H5N1

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

Thanks to Doug McB for alerting me to this development, reported on bioRxiv: Close relatives of MERS-CoV in bats use ACE2 as their functional receptors. The abstract:

Middle East Respiratory Syndrome coronavirus (MERS-CoV) and several bat coronaviruses employ Dipeptidyl peptidase-4 (DPP4) as their functional receptors. However, the receptor for NeoCoV, the closest MERS-CoV relative yet discovered in bats, remains enigmatic. 

In this study, we unexpectedly found that NeoCoV and its close relative, PDF-2180-CoV, can efficiently use some types of bat Angiotensin-converting enzyme 2 (ACE2) and, less favorably, human ACE2 for entry. The two viruses use their spikes' S1 subunit carboxyl-terminal domains (S1-CTD) for high-affinity and species-specific ACE2 binding. Cryo-electron microscopy analysis revealed a novel coronavirus-ACE2 binding interface and a protein-glycan interaction, distinct from other known ACE2-using viruses. 

We identified a molecular determinant close to the viral binding interface that restricts human ACE2 from supporting NeoCoV infection, especially around residue Asp338. Conversely, NeoCoV efficiently infects human ACE2 expressing cells after a T510F mutation on the receptor-binding motif (RBM). Notably, the infection could not be cross-neutralized by antibodies targeting SARS-CoV-2 or MERS-CoV. 

Our study demonstrates the first case of ACE2 usage in MERS-related viruses, shedding light on a potential bio-safety threat of the human emergence of an ACE2 using 'MERS-CoV-2' with both high fatality and transmission rate.

T-cell responses to MERS coronavirus infection in people with occupational exposure to dromedary camels in Nigeria: An observational cohort study

Via The Lancet Infectious Diseases, a very interesting report: T-cell responses to MERS coronavirus infection in people with occupational exposure to dromedary camels in Nigeria: an observational cohort study. The summary:

Background 

Middle East respiratory syndrome (MERS) remains of global public health concern. Dromedary camels are the source of zoonotic infection. Over 70% of MERS coronavirus (MERS-CoV)-infected dromedaries are found in Africa but no zoonotic disease has been reported in Africa. We aimed to understand whether individuals with exposure to dromedaries in Africa had been infected by MERS-CoV. 

Methods 

Workers slaughtering dromedaries in an abattoir in Kano, Nigeria, were compared with abattoir workers without direct dromedary contact, non-abattoir workers from Kano, and controls from Guangzhou, China. Exposure to dromedaries was ascertained using a questionnaire. Serum and peripheral blood mononuclear cells (PBMCs) were tested for MERS-CoV specific neutralising antibody and T-cell responses. 

Findings 

None of the participants from Nigeria or Guangdong were MERS-CoV seropositive. 18 (30%) of 61 abattoir workers with exposure to dromedaries, but none of 20 abattoir workers without exposure (p=0·0042), ten non-abattoir workers or 24 controls from Guangzhou (p=0·0002) had evidence of MERS-CoV-specific CD4+ or CD8+ T cells in PBMC. 

T-cell responses to other endemic human coronaviruses (229E, OC43, HKU-1, and NL-63) were observed in all groups with no association with dromedary exposure. Drinking both unpasteurised camel milk and camel urine was significantly and negatively associated with T-cell positivity (odds ratio 0·07, 95% CI 0·01–0·54). 

Interpretation 

Zoonotic infection of dromedary-exposed individuals is taking place in Nigeria and suggests that the extent of MERS-CoV infections in Africa is underestimated. MERS-CoV could therefore adapt to human transmission in Africa rather than the Arabian Peninsula, where attention is currently focused.

See also this comment on the study, which suggests implications for dealing with SARS-CoV-2.

Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics

Via The Lancet Infectious Diseases, a personal view: Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics. The summary:

The objective of this Personal View is to compare transmissibility, hospitalisation, and mortality rates for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with those of other epidemic coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and pandemic influenza viruses. 

The basic reproductive rate (R0) for SARS-CoV-2 is estimated to be 2·5 (range 1·8–3·6) compared with 2·0–3·0 for SARS-CoV and the 1918 influenza pandemic, 0·9 for MERS-CoV, and 1·5 for the 2009 influenza pandemic. SARS-CoV-2 causes mild or asymptomatic disease in most cases; however, severe to critical illness occurs in a small proportion of infected individuals, with the highest rate seen in people older than 70 years. 

