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Viral infections of the upper and lower respiratory tract are among the most common illness in humans. Children and infants bear the major burden of infection, typically presenting with 5 to 6 episodes annually. These infections are often associated with significant patient morbidity and related mortality. For this reason, URTIs and LRTIs represents the leading cause of death in children younger than five years of age worldwide; this accounts for approximately 4 million deaths annually. Acute respiratory tract disease is the leading cause of hospitalization in children and febrile episodes in infants younger than three months of age.
Bacteria only represent approximately 10% of all upper respiratory tract infections with the subsequent 90% of infections caused by respiratory viruses. Despite the viral aetiological origin of most respiratory infections, antibiotics are often prescribed in the treatment of such diseases, exacerbating antibiotic abuse. The morbidity and fiscal implications associated with respiratory infections are significant, with approximately 500 million cases reported in the United States alone each year with subsequent direct and indirect costs to the US economy estimated at $40 billion annually. The burden of respiratory tract infections is increased in patients with chronic comorbidities or clinical risk factors including asthma, chronic obstructive pulmonary disease (COPD), young, elderly and immunocompromised.
The viruses primarily associated with upper respiratory tract infections commonly include rhinoviruses, enteroviruses, adenoviruses, parainfluenza viruses (PIV), influenza viruses, respiratory syncytial viruses (RSV) and coronaviruses. In recent years six new human respiratory viruses have been reported including human metapneumovirus (hMPV), bocavirus and four new human coronaviruses including Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63), HCoV-HKU1 and Middle East Respiratory Syndrome coronavirus (MERS-CoV). This review will detail these newly discovered and emerging respiratory viruses.
The median incubation period for human-to-human transmission is approximately 5 d (range 1.9–14.7 d). The median time from onset of MERS to hospitalization is approximately 4 d. The median time from onset of illness to ICU admission is approximately 5 d. The median onset to death is approximately 12 d. The median duration of mechanical ventilation is 16 d and the median duration of an ICU stay is 30 d. The mortality for MERS patients in the ICU for 90 d is 58%.5,17,18
Patients with MERS present as an influenza-like illness (ILI). SARS and MERS have some features in common, i.e., fever with chills, headache, and dry cough, but SARS was a biphasic illness, and not an ILI.5 Some patients are asymptomatic or present with mild respiratory symptoms without fever or diarrhea before developing MERS.19 Typically, MERS rapidly progresses to viral pneumonia about a week after the onset of the infection. As with influenza, some patients report a sore throat. The chest radiograph is abnormal in patients ill enough to be hospitalized. A unilateral basilar infiltrate is common initially resembling a lobar/segmental bacterial pneumonia. More commonly, MERS presents with bilateral interstitial infiltrates which may be somewhat ovoid or nodular in appearance.5 Small pleural effusions are not uncommon. Consolidation may occur but cavitation is not a feature of MERS pneumonia.17 Bacterial co-infection does not occur with MERS.15 Patients rapidly progress to ARDS (small lung volumes without cardiomegaly) with severe hypoxemia and bilateral interstitial infiltrates as with severe pandemic influenza (H1N1) or severe avian influenza (H7N9). Death is from hypoxemia from acute respiratory failure and or ARDS. As with any patient intubated with respiratory failure on prolonged ventilatory support, nosocomial pneumonia (not co-infection) may complicate MERS.5
Non-specific laboratory tests with MERS include leukopenia, relative lymphopenia, and thrombocytopenia. Thrombocytopenia occurs less frequently than in influenza pneumonia where it is a near universal finding in hospitalized adults. Serum transaminases are often mildly to moderately elevated in hospitalized patients with MERS. MERS-CoV is present in blood, urine, and feces, but the diagnosis is made by demonstrating the SARS-CoV in lower respiratory secretions by RT PCR. In hospitalized patients with severe viral pneumonia, the likelihood of recovery of MERS is highest in lower respiratory tract specimen secretions rather than nasal swabs.5,17,18 Without a travel history linking the patient to the Arabian peninsula or a known MERS case, the clinical presentation may be indistinguishable from other severe viral pneumonias.17 The clinical feature which distinguishes MERS from influenza is the relatively high frequency of renal involvement, i.e., renal failure with MERS5,14-16 (Table 1).
