Do Medical Complications and Lingering Effects Make COVID-19 an Unusually Dangerous Diseases?

This is a review of the evidence concerning the medical complications and lingering effects of COVID-19 by an epidemiologist and a retired Professor of Forensic and Biological Anthropology.

COVID-19 death rates have fallen across much of Europe since a peak in early April, irrespective of governments’ responses to the virus. Even in those countries at lower latitudes – Brazil, India and the southern United States – death rates also appear to be falling, following a flatter trajectory. These patterns are akin to those of another seasonal respiratory virus – influenza, where declining fatality rates reflect a natural seasonal waning of the disease.

In the absence of a high seroprevalence of anti-SARS-CoV-2 antibodies, the evidence of natural immunity – including innate and T-cell mediated immunity and cross-immunity conferred by exposure to other coronaviruses – offers an explanation at the community, cellular and molecular level for how immunity to COVID-19 may be leading to a decline in infection rates across the world.

Nonetheless, acute complications of COVID-19 in children, and the persistence of symptoms following serious and, as noted in the media, mild illness may be seen as posing sufficient risk to justify attempts to maximally suppress SARS-CoV-2 through ongoing or intensified Non-Pharmaceutical Interventions.

But how substantial are the complications of COVID-19 in children? What are the connotations of symptom persistence? And are these conditions unique to COVID-19, or more generally true of influenza? Therefore, are maximum suppression (i.e. Zero-COVID) measures warranted for COVID-19?

MIS-C

While children are at relatively low risk from COVID-19, concern has focused on multisystem inflammatory syndrome in children and adolescents (MIS-C). This is a novel inflammatory syndrome, with multiple organ involvement, associated with COVID-19. Heart inflammation (myocarditis) is commonly diagnosed in MIS-C patients –as it is in adults – although gastrointestinal and other symptoms may be more frequent, especially in under-13s. While MIS-C is serious, reports (below) demonstrate that the syndrome is rare with a low fatality rate and cases have declined since May.

A recent (August 17th 2020) meta-analysis of MIS in children and adolescents published in the Lancet reviewed over 660 cases, including 11 fatalities. Not all had a clear SARS-CoV-2 PCR or antibody diagnosis, however. The largest constituent study, reported in the New England Journal of Medicine, was a targeted surveillance carried out between March 15^th and May 20^th. Of 186 patients diagnosed with MIS-C, 27% had at least one underlying health condition and a further 37% were obese. At the time of publication, 28% remained in hospital, 70% had been discharged and two per cent (four patients) had died.

A July 23rd study in New York State reported two deaths from 99 laboratory confirmed and suspected MIS-C cases, of which 36 had pre-existing conditions including 29 who were obese. In this study, the population incidence of MIS-C was two per 100,000 of those under 21 years of age. These two studies suggest the total population fatality rate of MIS-C may be 100^th of that figure.

An August 17th United Kingdom study in the British Medical Journal included over 600 confirmed SARS-CoV-2 patients under 19, of whom 42% had comorbidities. Only a minority (11%) were diagnosed with MIS-C against WHO criteria. The authors note limitations of being unable “to differentiate between people whose symptoms were directly attributable to SARS-CoV-2 infection and those who had been admitted for other reasons and then found to be positive for the virus” and allude to the question of nosocomial infections. They conclude “severe disease was rare and death exceptionally rare” and “ethnicity seems to be a factor in both critical care admission and MIS-C”.

More recent media reports (June 30^th) referring to the New York State study include interviews with hospital doctors indicating potential MIS-C cases had fallen from dozens a week to “one patient every few days to even a week” and from one or two cases per day during May to “one case every one to two weeks” and that the New York death toll had been revised down from three to two. This contrast with some high profile media reports (May 4th) of emergency admissions of children experiencing cardiac arrest with COVID-19 symptoms.

