AIDS Reviews.

2021;23

Contents available at PubMed

www.aidsreviews.com PERMANYER AIDS Rev. 2021;23:40-47
www.permanyer.com

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The Importance of Understanding the Stages of
COVID-19 in Treatment and Trials
Daniel O. Griffin1,2,3*, Denise Brennan-Rieder4, Binh Ngo5, Pierre Kory6, Marco Confalonieri7, Leland Shapiro8,
Jose Iglesias9, Michael Dube5, Neha Nanda5, Gino K. In5, Daniel Arkfeld5, Preet Chaudhary5,
Vito M. Campese5, Diana L. Hanna5, David Sawcer5, Glenn Ehresmann5, David Peng5,
Miroslaw Smorgorzewski5, April Amstrong5, Eivind H. Vinjevoll10, Rajkumar Dasgupta5, Fred R. Sattler5,
Cristina Mussini11, Oriol Mitjà12, Vicente Soriano13, Nicolas Peschanski14, Gilles Hayem15,
Maria Carmela Piccirillo16, António Lobo-Ferreira17, Iraldo B. Rivero18, Ivan F. H. Hung19, Marc Rendell20,
Stephen Ditmore21, Joseph Varon22, and Paul Marik23

No part of this publication may be reproduced or photocopying without the prior written permission o
1
Department of Medicine, Division of Infectious Diseases, Columbia University, College of Physicians and Surgeons, New York, USA; 2Research
and Development at United Health Group Minnetonka, Minnesota, USA; 3ProHealth NY Lake Success, New York, USA; 4CoronaTracker Community
Research Group, 5Keck School of Medicine, University of Southern California, California, USA; 6Pulmonary and Critical Care Medicine, Aurora St.
Luke’s Medical Center, Milwaukee, WI, USA; 7Azienda Ospedaliero-Universitaria di Trieste, Trieste, Italy; 8Rocky Mountain Regional Veterans Affairs
Medical Center in Aurora, CO and University of Colorado Anschutz Medical Campus in Aurora, CO, USA; 9Jersey Shore University Medical Center,
Neptune NJ, Hackensack Meridian School of Medicine at Seton Hall, Hackensack University, NJ, USA; 10Volda Hospital HMR, Volda, Norway;
11University of Modena and Reggio Emilia, Modena, Italy; 12Hospital Universitari Germans Trias i Pujol, Badalona, Spain, 13UNIR Health Sciences

School and Medical Center, Madrid, Spain; 14University Hospital of Rennes, Rennes, France, 15Hôpital Paris Saint-Joseph, Paris, France; 16Istituto
Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy; 17Unidade de Investigação Cardiovascular, Faculdade de Medicina da Universidade
do Porto, Centro Hospitalar Universitário de São João, Porto, and Hospital Rainha Santa Isabel, Marco de Canaveses, Portugal; 18Department of
Clinical Investigations, Center for Genetic Engineering and Biotechnology, Havana, Cuba; 19Ivan FN Hung, Li Ka Shing Faculty of Medicine, University
of Hong Kong, Hong Kong; 20The Rose Salter Medical Research Foundation, Newport Coast, CA, USA; 21Parkchester Times, 22United Memorial
Medical Center and United General Hospital, UT Health Science Center at Houston, University of Texas School of Medicine, Houston, Texas, USA,
Baylor College of Medicine, UAT, UDEM, UABC, UNE, USON, UPAEP – Mexico, Caribbean Medical University; 23Eastern Virginia Medical School|,
Department of Internal Medicine, Chief, Pulmonary and Critical Care Medicine, Norfolk, VA, USA

Abstract
COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan,
China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to
treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease
and the importance of timing for investigation and use of various agents. We considered articles related to
COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the
medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure,
incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflamma-
tory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This
common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or
currently in use is likely to provide benefit rather than harm. (AIDS Rev. 2021;22:40-47)
Corresponding author: Daniel O. Griffin, dgriffin@ProHealthcare.com

Key words
COVID-19. SARS-CoV-2. Phases. Cytokine storm. Antivirals. Immunotherapy.