Interferon-α 2b and ribavirin reduce coronavirus replication and moderates the host’s immune response in experimental studies in monkeys, but there is no definitive treatment for MERS in humans.21,22 Therapy is supportive and may require mechanical ventilation or extra-corporal membrane oxygenation (ECMO).
Symptomatic differentiation between hMPV and other respiratory viruses cannot be made as there is a significant overlap in clinical presentation. The most common presentation of hMPV in children includes complications of the upper respiratory tract with rhinorrhoea, cough and fever. Acute otitis media is also frequently reported and conjunctivitis, rash, diarrhea and vomiting are reported but infrequently. Bronchiolitis, pneumonia, croup and asthmatic exacerbations are the most frequently associated lower respiratory tract complications and viral load is directly associated with disease severity. hMPV infection in the young and elderly frequently requires hospitalization and fatalities have been reported in the elderly. An increased morbidity in elderly patients with a delayed clearance of symptoms has been reported and is likely related to the age related impairment of the innate and adaptive immunity or an over stimulated immune response leading to inflammation. Elderly patients requiring hospitalization most frequently present with acute bronchitis, COPD exacerbations, pneumonia and congestive heart failure. In healthy adults asymptomatic infections or cold- and flu-like symptoms are the most prevalent presentation.
Metapneumovirus was first recognized in 2001 in the Netherlands from nasopharyngeal aspirates collected during a 20-year period in 28 hospitalized children and infants with acute respiratory tract infection (RTI) having signs and symptoms similar to that of RSV infection. The virus genomic sequence was identified by using a randomly primed PCR protocol and revealed to be closely related to the avian pneumovirus, a member of the Metapneumovirus genus, in the Paramixoviridae family, Initial studies following the first hMPV identification indicate that it causes upper and lower RTIs in patients of all ages, but mostly in children aged below 5 years. A large epidemiological retrospective study examined nasal washes collected over a 20-year period during acute respiratory illnesses in an outpatient cohort of children. Over the entire study period, hMPV was detected in 1%-5% of pediatric upper RTIs (UTRIs), with variation from year to year. Several reports indicate that hMPV is a commonly identified cause of pediatric lower RTIs, and is second only to RSV as cause of bronchiolitis in early childhood. While bronchiolitis, is the most common presentation of hMPV illness, other reported syndromes have included asthma exacerbation, otitis media, flulike illness, and community-acquired pneumonia. Several studies have found hMPV –RSV co-infection rates of approximately 5-14%. Nevertheless, in a study conducted in the Netherlands in children admitted to hospital for lower RTIs (LRTIs), no virus co-infection between RSV and hMPV was detected. Different controversial reports suggest an association between RSV-hMPV coinfection and an increase in the disease severity or the absence of an association between dual infection and disease severity. Greensill and colleagues reported a 70% rate of co-infection with hMPV in a cohort of infants with critical RSV bronchiolitis who required intensive care in the United Kingdom, suggesting that dual infection with RSV and hMPV may predispose for a more severe disease. In another study from the United Kingdom, hMPV and RSV co-infection was associated with increased disease severity and higher risk of admission to the pediatric intensive care unit. Similar findings are supported by other studies suggesting that in young children, coinfections with RSV and hMPV are more severe than infections with either RSV or hMPV alone, requiring a longer hospitalization and supplemental oxygenation. However, such synergistic association has not been found in other population-based and case–control studies of hospitalized children. In particular, two studies evaluated the epidemiology of hMPV coinfection in children with LRTI caused by RSV and demonstrated no hMPV and RSV co-infection in mechanically ventilated children suggesting that co-infection with hMPV is not associated with a more severe course of RSV-LRTI. In addition, in a prospective 2-year study in hospitalized infants with acute respiratory diseases, the role of RSV as a major respiratory pathogen was not influenced by the co-circulation of other emerging viral agents with similar seasonal distribution. In particular, RSV-hMPVs co-infections were significantly observed in less severe respiratory disease when compared to unique RSV infections. The possible synergistic interaction between hMPV and the severe acute respiratory syndrome (SARS) coronavirus was also suggested during the 2003 SARS outbreak in Hong Kong and Canada. In one case report, in an infant with SARS CoV infection, fatal encephalitis was correlated with hMPV infection as hMPV RNA was detected post-mortem in brain and lung tissue. Nevertheless, in experimental studies performed in macaques, a synergy between hMPV and SARS was not confirmed. In addition, infections of hMPV with respiratory viruses different from RSV, have also been occasionally reported but no sufficient data are available to discuss epidemiology or association with clinical disease presentation (Table 1).
