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MERS is a viral pneumonia with rapidly progressive respiratory failure leading to ARDS. As with severe pandemic influenza (H1N1), and severe avian influenza (H7N9) death is due to hypoxemia from acute respiratory failure.14-16 Like SARS and avian influenza (H7N9), MERS has not been complicated by bacterial co-infections.5,28-30 Pandemic influenza, in contrast, which may be complicated by simultaneous bacterial co-infection, with S. aureus (MSSA or MRSA), or sequential co-infection in patients who improve ~1 wk who then may develop a secondary bacterial pneumonia due to Haemophilus influenzae or S. pneumoniae.14,15 Since any patient, including MERS or influenza patients, that receive prolonged mechanical ventilation may develop late nosocomial bacterial pneumonia.5 These are not co-infections, per se, but rather are nosocomial complications of mechanical ventilation. Like pandemic influenza, MERS mortality can be high in normal young adults, but mortality is highest in those with comorbidities.5
Two new polyomaviruses were identified in 2007 in respiratory tract samples following large scale molecular screening using high throughput DNA sequencing of random clones and have been named after the institutes where they were found: KI (Karolinska Institute) polyomavirus (KIPyV) and WU (Washington University) polyomavirus (WUPyV). Data on seroprevalence indicate that infection is widespread ranging from 54.1 and 67% for KI and from 66.4% and 89% for WU in North American and German blood donors. Since their first identification, KI and WU viral sequences have been confirmed worldwide in respiratory samples from children with respiratory tract disease ranging from 0.2% to 2.7% and from 1.1 to 7%, respectively. However WUPyV and KIPyV were found at similar frequencies in control groups without respiratory diseases so the link between these polyomaviruses and acute respiratory diseases remains speculative.
Careful analysis is complicated by high co-infection rates with other well-characterized viral respiratory pathogens. A co-detection rate of 74% has been observed for KIPyV and rates ranging from 68 to 79% for WUPyV. Therefore, in a recent study in Southern China, hospitalized children with WUPyV infection displayed predominantly cough, moderate fever, and wheezing, but were also diagnosed with pneumonia, bronchiolitis, upper respiratory tract infections and bronchitis. As in most of infected children a single WUPyV infection was detected, it was suggested that the newly described polyomavirus can cause acute respiratory tract infection with atypical symptoms, including severe complications. Nevertheless these data have to be confirmed in further studies.
The presence of WUPyV and KIPyV in samples from children but not from immunocompetent adults suffering from LRTIs suggests that these viruses primarily infect the young population. A correlation between immunosuppression and reactivation of the two novel polyomaviruses has been suggested in immunocompromised patients and in AIDS patients at the molecular level, but no evidence of a role of these viruses as opportunistic pathogens has been given.
Overall, these data support the hypothesis that, in analogy with BK and JC polyomaviruses, KIPyV and WUPyV can establish persistent infection, and that virus replication may increase in immunocompromised hosts. However, in a recent study on immunocompetent and immunocompromised adult patients, real-time PCR detected KIPyV and WUPyV in 2.6% and 4.6% of HIV-1–infected patients respectively and in 3.1% and 0.8% of blood donors respectively, while no association was found between CD4+ cell counts in HIV-1 positive patients and infection with KIPyV or WUPyV.
KIPyV and WUPyV are also incidentally detected in adults with community acquired pneumonia, in immunocompromised hosts, and in patients with lung cancer; they are more often found in patients suffering an underlying medical condition and coinfections with KIPyV and WUPyV with other respiratory viruses are common. A recent study evaluating the prevalence and viral load of WUPyV and KIPyV in respiratory samples from immunocompromised and immunocompetent children showed that the prevalence of WUPyV and KIPyV is similar in hematology/oncology patients compared with that of the general pediatric population. High co-detection rates with other respiratory viruses, mainly RSV and enterovirus or rhinovirus, were found for WUPyV and KIPyV in both groups, in analogy with previous reports. However, higher viral loads for KIPyV in the immunocompromised group were detected, suggesting that there may be an increased replication of this virus in this population.
A similar association was not observed for WUPyV. Furthermore, in the immunocompromised group, infection with either virus occurred in older children compared with controls, which may indicate viral-reactivation Table 1.
High rates of co-infection with other respiratory viruses are commonly reported. Viruses frequently associated with co-infection include enterovirus, rhinovirus and PIV however reports of co-infection with two human coronaviruses are limited. Dijkman et al. recently demonstrated that HCoV-OC43 and HCoV-NL63 may elicit immunity that protects against HCoV-HKU1 and HCoV-229E, respectively. Clinical progression and outcomes of disease in patients presenting with co-infection are however similar to patients presenting with mono-infection. There is also no substantial difference in coronaviral load between co-infected and mono-infected patients. No substantial difference in disease progression in co-infected versus mono-infected patients has been reported and therefore understood to have little impact; however, the role in facilitation of infection of one respiratory virus by another is still speculative.
The pathogenesis of hMPV infection is strongly affected by bacterial coinfections with pneumococcus. One study has shown that administration of a conjugate pneumococcal vaccine is sufficient to reduce the incidence of hMPV infection of the lower respiratory tract and the incidence of clinical pneumonia in both HIV positive and negative patients. These finding suggest that the incidence of hospitalizations in hMPV infections may be decreased by vaccination with a conjugate pneumococcal vaccine. Another case report of severe respiratory failure was found to be caused by coinfection with hMPV and Streptococcus pneumonia in a 64 year old patient. Both in vitro and in vivo studies have shown that infection with hMPV facilitates adhesion of pneumococcal bacteria, which may provide an explanation for the coinfection with pneumococcal strains and hMPV.
