REPORT : COVID-19 – The concept of so-called “super-spreaders”

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Can a single COVID-19 patient infect dozens of others?

Although transmission rates in the current outbreak appear to be far lower, a variety of factors can lead to an individual infecting many.

The concept of so-called “super-spreaders” – patients who typically infect far more people than the standard transmission rates – emerged in previous outbreaks of diseases such as Sars and Mers.

Amesh Adalja, an expert in emerging infectious diseases at John Hopkins University, said the term was not scientific and there was no set quantity of transmissions that would define a super-spreader.

“But, in general, it is usually a markedly higher figure when compared to that of other individuals,” he told AFP.

A range of variables govern how many people an individual infects, from how fast they shed the virus to how many people they come in to close contact with.

The novel coronavirus has a typical transmission rate of 2-3 – that is, every confirmed case appears to infect between 2 and 3 other people on average.

But the pandemic has thrown up at least two patients who appear to have been super-spreaders.

Suspected super-spreaders

One suspected super-spreader, a British national, appears to have infected a dozen others when he returned from Singapore and then went skiing in the Alps.

He recovered, but may have infected another five people after returning home.

In South Korea, which has the second highest number of COVID-19 cases outside of Italy, a woman known as Patient 31 appears to have infected dozens of others.

But in an ever better-connected world, it can be challenging to definitively link transmissions to an individual patient.

“It’s possible that what we call super-spreaders exist, those patients who don’t only infect 2-3 others but could infect dozens,” said Eric Caumes, head of infectious and tropical diseases at Paris’ Pitie-Salpetriere Hospital.

“The problem is we aren’t spotting them.”

According to Olivier Bouchaud, head of infectious diseases at that Avicenne hospital in Paris’ suburbs, variable transmission rates could be down to how fast a patient sheds the virus once infected.

“That’s just a hypothesis at this point,” he said. “Obviously we don’t have a clear explanation, and there’s nothing specific to COVID-19.”

Another unknown is the role played by young children, who are less severely affected by the virus but are capable of transmitting it – part of the reason many countries have moved to close schools in recent days.

Highly variable

Cristl Donnelly, professor of Applied Statistics at the University of Oxford, said all disease transmission was by nature “highly variable”.

“But we are not all the same, we vary in our immune systems, in our behaviour, and in where we happen to be,” she said.

“All of these things can affect how many people we would transmit to.”

Bharat Pankhania, an infectious diseases expert at Britain’s Exeter University, even disputed whether super-spreaders existed.

He said that the biggest factors determining transmission were environmental, made worse in dense-populated cities.

“These circumstances often are: crowding; a confined space with poor ventilation; poor infection control, meaning lots of non-porous, hard surfaces which can keep a virus viable for a longer time; a favourable ambient humidity; and the infected person usually being in the early phase of their illness, when virus secretions are at their peak,” he said.

It’s due to these contributing factors that many experts are reluctant to talk in terms of super-spreaders.

Added to this, as France’s health minister has pointed out, the term might be used to stigmatise individuals, when it is likely they transmitted COVID19 without realising.


Analysis – dangerousness – spreading

COVID-19 is a non-segmented, positive sense RNA virus. COVID-19 is part of the family of coronaviruses. This contains:

  • Four coronaviruses which are widely distributed and usually cause the common cold (but can cause viral pneumonia in patients with comorbidities).
  • SARS and MERS – these caused epidemics with high mortality which are somewhat similar to COVID-19. COVID-19 is most closely related to SARS.

It binds via the angiotensin-converting enzyme 2 (ACE2) receptor located on type II alveolar cells and intestinal epithelia (Hamming 004(https://www.ncbi.nlm.nih.gov/pubmed/15141377) ).

This is the same receptor as used by SARS (hence the technical name for the COVID-19, “SARS-CoV-2”).

When considering possible therapies, SARS (a.k.a. “SARS-CoV-1”) is the most closely related virus to COVID-19.

COVID-19 is mutating, which may complicate matters even further (fgure below). Virulence and transmission will shift over times, in ways which we cannot predict.

