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An Update and Guidance on 2019 Novel Coronavirus (2019-nCov) for Transplant ID Clinicians
Updated 27 January 2020

We have prepared the following Update for Transplant Infectious Diseases Clinicians about the novel 2019 Coronavirus associated with viral pneumonia from Wuhan, China.  As this is a rapidly changing topic, consult your local public health authority for the most up to date data.  We will continue to update this document over time.

Background and Timeline

On 31 December 2019, the World Health Organization received reports from Chinese authorities about a cluster of pneumonia cases at a hospital in Wuhan, China.  All patients seemed to be epidemiologically linked to a fresh seafood market that also sold live animals like snakes and marmots. It appeared that common respiratory viruses like influenza and adenovirus had been excluded, as had SARS Co-V and MERS Co-V. (eCDC)

On 9 January 2020, WHO revealed that Chinese scientists had found a novel coronavirus from respiratory samples of one of the patients involved in the cluster. (WHO 0901) The full sequence was subsequently shared with WHO and the GISAID website. (WHO lab guidance 17 January 2020)  This virus has been named the 2019 novel coronavirus (2019-nCoV).

On 14 January 2020, Thai authorities reported that a Chinese tourist from Wuhan had been admitted for fever and had been found to have the novel coronavirus, 2019-nCoV. (CIDRAP 13 Jan) The history of contact with the seafood market was not initially available, but it was subsequently reported that she had not had such contact. (CIDRAP 14 Jan 2020)

As more countries reported cases of 2019-nCoV among persons who had been to Wuhan, the suspicion that there was human-to-human transmission increased. On 20 January 2020, reports emerged that healthcare workers were infected with the novel coronavirus (CIDRAP 20 Jan 2020).  It was unclear if these workers had had contact with the initial cohort of patients reported on 31 December 2019, or if they were from one or several healthcare facilities. Nevertheless this report heightened already increasing concerns about human-to-human transmission. Using sequences publicly shared by laboratories from China and Thailand, preliminary phylogenetic analysis has been performed, with results suggesting limited diversity thus far. (virological.org) A recent report of intra-family transmission (Family cluster Lancet, Lancet 24 Jan 2020) confirmed human-to-human transmission of the virus.

Most worrying is the statement made by the Chairman of China’s National Health Commission that the asymptomatic may also be infectious. (Anon, weixin.qq.com) There is as yet no published data to support this. It is also difficult to dismiss this, as this statement was made at a press conference held by a government body. One patient in the Shenzhen family cluster was asymptomatic, but it is not possible to determine the direction of transmission as all patients were part of the same family. (Shenzhen) 

Transplant physicians are likely to encounter transplant candidates, transplant recipients, and potential donors who have travelled to or are planning to travel to Wuhan, or more generally, China. This document provides preliminary guidance on the approach to this new infection in the transplant setting. As the situation is fluid, we advise transplant physicians to work closely with their Transplant Infectious Diseases (TID) colleagues, and we urge TID specialists to keep abreast of developments by referring regularly to reputable websites such as those of US CDC (https://www.cdc.gov/coronavirus/2019-ncov/index.html), WHO (www.who.int) and Public Health England (PHE) (www.gov.uk/government/organisations/public-health-england).

2019-nCoV

To date, data on modes of transmission, incubation period, and degree or duration of infectiousness is preliminary. The incubation period of SARS was estimated to range from 2 to 11 days (Tsang). The median incubation period of MERS was calculated to be 5.2 days (Assiri). Based on one family cluster, the authors concluded that the incubation period of 2019-nCoV was similar to that of SARS. (Shenzhen cluster)

In a case definition advocated by PHE, an acute respiratory illness in a person who had been to Wuhan or confirmed to be infected with the 2019-nCoV in the previous 14 days constituted a possible case; the US CDC gives almost identical case definitions. (PHE guidance, CDC guidance) Interim guidance from WHO also uses a 14-day time period between last contact with a case or travel to China/Wuhan and symptom onset. (WHO interim guidance 21012020). While most patients had fever and cough, patients may be asymptomatic initially.  Contact with a known or suspected case of  2019-nCoV should be a flag.