Viral coinfections between hMPV and RSV have been reported, but remain a contentious issue. The typical seasonal overlap of the two viruses has been suggested to promote viral coinfection. One study reported a 10-fold increase in risk of admission to an intensive care unit in pediatric patients coinfected with RSV and hMPV and associated the dual infection as capable of augmenting severe bronchiolitis. Other studies do not support this finding and further report a decreased correlation between hMPV-RSV coinfections and hospitalization and additionally lists dual infection, along with breastfeeding, as having protective effects.
HRVs are currently classified in the Picornaviridae family, genus Enterovirus, that includes 3 species: HRV-A, HRV-B, and HRV-C. Within each species there are multiple HRVs designated as “serotypes”, “types”, or “strains”. Several recent epidemiological studies suggest that HRV-A and HRV-C are the predominant species associated with acute respiratory illnesses in hospitalized children and adults, compared to HRV-B which are rarely detected.
The new HRV lineage designated HRV-C has been identified using molecular methods and associated with severe clinical presentations in infants and immunocompromised adults. Symptoms of patients infected with this new strain were mainly bronchiolitis, wheezing, and asthmatic exacerbation in cases from Australia and Hong Kong, which peaked in fall and winter whereas in New York the new rhinovirus genotype was detected in cases of influenza like illness (ILI) that were clustered within an 8-week period from October to December. A recent study describes a clinical case of severe respiratory and pericardial disease in an infant infected by HRV-C suggesting tha viral tropism is not strictly restricted to the respiratory tract. A study focusing on the global distribution of novel rhinovirus indicates its association with community outbreaks and pediatric respiratory disease also in Africa and in symptomatic subjects living in remote locations having limited contacts with other human populations. Moreover evidence for a role of HRV-C in lower respiratory tract disease and febrile wheeze in infants and asthma exacerbations in older children was reported. Recent studies making comparisons between HRVs species, found the HRV Cs more so than As or Bs as the major contributors to febrile wheeze and asthma exacerbation in infants and children, respectively . However, the severity of clinical manifestations for HRV-C is comparable to that for HRV-A in children with community-acquired pneumonia. In HRV C studies so far, no clear clinical difference has been noted between patients with single or mixed HRV-C infection. In a study, monoinfection was observed in more than half of cases and was more common than RSV monoinfection in patients with upper RTD, however the duration of hospitalizations was not significantly different between the HRV-C monoinfection group, HRV-A or HRV-B monoinfection group and RSV group suggesting that HRV-C is an important etiological factor in children with RTI. Most HRV-C co-detections are with RSV, however in a large study HRVs were statistically the least likely virus of 17 examined to be associated with co-infections Table 1.
Infection control aspects of MERS have to do with preventing MERS exposures and minimizing person-to-person spread. Patients particularly from countries near the Arabian Peninsula who have an influenza-like illness should avoid travel until they are well. The following are based on CDC recommendations. If any patient has been exposed to a potential or known MERS case travel should be avoided. Household or family members exposed to potential or actual MERS cases should use masks. Such household and family members, while ill, if a family household member develops an ILI they should avoid public transportation, school, and work while ill. The individuals who are at increased risk for MERS include recent travelers from the Arabian Peninsula, particularly if such travelers develop fever and an ILI, including cough and shortness of breath, within 14 d after traveling from countries in or near the Arabian Peninsula. Those that have had close contact with someone that has recently traveled with respiratory symptoms and fever from countries in or near the Arabian Peninsula should be observed for 14 d starting from the day the patient was last exposed to the person.20 Those with increased risk for MERS also include those with close contact with a probable or confirmed case of MERS. Care should be taken with the exposed individual to monitor fever, cough, shortness of breath, and other symptoms, i.e., chills, myalgias, sore throat, nausea, vomiting, or diarrhea for 14 d counting from the last day of exposure to the ill contact. Healthcare personnel not utilizing proper infection control precautions are at increased risk for MERS.23,24 Close contact may be defined as any person that provides care for a patient, including healthcare workers, family members, or someone who had similarly close physical contact or any person who stayed at the same place, lived with, or visited the patient when the patient was ill.21-23 Infection control contact, and airborne precautions should be used while in close contact with symptomatic individuals or patients with MERS in the differential diagnosis.25 Infection control precautions should be observed when obtaining or conducting respiratory specimen testing for MERS. To prevent transmission to household members, masks should be worn in the house. Since person-to-person transmission has been demonstrated with MERS the use of masks and handwashing are important interventions to reduce transmission.
It has been shown that healthcare workers in contact with or taking care of MERS patients are at particularly high risk for developing MERS.23,26,27 Contact and airborne precautions should be used with appropriate personal protective devices to minimize the exposure of healthcare workers to suspected or known hospitalized MERS cases.26 Since it is not known how long MERS-CoV is present in respiratory secretions, it seems prudent that MERS patients remain on contact and airborne precautions until discharged.
2019-nCoV pneumonia are emerging attack at China and worldwide in the winter of 2019-2020. The identified 2019-nCoV genome has been sequenced the closest to some beta-coronaviruses detected in bats. Person-to-person transmission in family homes or hospital, and intercity spread of 2019-nCoV are occurring. At present, the mortality of 2019-nCoV in China is 2.3%, compared with 9.6% of SARS and 34.4% of MERS reported by WHO. It seems the new virus is not as fatally as many people thought. The most common symptoms were onset of fever, generalized weakness and dry cough. Notably, some patients were afebrile or confirmed biologically to have an asymptomatic infection. And the ground glass changes on chest CT scan were earlier than the positive for RT-PCR test in some cases. Repeat testing of nasopharyngeal swab or sputum samples are recommended in clinical suspected cases with an initially negative result. According to the current status, blocking transmission, isolation, respiratory and eye protection, and hand hygiene are the urgent management strategies against 2019-nCoV.