New evidence suggests that there are roughly two different groups of COVID-19. This explains why initial reports from Wuhan described a higher mortality than some more recent case series (Tang et al. 2020 (https://academic.oup.com/nsr/advance- article/doi/10.1093/nsr/nwaa036/5775463#.XmA64GbsBuI.twitter) ; Xu et al 2020 (https://www.bmj.com/content/368/bmj.m606) ).

(Ongoing phylogenetic mapping of new strains can be found here (https://nextstrain.org/ncov) .)

Genomic epidemiology of novel coronavirus (hCoV-19)

Showing 494 of 494 genomes sampled between Dec 2019 and Mar 2020.

Symptoms

The symptoms of COVID-19 infection appear after an incubation period of approximately 5.2 days [12]. The period from the onset of COVID-19 symptoms to death ranged from 6 to 41 days with a median of 14 days [8].

This period is dependent on the age of the patient and status of the patient’s immune system. It was shorter among patients >70-years old compared with those under the age of 70 [8].

The most common symptoms at onset of COVID-19 illness are fever, cough, and fatigue, while other symptoms include sputum production, headache, haemoptysis, diarrhoea, dyspnoea, and lymphopenia [5,6,8,13].

Clinical features revealed by a chest CT scan presented as pneumonia, however, there were abnormal features such as RNAaemia, acute respiratory distress syndrome, acute cardiac injury, and incidence of grand-glass opacities that led to death [6].

In some cases, the multiple peripheral ground-glass opacities were observed in subpleural regions of both lungs [14] that likely induced both systemic and localized immune response that led to increased inflammation. Regrettably, treatment of some cases with interferon inhalation showed no clinical effect and instead appeared to worsen the condition by progressing pulmonary opacities [14] (Fig. 2).

Fig. 2
Fig. 2. The systemic and respiratory disorders caused by COVID-19 infection. The incubation period of COVID-19 infection is approximately 5.2 days. There are general similarities in the symptoms between COVID-19 and previous betacoronavirus. However, COVID-19 showed some unique clinical features that include the targeting of the lower airway as evident by upper respiratory tract symptoms like rhinorrhoea, sneezing, and sore throat. Additionally, patients infected with COVID-19 developed intestinal symptoms like diarrhoea only a low percentage of MERS-CoV or SARS-CoV patients exhibited diarrhoea.

It is important to note that there are similarities in the symptoms between COVID-19 and earlier betacoronavirus such as fever, dry cough, dyspnea, and bilateral ground-glass opacities on chest CT scans [6].

However, COVID-19 showed some unique clinical features that include the targeting of the lower airway as evident by upper respiratory tract symptoms like rhinorrhoea, sneezing, and sore throat [15,16].

In addition, based on results from chest radiographs upon admission, some of the cases show an infiltrate in the upper lobe of the lung that is associated with increasing dyspnea with hypoxemia [17].

Importantly, whereas patients infected with COVID-19 developed gastrointestinal symptoms like diarrhoea, a low percentage of MERS-CoV or SARS-CoV patients experienced similar GI distress.

Therefore, it is important to test faecal and urine samples to exclude a potential alternative route of transmission, specifically through health care workers, patients etc (Fig. 2) [15,16].

Therefore, development of methods to identify the various modes of transmission such as feacal and urine samples are urgently warranted in order to develop strategies to inhibit and/or minimize transmission and to develop therapeutics to control the disease.

Traditional physical examination

This is generally unrevealing.

Patients may have hypoxemia without signs of respiratory distress (“silent hypoxemia”)(Xie et al 3/2 (https://link.springer.com/article/10.1007/s00134-020-05979-7) ).

~2% may have pharyngitis or tonsil enlargement – but of course this is an entirely nonspecific finding (Guan et al 2/28 (https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true) ).

The rate of abnormal chest auscultation is unclear (but lung sonography is likely more accurate; more on this below).