Following the discovery of SARS-CoV, other human coronaviruses, HCoV-NL63 and HCoV-HKU1, were identified and recognized to be common causes of community-acquired respiratory infections.
HCoV-NL63, a member of the group I coronaviruses, was first detected in 2004 in the Netherlands from a child with bronchiolitis by using a new method for virus discovery based on the cDNA-amplified restriction fragment−length polymorphism technique (cDNA-AFLP).
HCoV-HKU1, a group II coronavirus, was first detected in Hong Kong in 2005 from an adult patient with chronic pulmonary disease. All attempts to grow a virus from his respiratory secretions failed until recently, but coronavirus RNA was initially detected by RT-PCR using pol gene consensus primers.
Like other coronaviruses, NL63 and HKU1 can also be detected in individuals of all ages, including elderly patients with fatal outcome and those with underlying diseases of the respiratory tract. However most frequently, the newly discovered coronaviruses are reported in 7 to 12-month old children with both upper and lower RTIs. In studies conducted in children hospitalized with RTIs in China, from 2.6% to 3.8% of patients were positive for HCoV-NL63 and, in addition to causing upper respiratory disease, HCoV-NL63 was found in croup, asthma exacerbation, febrile seizures, wheezing and high fever cases. The occurrence of co-infection with NL63 and other respiratory viruses, including other human coronaviruses, RSV, PIV, influenza A and B viruses and hMPV has been reported. In a large study from Germany evaluating children under 3 years of age with LRTIs, most co-infections were with RSV-A, probably because of the high percentage of RSV-A infections and an overlap in seasonality. In addition, double infection of NL63 with RSV-B, and with PIV3 occurred in a minority of cases. HCoV-NL63 co-infection with RSV-A occurred predominantly in the hospitalised patients in contrast to HCoV-NL63 co-infections with PIV3 that were exclusively present in the outpatient group.
Following the first identification, HKU1 was found in respiratory samples from elderly patients and children mainly with underlying diseases. The most common symptoms are rhinorrhea, fever, and abdominal breath sounds, but pneumonia, bronchopneumonia, bronchiolitis, and acute asthma exacerbations were also described in children in China.
In a study aimed to evaluate the overall prevalence of 10 respiratory viruses in children with acute LRTIs in China from 2006 to 2009, 73.47% of the HCoV-HKU1 and HCoV-NL63-positive samples tested positive for at least one other virus, most commonly HRV and RSV. Similar data describing a high rate of coinfection of coronaviruses with RSV has also been previously reported. In a report from the UK both dual and single infections associated with respiratory outcomes were observed for HKU1 as well as for NL63 and OC43 coronaviruses. In this study a high number of coinfections was observed for HKU1, NL63 as well as for OC43, mostly with RSV. Similar rates of lower and upper infections were observed in single HKU1 or OC43 infection compared with coinfection, whereas both URTI and LRTI were observed more frequently in single compared to mixed infection with NL63. No differences in clinical outcome were observed between single and dual infections with RSV and Coronaviruses NL63, HKU1 or OC43 indicating that RSV may presumably facilitate coronavirus infection without increasing disease severity. However, in the same study considering viral load data, a role of these coronaviruses in coinfections in respiratory disease was suggested. In fact no differences were observed when coronavirus load was evaluated in single infection and in RSV coinfection, indicating both that infection with another respiratory virus does not affect the ability of NL63, HKU1 or OC43 to establish infection and replicate, and that detection of coronaviruses in mixed infection should not be considered a secondary infection without contribution to disease pathogenesis. This quantitative evaluation is in contrast with previous results obtained by van der Hoek and colleagues describing a significantly lower HCoV-NL63 viral load in patients coinfected with RSV or PIV3 than in patients infected with HCoV-NL63 alone. However, the prolonged persistence of HCoV-NL63 at low levels, the different time of sampling relative to the time of disease onset, or the use of different diagnostic technologies could have affected these evaluations (Table 1).