As of 15 February 2013, a total of 12 laboratory confirmed cases of NCoV have been reported to WHO. The first 9 of these cases have been from the Middle East: 5 cases (3 fatal) from Saudi Arabia, 2 cases from Qatar and 2 cases (both fatal) from Jordan (Figure 1). The most recent 3 cases (1 fatal) were in individuals living in UK.
Primary TB occurs most commonly in children.The most typical form of pulmonary NTMB infection is frequently associated to elderly non-smoking white women without underlying lung disease (Lady Windermere syndrome).With respect to the morbidity and mortality, influenza type A is the most important of the respiratory viruses in the general population.
Adenovirus accounts for 5–10% of acute respiratory infections in infants and children but for less than 1% of respiratory illnesses in adults. Swyer-James-MacLeod syndrome is considered to be a post-infectious bronchiolitis obliterans (BO) secondary to adenovirus infection in childhood.
Except for 2 patients who showed no symptoms, six among 26 patients showed clinical deterioration during the hospitalization and needed supplemental oxygen therapy (Supplementary Fig. 2). The others showed little limitation in daily activity during the hospitalization.
While neutrophilia or neutropenia was not common regardless of clinical severity (Fig. 1A and B), lymphopenia (defined as ≤ 1.0 × 109/L) was more common in severe cases (33.3%, 2/6) than mild cases (18.2%, 4/22) during the clinical course (Fig. 1C and D). High levels of C-reactive protein in the blood were more frequently observed in severe cases (Fig. 1E and F) as the clinical course became worse during the 5–7 day period after symptom onset.
We could evaluate viral kinetics by serial RT-PCR of respiratory specimens from 9 patients from the early course of illness. Viral shedding from upper respiratory tract (URT) and lower respiratory tract (LRT) was shown in Fig. 2A and B as cycle threshold (Ct) value, respectively (Supplementary Table 1). Viral shedding was high during the first 5 days of illness and higher in URT than LRT. It decreased after day 7 of illness.
Infiltration on initial chest X-ray was observed in 13 patients (46.4%), but pneumonia was confirmed in most patients who underwent computed tomography (CT) scan initially (16/18, 88.9%) (Table 1). The chest radiographic scores remained relatively stable during the first week of illness. However, around day 7 of illness, the scores began to increase in some patients, suggesting progression of pneumonia (Fig. 2C).
Recently, a novel coronavirus has been identified in patients with severe acute respiratory illness. This new virus, provisionally referred to as novel coronavirus (NCoV) has been fully sequenced and shown to belong to group C β-coronaviruses. The genome, which is just over 30 KB, contains at least 10 predicted open reading frames (ORFs). The genome size, organization and sequence analysis revealed that the NCoV is most closely related to bat coronaviruses BtCoV-HKU4 and BtCoV-HKU5 first isolated in 2006 from bats captured in Hong Kong. The major difference between NCoV and these bat coronaviruses is in the region between the spike and the envelop genes. The NCoV has 5 ORFs while the bat viruses have 4 in this region. The nearest human coronavirus related to NCoV is SARS-CoV. This virus was responsible for the outbreak of severe acute respiratory syndrome in 2002–2003 which resulted in 8,422 cases worldwide with 916 deaths. With a mortality of approximately 11% seen with SARS-CoV infection, the identification of NCoV from patients with similar acute respiratory illness as with SARS-CoV is of a real concern. Coronaviruses are a large family of enveloped, single-stranded RNA viruses that infect a number of different species, including humans. They are usually species specific, however interspecies transmission of coronaviruses can occur. Worryingly, in vitro studies show that NCoV is also capable of infecting cells from different species, including monkeys, humans, bats and pigs. Indeed, NCoV was first isolated using monkey kidney epithelial cell lines, Vero and LLC-MK20, both of which are susceptible to infection and can propagate the virus relatively easily. Prior to the isolation of NCoV, only five coronaviruses, namely 229E, OC43, SARS-CoV, HKU1 and NL63, were known to cause infections in humans. In the absence of any underlying co-morbidities, all of these coronaviruses, except for SARS-CoV, are generally associated with mild upper respiratory tract infections. SARS-CoV has an unusual predilection for infecting cells in the lower respiratory tract. Although NCoV also causes lower respiratory tract infection, the viral receptor appears to be different from that used by SARS-CoV.
Starting from the December 2019 identification of the 2019 novel coronavirus (2019-nCoV), an overwhelming sense of panic has enveloped public discourse. This is likely to be amplified by WHO recently declaring the novel coronavirus outbreak a public health emergency of international concern. It is the third significant occurrence of a zoonotic coronavirus crossing the species barrier to infect humans, and it likely will not be the last. Hope is not lost; and a measured approach, one that is cognizant of the seriousness of this public health crisis without giving into hysteria, is imperative.
The coronavirus was identified in a wet food market in Wuhan, China, and has been the subject of a robust public health response by both Chinese authorities and the international community ever since. While debates about the primary reservoir of the virus are still ongoing, the virus is closely related to several bat corona-viruses. Coronaviruses (CoV) are positive-sense, single-stranded RNA viruses, possessing the largest viral RNA genome known to-date. They are known for their rapid spread, unpredictable emergence, and their threat to human health, magnified by the wide range of animal reservoirs and the lack of preventive or curative treatments [1, 2, 3, 4].
The 2019-nCoV is a beta-CoV similar in sequence (80%) with the severe acute respiratory syndrome coronavirus (SARS-CoV), the coronavirus strain implicated in the 2002 SARS outbreak, but even more closely related to several bat coronaviruses. Bats were also identified as the primary reservoir for SARS-CoV, although coronaviruses are found in many species. The Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic CoV responsible for the 2012 MERS outbreak, has been transmitted through contact with camels, although with a different human tropism. The novel coronavirus is believed to infect human cells through its interaction with the human angiotensin-converting enzyme 2 (ACE2) receptor, similarly to SARS-CoV. Despite the differences between the SARS, MERS and novel coronavirus, the similarities within the beta-CoV genus allow us to extrapolate from our previous experience with corona-virus outbreaks and increase our understanding of the current one.