COVID-19 persistent symptoms and acute sequelae

Persistence of non-life threatening symptoms from COVID-19 in adults has been shown to be common in a number of studies examining recovery from acute disease. For example, a July 9th Italian study reported persistence of at least one symptom in 87% of recovered patients – typically fatigue and shortness of breath. A range of comorbidities were represented in the sample of mean age 57 years, studied at a mean of 60 days since onset of symptoms and 36 days since discharge. The authors note “patients with community-acquired pneumonia can also have persistent symptoms, suggesting that these findings may not be exclusive to COVID-19”. The European Centre for Disease Prevention and Control (ECDC) reports a further study on COVID-19 as follows: “There are limited data on long-term effects on pulmonary function. However, results from a study that evaluated 57 patients, showed that 43 (75%) of the patients had abnormal pulmonary function tests one month after discharge.”

The terms ‘long-haulers’ and ‘long-COVID’ have been coined to depict persistence and fluctuation in symptoms in both hospitalised and mildly affected patients. Long-haulers have established social media support groups which have a few thousand members and have attracted some press coverage. Support group members interviewed by the press, including health care staff, report symptoms some 20 weeks after infection, including in previously healthy individuals.

One long-hauler patient-led research team has produced a self-study survey of 640 respondents experiencing prolonged COVID-19 symptoms, where 58% reported a pre-existing condition and 71% reported being sedentary or mostly sedentary. The most prevalent symptoms were shortness of breath and tightness of chest; fatigue; chills, sweats and aches; a dry cough, headaches and confusion. These observations are reflected in a UK survey of general practitioners conducted between August 6th and 12th, where about one third reported patients experiencing similar symptom. The report makes no reference to the presence or absence of other pre-existing conditions. A US survey of laboratory confirmed COVID-19 patients interviewed at 14-21 days after testing yielded a similar portion (35%) of respondents experiencing these symptoms and not returning to their usual state of health. Symptom persistence tended to be greater in those patients with underlying health conditions – although the majority of those had also recovered.

By contrast, a UK survey of 110 acute hospitalised patients, found a higher proportion (74%) experienced persistent symptoms – particularly breathlessness and fatigue – after eight to 12 weeks. The authors report that 11 of 13 patients with abnormal chest X-rays showed improvement and abnormal blood tests returned to baseline in 104 of 110 cases.

More serious long-term symptoms from COVID-19 may also be common. A cardiac magnetic resonance (CMR) imaging study showed abnormal findings in 15 of 26 recovered patients aged 32-45 with negligible underlying disease. The authors note the lack of available follow-up and caution against extrapolation of their findings beyond the study. However, a more recent CMR study has yielded similar findings irrespective of pre-existing conditions, severity of illness and time since diagnosis [78/100 patients had abnormal CMR findings a median of 71 days from testing positive to COVID-19].

By contrast, acute ischemic stroke following COVID-19 infection has been reported in a only small number of under 50s with COVID-19 in the US and internationally.

Flu – epidemiology, complications and symptom persistence

Influenza (flu) is an illness caused by a different class of respiratory viruses (influenza viruses). The basic symptoms of influenza given by the WHO also feature among those given as basic symptoms of COVID-19.

The World Health Organisation (WHO) notes that the people at risk of severe disease from influenza are pregnant women; children under five and the elderly; people with certain chronic medical conditions, and health care workers experiencing increased exposure – who may themselves become the source of infection. They estimate epidemic flu results in 290,000 to 650,000 respiratory deaths annually. As of September 1st, the Johns Hopkins University dashboard reports about 850,000 COVID-19 deaths from all causes.

The US CDC gives annual estimates of disease burden by age group for each influenza season. In the most recent two seasons, for example, estimates for the number of deaths associated with influenza in under-18s in the US has been relatively low – 477 in 2018-19 and 643 in 2017-18, and estimates for hospitalisations and medical visits broadly similar at about 46,000 hospitalisations and 6.5 million medical visits per season. Overall, under-18s may account for roughly one or two per cent of deaths, five to 10% of hospitalisations and about a third of medical visits associated with influenza. By comparison, the CDC’s most recent update (August 26^th 2020) indicates 91 deaths in under-18s involving COVID-19 since February 1st, some of which may also involve influenza.

Although a high age-related risk to the over-65s, influenza also represents a disproportionately high risk to children, particularly in developing countries. Seasonal influenza may cause 10 million acute lower respiratory tract infections (ALRI) annually in children under five, leading to about 35,000 deaths, despite the availability of vaccines.