The measured case fatality rate varies between countries, probably because of differences in testing strategies. Population-based mortality estimates vary widely across Europe, ranging from zero to high. Numbers from the first affected region in Italy, Lombardy, show an all age mortality rate of 154 per 100 000 population. Differences are most likely due to varying demographic structures, among other factors. 

However, this new virus has a focal dissemination; therefore, some areas have a higher disease burden and are affected more than others for reasons that are still not understood. Nevertheless, early introduction of strict physical distancing and hygiene measures have proven effective in sharply reducing R0 and associated mortality and could in part explain the geographical differences.

COVID-19 origin research hit by political agendas: Zhong Nanshan

Via the South China Morning Post: Coronavirus origin research hit by political agendas, China’s ‘Sars hero’ says. Excerpt:

In an exclusive, wide-ranging interview with the Post, veteran Chinese infectious disease expert Zhong Nanshan shares his insights into the global battle to control the Covid-19 pandemic. In this third part of a four-part series, Zhong says the blame game between the US and China is putting important research at risk at a time when the world’s scientific community needs to join hands and work together.

 

The politicisation of the Covid-19 pandemic could stall vital global scientific cooperation into an investigation of its origins, according to China’s most respected respiratory expert. 

 

Zhong Nanshan, 83, known as a “Sars hero” for his role in fighting the 2002-03 severe acute respiratory syndrome epidemic, said scientists around the world needed to team up to establish where the new coronavirus, which causes Covid-19, had come from. 

 

Zhong, from the Chinese Academy of Engineering and a senior adviser to the government in its drive against Covid-19, said he had been approached by Ian Lipkin, the US epidemiologist, to use molecular tools to establish how the virus jumped to humans but the endeavour could be stalled for fear it would be distorted by political agendas.

 

Lipkin, professor of epidemiology at Columbia University, was an adviser on the film Contagion and himself contracted Covid-19. His association with Zhong dates back 17 years when they worked together on the Sars outbreak in China.  

 

Lipkin has been working since 2018 with professor Lu Jiahai’s team at Sun Yat-sen University’s public health school in Guangzhou, southern China, on emerging infectious diseases. They have been trying to establish the origin of the new coronavirus since February. Zhong, Lu and Lipkin met in Guangzhou in January and are in regular contact. 

“Professor Lipkin has a very good technology, called molecular capture, which can capture and analyse the key gene to identify the source of the virus,” Zhong said. “It will be a large amount of work that involves not only drawing [human] blood but also blanket investigation into animals.”

 

But Zhong said US politicisation of the pandemic, which aimed to lay blame on China, was putting the project at risk. “[Origin tracing] should have been an important scientific issue that called for joint research and I am all for it but now, with the political labelling, it is very difficult to do so,” he said. 

 

US President Donald Trump and Secretary of State Mike Pompeo have claimed, without evidence, that the virus escaped from a laboratory in Wuhan — the central Chinese city where the first cases were reported — and called for an investigation into the outbreak. They have also blamed China’s initial handling of the outbreak for causing the spread of the disease around the world.

 

China has rejected the claims and accused the US of spreading unfounded conspiracy theories. Beijing has repeatedly said it opposes politically-driven investigations into the origin of the coronavirus and would accept objective and science-based probes within the framework of the World Health Organisation, when the epidemic has waned. 

 

Zhong said the Chinese government had investigated the claims about the Wuhan laboratory and found no improprieties. “After the US made the allegations, the Chinese Centre of Disease Control and Prevention and the National Health Commission sent a special team to investigate the Wuhan Institute of Virology for two weeks,” he said. “The investigators found nothing improper and there was nothing that could show [the coronavirus] was manufactured by the laboratory. We also know that, based on their manpower, technological capability, and finance, it is just impossible for them to have manufactured it (the virus).”  

 

Available evidence suggests bats were the reservoir host for the new coronavirus which then possibly passed through an animal intermediary host to humans. Wuhan’s Huanan Seafood Wholesale Market – where wild animals were traded and which was linked to 27 of the 41 early cases – was initially believed to be the source of infection. However, epidemiologists had found only traces of the virus in samples taken at the market.

 

In addition, Zhong said, the first known case of the coronavirus in Wuhan, as well as most of 1,099 cases nationwide with links to Wuhan that were studied in January, had no connection to the market at all. Zhong said investigations into the origins of the coronavirus were important for preparing for the next outbreak, as there had already been three this century – Sars in 2002, Middle East respiratory syndrome (Mers) in 2015 and now Covid-19. But, he said, investigations should cover other countries as well as China. 