The infection affects patients with and without underlying diseases, although the majority of the fatalities are older patients or patients with significant comorbidities. The vast majority of reported cases have been in adults, decreasing our ability to draw inferences and make recommendations for pediatric patients. Despite its apparent increased infectivity (R0=2.2) the 2019-nCoV strain appears to be less virulent than SARS-CoV (case-fatality rate=9.5%) and MERS-CoV (case-fatality rate=34.4%); currently reported case-fatality rate of 2019-nCoV is 2.2% [3, 4]. Superspreaders (R0>10) have been identified in both MERS-CoV and SARS-CoV outbreaks and there are similar reports of 2019-nCoV superspreaders. One should be mindful of the possibility of systematic underreporting in our current dataset, but the numbers represent our best estimates as of January 31, 2020, 02:30 GMT. (For updated information see: https://tinyurl.com/Hopkin-sCSSE)
Recent case reports of human to human transmission, including in patients who have not visited Wuhan, are concerning but not surprising. Transmission is believed to occur only after symptoms of lower respiratory tract infections present, due to its tropism for intrapulmonary epithelial cells. A crucial lesson learned from our experience with SARS-CoV and MERS-CoV is that community transmission occurs primarily through large droplets, not aerosols. Transmission is also to a large degree nosocomial, which is why a measured approach, one that prevents overutilization of medical resources and panic in the general population.
From an infection-control perspective, medical professionals should exercise droplet and contact precautions, as well as airborne precautions when performing procedures that generate aerosols (i.e. endotracheal suctioning, intubation) in patients suspected of having 2019-nCoV. From a public-health perspective, patients presenting with acute respiratory illness require screening according to the WHO criteria. Patients suspected of being infected with 2019-nCoV should be managed according to governmental protocols. Patients who do not meet the criteria are unlikely to be infected with 2019-nCoV. Patients with acute respiratory illness, without positive WHO criteria, should not have their management changed solely based on unspecific symptoms. For patients without exposure to the virus, the immediate health risk is low; this should be communicated to both providers and patients.
Patients infected with 2019-nCoV typically present with symptoms indicative of viral pneumonia such as fever, cough, fatigue, and dyspnea. This is similar to the Middle East respiratory syndrome corona-virus (MERS-CoV) and the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreaks. Patients typically exhibit radiographic findings of bilateral multiple lobular and subsegmental consolidations, progressing to ground-glass opacities on chest CT images. Secondary complications of 2019-nCoV include acute respiratory distress syndrome (ARDS), RNAemia (viremia), acute cardiac injury as well as secondary infections, with 23% requiring admission to the intensive care unit.
The competent critical care provider should not fear 2019-nCoV. While this is a new, incompletely understood strain, its management remains similar to previous CoV outbreaks. Patients may present with clinical pictures including uncomplicated respiratory infections, pneumonia, ARDS, sepsis or septic shock. Despite 2019-nCoV being a viral infection, patients meeting sepsis criteria should receive the customary treatment, including early initiation of broad-spectrum antibiotic therapy, due to the potential of secondary infections. The usage of corticosteroids for viral pneumonia or ARDS is discouraged in patients suspected of having 2019-nCoV unless otherwise indicated. With that being said, our current guidance is interim and good clinical judgment is still necessary when managing patients with 2019-nCoV. While 2019-nCV is novel, coronaviruses are not and the general principles of managing viral pneumonia still apply. Both local reporting guidelines, as well as WHO guidance on the management of 2019-nCoV, will continue to evolve as we better understand the outbreak.
Is the novel coronavirus the crown-jewel of pandemics? No. It is a serious infectious disease, but not one that is incredibly unusual. In the recent past, we have managed SARS, MERS, Ebola, and Zika. Our scientific community is prepared and vigilant, which is evidenced in the incredibly fast response to the current outbreak. This is also not the last time we will hear about coronaviruses. They have a significant infectivity potential, and more scientific resources should be devoted to understanding and reducing the severity of future outbreaks. However, due to our experience with managing coronaviruses outbreaks in the past, we are well prepared to tackle the current one. Despite the high infectivity, the case-fatality rate remains low; state governments and the WHO are implementing the necessary measures to reduce the spread of the infection.
An increasing number of cases evidenced the 2019-nCoV have the ability to transmit among humans [13, 14]. To date, no research found the special susceptible population of the new virus seems like SARS, 2019-nCoV is easily transmissible in human generally, but disease severity is not correlated to transmission efficiency. According to the Chinese Center for Disease Control and Prevention (China CDC) reported that laboratory tests ruled out SARS-CoV, MERS-CoV, influenza, avian influenza, adenovirus and other common respiratory pathogens. CDC considered the 2019-nCoV as a possible pathogen causing the outbreak. The 2019-nCoV can cause severe illness in old patients with comorbidities and transmit readily among people. At present, the mortality of 2019-nCoV in China is 2.3%, compared with 9.6% of SARS and 34.4% of MERS reported by WHO [16, 18]. Based on the current data, the new virus is not as fatally as many people thought.
The climate of temperature, relative humidity, and wind velocity should also be attention to the transmission. 2019-nCoV pneumonia emerging attacks in the cold seasonal nature akin to viruses such as SARS and influenza.
During the hospitalization, six patients (21.4%) required oxygen supplement therapy: four with nasal cannula and two with face mask. No one required mechanical ventilator or ECMO therapy. Nineteen patients (67.9%) received lopinavir/ritonavir for antiviral therapy. Ultimately, pneumonia was present in 22 patients (78.5%) and the proportion of pneumonia was 91.3% (21/23) among the patients who received a CT scan (Table 2). Seventeen patients (60.7%) developed fever and became afebrile during the hospitalization and the median day of defervescence was 9 days (range, 3–18) after symptom onset (Supplementary Fig. 1). By February 17, 10 patients were off isolation or discharged, and the median day of off-isolation/discharge was 18.5 days after symptom onset (range, 11–27).