Typical disease course

  • Typical evolution of severe disease (based on analysis of multiple studies by Arnold Forest
  • Dyspnea ~ 6 days post exposure.
  • Admission after ~8 days post exposure.
  • ICU admission/intubation after ~10 days post exposure.

Performance of COVID-19 RT-PCR

  • Test performance is unclear; this is impossible to sort out in the absence of a definitive “gold
    standard” diagnostic test for COVID-19.
  • Specificity seems to be high.
  • Sensitivity may not be terrific.
    – In a case series diagnosed on the basis of clinical criteria and CT scans, the sensitivity of
    RT-PCR was only 60-70% (Kanne 2/28). However, it’s probable that some patients diagnosed based on CT scanning had other respiratory viruses rather than COVID-19, causing this study to under-estimate the sensitivity of the RT-PCR assay.
    – A single negative RT-PCR doesn’t exclude COVID-19 (especially if obtained from a nasopharyngeal source and if taken relatively early in the disease course).
    – If the RT-PCR is negative but suspicion for COVID-19 remains, then ongoing isolation and
    re-sampling should be considered.

General description of imaging findings on chest x-ray and CT scan

– Findings which aren’t commonly seen, and might argue for an alternative or superimposed diagnosis: Pleural effusion is uncommon (seen in only ~5%).

– COVID-19 doesn’t appear to cause masses, cavitation, or lymphadenopathy.

sensitivity and time delay in chest X-ray and CT scan

Limitations in the data

Data from different studies conflict to a certain extent. This probably reflects varying levels of exposure intensity and illness severity (cohorts with higher exposure intensity and disease severity will be more likely to have radiologic changes).

Sensitivity of CT scanning?

 Guan et al. (https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true) found CT abnormalities among 86% of symptomatic patients presenting to the hospital. Likewise, Fang et al. found CT abnormalities among 50/51 patients.

Among patients with constitutional symptoms only (but not respiratory symptoms), CT scan may be less sensitive (e.g. perhaps ~50%) (Kanne 2/27 (https://pubs.rsna.org/doi/10.1148/radiol.2020200527) ).

CT scan abnormalities might emerge before symptoms?

Shi et al (https://www.thelancet.com/action/showPdf?pii=S1473-3099%2820%2930086-4) performed CT scanning in 15 healthcare workers who were exposed to COVID-19 before they became symptomatic.

Ground glass opacification on CT scan was seen in 14/15 patients! 9/15 patients had peripheral lung involvement (some bilateral, some unilateral).

Emergence of CT abnormality before symptoms could be consistent with the existence of an asymptomatic carrier state (discussed above).

Chest X-ray

Less data has focused on the sensitivity of chest X-ray than CT scan.

It’s fair to assume that the sensitivity of chest X-ray must be lower than CT scan.

The sensitivity of chest X-ray was found to be 59% among symptomatic patients presenting to the hospital in one series (Guan et al 2/28 https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true) ).

Lung ultrasonography

  • There isn’t any data available currently regarding the use of lung ultrasonography for COVID-19.  However, a peripheral ground-glass pattern  on CT scan will generate patchy B-lines on lung ultrasonography (regardless of what the underlying disease is – this is simply a matter of ultrasound physics). This allows us to a make some educated guesses regarding lung ultrasonography findings:
  • 1 The most common pattern seen on lung ultrasonography will likely be patchy B-lines (areas with B-lines, with interspersed areas of normal lung in between).
  • 2 The sensitivity of lung ultrasonography will increase in parallel with disease severity (more severe illness involves more lung segments, which will be easier to detect on lung ultrasonography).
  • 4 Some patients will probably have early, mild pneumonitis which may be detectable via ultrasonography, but not via traditional chest X-ray (ultrasonography is more sensitive for subtle, pleural-based ground glass opacity).
  • 5 In order to achieve sensitivity, a thorough lung examination would be needed (taking a “lawnmower” approach, attempting to visualize as much lung tissue as possible). Simple two-point lung ultrasonography examinations will miss focal ground-glass opacities.
  • Lung ultrasonography has some advantages in the context of a COVID-19 outbreak:

– Ultrasonography may be performed at the point of care (including outside the hospital). This avoids transporting the patient to radiology, with possible exposure to hospital staff.