The symptoms of 2019-nCoV infection were nonspecific. The most common symptoms were onset of fever, generalized weakness and dry cough. Some patients had headache and/or myalgia, but upper respiratory symptoms such as runny nose were rare. Diarrhea was often identified, which had been reported 10.6% in SARS and up to 30% in MERS. More than half of patients developed shortness of breath, the median duration from disease onset to dyspnea was 8 days. Patients infected with 2019-nCoV might develop acute respiratory distress syndrome (ARDS), followed by septic shock, refractory metabolic acidosis and coagulation dysfunction, if the disease could not be controlled.
Notably, some patients were afebrile or confirmed biologically to have an asymptomatic infection. These cryptic cases of walking pneumonia might serve as a possible source to propagate the outbreak. Further studies on the epidemiological significance of these asymptomatic cases are warranted.
Escherichia coli accounts for 4% of cases of CAP and 5–20% of cases of HAP or HCAP. It occurs most commonly in debilitated patients. The typical history is one of abrupt onset of fever, chills, dyspnea, pleuritic pain, and productive cough in a patient with preexisting chronic disease.
The radiographic manifestations usually are those of bronchopneumonia; rarely a pattern of lobar pneumonia may be seen.
Primary infection with EBV occurs early in life and presents as infectious mononucleosis with the typical triad of fever, pharyngitis, and lymphadenopathy, often accompanied by splenomegaly. Mild, asymptomatic pneumonitis occurs in about 5–10% of cases of infectious mononucleosis. The CT manifestations of EBV pneumonia are similar to those of other viral pneumonias. The findings usually consist of lobar consolidation, diffuse and focal parenchymal haziness, irregular reticular opacities, and multiple miliary nodules or small nodules with associated areas of ground-glass attenuation (“halo”).
All of the cases had one thing in common: they suffered from severe respiratory illness which was not due to any of the known viral or bacterial causes. The most common initial symptoms were reported to be fever, cough and shortness of breath. Patients rapidly progressed to severe pneumonia and renal failure. The latter presentation has not been seen in all patients. For examples, none of the cases in the Jordanian cluster had renal failure. The two fatal cases in this cluster, one developed pericarditis and the other had disseminated intravascular coagulation. Coronaviruses predominantly cause mild self-limiting upper respiratory tract infections. The only other human coronavirus that is associated with severe lower respiratory infection is SARS-CoV. However, in contrast to SARS-CoV, this novel coronavirus does not appear to cause diarrhea. Of 12 laboratory confirmed cases, 6 have died and 1 is currently in ICU. This would imply a relatively high mortality rate. However, caution has to be exercised, since we do not know the true prevalence of infection with NCoV. It is possible that in some cases, the virus is associated with mild respiratory tract infection which goes unseen and only those patients who develop severe disease seek medical attention. It is also worth noting that all of laboratory confirmed cases have been adults.
Coronaviruses have worldwide distribution and previously were associated with mild upper respiratory tract infections, e.g., the common cold is caused by coronavirus types 229E and OC 43.1 From Guangdong Province in southern China in the fall of 2002, a new coronavirus emerged causing severe viral pneumonia, i.e., severe acute respiratory syndrome (SARS). This new coronavirus variant was termed SARS-CoV. The intermediate host of SARS-CoV was the masked palm civet cat.2 From China this new zoonotic viral pneumonia rapidly spread worldwide to 30 countries. In one year, 8273 SARS cases occurred with 774 deaths. In addition, the financial impact from limiting travel, tourism, disruption of trade and commerce, shifting of hospital services, quarantine of exposed patients and health care workers, and lost wages suffered from victims of SARS, isolation of patients suspected of carrying the contagious virus was enormous. Mutation of SARS-CoV surface spike proteins found in the coronavirus that usually circulates in the animal reservoir permitted binding to human ACE 2 receptors with a sudden switch in susceptible vertebrate hosts facilitating transmission to humans.1,2 As mysteriously as SARS appeared in 2002, it disappeared in the summer of 2003.