On 29 December 2019, the first four cases of an acute respiratory syndrome of unknown etiology were reported in Wuhan City, Hubei Province, China among people linked to a local seafood market (“wet market”). Research is underway to understand more about transmissibility, severity, and other features associated with COVID-19. It appears that most of the early cases had some sort of contact history with the original seafood market [2, 12–14]. Soon, a secondary source of infection was found to be human-to-human transmission via close contact. There was an increase of infected people with no history of exposure to wildlife or visiting Wuhan, and multiple cases of infection were detected among medical professionals [2, 14–17]. It became clear that the COVID-19 infection occurs through exposure to the virus, and both the immunosuppressed and normal population appear susceptible. Some studies have reported an age distribution of adult patients between 25 and 89 years old. Most adult patients were between 35 and 55 years old, and there were fewer identified cases among children and infants [14, 18]. A study on early transmission dynamics of the virus reported the median age of patients to be 59 years, ranging from 15 to 89 years, with the majority (59%) being male. It was suggested that the population most at risk may be people with poor immune function such as older people and those with renal and hepatic dysfunction.
The COVID-19 has been found to have higher levels of transmissibility and pandemic risk than the SARS-CoV, as the effective reproductive number (R) of COVID-19 (2.9) is estimated to be higher than the reported effective reproduction number (R) of SARS (1.77) at this early stage. Different studies of COVID-19 have estimated the basic reproduction (R0) range to be from 2.6 to 4.71 (Table 4). The average incubation duration of COVID-19 was estimated to be 4.8 ± 2.6, ranging from 2 to 11 days and 5.2 days (95% confidence interval, 4.1 to 7). The latest guidelines from Chinese health authorities stated an average incubation duration of 7 days, ranging from 2 to 14 days. Table 4 summarizes the findings on important indicators from these epidemiological studies.
In China, 11 791 cases were confirmed and 17 988 cases were suspected in 34 provinces as of 24:00, 31 January 2020 (Fig. 4). Studies indicated that the spread of COVID-19 was relatively quick and reported that it had spread to several other countries after its outbreak in China. On 31 January 2020, there were 213 deaths reported globally. Confirmed cases were reported in the following 19 countries outside of China: Australia (9), Canada (3), Cambodia (1), France (6), Finland (1), Germany (5), India (1), Italy (2), Japan (14), Nepal (1), Malaysia (8), the Philippines (1), the Republic of Korea (11), Singapore (13), Sri Lanka (1), Thailand (14), the United States of America (6), United Arab Emirates (4) and Vietnam (5) (Fig. 5).
On 31 December 2019, Wuhan Municipal Health Commission reported a number of unknown pneumonia cases related to Huanan Seafood Wholesale Market, 27 cases were hospitalized, seven of which were in serious condition. On 5 February 2020, Wuhan Municipal Health Committee reported that 59 cases of viral pneumonia with unknown etiology were detected in Wuhan, including seven severe cases, but no clear evidence was found for “human-to-human” transmission. On Jan 11, Wuhan Municipal Health Committee issued a new report confirming that the pathogen of the viral pneumonia of unknown cause was initially determined as a new coronavirus. On 20 February 2020, it was officially confirmed that “human-to-human” transmission and nosocomial infection had occurred.
Since 16 February 2020, the cumulative COVID-19 case number increased quickly; meanwhile, the daily emerging case number increased steadily to 3886 on 4 February 2020, and then fluctuated to 2015 on 11 February 2020. The fatality cases number increased steadily to 2004 cases on 18 February 2020. The cumulative and daily emerged cases number jumped to 59,804 and 15,152, respectively, on 12 February 2020 (Figure 1). This fierce growth of cumulative and daily emerged cases number in one day is due to the improvement of diagnosis standard for confirmed cases in Hubei province, in which the suspected cases with pneumonia imaging characteristics are categorized as clinical diagnosis cases. As a result, the patients can receive standard treatment as soon as possible. All data are from the National Health Commission of the People’s Republic of China.
The COVID-19 resulted in much lower mortality (about 2.67% up-to-date) among the confirmed cases, compared with Severe Acute Respiratory Syndrome (SARS) at 9.60% (November 2002–July 2003) and Middle East Respiratory Syndrome (MERS) at 34.4% (April 2012–November 2019) (Table 1). The median ages for the patients of COVID-19, SARS, and MERS are 55.5, 41.3, and 52.8 years old, respectively. COVID-19 and MERS patients share similargender composition of females (32%) and males (67%), but SARS patients show almost the same proportion of males (46.9%) and females (53.1%).
According to the “Diagnosis &Treatment Scheme for Novel Corona Virus Pneumonia (Trial) 6th Edition”, the source of infection is majorly the COVID-19 patients, even the asymptomatic patients can also be the source of infection. The transmission way is majorly through respiratory droplets and contacting. People are generally susceptible to this virus.
In 2003, the Chinese population was infected with a virus causing Severe Acute Respiratory Syndrome (SARS) in Guangdong province. The virus was confirmed as a member of the Beta-coronavirus subgroup and was named SARS-CoV,. The infected patients exhibited pneumonia symptoms with a diffused alveolar injury which lead to acute respiratory distress syndrome (ARDS). SARS initially emerged in Guangdong, China and then spread rapidly around the globe with more than 8000 infected persons and 776 deceases. A decade later in 2012, a couple of Saudi Arabian nationals were diagnosed to be infected with another coronavirus. The detected virus was confirmed as a member of coronaviruses and named as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The World health organization reported that MERS-coronavirus infected more than 2428 individuals and 838 deaths. MERS-CoV is a member beta-coronavirus subgroup and phylogenetically diverse from other human-CoV. The infection of MERS-CoV initiates from a mild upper respiratory injury while progression leads to severe respiratory disease. Similar to SARS-coronavirus, patients infected with MERS-coronavirus suffer pneumonia, followed by ARDS and renal failure.