 

“We need to find out exactly how the virus transmitted,” he said. “It’s a process of evolution and that can happen anywhere. Data showed it happened in China, France and the United States. We really need to find out how this happened.” Zhong said it was now established that the earliest cases had occurred in September and November.

 

“It occurred in November in the US and also in France and Italy, so it’s a world problem that the virus might have existed long before [it was reported in China],” he said.

Pulmonary fibrosis secondary to COVID-19: A call to arms?

Via The Lancet Respiratory Medicine, an alarming report: Pulmonary fibrosis secondary to COVID-19: a call to arms? Excerpt:

Other strains of the coronavirus family, namely severe acute respiratory syndrome coronavirus (SARS-CoV; known as SARS) and Middle East respiratory syndrome coronavirus (MERS-CoV; known as MERS), are genetically similar to SARS-CoV-2 and cause pulmonary syndromes similar to COVID-19. At the end of the SARS epidemic in June, 2003, 8422 individuals were affected and 916 died; whereas MERS, which was first identified in April, 2012, has infected 2519 individuals worldwide to date, including 866 deaths. 

The predominant CT abnormalities in patients with SARS included rapidly progressive ground glass opacities sometimes with consolidation. Reticular changes were evident approximately 2 weeks after symptom onset and persisted in half of patients beyond 4 weeks. However, a 15-year follow-up study of 71 patients with SARS showed that interstitial abnormalities and functional decline recovered over the first 2 years following infection and then remained stable. 

At 15 years, 4·6% (SD 6·4%) of the lungs showed interstitial abnormality in patients who had been infected with SARS. In patients with MERS, typical CT abnormalities included bilateral ground glass opacities, predominantly in the basal and peripheral lung zones. Follow-up outcomes are less well described in patients with MERS. In a study of 36 patients who had recovered from MERS, chest x-rays taken a median of 43 (range 32–320) days after hospital discharge showed abnormalities described as lung fibrosis in about a third of the patients. Longer-term follow-up of patients who recovered from MERS has not been reported. 

Pulmonary fibrosis can develop either following chronic inflammation or as a primary, genetically influenced, and age-related fibroproliferative process, as in idiopathic pulmonary fibrosis (IPF). Pulmonary fibrosis is a recognised sequel of ARDS. However, most follow-up studies—which have included both physiological measures and chest CT—have shown that persistent radiographic abnormalities after ARDS are of little clinical relevance and have become less common in the era of protective lung ventilation.

Available data indicate that about 40% of patients with COVID-19 develop ARDS, and 20% of ARDS cases are severe. Of note, the average age of patients hospitalised with severe COVID-19 appears to be older than that seen with MERS or SARS, which is perhaps a consequence of wider community spread. In inflammatory lung disorders, such as those associated with autoimmune disease, advancing age is a risk factor for the development of pulmonary fibrosis. Given these observations, the burden of pulmonary fibrosis after COVID-19 recovery could be substantial. 

Progressive, fibrotic irreversible interstitial lung disease, which is characterised by declining lung function, increasing extent of fibrosis on CT, worsening symptoms and quality of life, and early mortality,10 arises, with varying degrees of frequency, in the context of a number of conditions including IPF, hypersensitivity pneumonitis, autoimmune disease, and drug-induced interstitial lung disease. 

Although the virus is eradicated in patients who have recovered from COVID-19, the removal of the cause of lung damage does not, in itself, preclude the development of progressive, fibrotic irreversible interstitial lung disease. Furthermore, even a relatively small degree of residual but non-progressive fibrosis could result in considerable morbidity and mortality in an older population of patients who had COVID-19, many of whom will have pre-existing pulmonary conditions. 

At present, the long-term pulmonary consequences of COVID-19 remains speculative and should not be assumed without appropriate prospective study. Nonetheless, given the huge numbers of individuals affected by COVID-19, even rare complications will have major health effects at the population level. It is important that plans are made now to rapidly identify whether the development of pulmonary fibrosis occurs in the survivor population. By doing this, we can hope to deliver appropriate clinical care and urgently design interventional trials to prevent a second wave of late mortality associated with this devastating pandemic.

BC’s top doctor wrote a book about fighting viruses in 2009

The Tyee has published my article: BC’s Top Doctor Wrote a Book about Fighting Viruses in 2009. Excerpt:

Soap and Water & Common Sense: The Definitive Guide to Viruses, Bacteria, Parasites, and Disease By Dr. Bonnie Henry House of Anansi, 2009. 

Dr. Bonnie Henry’s news conferences have become a part of daily life in B.C. When they attend her briefings, Premier John Horgan, Health Minister Adrian Dix, and Public Safety Minister Mike Farnworth fade into the background, at a safe distance from her and one another. They speak chiefly to endorse what their chief medical officer says. The contrast with Trump’s press conferences is impossible to miss. 