Correspondence to: Received in original form: 19-12-2020

*Daniel O. Griffin Accepted in final form: 14-01-2021
E-mail: dgriffin@ProHealthcare.com DOI: 10.24875/AIDSRev.200001261

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 Griffin, et al.: Stages of COVID-19

Introduction manifestations and immunologists the cytokine signa-

ture. Rather than selecting one of those options, we
elected to use inclusive terminology. As COVID-19
COVID-19 continues to be a major health threat de-

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manifestations are identified and the mechanisms of
spite the introduction of mitigation strategies, various
these stages are revealed, it is preferable to have a
therapeutics, and vaccines. As we study and recom-
consensus framework regarding the different process-
mend therapeutics, we need a common terminology in
es, symptomatology, complications, and therapeutics
order to reference the observed stages of COVID, and
relevant in the course of the disease.
target interventions to the appropriate phase. Our cur-
We have determined three periods and five phases
rent therapeutics include: monoclonal antibody thera-
that comprise the stages of COVID-19. These stages
pies, convalescent plasma, the antiviral agent are: the Pre-Exposure Period, the Incubation Period,
remdesivir, steroids, and anticoagulation. With each of the Detectable Viral Replication Period, the Viral
these options, determining the correct timing, phase of Symptom Phase, the Early Inflammatory Phase, the
disease, and severity of disease is critical to maximiz- Secondary Infection Phase, the Multisystem
ing benefit and reducing harm. Our experience in the Inflammatory Phase, and the Tail Phase. The Pre-
treatment of patients with HIV/AIDS taught us this les-

No part of this publication may be reproduced or photocopying without the prior written permission o
exposure period ends and the Incubation period start
son about determining the correct timing and disease at TE (Time of exposure); the Detectable Viral Replication
severity before treatment. Treatment depends on the Phase starts at TDVR (Time of detectable viral replica-
phase of disease: in the pre-exposure period, we rec- tion). The Viral Symptom Phase starts at symptom on-
ommend pre-exposure prophylaxis (PreP) and con- set and shortly after the rise in detectable viral RNA TS
doms, with acute exposure use PEP-post-exposure (Time of symptom onset), the Early Inflammatory Phase
prophylaxis, and in acute infection and chronic infec- starts 7-14 days after symptom onset at TEI (Time of
tion we use HAART-highly active antiretroviral therapy. early inflammation), and includes the start of a coagu-
With HIV/AIDS, it is also important to determine mea- lation disturbance whose macrovascular manifesta-
surements of viral load and CD4 counts before decid- tions are not always evident until week three, the
ing the timing of intervention. We suggest that a similar Secondary Infection Phase starts at TSI (Time of sec-
paradigm applies to COVID-19. ondary infection), the multisystem inflammatory phase
starts at TMI (Time of multisystem inflammation onset),
Methods and the Tail starts at TT (Time of the tail onset) and
may continue for months.
We manually searched for articles related to During the Pre-Exposure Period susceptible individu-
COVID-19 indexed on PubMed published January 1, als can employ a variety of measures to minimize their
2020 through November 15, 2020, and also considered likelihood of exposure to potential infection with
papers on the medRxiv preprint server. Initial search SARS-CoV-2, the virus that causes COVID-19. Masks,
parameters revealed 1175 articles. Articles were in- distancing, ventilation, cleaning, hygiene, minimizing
cluded if they provided relevant information and were contact with potentially infected individuals, and opti-
judged by the authors to be consistent and of ade- mizing management of pre-existing conditions such as
quate quality. Of these, 71 articles were selected and diabetes, hypertension, asthma, and COPD are among
then reviewed by the authors and are referenced in this the measures that are most relevant during this period1.
paper. This is also the ideal time to employ active immuniza-
tion (vaccination) and perhaps passive immunization
Results (monoclonal antibodies).
Despite a lack of endorsement of masks early in the
Based on our investigations, we arrived at terminol- COVID-19 pandemic, multiple observational studies
ogy that was broadly descriptive of each phase yet indicate that masks are associated with reduction in
precise and not overly specific to any one organ sys- the relative risk of acquiring infection for multiple
tem. Pulmonologists and critical care specialists might pathogens including SARS-CoV-22,3. Governmental
focus on the pulmonary manifestations during the 2nd and community encouragement of physical distancing
week after symptom onset after viral replication de- in the form of “social distancing” has been associated
creases. Cardiologists might emphasize the cardiac with a reduction in case numbers and there have been
dysfunction of this period, nephrologists the renal subsequent rises in case counts upon relaxation of
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restrictions4. Several studies have suggested an in- does not necessarily indicate infectiousness. Detection
creased risk of transmission indoors, particularly in of sub-genomic RNA, indicative of replicative interme-
environments with poor ventilation5. diates of the virus, within the 1st 8 days after onset of

