Coronavirus

Coronavirus is obviously not a neurological disease, apart from an isolated case report of encephalitis associated with the condition, which is to be expected very rarely in association with viral infections, but because it is so topical this paper Clinical Characterisics of Coronavirus Disease 2019 in China, published in haste in the New England Journal of Medicine on 3rd March, 2020, was nevertheless presented.

Background

A novel enveloped RNA virus of coronavirus type, similar to SARS coronavirus, was first identified as causing viral pneumonia in early December 2019 and named as Covid-19 disease. It is believed to have first been transmitted through livestock in a large market in Wuhan, Hubei province. It is thought in general that such viruses are endemic in wildlife, such as in bats, and mutate to become transmissible to other animals and to humans.

As of Friday 6th March, there were 100,645 confirmed cases worldwide, and 3411 deaths linked to the virus. There were 55,753 cases who had recovered. In Hubei province, for the first day since the outbreak no new cases had been reported.

The details are unclear, but the fact that the UK government is said to be moving from a containment to a delay phase suggests that at least some UK cases have been identified that appear to have had no contact with potential suffers in China, Iran, Italy or other hotspots, nor with other UK individuals known to have the disease.

Journal Club Article

The paper discussed is an early report focusing on numbers affected, initial outcomes and clinical presentation. It was approved by the Chinese authorities.

Data were sourced from records of laboratory confirmed cases using assay of nasal and pharyngeal swabs between 11th December 2019 and 29th January 2020. Certain hospitals were sampled, so by no means were data collected from all cases.  In all, 14.2% of all known hospitalised cases were included in the study. It is not clear how widespread was the screening of the population by these laboratory tests; all the patients in this study were hospitalised.

26% of these cases had not had contact with Wuhan residents, indicating widespread serial human to human transmission.

Clinical information is as follows:

  • Incubation period (presumably from ascertaining likely time of exposure was median 4 days (2 to 7 days interquartile).
  • Fever in only 44% on admission, but developed later.
  • Cough in 68%.
  • Viraemic symptoms occurred in some patients, but upper respiratory tract symptoms, lymphadenopathy and rash were very rare.
  • CT chest abnormalities were very common (86%) in both mild and severe cases.
  • Lymphopaenia was common (83%).
  • Only 1% of cases were under 15 years old.

Of these hospitalised cases, 926 were considered mild and 173 severe. The main factors predicting this were advanced age and comorbid disease (especially coronary heart disease, diabetes, COPD and hypertension), also breathlessness at 38% versus 15% (unsurprisingly as this would be a criterion for severity). Similarly, inflammatory markers and markers of multi-organ involvement were associated with more severe disease. The main complicating feature of severe cases was acute respiratory distress syndrome, occurring in 16%.

The outcomes were 25% risk in severe cases of intensive care admission, mechanical ventilation or death (8%). Only 0.1% of cases categorised as non-severe died. The overall death rate was 1.4%. The national statistics at the time had a death rate of 3.2%.

By the data cut-off point, 95% of mild cases and 89% of severe cases were still hospitalised; the median lengths of hospital stay were 11 and 13 days respectively. Perhaps mild cases were hospitalised for purposes of isolation.

Journal Club Discussion

The paper reports likely ascertainment bias from milder cases not being tested. Nevertheless, the scale of the morbidity and mortality of the disease is not underestimated. Ascertainment bias becomes more relevant if one expects a pandemic and most of the population to become exposed. By these means the population risk can be inferred.

The paper also reports the fact that many patients were still in hospital, and perhaps very unwell, by the study’s end point. In the study, the number of cases requiring intensive care treatment is three times the death rate. Perhaps the death rate of already infected cases may climb. On the other hand, ARDS, the major serious complication of coronavirus infection, has a mortality of around 40%, and since 16% had this condition and 8% died, perhaps few more would be expected to die.

There does appear to be an opportunity for more information to be gleaned from these data or similar studies. The large number of cases could be randomised to have treatments not clear to be effective, such as oseltamivir, steroids and intravenous immunoglobulin. Less than half of cases had these treatments, but nevertheless appreciable numbers. It would have been helpful to know the death rates for patients who did or did not have these treatments rather than only the end point rates, as in reality some of these treatments might be most relevant when patients have already reached the ITU admission end point.

A follow up study would give better indicators of important epidemiological issues such as ultimate death rates and morbidity, the possibility of reinfection versus lasting immunity and any signs that more recently infected cases, where transmission has been via several human hosts, have any milder disease than those directly exposed to the transmitting animals.

A population based study that tested all individuals in high risk areas would determine the likely proportion of individuals who have been infected but not become very symptomatic.

Worldwide, we would also want to know how ambient temperature and sunlight levels affect transmissibility.

One suspects that epidemiologists in charge of advising governments have more information than is released to the public, and various advanced tools to model infection spread, but from the recent explosion of cases in Italy and now elsewhere, where talk is of delay rather than containment, there is little confidence that the slowing up of cases in China is going to be replicated worldwide.

From the death rates reported in Italy, there appears to be no clear evidence that the disease is becoming milder, but from the delay of many days from exposure to developing critical illness, perhaps it is too early to tell.

The lack of cases in hot or southern hemisphere countries would suggest a seasonal effect of the virus, and some reassurance to northern hemisphere countries approaching Spring. But in Australia there were already 40 cases confirmed by 4th  March and at least three cases had had no recent foreign travel and no traceable contact.

It seems that one scenario for the UK is that the infection eventually replicates that of Hubei province, which has a similar population to the UK and had around 11,000 cases with few new cases to come, and with around a 1-3% mortality rate, mainly in the elderly and infirm for whom ‘flu’ is also a significant source of mortality. With around 20% of cases classed as severe, this would require an extra 2000 of some form of high dependency inpatient beds for several days and spread over only a month or two.

However, we do not have an explanation for the slowing of new infection rates in China. It could be that most of the local population has already been exposed and most were resistant to severe symptoms, or it could be that containment measures have been very effective. If the latter is the explanation and is in reality only delaying inevitable spread through the population, or if containment is not replicated to the same degree in Western countries and if there is no seasonal dip in transmission, one could imagine hundreds of thousands of cases in the UK spread over the next year. And with a current mortality rate seemingly up to 3% this is unlikely to drop when there are insufficient hospital resources to manage such numbers.

The paper on which this journal club article is based was presented by Dr Bina Patel, Specialist Registrar in Neurology at Queens Hospital, Romford.

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