General Measures

It is presumed that hospitals receiving and managing transplant candidates and recipients have put themselves and their staff on the alert for this novel coronavirus.  Protocols should be in place for frontline staff (those in clinic or Emergency) to perform questionnaire-based screening for respiratory symptoms and a travel history. US CDC recommends that persons who fit the criteria should immediately be given a surgical mask and evaluated in a private room with the door closed. (CDC IPC guide) 

As authoritative bodies have already published guidance on case definitions, testing, and infection prevention precautions, this document will highlight mainly issues pertinent to transplantation. It is also obvious that information is lacking on many aspects of the virus and the disease. As more information become available, these guidelines will likely require modification.

Case Definition

A case definition should be developed - using one promulgated by the local government or by the hospital’s ID team or published by reputable bodies may simplify preparations. Patients fulfilling the case definition should be managed in respiratory isolation rooms, with one guideline stating that both negative-pressure and neutral pressure rooms are acceptable. (PHE infection control guidance)  US CDC notes that an airborne infection isolation room is ideal (US CDC). As transplant patients should not be placed in negative pressure rooms, neutral pressure rooms are an option. The WHO recommends “adequately ventilated single rooms”. (WHO IPC guide 25 Jan)   It is important that the room has an attached bathroom. (PHE)

Case definitions available thus far combine a travel and/or a contact history (with Wuhan/China/patients hospitalised in Wuhan) with respiratory symptoms. (PHE, WHO interim guidance) Prominent among symptoms highlighted is fever. Indeed the first available case series from Wuhan noted that fever was present in 98% of the patients. (Huang first case series) The presence of fever in a case series does not mean every patient presents with fever. Two of the patients in the Shenzhen family cluster were actually afebrile at presentation – they had diarrhoea and upper respiratory symptoms. (Shenzhen family cluster) It is well known that immunocompromised patients may have atypical or muted presentations. Therefore transplant physicians may want to have a low threshold to isolate and test patients with mild symptoms but the relevant epidemiological exposures.

Patients can experience non-respiratory symptoms (TTT paper in EID).  Although largely thought of as a respiratory illness, 35% of MERS CoV patients had gastrointestinal symptoms. (Assiri)  A small percentage of patients with 2019-nCoV have diarrhoea, though it is unclear from available reports if this may be the presenting symptom. (Huang, First case series, Shenzhen family cluster)

Transplant Specific Recommendations

Deceased Donors
As little is known about the virus, persons dying of or with 2019-coV should not be eligible for deceased donation.

Living Donors
Living donation should not be performed within 14 days of return from China/Wuhan.

Transplant Candidates
Transplant candidates should not undergo a transplant within 14 days of return from China/Wuhan. This will allow sufficient time for symptoms to develop.

Transplant Recipients
Like all persons, transplant recipients should adhere to travel advisories issued by their respective health authorities/government bodies.  This may necessitate postponing non-essential travel to Wuhan and Hubei province, and depending on how the situation evolves, China.

An intra-departmental guide should be developed for transplant patients who are within 14 days of return from China/Wuhan, or who have had contact with a patient infected with the 2019-nCoV, and who need a surgical procedure, e.g., scheduled BAL in a lung transplant recipient. Re-scheduling an elective procedure is prudent. If the procedure is urgent, then full infection prevention precautions should be applied. It is also prudent for transplant patients with the relevant epidemiological exposures who get admitted for intercurrent illnesses like appendicitis to be managed under full infection prevention precautions. The development of fever or dyspnoea post-operatively will be a particularly challenging and difficult situation, but prudence would indicate that efforts to rule out the 2019-nCoV should be undertaken.