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The Incubation Period begins when an effective symptoms in patients with mild disease, and in vitro
exposure results in the initiation of infection. Many culture of live virus no later than day 9 after symptom
individuals who are advised to quarantine for the 14- onset suggest that the risk of transmission is greatest
day period will have had an exposure that is consid- just before and for several days after symptom
ered significant but will never progress to infection onset22-24.
with associated viral replication or symptoms6. It is clear that transmission can occur both before
Although there are nuanced models to stratify risk, a symptoms and in asymptomatic individuals as was
significant exposure which prompts the recommenda- documented in the Diamond Princess Cruise Ship
tion for quarantine is an unprotected encounter of Cohort and in other follow-up and modeling studies25.
more than 15 min, continuous or cumulative, with a The Viral Symptom Phase starts after viral RNA levels
proximity of 6 ft or less7. The incubation period from have peaked and as the viral RNA copy number is
exposure to symptoms is now well defined as 2-14 decreasing. We define this period as starting at TS

No part of this publication may be reproduced or photocopying without the prior written permission o
days8. If a person reaches day 14 and is not shedding (Time of symptom onset). The symptoms described
virus, the likelihood of infection has most likely passed. during this phase range from the less common but
A certain percentage of exposed and infected indi- highly suggestive loss of taste and smell to a predomi-
viduals will shed virus without ever developing nantly gastrointestinal presentation. Early descriptions
symptoms9-11. of cough, fever, and myalgia are still common, but a
The Detectable Viral Replication phase follows an growing list of nonspecific symptoms has clearly es-
exposure that results in infection. Viral replication may tablished that this is an influenza-like viral illness in its
be detectable as early as 1 day after infection, peaking myriad of presentations26-28. Certain biomarkers and
3-4 days post-infection12. Viral replication in a success- clinical features including patient age and comorbidi-
ful infection likely begins shortly after exposure but is ties appear to have some predictive value regarding
not initially detectable with current technologies. The the risk of progression from this phase to severe
level of viral RNA copies rises from undetectable to disease29-31.
millions in the 1-3 days before development of symp- While the onset of viral replication precedes symp-
toms and then decreases after the time of symptom toms, it is usually only after symptom onset that most
onset13-16. cases of COVID-19 are recognized and treatment can
The RNA copy number decreases to below an infec- be initiated. It is theorized that this is the critical period
tious level by day 10 in most patients with mild infec- to initiate antiviral therapies, such as direct-acting
tion. However, it may remain elevated above infectious small molecule inhibitors (remdesivir) or monoclonal
levels in patients with severe disease or immune com- antibodies32. Randomized prospective trials have sup-
promise until day 20 and viral RNA is still detectable ported the importance of timing for remdesivir and the
in some individuals over 3 weeks after discharge from monoclonal antibody bamlanivimab (LY-CoV555) dem-
the hospital17-20. onstrating efficacy if started early and potential harm
Real-time PCR (RT-PCR) and transcription-mediated if treatment is initiated during later phases, such as
amplification (TMA), currently the most sensitive de- when patients are requiring mechanical ventilation33.
tection methods, can detect low levels of virus RNA The Early Inflammatory Phase which starts at TEI
with limits of detection (LoD) of approximately 10- (Time of early inflammation) begins during the 7-14
1,000 RNA copies/ml or NAAT detectable units/mL days after TS (Time of symptom onset) with earlier
(NDU), depending on the gene and the manufacturer onset in the elderly and those with comorbidities, and
of the assay21,22. However, contact tracing to deter- a later onset in younger, healthier individuals20,34. The
mine the correlation between infectiousness and Ct first obvious clinical manifestations of the early inflam-
(cycle threshold) values or RNA copy numbers is chal- matory phase in most cases are pulmonary, with the
lenging. It is difficult to determine the RNA copy num- onset of hypoxemia, followed by increasing respiratory
ber or Ct value at the time of exposure and rate and then increasing hypoxemia, which in many
transmission23. Furthermore, although virus shedding cases can be rapid and require significant supportive
can occur for weeks, the period of virus viability ap- care35,36. In untreated individuals this can progress to
pears to be limited and quantitative RNA detection cardiac dysfunction, renal failure, neurological
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manifestations, and multi-organ dysfunction37-40. During D-dimer, ventilation perfusion (V/Q) mismatches, and
this stage, dysfunction of the coagulation system ap- other manifestations are the result of microvascular
pears to b ­ egin41-44. There is also a rise in inflammatory thrombi triggered by endothelial dysfunction which is