Nearly a decade following the SARS epidemic, a new coronavirus causing severe viral pneumonia in the Arabian peninsula has emerged, i.e., middle east respiratory syndrome (MERS). In June 2012, the index case of MERS-CoV occurred in Saudi Arabia.3,4 Since that time, according to the World Health Organization, there have been 688 confirmed cases and 282 deaths in 20 countries. Most cases have occurred in the Arabian peninsula, i.e., Saudi Arabia, United Arab Emirates, Qatar, Oman, Jordan, Kuwait and Lebanon. In addition, travel-related MERS cases have been reported from Europe (United Kingdom, Italy, Greece, Netherlands, France, and Germany) as well as Tunisia, Malaysia, Philippines, Egypt, and most recently Iran and the United States. The zoonotic vector and possible reservoir of MERS has been found to be dromedary camels, with bats as another possible vector for transmission to humans.5 Although both SARS and MERS are caused by coronaviruses, SARS was characterized by efficient human transmission and relatively low mortality rate while MERS is relatively inefficiently transmitted to humans but has a high mortality rate, i.e., 35–50%.6 In terms of virulence, MERS most closely resembles pandemic influenza (H1N1) and avian influenza (H7N9) not SARS, but MERS potential for widespread transmissibility is less than avian influenza (H7N9).
According to the “Diagnosis & Treatment Scheme for Novel Coronavirus Pneumonia (Trial) 6th Edition” enacted by the National Health Commission of the People’s Republic of China on 19 February 2020, the incubation time after exposure is about 1–14 days. Fever, fatigue, and a dry cough are the main manifestations. Nasal obstruction, runny nose, and other upper respiratory symptoms are rare. About half of the patients developed dyspnea one week later, and severe cases developed rapidly into acute respiratory distress syndrome, septic shock, hard-to-correct metabolic acidosis, and coagulation dysfunction. Severe and critical patients may present moderate to low fever, or even no obvious fever. Some patients have mild onset symptoms, no fever, and mostly recovered after one week. Most patients have a favorable prognosis, although some patients are left in a critical condition, or do not survive. The aged patients and the patients with basic diseases have worse prognosis. Children cases are relatively mild.
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.
The unconfirmed cases met the criteria of the suspected cases and are identified positive with SARS-CoV-2 RNA, by real-time RT-PCR or gene sequencing, from the sputum, throat swab, lower respiratory tract secretion, or other samples collected from patients.
Middle East Respiratory Syndrome coronavirus (MERS-CoV) is a novel coronavirus known to cause severe acute respiratory illness associated with a high risk of mortality. As of August 17 2015, 1432 laboratory-confirmed cases of infection with MERS-CoV, including at least 507 deaths, have been confirmed worldwide. In pregnant women, the risk of viral pneumonia is significantly higher than for the rest of the population according to data collected from the previous 1957–1958 pandemics, and the H1N1 influenza pandemic of 2009 [2, 3]. Pregnant women with severe acute respiratory syndrome (SARS) appear to have a worse clinical outcome and a higher mortality rate compared to non-gravid women [4, 5]. Rates of maternal mortality, stillbirth, spontaneous abortion, and preterm delivery have all been elevated in viral pneumonia such as influenza-A, virus subtype H1N1, and SARS. While there are no clinical or serologic reports suggesting transmission of SARS coronavirus to the fetus, vertical transmission has been reported for H1N1 and Respiratory Syncytial Virus (RSV) [4, 6]. Data on the effects of MERS-CoV on pregnancy are limited; two cases of MERS-CoV in pregnancy have been reported to this day. The first report involved a stillbirth at 5 months of gestation in a woman with MERS-CoV infection in Jordan. The other involved a woman in the United Arab Emirates with MERS-CoV infection during the 3rd trimester who died after giving birth to a healthy baby with no evidence of MERS-CoV infection. We report the clinical course of MERS-CoV infection in a pregnant woman who acquired the infection during the last trimester of pregnancy during a large hospital outbreak.
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.
The sudden outbreak of the severe acute respiratory syndrome (SARS) virus in early 2003 disturbed the world, especially China.1–3 Physicians and microbiologists have made great achievements in understanding the pathogen and effectively controlling its spread. The World Health Organization identified the source of the disease as SARS-CoV coronavirus on April 16, 2003.4–6 A total of 5327 individuals were diagnosed with SARS in China, and 349 patients died.7 In Beijing, SARS first broke out in Peking University People’s Hospital, where 80 medical staff contracted the virus, two of whom died subsequently. This cohort became the largest patient population worldwide and was composed of healthcare workers infected during their employment. Under the guidance on managing infectious diseases, Peking University People’s Hospital was isolated by the government for 22 days. The main clinical manifestation after infection was high fever and severe lung inflammation.5,6 The patients who survived had residual pulmonary fibrosis as well as osteonecrosis resulting from treatment with large doses of steroid pulse therapy. Several studies have investigated the long-term outcomes of recovered SARS patients, especially with respect to lung and bone damage, but no follow-up periods of more than 7 years have been reported. We conducted a comprehensive 15-year follow-up of healthcare workers with nosocomial SARS to evaluate their health utility after rehabilitation and obtain a new understanding of the associated pulmonary damage and femoral head necrosis.