It certainly helps that Dr. Henry can deliver alarming news in a calm tone of voice, without relying on technical jargon; we pay attention, we absorb the news, but we don’t freak out. Treated like adults, we respond like adults.  

Those same communication skills are evident throughout her 2009 book Soap and Water & Common Sense, written years before she became B.C.’s provincial health officer. The book is now available with a new introduction, written in March, and the content itself is still very timely: while our healthcare system is fighting COVID-19, other diseases are going to exploit their opportunity.

China confirms new coronavirus as it investigates mystery Wuhan illness

Via the South China Morning Post: China confirms new coronavirus as it investigates mystery Wuhan illness.

Chinese scientists investigating a mystery illness that has infected dozens in the central city of Wuhan have said it is a new strain of coronavirus from the same family that caused the 2002-03 Sars epidemic. 

Laboratory tests have found a new type of coronavirus and the whole genome sequence of the new virus has been obtained, state broadcaster China Central Television (CCTV) reported on Thursday, citing a task force of experts. 

Fifteen patients had tested positive for the new coronavirus, the report stated. It said the virus had been isolated from one of the 15 patients and showed “typical coronavirus morphology” under electron microscope observation. 

“The pathogen of these unexplained cases of viral pneumonia was initially identified as a new type of coronavirus,” the report quoted the expert group as saying.

There have been 59 reported cases of the mysterious virus in Wuhan since late December, some of them connected to a seafood market in which wild animals had been sold. The market has since been closed. 

Retrospective study identified that the first case had been identified on December 12 and the latest on December 29. No deaths have been reported and eight patients, no longer showing pneumonia symptoms, had been discharged from hospital by Wednesday. 

The Wuhan health authority has said that no human-to-human transmission has so far been detected.  

Coronaviruses can infect mammals such as pigs, cattle, cats, dogs, camels, bats and mice, as well as humans. Of the six previously known human coronaviruses, four were common and caused only minor respiratory symptoms similar to those of a cold.

The other two were serious respiratory diseases: the Severe Acute Respiratory Syndrome (Sars) coronavirus that killed more than 700 people worldwide after originating in China, and the Middle East Respiratory Syndrome coronavirus that had caused 449 deaths by 2015. 

The CCTV report said that the laboratory had used genomic sequencing, nucleic acid detection, virus isolation and other methods to analyse samples from patients. 

Although it is possible to find evidence of a pathogen in a short period of time, it could take years to produce a vaccine. 

The expert group said the initial identification needed to be followed up with further research, according to the television report. Professor David Hui Shu-cheong, a respiratory medicine expert from the Chinese University in Hong Kong, said some important details were still to be established. 

“Some key information, including which animal is the source of the virus, the incubation period and the transmission route, are still missing,” Hui said.

WHO: Middle East respiratory syndrome coronavirus (MERS-CoV) – The United Arab Emirates

WHO has published Middle East respiratory syndrome coronavirus (MERS-CoV) – The United Arab Emirates. Excerpt:

On 29 December 2019, the National IHR Focal Point of the United Arab Emirates (UAE) reported one laboratory-confirmed case of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to WHO.  

The case is a 74-year-old male national who owns a camel farm located in Al Ain City, Abu Dhabi region in UAE where he is living. He developed fever, cough and sore throat on 8 December 2019 and was admitted to hospital on 10 December, then transferred to ICU on 16 December. A nasopharyngeal aspirate was collected and tested positive for MERS-CoV by reverse transcription polymerase chain reaction (RT-PCR) (UpE and Orf1a genes) on 16 December by the Shiekh Khalifa Medical Center laboratory. He has underlying comorbidities including hyperkalemia, diabetes mellitus with diabetic nephropathy, heart disease, asthma and hypertension. He has a history of close contact with dromedary camels and sheep at his farm in the 14 days prior to the onset of symptoms. He has no history of recent travel and has not been involved in slaughtering animals. Currently, the patient is in stable condition in intensive care unit isolation.  

Since 2012, UAE has reported 89 cases of MERS-CoV (including this case) and 12 associated deaths. From 2012 through 29 December 2019, the total number of laboratory-confirmed MERS-CoV infection cases reported globally to WHO is 2494 with 858 associated deaths. The global number reflects the total number of laboratory-confirmed cases reported to WHO under IHR to date. The total number of deaths includes the deaths that WHO is aware of to date through follow-up with affected member states.  