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markers, D-dimers, and several cytokines. A dominant driven by the cytokine cascade rather than by direct
cytokine during this period may be interleukin-6 (IL-6), viral invasion56,57.
however, its levels may be lower than in other syn- The Secondary Infection Phase starts at TSI (Time of
dromes such as ARDS where median IL-6 levels in secondary infection) and is characterized by a period
patients with the hyperinflammatory phenotype of during which bacteremia, fungemia, pneumonia, and
ARDS are 10- to 200-fold higher than levels in patients other secondary bacterial infections occur at an in-
with severe COVID-19 or in CAR-T patients with creased incidence. This appears to be a characteristic
CRS45,46. Furthermore, in experimental viral infection feature of the disease process and does not only occur
models, IL-6 is pleiotropic having both pro- and anti- in patients having undergone treatment58. Not all pa-
inflammatory effects47. tients will develop a secondary infection during this
This stage was initially described as the “cytokine phase.
storm phase” or the “pulmonary phase” and while The Multisystem Inflammatory Phase starts at TMI

No part of this publication may be reproduced or photocopying without the prior written permission o
these descriptions are perhaps accurate regarding the (Time of multisystem inflammation onset) and is char-
underlying drivers and the obvious clinical manifesta- acterized by peak levels of IgG, secondary infections,
tions, it is now appreciated that there is significant and many manifestations that are suspected to be
additional complexity48,49. This has led to controversy secondary to autoimmune phenomena59,60. This phase
regarding the term “cytokine storm” and thus it is felt gained significant attention when it was described as
that “early inflammatory phase” is more descriptive and the Multisystem Inflammatory Syndrome in Children
leaves open the ability to advance understanding of (MIS-C) and the Multisystem Inflammatory Syndrome
this phase. The term early inflammatory phase and the in Adults (MIS-A)61,62. It is now clear that similar mani-
timing of this phase in COVID-19 is also supported by festations occur in children and adults. During this
studies demonstrating some modest benefits of ste- stage processes such as vasculitis, Guillain-Barré syn-
roids use during this phase but not earlier in drome, facial palsies, immune mediated thrombocyto-
disease49,50. penia, and other manifestations can occur co-temporally
Some of the most prominent clinical manifestations with the rise in IgG63-65.
during the early inflammatory phase are those involving The post-acute Tail Phase does not so much start as
the pulmonary system. Many argue that this organ is continue when a patient passes through the acute pe-
critical to understanding COVID-19 and observations riod, yet has residual symptoms. In certain circum-
suggesting improvements in patient outcomes result- stances, patients experience a bimodal pattern of
ing from non-invasive ventilation and positioning have disease, with improvement followed by worsening or
changed the standard of care away from early recom- recurrence of symptoms66. For understanding when
mendations of early intubation51. certain therapeutics might be efficacious it is useful to
Some of the milder pulmonary aspects of COVID-19 define this period as starting at TT (Time of the tail
may be initially evident during the 1st week of illness onset). During this phase, individuals have both sub-
with cough while more pronounced pulmonary symp- jective as well as objective manifestations ranging from
toms are seen in a large number of patients during the fatigue to documented cardiac and pulmonary dys-
early inflammatory phase and may continue to be function67,68. There is still a lack of consensus regard-
manifest into later phases of the disease27,52. Growing ing the terminology best used to refer to patients that
evidence from autopsy and other studies suggests that suffer past the initial 4 weeks and terms such as long
a majority of COVID-19 patients with pulmonary mani- hauler COVID, long COVID, and long-term COVID
festations develop secondary organizing pneumonia (LTC) are used in different countries by different physi-
(OP) or its histological variant, acute fibrinous and or- cians and patients.
ganizing pneumonia53-55.
While there is evidence that coagulopathy begins Discussion
during this phase and anticoagulation is beneficial, the
clinical consequences, in the form of major thrombo- While some infectious disease specialists have de-
embolic complications, are often not apparent until the veloped significant experience treating patients with
3rd week of illness42,44. There is evidence that rise in COVID-19, many therapies continue to be used without
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 AIDS Reviews. 2021;23

evidence of benefit and without regard to timing, po- target viral replication and augment the innate immune
tentially causing harm. Consensus regarding the termi- response such as interferons have a decreasing likeli-
nology and phases of COVID-19 is critical for hood of benefit at this later stage of disease.

