COVID-19 disease progression

19th Nov 2020

Infection with SARS-CoV-2 (or COVID-19) can be classified into three stages of increasing severity:1

  1. Stage I: The early infection or viral response phase during which symptoms of upper respiratory tract infection dominate.
  2. Stage II: The pulmonary phase when the patients develop full-blown pneumonia with all its associated symptoms.
  3. Stage III: The hyperinflammation phase when patients develop acute respiratory distress syndrome (ARDS), sepsis, and kidney and other organ failures. 

Graph showing the stages of COVID-19 infection over time, divided into three stages of increasing severity.

Figure 1. Infection with SARS-CoV-2 (COVID-19) can be classified into three stages of increasing severity: early infection, pulmonary phase, and hyperinflammation phase (Adapted from Siddiqi, HK, and Mehra, MR. 2020​).

It’s important to note that some patients only have milder symptoms associated with an upper respiratory infection or stage I, whereas others progress to more advanced stages.

 

Stage I: Early infection

Modes of transmission of COVID-19

Most of the time, the infection starts when an uninfected person inhales virus-laden droplets or aerosols into their nose and throat—47% of the time transmission comes from a presymptomatic person, through aerosol transmission or droplet inhalation, while 38% of the time it occurs from a symptomatic person through aerosol transmission or droplet inhalation. In 10% of patients, infection can also occur when someone touches a contaminated surface, then touches their face with their hands which contain the virus. And 6% of the time an asymptomatic person may be responsible for transmission, likely also through aerosol transmission or droplet inhalation.2

Four cartoons showing the modes of transmission of COVID-19, presymptomatic (47%), symptomatic (38%), asymptomatic (6%), and environmental (10%).

Figure 2. The modes of transmission of COVID-19: 47% of cases are transmitted by contact with presymptomatic individuals, 38% from contact with symptomatic individuals, 6% from contact with asymptomatic individuals, and 10% are transmitted through environmental factors (Ferretti, L, Wymant, C, Kendall, M, et al. 2020).


When are people with COVID-19 most contagious?

It seems that infectiousness is highest in the one to two days before symptoms start (coinciding with a high rate of presymptomatic transmission), and that seven days after symptom onset there is very little chance that infections will be transmitted.3

Graph showing the chance of infection over time (days after symptom onset).

Figure 3. The infectiousness of a person with COVID-19 is highest in the one to two days prior to symptom onset; whereas seven days after onset, there is little chance of transmission (Adapted from He, X, Lau, EHY, Wu, P, et al. 2020​).

Note stating the importance of presymptomatic transmission in COVID19.

Infection

The cells of the nose have a cell surface receptor called angiotensin-converting enzyme 2 (ACE2) ("Fig. 4a"). This receptor is also present in other organs, but cells of the nose exhibit a very high receptor density. And since the virus is inhaled through the nose, that’s where it will likely attach first. Once bound to this receptor ("Fig. 4b"), the SARS-CoV-2 virus is able to enter the cells ("Fig. 4c"). And once inside, the virus uses the cell’s machinery to make numerous copies of itself ("Fig. 4d–f") to invade even more cells. 

Series of six images showing the sequence of infection with SARS-CoV-2. Illustration

Figure 4. Infection and replication of SARS-CoV-2 in human cells, a) virus particle in proximity to host cell with ACE2 receptor, b) virus binding to the host cell, c) insertion of viral RNA, d) viral RNA in the cell, e) viral RNA replication, f) new viral particles released.


Watch a short animation of infection and replication of SARS-CoV-2:


Incubation

The median incubation period, the time between infection and the onset of symptoms, is 5.2 days, but it can be as long as 14 days in some cases.3

Graph of the incubation period of SARS-CoV-2.

Figure 5. The incubation period of SARS-CoV-2. The time between infection and the onset of symptoms is 5.2 days on average, but can be as long as 14 days (Adapted from He, X, Lau, EHY, Wu, P, et al. 2020​).

If a patient remains asymptomatic 14 days after exposure, the patient is unlikely to develop symptoms. This is why people have been told to self-isolate or quarantine for 14 days. 

Symptom onset

As mentioned before, in most patients, the disease starts as a mild infection with upper respiratory tract symptoms. In some patients, the infection will worsen and enter the lungs and cause pneumonia by the end of the first week or the beginning of the second week. 

The terminal alveoli in the lungs are also lined with cells rich in the ACE2 receptors. As the virus enters these alveolar cells, pneumonia develops. White blood cells release chemokines in order to kill virus-infected cells. 

Sequence of six steps in immune response to Sars-CoV-2. Illustration.

Figure 6. Immune response to SARS-CoV-2 in the alveoli, a) host alveolar cells with ACE2 receptor, b) virus particles binding to ACE2 receptor on the host cells, c) immune cells approaching the virus-infected cell, d–f) immune cells releasing chemokines and killing the virus-infected cell.