Different strains of influenza virus vary in infectiousness and pathogenicity. Even those associated with less severe pandemics may be associated with serious complications. For example, H7N9 Asian Flu has been shown to cause long term pulmonary disfunction. In general, cough and fatigue from influenza may persist for weeks.

Also similar to COVID-19, influenza may affect multiple organs. The CDC lists pneumonia, inflammation of the heart (myocarditis), brain (encephalitis) and muscle, and multi-organ failure – such as that involving the lungs and kidneys – as complications of flu. An extreme inflammatory response to respiratory tract infection can trigger sepsis. Among extra-pulmonary complications of influenza, myocarditis and encephalitis are the most frequent. They may affect children and adults alike and may lead to long term disease. For example, neurological complications – seizures and encephalopathy – with potential long term sequelae have been reported in a number of children and adults affected by the H1N1 influenza A pandemic in Europe, the UK and Australia in 2009, as well as in seasonal Influenza B flu in 2000-2001. Acute and fulminant (sudden) myocarditis and other heart complications have been reported in both Influenza B and Influenza A H1N1 patients, often with high rates of mortality.

Comparison – flu and COVID-19

Distressing though COVID-19 associated MIS-C is, these cases have decreased from an already low population incidence and risk of fatality. While symptoms may persist in COVID-19 and may sometimes be serious, they are not typically so, and appear to measurably diminish with time, even within the short time frame of the COVID-19 pandemic.

In some years, epidemic – let alone pandemic – flu may lead to a broadly similar number of deaths to COVID-19, even given widely available vaccination.

Like COVID-19, influenza poses an elevated risk to the over-65s. However, influenza presents a clearly greater risk to all other ages, including children and adults. While seasonal flu leads to higher mortality rates at the extremes of age, 2009 H1N1 flu, for example, may have posed a particular threat to ‘working age’ adults.

Multi-organ complications, including myocarditis and encephalitis, occur in both flu and COVID-19. In both cases, these complications have the potential to be persistent and serious, but such instances are rare and may be complicated by pre-existing disease. Patients typically recover in a few weeks and where symptoms do persist, they diminish – if sometimes gradually – in frequency with time. The most persistent symptoms are predominately those such as fatigue, aches and pains, and shortness of breath and are not life-threatening.

It is far from evident that COVID-19 presents a greater risk of complications or persistent symptoms than flu and – given the demographic most affected – COVID-19 does not present as great a threat as flu to children and younger adults and the otherwise healthy.

Epidemiologically and clinically flu may be as bad as COVID-19. In children, juveniles and productive adults flu appears worse.

Response to COVID-19

On the basis of the above comparison, it is difficult to find a justification for implementing lockdowns or similar restrictive measures for SARS-CoV-2 when they have not been applied in recent serious seasonal, epidemic or pandemic influenza outbreaks – and, for the most part, are not recommended.

Do MIS-C and symptom persistence in COVID-19 amount to an independent problem warranting unusually restrictive measures such as travel bans, mandatory self-isolation, local lockdowns, mask compliance, social distancing, sustained mass testing and contact tracing, and repetitive testing of returning travellers?

It might be argued that for MIS-C – if cases continue to occur – resources could be better devoted to developing improved acute and long term care if needed, and in promoting child health, particularly in Black, Hispanic and other non-White children, who – these studies show – are disproportionately affected.

Persistent symptoms of COVID-19 are also evident in influenza, pneumonia, rheumatic fever and other related diseases, and they are the subject of well-understood clinical interventions. Susceptibility to and prognosis in COVID-19 are frequently related to modifiable ‘lifestyle associated’ risk factors such as drinking and smoking for ARDS, for example, where higher risk to Black and Hispanic people is also again evident.

In both cases, targeted mitigation of disease and risk may offer a fairer, more plausible and cost-effective alternative to large-scale maximum suppression strategies and, as it has been argued, “a more holistic approach focussing on rehabilitation and general wellbeing is paramount”. Such an approach may always be tailored to more at risk demographics.