Recently, by the end of 2019, WHO was informed by the Chinese government about several cases of pneumonia with unfamiliar etiology. The outbreak was initiated from the Hunan seafood market in Wuhan city of China and rapidly infected more than 50 peoples. The live animals are frequently sold at the Hunan seafood market such as bats, frogs, snakes, birds, marmots and rabbits. On 12 January 2020, the National Health Commission of China released further details about the epidemic, suggested viral pneumonia. From the sequence-based analysis of isolates from the patients, the virus was identified as a novel coronavirus. Moreover, the genetic sequence was also provided for the diagnosis of viral infection. Initially, it was suggested that the patients infected with Wuhan coronavirus induced pneumonia in China may have visited the seafood market where live animals were sold or may have used infected animals or birds as a source of food. However, further investigations revealed that some individuals contracted the infection even with no record of visiting the seafood market. These observations indicated a human to the human spreading capability of this virus, which was subsequently reported in more than 100 countries in the world. The human to the human spreading of the virus occurs due to close contact with an infected person, exposed to coughing, sneezing, respiratory droplets or aerosols. These aerosols can penetrate the human body (lungs) via inhalation through the nose or mouth (Fig. 2),,,.
Q fever, caused by C. burnettii, is a worldwide zoonotic disease. Outbreaks in humans have been linked to abattoirs and carriage of C. burnettii by wind from farms of affected animals. Ticks can also act as a reservoir. It is not strictly a travel-related illness but it is most likely found in areas where contamination with animal waste is common. It presents as an acute febrile illness with non-specific signs such as atypical pneumonia. Rural travelling is the greatest risk factor for acquiring the disease. Most recently, Q fever outbreaks have occurred in Hungary, where 70 cases were confirmed by micro-immunofluorescence testing and treated with 3 weeks of a tetracycline. No deaths occurred. Efforts to reduce the spread of Q fever after an outbreak include elimination of manure and disinfection of affected farms.
The 2015 outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in the Republic of Korea developed from a traveler returning from the Middle East,1 which is the largest outbreak outside of the Arabian Peninsula to date. This unprecedented nationwide outbreak resulted in 186 laboratory-confirmed cases with 38 fatalities and > 16,000 individuals being quarantined.234 During the outbreak, a comprehensive screening test including MERS-CoV real-time reverse transcription polymerase chain reaction (rRT-PCR) was performed in all possible contactors to prevent further spread of the disease. Positive MERS-CoV rRT-PCR findings were observed in patients with no or mild symptoms, who were also subjected to epidemiological investigation and follow-up.1
There have been many reports of long-term sequelae of severe acute respiratory syndrome (SARS),5678910 but to the best of our knowledge no report has addressed long-term sequelae in the follow-up of patients with MERS-CoV infection. The present study aimed to evaluate pulmonary function and radiological sequelae 1 year after MERS-CoV infection according to the severity of the infection.
In this nationwide cohort study the researchers tried to contact all survivors with laboratory-confirmed MERS-CoV infection during the outbreak by phone or mail. The patients who provided written informed consent were enrolled. The patients were followed up in five hospitals. The Institutional Review Board of each hospital approved the study protocol (National Medical Center, H-1510-059-007; Seoul National University Hospital, 1511-117-723; Seoul National University Boramae Medical Center, 26-2016-8; Seoul Medical Center, Seoul2015-12-102; Dankook University Hospital, DKUH2016-02-014; and Chungnam National University Hospital, CNUH2015-08-029).
The pulmonary function test, a standardized 6-minute walk test, and chest computed tomography (CT) were performed 1 year after MERS-CoV infection. The pulmonary function tests included total lung capacity (TLC), forced volume vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity of the lung for carbon monoxide (DLCO). All pulmonary function values were presented as predicted percentage considering age, sex, height, body weight, and race. Radiological sequelae were scored as the number of involved lung segments (total score = 19) on chest CT that were suspected to be post-inflammation sequelae, including sub-segmental atelectasis, ground glass opacity, and consolidation by a radiologist.10 Emphysema, sequelae of tuberculosis, and bronchiectasis were excluded. Severe pneumonia was defined as the patient requiring oxygen therapy, mild pneumonia was defined as the patient presenting with infiltration on chest X-ray but not requiring oxygen therapy, and no pneumonia was defined as the patient without radiographic evidence of pneumonia.11
Linear regression or linear by linear association was used to evaluate the association between the severity of pneumonia and continuous or categorical variables, as appropriate. The correlation between pneumonia severity and pulmonary function or radiological sequelae was evaluated using a multivariable linear regression model including age, sex, underlying lung diseases, and smoking. P < 0.05 was considered significant. IBM SPSS Statistics (version 22; IBM Corp., Armonk, NY, USA) was used for all statistical analyses.
Among a total of 146 survivors in the outbreak, 49 (34%) refused to participate in the study and 24 (16%) could not be contacted by any method. Therefore, 73 patients were enrolled in the study: 18 (25%) patients without pneumonia, 35 (48%) patients with mild pneumonia, and 20 (27%) patients with severe pneumonia. The mean patient age was 51 ± 13 years, 30 (41%) were female, and the severe pneumonia group tended to have more male patients (Table 1). Fourteen patients (19%) had a history of smoking and the patients with pneumonia were more likely to have a history of smoking. None of the underlying diseases were associated with the severity of pneumonia.