Check out a short animation of how the immune cells respond to SARS-CoV-2 in the alveoli:


Pus, a collection of fluid and dead cells, is left behind and interferes with the lungs’ ability to transfer oxygen to the blood and CO2 out of it. By this point, the patient will likely have a worsening cough, fever, and rapid, shallow respiration. It is at this stage where most patients with COVID-19 would need to be hospitalized for close observation, management, and possibly oxygen therapy. 

Alveoli with pus accumulation and reduced oxygen in COVID-19. Illustration.

Figure 7. The pus causes a barrier to gas exchange in the alveoli, reducing the efficiency of respiration, a) normal gas exchange in the alveoli, b) accumulation of pus in the alveoli, c) reduction of oxygen transfer in the alveoli.
 

Stage II: Pulmonary phase

This pulmonary phase is divided into two distinct parts. Stage IIA is the pneumonia patient without hypoxia and Stage IIB is the pneumonia patient with hypoxia who will likely require hospitalization and oxygen supplementation. 

Graph highlighting stage II of COVID-19 infection.

Figure 8. Stage II of a COVID-19 infection, the pulmonary phase, is divided into two distinct parts: Stage IIA, the pneumonia patient without hypoxia, and Stage IIB, is the pneumonia patient with hypoxia who will likely require hospitalization and oxygen supplementation (Adapted from Siddiqi, HK, and Mehra, MR. 2020​).

Studies in China and the US suggest that most patients, on average, are admitted to the hospital about one week after symptoms begin. Patients in the pulmonary phase of the disease can quickly progress to the hyperinflammatory phase where the infection runs wild. 

 

Stage III: Hyperinflammation phase

Graph highlighting Stage III of a COVID-19 infection.

Figure 9. Stage III of a COVID-19 infection, the hyperinflammation phase, in which the infection runs wild and patients often deteriorate suddenly (Adapted from Siddiqi, HK, and Mehra, MR. 2020​).

These patients often deteriorate suddenly, usually developing ARDS. Acute respiratory distress syndrome involves inflammation and fluid build-up in the lungs, which prevents oxygen transfer from the air to the blood. 

Series of four images of alveoli with increased fluid and decreased oxygenation in COVID-19.

Figure 10. Fluid build-up in the alveoli and inflammation prevents oxygen transfer in patients with acute respiratory distress syndrome (ARDS), a) normal alveoli with efficient gas exchange, b) inflammation of the airway as seen in ARDS, c) inflammation of the airway and fluid build-up in the alveoli as seen in ARDS, d) decreased oxygen transfer due to fluid accumulation and inflammation of the airway.
 

Blood oxygen levels drop rapidly and the patient struggles harder to breathe. Patients with ARDS usually require mechanical ventilation in the intensive care unit (ICU). On average, patients are intubated between 14.5 days after symptom onset. Depending on the country, and the ICU setting, approximately half of ARDS patients will recover, and half will die. 

 

How long does it take COVID-19 patients to recover overall?

One study of hospitalized patients in Wuhan, China showed that the median duration from symptom onset to discharge from the hospital was 22 days, and the median time from symptom onset to death was 18.5 days.4

 

Clickable call to action, "Start learning for free", with direct link to sign up for a free Medmastery trial account.

References

  1. Siddiqi, HK and Mehra, MR. 2020. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant39: 405–407. PMID: 32362390
  2. Ferretti, L, Wymant, C, Kendall, M, et al. 2020. Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Science. 368: eabb6936. PMID: 32234805
  3. He, X, Lau, EHY, Wu, P, et al. 2020. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nature Med. 26: 672–675. PMID: 32296168
  4. Zhou, F, Yu, T, Du, R, et al. 2020. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 395: 1054–1062. PMID: 32171076  

Recommended reading

  • Bhatraju, PK, Ghassemieh, BJ, Nichols, M, et al. 2020. Covid-19 in critically ill patients in the Seattle region — case series. N Engl J Med382: 2012–2022. PMID: 32227758
  • Centers for Disease Control and Prevention. 2020. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). cdc.govhttps://www.cdc.gov
  • Chung, E. 2020. How COVID-19 symptoms develop, and how long they last. cbc.ca. https://www.cbc.ca
  • Fraser Health. 2020. Updated testing guidelines for novel coronavirus (COVID-19) - April 8, 2020. fraserhealth.ca. https://www.fraserhealth.ca
  • Government of Canada. 2020. Coronavirus disease (COVID-19): Summary of assumptions. canada.ca. https://www.canada.ca
  • Wadman, M, Couzin-Frankel, J, Kaiser, J, et al. 2020. How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes. Science. https://www.sciencemag.org
  • Wang, D, Hu, B, and Hu, C. 2020. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 323: 1061–1069. PMID: 32031570