Staff
This outbreak is occurring across the Chinese New Year, a time when many native Chinese go back to their home cities/villages to celebrate with families. As the festive period winds down, many will return to their places of residence.  Programs should develop policies related to handling of staff returning to work after potential exposure to areas with active transmission of nCoV 2019.  Policy should include requirement for patients who become ill to not report to work but to instead report to their occupational health clinic.  Such potentially ill staff should call the clinic to alert them that they were exposed and are sick so that appropriate preparations can be made.

Summary

We have proposed rather strict guidelines for the safety of the transplant patients in our care. As this is a rapidly evolving situation, new data will emerge that may render these recommendations outdated. Uncertainties may well persist for some time into the future, and prudence might dictate the need to practise under stringent infection prevention precautions for a longer period than necessary. The importance of strict adherence to good hand hygiene, the most important of infection prevention precautions, cannot be over-emphasized.

References

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Read more: An Update and Guidance on 2019 Novel Coronavirus (2019-nCov) for Transplant ID Clinicians

Zika virus (ZIKV) is a RNA virus of the Flaviviridae family, genus Flavivirus, which includes other well-known arboviruses such as West Nile virus (WNV), dengue virus (DENV) and yellow fever virus (YFV), the latter two also transmitted by Aedes mosquitoes.

Clarisse M. Machado, M.D.
Head, Virology Laboratory
Institute of Tropical Medicine
University of São Paulo, Brazil
TID President

More than half of the world’s human population lives in areas infested with Aedes; consequently, large urban epidemics of Zika, dengue, chikungunya, and even yellow fever have been expected for decades.

Although ZIKV was isolated from a rhesus monkey in the Zika forest of Uganda in 1947, the virus was largely ignored until 2007 when it caused an epidemic on the island of Yap in Micronesia and Gabon[1] followed by an outbreak in French Polynesia during 2013[2]. Deleterious consequences of these epidemics were not noticed in those countries, possibly due to the low population density. However, in early 2015, when ZIKV epidemics hit the northeast region of Brazil, a populous country infested by both Aedes aegypti and A. albopictus, the epidemic showed its true colors. The apparently mild acute infection was associated with serious consequences, such as the increase in the number of cases of Guillain-Barre (already seen after the French Polynesia epidemic) and microcephaly, in ZIKV epidemic regions.

Although not yet proven, a causal relationship between Zika infection during pregnancy and microcephaly is strongly suggested[3]. Meanwhile, reports of sexual and blood transmitted ZIKV infections have increased the controversy associated with the epidemic[4],[5].

So far, no cases of Zika virus have been reported in transplant recipients. Transmission by solid organ or marrow transplantation is theoretically possible since the virus can be transmitted through blood transfusion. It is not known if the disease is more or less severe in the immunocompromised patient. Therefore, it is important for the transplant community to be aware of the risk of ZIKV infections.

Infection with ZIKV is asymptomatic in most people. In symptomatic patients, fever, rash, conjunctivitis, or joint pain are the most common symptoms. Myalgia, asthenia and headache can also occur. The incubation period varies from a few days to a week, and symptoms typically resolve within a week. Severe disease and/or death appear to be very rare in the immunocompetent population. There is currently no vaccine and no treatment for Zika infection. Management of immunosuppressive drugs may be helpful to avoid severe symptoms and lymphopenia. However, the level of evidence for this recommendation is low.

Clinical presentation may help in the differential diagnosis in case of co-circulation of DENV and Chikungunya (CHKV). The main signs and symptoms observed in infections caused by ZIKV, DENV and CHKV are shown in the table below.

Signs and Symptoms
Dengue
Chikungunya
Zika
Fever ++++ ++++ +
Rash (maculopapular) ++ ++ ++++
Conjunctivitis + + ++++
Myalgia/arthralgia +++ +++++ ++
Edema Absent ++++ +++
Retro-orbital pain +++++ ++ +
Lymphadenopathy + ++ +
Bleeding ++ Absent Absent
Hepatomegaly ++ +++ Absent
Lymphopenia/ thrombocytopenia +++ +++ Absent

Preventive policies are focused on vector control and infection avoidance. Community-based programs are important to keep the environment free of potential breeding sources.