– Ultrasonography could be helpful as an early detection tool in patients who are under suspicion of having COVID-19 (e.g. lung abnormalities might suggest the presence of an asymptomatic carrier state, which might indicate the need for quarantine).

All imaging modalities are nonspecific

  • All of the above techniques (CXR, CT, sonography) are nonspecific. Patchy ground-glass opacities may be caused by a broad range of disease processes (e.g. viral and bacterial pneumonias). For example, right now in the United States, someone with patchy ground-glass opacities on CT scan would be much more likely to have a garden variety viral pneumonia (e.g. influenza or RSV) rather than COVID-19.
  • Imaging cannot differentiate between COVID-19 and other forms of pneumonia.
  • Imaging could help differentiate between COVID-19 and non-pulmonary disorders (e.g. sinusitis, non-pulmonary viral illness).
  • Ultimately, the imaging is only one bit of information which must be integrated into clinical context.

Possible approach to imaging in COVID-19

Below is one possible strategy to use for patients presenting with respiratory symptoms and possible COVID-19.

The temptation to get a CT scan in all of these patients should be resisted. In most cases, a CT scan will probably add little to chest X-ray and lung ultrasonography (in terms of actionable data which affects patient management).

From a critical care perspective, CT scanning will likely add little to the management of these patients (all of whom will have diffuse infiltrates).

more information:

RSNA focus page on coronavirus (https://pubs.rsna.org/2019-nCoV#images) (contains fantastic slide show that provides an appreciation of possible imaging fndings in a few minutes)

Transmission

Based on the large number of infected people that were exposed to the wet animal market in Wuhan City where live animals are routinely sold, it is suggested that this is the likely zoonotic origin of the COVID-19.

Efforts have been made to search for a reservoir host or intermediate carriers from which the infection may have spread to humans. Initial reports identified two species of snakes that could be a possible reservoir of the COVID-19.

However, to date, there has been no consistent evidence of coronavirus reservoirs other than mammals and birds [10,18]. Genomic sequence analysis of COVID-19 showed 88% identity with two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses [19,20], indicating that mammals are the most likely link between COVID-19 and humans.

Several reports have suggested that person-to-person transmission is a likely route for spreading COVID-19 infection. This is supported by cases that occurred within families and among people who did not visit the wet animal market in Wuhan [13,21].

Person-to-person transmission occurs primarily via direct contact or through droplets spread by coughing or sneezing from an infected individual.

In a small study conducted on women in their third trimester who were confirmed to be infected with the coronavirus, there was no evidence that there is transmission from mother to child.

However, all pregnant mothers underwent cesarean sections, so it remains unclear whether transmission can occur during vaginal birth.

This is important because pregnant mothers are relatively more susceptible to infection by respiratory pathogens and severe pneumonia (https://www.thelancet.com, DOI:https://doi.org/10.1016/S0140-6736(20)30360-3).

The binding of a receptor expressed by host cells is the first step of viral infection followed by fusion with the cell membrane. It is reasoned that the lung epithelial cells are the primary target of the virus.

Thus, it has been reported that human-to-human transmissions of SARS-CoV occurs by the binding between the receptor-binding domain of virus spikes and the cellular receptor which has been identified as angiotensin-converting enzyme 2 (ACE2) receptor [20,22].

Importantly, the sequence of the receptor-binding domain of COVID-19 spikes is similar to that of SARS-CoV. This data strongly suggests that entry into the host cells is most likely via the ACE2 receptor [20].