The frequency of patients with lung function parameters < 80% of predicted values was as follows: FVC (6/73, 8%), FEV1 (6/73, 8%), and DLCO (25/68, 37%). After adjusting for age, sex, underlying lung disease, and smoking, FVC and DLCO significantly correlated with the severity of pneumonia (P = 0.008 and P = 0.046; Table 2). The patients with severe pneumonia had lower FVC and DLCO than the patients with no or mild pneumonia (Fig. 1). TLC, FEV1, FEV1/FVC, and the walking distance in the 6-minute walk test were not significantly associated with the severity of pneumonia.
CT was performed 1 year after MERS-CoV infection in 65 (89%) patients. Radiological sequelae were revealed in 25% (4/16), 63% (19/30), and 95% (18/19) of patients in the no, mild, and severe pneumonia groups, respectively (P < 0.001). The median radiological sequelae score was 0, 1, and 3 in the no, mild, and severe pneumonia groups, respectively, and the radiological sequelae scores were significantly correlated with the severity of pneumonia (P < 0.001, Table 2).
This is the first cohort study showing long-term pulmonary complications of MERS-CoV infection. The findings suggest that more severe MERS pneumonia can result in more impaired lung function at least 1 year after MERS-CoV infection. These findings were compatible with radiological sequelae.
Several studies have examined the effect of SARS on pulmonary function 1 year after infection.5,10,12 A previous study showed that 24% of SARS survivors have impaired DLCO and 5% reduced lung volume at 12 months.5 Several studies on acute respiratory distress syndrome survivors showed that their pulmonary function usually returns to normal or near normal by 6–12 months,13,14 but a mild reduction of DLCO may persist in up to 80% of patients at 1 year after recovery.15 These findings were very similar to the results of the present study. We also showed that 37% of MERS survivors have impaired DLCO at 12 months, whereas only 8% of patients had a reduced FVC.
The Korean MERS outbreak in 2015 occurred in a hospital setting, and most patients with MERS had been admitted before the outbreak, though one-fourth of patients were healthcare providers.16 Thus, a comparison of lung function and exercise capacity between these MERS survivors and the general healthy population may mislead the results, as the underlying lung condition before MERS-CoV infection could impact lung function after illness. For this reason, we compared lung function according to the severity of pneumonia in order to evaluate the effect of MERS-CoV infection on pulmonary function. The finding that more severe MERS pneumonia resulted in more impaired lung function strongly suggests that pulmonary sequelae can remain at least 1 year after MERS-CoV pneumonia, which is also supported by the correlation of radiological sequela correlated with the severity of MERS pneumonia.
The previous study found that SARS survivors who required intensive care unit admission had lower predicted FVC and DLCO than those who did not, but there were no differences in the 6-minute walking test.5,12 These findings were also compatible with our results, which showed that severe pneumonia requiring oxygen therapy is associated with more impaired lung function, but there was no difference in exercise capacity.
The present study has several limitations. First, the patients with underlying lung diseases and impaired lung function may have more severe MERS pneumonia. The patients with severe pneumonia had more underlying lung diseases, though the difference was not significant. However, even after adjusting for underlying lung diseases and smoking, the correlation between the MERS pneumonia severity and lung function impairment was significant. Second, because we defined pneumonia as infiltration on chest X-ray, we may classify a patient with mild pneumonia in the group without pneumonia. In fact, radiological sequelae on chest CT was observed in approximately 25% of the patients without pneumonia. Third, only 50% of the eligible MERS-CoV infected survivors were enrolled, which may not represent all of the MERS-CoV survivors in Korea. Forth, no baseline pulmonary function or CT scans were not available. Lastly, our definition of severe pneumonia as requirement of oxygen therapy may be broad and subjective. Ventilator care or mortality may indicate the patients with more severe pneumonia, although small number of patients hampered further classification in this study.
In summary, patients with more severe MERS-CoV pneumonia may have more impaired pulmonary function at 1 year, which is compatible with the radiological sequelae.
In West China Hospital of Sichuan University at Chengdu, one of the top hospitals in China, we found that infections caused by human coronaviruses (HCoVs) have a seasonal pattern that varies among age groups (Fig. 2). Winter and spring are associated with the highest incidence of coronavirus epidemics, which is consistent with the current epidemic of 2019-nCoV. In this sense, the particularities of 2019-nCoV incidence should not be overemphasized.
To date, seven strains of coronaviruses have been confirmed to infect humans: HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, Human coronavirus HKU1, MERS-CoV, and 2019-nCoV.1,3 Since HCoV-229 and HCoV-OC43 were identified in 1966 and 1967, respectively,8,9 the coronaviruses have been known to cause mild-to-severe respiratory disease. In the SARS-CoV epidemic in 2002 and 2003, more than 8000 people were infected and 916 died.10 Subsequently, by 28 February 2018, 2066 confirmed cases were attributed to MERS-CoV while more than 720 deaths were reported.10
Patients with SARS or MERS infections present with a spectrum of symptoms ranging from upper respiratory tract infection to ARDS, whereas other HCoVs cause severe lower respiratory tract infection, primarily in the elderly and neonates.10
Currently, the most common diagnostic method of coronaviruses is molecular detection.10 A precision medicine approach is crucial to quickly confirm the diagnosis with laboratory methods, control the spread of the virus, and better allocate hospital resources.
Pertussis and diphtheria are vaccine-preventable pulmonary infections; poor vaccine uptake has led to a recent increase in cases in developed countries. It is important, therefore, to take a full vaccination history in returned travellers who present with pulmonary symptoms.
Pertussis is a worldwide endemic-epidemic disease with outbreaks most likely during summer/autumn time. Pertussis is thought to still cause around 63,000 deaths per year in children under 5 years of age, although there is uncertainty over these estimates in view of the paucity of reliable surveillance data.