An outbreak of novel coronavirus pneumonia is ongoing, called 2019-nCoV, was first identified in Wuhan, Hubei province, China at the end of 2019 [1, 2]. As of February 10th, 2020, at least 40,261 cases confirmed, 23,589 cases suspected, 909 cases death and 3444 cases were cured in China (Fig. 1). 24 countries (Fig. 2) such as Japan, Singapore, Thailand, Korea, and the United States have 383 cases being diagnosed, with 1 case death so far. Although Chinese authorities improved surveillance network, made the laboratory be able to recognize the outbreak within a few weeks and announced the virus genome that provide efficient epidemiological control, World Health Organization (WHO) assessed the risk as ‘very high’ in China and ‘high’ in global level in the coming weeks, and declared the public health emergency of international concern (PHEIC) over the global outbreak of 2019-nCoV in January 31, 2020.
Based on the current epidemiological survey and data, more comprehensive information is required to understand 2019-nCoV feature, epidemiology of the outbreak including the source, transmission, extent of infection, and the clinical picture. Further strategies are required to determine according to the current status.
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).
The complete clinical manifestation is not clear yet, as the reported symptoms range from mild to severe, with some cases even resulting in death. The most commonly reported symptoms are fever, cough, myalgia or fatigue, pneumonia, and complicated dyspnea, whereas less common reported symptoms include headache, diarrhea, hemoptysis, runny nose, and phlegm-producing cough [3, 16]. Patients with mild symptoms were reported to recover after 1 week while severe cases were reported to experience progressive respiratory failure due to alveolar damage from the virus, which may lead to death. Cases resulting in death were primarily middle-aged and elderly patients with pre-existing diseases (tumor surgery, cirrhosis, hypertension, coronary heart disease, diabetes, and Parkinson’s disease). Case definition guidelines mention the following symptoms: fever, decrease in lymphocytes and white blood cells, new pulmonary infiltrates on chest radiography, and no improvement in symptoms after 3 days of antibiotics treatment.
For patients with suspected infection, the following procedures have been suggested for diagnosis: performing real-time fluorescence (RT-PCR) to detect the positive nucleic acid of SARS-CoV-2 in sputum, throat swabs, and secretions of the lower respiratory tract samples [13, 14, 43].
A typical characteristic of the SARS-CoV-2 infected patient is pneumonia, now termed as Coronavirus Disease 2019 (COVID-19), demonstrated by computer tomographic (CT) scan or chest X -ray 3,8,18. In the early stages, the patients showed the acute respiratory infection symptoms, with some that quickly developed acute respiratory failure and other serious complications 20. The first three patients reported by the China Novel Coronavirus Investigating and Research Team all developed severe pneumonia and two of these three patients with available clinical profiles showed a common feature of fever and cough 8. A subsequent investigation of a family of six patients in the University of Hong Kong-Shenzhen Hospital demonstrated that all of them had pulmonary infiltrates, with a variety of other symptoms 18. The chest X-ray and CT imaging in a study showed that 75% of 99 patients demonstrated bilateral pneumonia and the remaining 25% unilateral pneumonia 21. Overall, 14% of the patients showed multiple mottling and ground-glass opacity 21. The first cases of coronavirus infection in the United States also showed basilar streaky opacities in both lungs by chest radiography. However, the pneumonia for this patient was only detected on the day 10 of his illness 22. It is also of note that one of patients among the family of six patients did not present any other symptoms and signs, but had ground-glass lung opacities identified by CT scan 18.
At least four comprehensive studies on the epidemiological and clinical characteristics of SARS-CoV-2 infected patients have been performed 21,23-25. The most common signs and symptoms of patients are fever and cough 21,23-25. Fatigue was complained by 96% of patients (n=138) in one study 24, but was less outstanding (18%, n=44) in another report 23. A combinational analysis of the common recorded signs or symptoms of the reported cases found that fever was observed in around 90% of the SARS-CoV-2 infected patients; the number of patients with cough is relatively less (68%) compared to fever (Table 1). In addition, shortness of breath or dyspnea, muscle ache, headache, chest pain, diarrhea, haemoptysis, sputum production, rhinorrhoea, nausea and vomiting, sore throat, confusion, and anorexia were also observed in a proportion of the patients 21,23-25 (Table 1).