Airborne transmission

  • It’s controversial whether COVID19 can be transmitted via an airborne route (small particles which remain aloft in the air for longer periods of time).  
  • Airborne precautions started being used with MERS and SARS out of an abundance of caution (rather than any clear evidence that coronaviruses are transmitted via an airborne route). This practice has often been carried down to COVID19.
  • Guidelines disagree about whether to use airborne precautions:
  • Using airborne precautions for all patients who are definitely or potentially infected with COVID19 will likely result in rapid depletion of N95 masks. This will leave healthcare providers unprotected when they actually need these masks for aerosol-generating procedures.
  • In the context of a pandemic, the Canadian and WHO guidelines may be more sensible in countries with fnite resources (i.e. most locales). However, infection control is ultimately local, so be sure to follow your hospital’s guidance regarding this.

Contact transmission (“fomite-to-face”)

This mode of transmission has a tendency to get overlooked, but it may be incredibly important. This is how it works:

  • Someone with coronavirus coughs, emitting large droplets containing the virus. Droplets settle on surfaces in the room, creating a thin film of coronavirus. The virus may be shed in a variety of other bodily fluids as well (e.g. sputum, nasal secretions, stool, saliva, urine, and blood) – so there are a variety of other ways that an infected person could shed virus into the environment.
  • Someone else touches the contaminated the surface hours or days later, transferring the virus to their hands.
    • If the hands touch the oropharynx or nasopharynx, this will result in transmission of infection.

Any effort to limit spread of the virus must block contact transmission. The above chain of events can be disrupted in a variety of ways:

  • Hand hygiene (high concentration ethanol neutralizes the virus and is easy to perform, so this might be preferable if hands aren’t visibly soiled)(Kampf 2017 (http://www.fha.org/flles/JohnW/EM/Ethanol-hand-sanitizer-and-HAV.pdf) ).
  • Avoidance of touching your face. This is nearly impossible, as we unconsciously touch our faces constantly. The main beneft of wearing a surgical mask could be that the mask acts as a physical barrier to prevent touching the mouth or nose.

Any medical equipment could become contaminated with COVID-19 and potentially transfer virus to providers (e.g. stethoscope earpieces and shoes). A recent study found widespread deposition of COVID-19 in one patient’s room, but fortunately this seems to be removable by cleaning with sodium dichloroisocyanurate (Ong et al 2020 (https://jamanetwork.com/journals/jama/fullarticle/2762692) ).

Asymptomatic transmission

Asymptomatic transmission could potentially occur in two ways.

(#1) Transmission despite a lack of symptoms seems to be possible (Carlos del Rio 2/28 (https://jamanetwork.com/journals/jama/fullarticle/2762510)).

(#2) An additional carrier state could occur in patients who have clinically recovered from the virus, but continue shedding the virus.

A recent study found that after convalescence, patients may continue to have a positive pharyngeal PCR for COVID-19 for weeks (Lan 2/27 (https://jamanetwork.com/journals/jama/fullarticle/2762452) ). However, the clinical signifcance of these PCR results is unknown. Convalescing patients probably have a low viral load and relatively low risk of transmission.

CDC guidance (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html) is vague on how long patients with known COVID-19 should be isolated. It may be advisable to obtain two paired RT-PCR tests (one of the nasopharynx and one of the pharynx), with each pair collected >24 hours apart, prior to discontinuing precautions.

R

R⌀ is the average number of people that an infected person transmits the virus to.

If R⌀ is <1, the epidemic will burn out.

If R⌀ = 1, then epidemic will continue at a steady pace. If R⌀ >1, the epidemic will increase exponentially.

Current estimates put R⌀ at ~2.5-2.9 (Peng PWH et al, 2/28 (https://bjanaesthesia.org/article/S0007-0912(20)30098-2/pdf) ). This is a bit higher than seasonal influenza.

R⌀ is a reflection of both the virus and also human behavior. Interventions such as social distancing and improved hygiene will decrease R⌀.

Control of spread of COVID-19 in China proves that R⌀ is a modifable number that can be reduced by effective public health interventions.

The R⌀ on board the Diamond Princess cruise ship was 15 – illustrating that cramped quarters with inadequate hygiene will increase

R⌀ (Rocklov 2/28 (https://academic.oup.com/jtm/advance-article/doi/10.1093/jtm/taaa030/5766334) ).

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