Recently, there has been an increase in the number of adolescent and young adults being diagnosed in some high-income countries, likely due to decreased vaccination uptake rates and a change in the vaccine itself. It is thought that the acellular vaccine currently used appears to have a short-lived immunity leading to increased infection rates. Macrolide antibiotics are given to affected individuals to prevent further spread of pertussis.
Diphtheria presents as an acute infectious disease affecting the upper pulmonary tract caused by toxins produced by the bacterium. Characteristic features are membranous pharyngitis with fever, enlarged anterior cervical lymph nodes and edema of the soft tissues of the neck. This manifestation may lead to airway obstruction. The bacterium has a short incubation period but untreated individuals may remain infectious for up to 4 weeks. Both pertussis and diphtheria are potentially fatal but easily preventable.
Treatment principle: based on symptomatic treatment, actively prevent and treat complications, treat basic diseases, prevent secondary infection, and timely apply organ function support.Respiratory support: apply noninvasive mechanical ventilation for two hours, if the condition is not improved, or the patient is intolerable to noninvasive ventilation, accompanied with increased airway secretions, severe coughing, or unstable hemodynamics, the patient should be transferred to invasive mechanical ventilation in time. The “lung-protective ventilation strategy” with low tidal volume should be adopted in invasive mechanical ventilation to reduce ventilator-associated lung injury. If necessary, ventilation in the prone position, recruitment maneuver, or extracorporeal membrane oxygenation (ECMO) can be used.Circulation support: improve microcirculation based on full fluid resuscitation, use vasoactive drugs, and apply hemodynamic monitoring if necessary.Others: according to the degree of dyspnea and the progress of chest imaging, use glucocorticoids appropriately for a short time (3–5 days) with the recommended dose no more than what is equivalent to methylprednisolone 1–2 mg/kg·day.
Similar to other human coronaviruses, HCoV-HKU1 is associated with both upper and lower respiratory tract infections. Respiratory tract infections associated with HCoV-HKU1 are indistinguishable from those associated with other respiratory viruses. For upper respiratory tract infections, most patients present with fever, running nose and cough; while for lower respiratory tract infections, fever, productive cough and dyspnea are common presenting symptoms. Most HCoVHKU1 infections are self-limiting, with only two deaths reported in patients with HCoV-HKU1 pneumonia. Both had underlying diabetes mellitus, cardiovascular diseases (myocardial infarction in one and cerebrovascular accident in the other) and cancers (gastric lymphoma in one and prostatic carcinoma in the other), lymphopenia and airspace shadows in both lungs. Interestingly, a recent study from rural Thailand that involved control patients showed the presence of human coronaviruses in >2% of control patients, which raised questions about the role of human coronaviruses in pneumonia. At the moment, no antiviral drugs or vaccines for HCoV-HKU1 and the other human coronaviruses are available. Symptomatic and supportive treatment is the mainstay of therapy given to patients suffering from infections caused by these viruses.
In addition to respiratory tract infections, HCoV-HKU1 has been found in other illnesses. In our one-year prospective study, it was observed that HCoV-HKU1 infection was associated with febrile seizures. On the other hand, in another French study, although six (17.6%) of the 34 HCoV-HKU1 infected children were admitted for epileptic seizures, HCoV-HKU1 infections were not shown to be associated with febrile seizures. In one study, HCoV-HKU1 was detected in the stool samples of two patients with respiratory tract infections but no gastrointestinal tract symptoms, but it was not detected in patients with diarrhea. In another study, HCoV-HKU1 was detected in a liver transplant recipient with hepatitis, which other causes of hepatitis, such as graft rejection, cytomegalovirus, etc. were excluded. The significance of HCoV-HKU1 febrile seizures, gastroenteritis and hepatitis remains to be determined.
Coronaviruses belong to the Coronaviridae family in the Nidovirales order. Corona represents crown-like spikes on the outer surface of the virus; thus, it was named as a coronavirus. Coronaviruses are minute in size (65–125 nm in diameter) and contain a single-stranded RNA as a nucleic material, size ranging from 26 to 32kbs in length (Fig. 1). The subgroups of coronaviruses family are alpha (α), beta (β), gamma (γ) and delta (δ) coronavirus. The severe acute respiratory syndrome coronavirus (SARS-CoV), H5N1 influenza A, H1N1 2009 and Middle East respiratory syndrome coronavirus (MERS-CoV) cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) which leads to pulmonary failure and result in fatality. These viruses were thought to infect only animals until the world witnessed a severe acute respiratory syndrome (SARS) outbreak caused by SARS-CoV, 2002 in Guangdong, China. Only a decade later, another pathogenic coronavirus, known as Middle East respiratory syndrome coronavirus (MERS-CoV) caused an endemic in Middle Eastern countries.
Recently at the end of 2019, Wuhan an emerging business hub of China experienced an outbreak of a novel coronavirus that killed more than eighteen hundred and infected over seventy thousand individuals within the first fifty days of the epidemic. This virus was reported to be a member of the β group of coronaviruses. The novel virus was named as Wuhan coronavirus or 2019 novel coronavirus (2019-nCov) by the Chinese researchers. The International Committee on Taxonomy of Viruses (ICTV) named the virus as SARS-CoV-2 and the disease as COVID-19,,. In the history, SRAS-CoV (2003) infected 8098 individuals with mortality rate of 9%, across 26 contries in the world, on the other hand, novel corona virus (2019) infected 120,000 induviduals with mortality rate of 2.9%, across 109 countries, till date of this writing. It shows that the transmission rate of SARS-CoV-2 is higher than SRAS-CoV and the reason could be genetic recombination event at S protein in the RBD region of SARS-CoV-2 may have enhanced its transmission ability. In this review article, we discuss the origination of human coronaviruses briefly. We further discuss the associated infectiousness and biological features of SARS and MERS with a special focus on COVID-19.