Based on current available information, the following recommendations should be shared with transplant patients:

Investigation of the epidemiological risk is mandatory and should focus especially upon travel to epidemic regions. Up until February 3rd 2016, 35 cases of travel-associated ZIKV diseases had been reported in the US[6].

Be aware that ZIKV infection results in an asymptomatic viremia in most people, consequently, donors travelling from epidemic regions might be infected. It is not known which organs might become infected with ZIKV or how long the infectious virus might be present in those organs.

In case of living donors with history of Zika infection, donation should be deferred whenever possible. For blood donation, the minimal deferral time recommended by the FDA is 28 days after returning from ZIKV regions.

Serological tests for Zika virus are not yet available, nor have they been validated for routine donor screening. The risk of donor-derived infection should be balanced with the benefits of transplantation on an individual basis.

At this moment, donor screening by PCR is not recommended in SOT, but should be considered in allogeneic HSCT in epidemic regions.

For symptomatic patients, diagnosis entails real time PCR in blood or urine samples within the first 7 days or up to 14 days, respectively. Serology is not yet available.

To avoid unnecessary testing, a case definition approach to ZIKV investigation should be applied. For example, rash and/or fever, along with one of the following symptoms: headache, myalgia, arthralgia and conjunctivitis should prompt diagnostic investigation of suspected cases.

Health services should provide rapid and sensitive diagnosis, and include DENV and CHKV tests in regions with co-circulation of the three viruses.

The Aedes is a domestic mosquito, living in or around homes or other places frequented by people such as schools or churches. It generally bites at dawn and dusk. However, even in the hottest daytime hours, it can attack in the shade, inside or outside the home.

The mosquitoes breed in calm, clear water. In favorable environmental conditions, development into an adult mosquito takes around 10 days after emergence from the egg. Therefore, the elimination of standing water should be performed at least once a week to interrupt the mosquito life cycle.

Avoid traveling to countries with ZIKV epidemics. Protective measures to avoid mosquito bites. Abstain from sexual activity or consistently and correctly use condoms during sex with a partner who has been to an area of Zika transmission. Pre-transplant screening by PCR is not recommended at this moment.

Asymptomatic:
Avoid traveling to countries with ZIKV epidemics; protective measures to avoid mosquito bites. Abstain from sexual activity or consistently and correctly use condoms during sex with a partner who has been to an area of Zika transmission.

Symptomatic:
Test for ZIKV (PCR) and exclude other relevant infections, such as CMV. Consider discontinuation of cell cycle agents (azathioprine or mycophenolate).

[1]. Grard G, Caron M, Mombo IM, Nkoghe D, Mboui Ondo S, Jiolle D, et al. Zika Virus in Gabon (Central Africa) - 2007: A New Threat from Aedes albopictus? PLoS Negl Trop Dis. 2014;8(2)

[2]. Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Med Mal Infect. Elsevier Masson SAS; 2014;44(7):302–7.

[3]. Schuler-Faccini L, Ribeiro EM, Feitosa IML, Horovitz DDG, Cavalcanti DP, Pessoa A, et al. Possible Association Between Zika Virus Infection and Microcephaly — Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(3):59–62.

[4]. Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of zika virus. Emerg Infect Dis. 2015;21(2):359–61.

[5]. Reuters. Zika Spread Through Blood Transfusion in Brazil [Internet]. 2016. Available from: http://time.com/4208187/brazil-zika-blood-transfusion

[6]. Centers for Disease Control and Prevention (CDC). Zika virus [Internet]. 2016. Available from: http://www.cdc.gov/zika/index.html

Read more: Zika Virus

News

Zika virus (ZIKV) is a RNA virus of the Flaviviridae family, genus Flavivirus, which includes other well-known arboviruses such as West Nile virus (WNV), dengue virus (DENV) and yellow fever virus (YFV), the latter two also transmitted by Aedes mosquitoes.

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