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understanding the appropriate timing for the study and As there is growing evidence that the manifestations
delivery of therapeutics. evident during this phase are driven by host immune
It is possible and likely that some of the failures in responses rather than ongoing viral replication or viral
randomized controlled trials seen to date may be due virulence factors, there is support for trials and re-
to timing of treatments. The context of disease phases search exploring the role of different immunomodula-
may explain the failure of remdesivir or monoclonal tory therapies at this stage.
antibody therapies when given late in disease69. At the outset of the pandemic, we lacked a robust in-
The Pre-Exposure Period represents the target for frastructure for establishing and running trials in the out-
vaccination (active and passive) and the ideal time for patient setting. It is critical to study therapeutics at the time
study of prophylactic medications with very low risk of when they are likely to make a difference, and therefore
adverse effects. Available evidence would suggest that new relationships with urgent care centers and outpatient
this is perhaps the time that vitamin D, zinc, targeting practices are a high priority. Our consensus framework

No part of this publication may be reproduced or photocopying without the prior written permission o
ideal body weight, smoking cessation, and other rou- should help guide the timing of various therapeutics and
tine health measures might have a role. It is during the the patient populations most likely to benefit.
Incubation Period that starts at TE (Time of exposure) The disturbances in the coagulation system also ap-
that the risk of developing disease is increased and a pear to begin during the early inflammatory phase in
targeted approach blocking viral replication and cel- the 2nd week of illness, but the macrovascular manifes-
lular entry can be considered. tations may not be evident until week three of illness.
The Detectable Viral Replication Phase is the time in It is clear from the October 2020 call to action from the
which antivirals, monoclonal antibodies, and therapies American Society of Hematology Guidelines panel that
that augment innate immune responses such as inter- high-quality evidence to direct the selection and dos-
ferons would have the highest potential for benefit ver- ing of anticoagulation is still not available for patients
sus harm (Fig. 1). The Viral Symptom Phase occurs very with mild disease who never require hospitalization,
soon after viral RNA is detectable. For most individuals, patients with severe disease during their hospitalization
this will be the time at which their illness comes to clini- time and for the period of increased risk that lasts for
cal attention. The population in this phase will be pre- months in both of these populations70.
dominantly an outpatient population, and studying During the Secondary Infection Phase, bacteremia,
therapeutics in this group will potentially prevent hospi- fungemia, pneumonia, and other secondary bacterial
talizations and viral transmission, having a significant infections occur at an increased incidence. This phase
impact on resource utilization. It is also critical during is also characterized by ongoing immune dysfunction
this period to have clear criteria identifying infectious- which is poorly understood and occurs due to COVID-19
ness for both public health considerations and at the and not due to any specific therapeutics. Many patients
individual level to determine when a patient can safely are exposed to unnecessary antibiotics early on in the
return to work and other social settings. An appreciation disease process, but it is only during this phase that
of the RNA level at which a person is infectious is criti- antibiotics are appropriate and beneficial for most pa-
cal for public health testing as the focus is different from tients. As the pandemic continues, the challenges of
clinical testing. Testing for infectiousness needs to take growing rates of antimicrobial resistance will become
into account not only the accuracy of diagnosis at an more manifest if inappropriate antibiotic use continues.
individual level but also focus on identifying infectious The Multisystem Inflammatory Phase is characterized
individuals who can spread disease in schools or other by manifestations which may be secondary to autoim-
places where humans congregate. mune phenomena. Better understanding and the intro-
The initial clinical manifestations of the Early duction of improved therapeutics may not only improve
Inflammatory Phase are pulmonary compromise with outcomes for patients with COVD-19, but may also
hypoxemia, followed by impacts on the cardiac, renal, translate to other diseases that for years have been
and other organ systems. Hospitalization is most likely suspected of being post-infectious.
to occur in this phase (Fig. 2). Even in severe cases, The Tail Phase is now appreciated to be a common
the viral RNA copy number is already decreasing at a feature of COVID-19. Growing numbers of individuals
rapid rate in most individuals at TEI. Therapeutics that are reporting suffering from this aspect of COVID-19
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No part of this publication may be reproduced or photocopying without the prior written permission o
Figure 1. High viral RNA levels precede the inflammatory phase and are decreasing at the time of hospital admission and need for ICU
level care.

Figure 3. COVID-19 progresses through various stages with certain degree overlap but with distinct mechanisms targeting each stage.
Dotted lines from left to right represent the Early Inflammatory Phase (blue), the Secondary Infection Phase (green), and the Hyperinflam-
matory Phase (red continuous line).

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No part of this publication may be reproduced or photocopying without the prior written permission o
Figure 3. Most appropriate phase for testing and use of various classes of therapeutics TE (Time of exposure), TDVR (Time of detectable
viral replication), TS (Time of symptom onset), TEI (Time of early inflammation), TSI (Time of secondary infection), THI (Time of multisystem
inflammation), and TT (Time of the tail onset).

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