Public health response 

Upon identification of the patient, an incident report, case investigation and contact tracing were initiated. The investigation is ongoing and includes screening of all close contacts, including occupational contacts in his farm, household contacts and healthcare workers at the hospital where he sought care. All identified contacts of the confirmed case will be monitored daily for the appearance of respiratory or gastrointestinal symptoms for 14 days after the last exposure to the confirmed case.  

A total of 88 contacts have been identified, including 70 health care contacts and 18 household contacts. All close contacts of the patient were tested negative for MERS-CoV.  

The veterinary authorities have been notified and investigations for MERS-CoV in animals are ongoing.

Hong Kong: Government launches Preparedness and Response Plan for Novel Infectious Disease of Public Health Significance

Via the Centre for Health Protection: Government launches Preparedness and Response Plan for Novel Infectious Disease of Public Health Significance. The full statement and then a comment:

The Government today (January 4) launched the Preparedness and Response Plan for Novel Infectious Disease of Public Health Significance (The Plan). In parallel, the Serious Response Level was activated with immediate effect.        

The Plan sets out the Government's preparedness and response plan in case of an outbreak of Novel Infectious Disease of Public Health Significance. A three-tier response level is adopted in the plan. Three response levels, namely Alert, Serious and Emergency, will be activated based on the risk assessment of the Novel Infectious Disease of Public Health Significance that may affect Hong Kong and its health impact on the community.        

Upon the risk assessment of the cluster of cases of viral pneumonia with unknown cause in Wuhan reported by the National Health Commission, the Serious Response Level was activated. Under the Serious Response Level, the immediate health impact caused by Novel Infectious Disease of Public Health Significance on local population is moderate.        

"'Novel Infectious Disease of Public Health Significance' refers to any infectious disease caused by a pathogen unknown to cause human disease before, but may have changed its property to cause human infection with or without the ability of efficient human-to-human transmission. The disease has the potential to lead to international spread and public health emergency. The current cluster of viral pneumonia cases in Wuhan can be regarded as a Novel Infectious Disease of Public Health Significance," a spokesman for the Centre for Health Protection (CHP) of the Department of Health said.        

"The Government will assess the risk from time to time in view of the latest scientific evidence and situation, activate or deactivate the response level and implement corresponding measures," the spokesman said.        

For more information, please refer to the Plan which has been uploaded to the CHP's website (www.chp.gov.hk/files/pdf/govt_preparedness_and_response_plan_for_novel_infectious_disease_of_public_health_significance_eng.pdf).

Hong Kong's CHP was established after the shock of the 1997 H5N1 outbreak, and ever since it's been an exemplar of a public health agency. If sniffles break out in a kindergarten, or someone comes home from Dubai a bit feverish, CHP will be on the scene and prepared to tell the world what's infected the kids and whether the traveller has MERS (so far, not a single person).

H5N1 may have fizzled out, but the Hong Kong Centre for Health Protection has not.

Saudi Arabia: The direct medical costs of MERS

Via Infection and Drug Resistance, the best research report I have yet seen on the MERS epidemic: Estimation Of Direct Medical Costs Of Middle East Respiratory Syndrome. The abstract:

Background: Among the countries affected by Middle East respiratory syndrome (MERS), Saudi Arabia was impacted the most, with 2,058 cases reported as of June 2019. However, the impact of the MERS epidemic on the Saudi economy is unknown. 

Purpose: The present study aimed to evaluate the direct medical costs associated with the management of MERS cases at a tertiary referral hospital in Riyadh, Saudi Arabia. 

Methods: The study involved a retrospective chart review of confirmed cases of MERS coronavirus (MERS-CoV) infections in a tertiary care referral center in Riyadh, Saudi Arabia, from January 2015 to October 2018. The collected data included sociodemographic characteristics, medical information, and the cost of hospitalization of each patient as estimated by micro-costing. 

Results: A complete set of relevant information was available only for 24 of 44 identified MERS-CoV cases. Patients were mostly females, and the mean age was 52 years. Diabetes, hypertension, and chronic kidney disease were the most frequent comorbidities. The length of hospital stay varied from 1 to 31 days, averaging 4.96 ± 7.29 days. Two of the 24 patients died. The total cost of managing a MERS case at the hospital ranged from $1278.41 to $75,987.95 with a mean cost of $12,947.03 ± $19,923.14. 

Conclusion: The findings of this study highlight the enormous expenses incurred by the Saudi health care system due to the MERS-CoV outbreak and the importance of developing an enforceable nationwide policy to control MERS-CoV transmission and infection.