emanuelsson F, Skou Thomsen AS, Hilden J, Brorson S. Bias
10.1002/jmv.27309. due to lack of patient blinding in clinical trials. A systematic review of trials
[10] Alkodaymi MS, Omrani OA, Fawzy NA, Shaar BA, Almamlouk R, Riaz M, et al. randomizing patients to blind and nonblind sub-studies. Int J Epidemiol
Prevalence of post-acute COVID-19 syndrome symptoms at different follow- 2014;43:1272e83. https://doi.org/10.1093/ije/dyu115.
up periods: a systematic review and meta-analysis. Clin Microbiol Infect [34] Bannister BA. Post-infectious disease syndrome. Postgrad Med J 1988;64:
2022;28:657e66. https://doi.org/10.1016/j.cmi.2022.01.014. 559e67. https://doi.org/10.1136/pgmj.64.753.559.
[11] National Institute for Health and Care Excellence (UK). COVID-19 rapid [35] Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD,
guideline: managing the long-term effects of COVID-19. 2020. https://www. et al. Post-infective and chronic fatigue syndromes precipitated by viral and
nice.org.uk/guidance/ng188. non-viral pathogens: prospective cohort study. BMJ 2006;333:575. https://
[12] World Health Organization. A clinical case definition of post COVID-19 con- doi.org/10.1136/bmj.38933.585764.AE.
dition by a Delphi consensus. 2021. https://www.who.int/publications/i/item/ [36] BioWorld. EU boosts funding for COVID-19 epidemic, encourages clinical trial
WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1. cooperation. 2022. https://www.bioworld.com/articles/433824-eu-boosts-
[13] Hayes LD, Ingram J, Sculthorpe NF. More than 100 persistent symptoms of funding-for-covid-19-epidemic-encourages-clinical-trial-cooperation?
SARS-CoV-2 (long COVID): a scoping review. Front Med 2021;8:750378. v¼preview.
https://doi.org/10.3389/fmed.2021.750378. [37] WHO. COVID-19 solidarity therapeutics trial. 2022. https://www.who.int/
[14] Joli J, Buck P, Zipfel S, Stengel A. Post-COVID-19 fatigue: a systematic review. emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-
Front Psychiatry 2022;13:947973. https://doi.org/10.3389/fpsyt.2022.947973. coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments.
[15] International Clinical Trials Registry Platform. Important information related [38] National Institutes of Health. RECOVER: researching COVID to enhance re-
to the COVID-19 outbreak. 2022. https://www.who.int/clinical-trials-registry- covery. 2022. https://recovercovid.org/.
platform. [39] WHO, Cochrane. The COVID-NMA initiative: a living mapping and living
[16] International Clinical Trials Registry Platform. WHO registry criteria. 2009. systematic review of Covid-19 trials. 2022. https://covid-nma.com/.
https://www.who.int/clinical-trials-registry-platform/network/registry- [40] Infectious Diseases Data Observatory. A living systematic review of registered
criteria. COVID-19 trials. 2022. https://www.iddo.org/covid-19/live-systematic-
[17] Schardt C, Adams MB, Owens T, Keitz S, Fontelo P. Utilization of the PICO review-trials.
framework to improve searching PubMed for clinical questions. BMC Med [41] Kuang Z, Li X, Cai J, Chen Y, Qiu X, Ni X. Calling for improved quality in the
Inform Decis Mak 2007;7:1e6. https://doi.org/10.1186/1472-6947-7-16. registration of traditional Chinese medicine during the public health emer-
[18] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. gency: a survey of trial registries for COVID-19, H1N1, and SARS. Trials
The PRISMA 2020 statement: an updated guideline for reporting systematic 2021;22:188. https://doi.org/10.1186/s13063-021-05182-z.
reviews. BMJ 2021;372:n71. https://doi.org/10.1186/s13643-021-01626-4. [42] Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT
[19] Dodd S, Clarke M, Becker L, Mavergames C, Fish R, Williamson PR. A taxonomy 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ
has been developed for outcomes in medical research to help improve 2013;346:e7586. https://doi.org/10.1136/bmj.e7586.
knowledge discovery. J Clin Epidemiol 2018;96:84e92. https://doi.org/ [43] Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guide-
10.1016/j.jclinepi.2017.12.020. lines for reporting parallel group randomised trials. BMJ 2010;340:c332.
[20] World Health Organization. Rehabilitation. 2021. https://www.who.int/news- https://doi.org/10.4103/0976-500X.72352.
room/fact-sheets/detail/rehabilitation. [44] Chan AW, Hro  bjartsson A. Promoting public access to clinical trial protocols:
[21] WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD index. challenges and recommendations. Trials 2018;19:116. https://doi.org/
2022. https://www.whocc.no/atc_ddd_index/. 10.1186/s13063-018-2510-1.
[22] European Medicines Agency. Medicines. 2022. https://www.ema.europa.eu/ [45] Nasserie T, Hittle M, Goodman SN. Assessment of the frequency and
en/medicines. variety of persistent symptoms among patients with COVID-19. JAMA
[23] U.S. Food & Drug Administration. Information by drug class. 2022. https:// Netw Open 2021;4:e2111417. https://doi.org/10.1001/jamanetworkopen.
www.fda.gov/drugs/drug-safety-and-availability/information-drug-class. 2021.11417.
[24] Royal Pharmaceutical Society of Great Britain. The traditional herbal medicine [46] Pletcher MJ, Pignone M. Evaluating the clinical utility of a biomarker. Circu-
registration scheme. 2022. https://www.rpharms.com/resources/quick- lation 2011;123:1116e24. https://doi.org/10.1161/CIRCULATIONAHA.110.
reference-guides/herbal-medicine-registration-scheme#moreinfo. 943860.
[25] Gov.uk. Herbal medicines granted a traditional herbal registration. 2022. [47] Selleck MJ, Senthil M, Wall NR. Making meaningful clinical use of biomarkers.
https://www.gov.uk/government/publications/herbal-medicines-granted-a- Biomark Insights 2017;12:117727191771523. https://doi.org/10.1177/
traditional-herbal-registration-thr/herbal-medicines-granted-a-traditional- 1177271917715236.
herbal-registration. [48] Munblit D, Nicholson T, Akrami A, Apfelbacher C, Chen J, de Groote W, et al.
[26] National Institute of Health (NIH) NC for C, IH (NCCIH). Herbs at a glance. A core outcome set for post-COVID-19 condition in adults for use in clinical
2022. https://www.nccih.nih.gov/health/herbsataglance. practice and research: an international Delphi consensus study. Lancet
[27] National Cancer Institute. Complementary and alternative medicine. 2021. Respir Med 2022;10:715e24. https://doi.org/10.1016/S2213-2600(22)
https://www.cancer.gov/about-cancer/treatment/cam. 00169-2.