A common feature of patients of SARS, MERS or COVID-19 is the presence of severe acute respiratory syndrome; however, the estimated fatality rate of COVID-19 (2.3%) is much lower than SARS (~10%) and MERS (~36%) 26,27. Furthermore, the viruses responsible for above three diseases are evolutionary distinct (See below for details) 19.
Since the identification of the first coronavirus – infectious bronchitis virus (IBV) isolated from birds – many coronaviruses have been discovered from such animals as bats, camels, cats, dogs, pigs, and whales. They may cause respiratory, enteric, hepatic, or neurologic diseases with different levels of severity in a variety of hosts, including humans. Coronaviruses have positive-sense single-stranded RNAs, their genomic size are 26 to 32 kilobases, the largest for an RNA virus. And the viruses themselves appear crown-shaped under electron microscopy. Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae in the order Nidovirales. Coronavirinae is further divided into four genera, Alpha-, Beta-, Gamma-, and Deltacoronavirus, based on their phylogenetic relationships and genomic structures.
Coronaviruses occasionally jump across host barriers, often with lethal consequences. The alpha- and betacoronaviruses only infect mammals and usually cause respiratory illness in humans and gastroenteritis in animals. Gamma- and deltacoronaviruses mainly infect birds, and no human infection has been reported. Six coronaviruses known to infect humans are 229E, NL63 (genus Alpha-), OC43, HKU1, SARS-CoV, and MERS-CoV (Beta-), whereas only SARS- and MERS-CoV have caused large worldwide outbreaks with fatality, others usually cause mild upper-respiratory tract illnesses. A novel coronavirus was identified in a pneumonia patient in Wuhan on January 9 of this year represents the seventh human-infecting coronaviruses.
Severe acute respiratory syndrome (SARS, induced by SARS-CoV) first emerged in Guangdong province, China in 2002 and quickly spread around the world, with more than 8000 people infected and nearly 800 died. The MERS-CoV is a new member of Betacoronavirus and caused the first confirmed case of Middle East Respiratory Syndrome (MERS) in Saudi Arabia in 2012. Over 2000 MERS-related infections have been reported as of 2019 with a ∼34% fatality rate (https://www.who.int/).
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.
Early identification of infected patients and timely medical intervention are key to preventing rapid spread of the virus. We attempt to adopt a strategy of screening patients for 2019-nCoV early after the admission. Currently, diagnosis is based on epidemiological associations, clinical manifestations, laboratory findings, and radiological characteristics.4 Both WHO and The National Health Commission have issued definitions of suspected cases.4,11(i) Patients must meet any one of the four epidemiological criteria:(a) A history of travel or residency in Wuhan, Hubei Province, China or other epidemic areas, since December 2019;(b) Close contact with a person who has traveled to Wuhan or other epidemic areas since December 2019 or presented with respiratory symptoms in the 14 days before the onset of signs and symptoms, or close contact with a patient confirmed to have the 2019-nCoV virus;(c) A health worker without enough protection but took care of patients who have the earlier-mentioned conditions;(d) An individual case in a cluster outbreak of the infection.(ii) Patients must present with the following clinical manifestations within 10 days of likely exposure:(a) A history of fever or a high temperature;(b) A dry cough or sore throat;(c) Malaise;(d) Shortness of breath.
Patients who meet any of these epidemiological criteria and who present with some of the above clinical manifestations should be quickly referred to designated hospitals for further examination.
Although highly pathogenic virus infections have the different epidemiology, there is a similar rapid progression to acute respiratory distress syndrome (ARDS).15 For example, histopathological changes in the lung from patients infected with H5N1 are highly similar to those of patients with SARS.16 Except for influenza A H5N1 virus, avian influenza A H7N9 virus in 2013 also caused severe pneumonia.17 Postmortem biopsy of 3 patients infected with H7N9 in 2013 showed acute diffuse alveolar damage: patient 1, who died 8 days after symptom onset, had intra-alveolar hemorrhage, whereas patients 2 and 3, who died 11 days after symptom onset, had pulmonary fibro proliferative changes.18
Patients infected with H5N1 develop rapidly progressive pneumonia, further resulting in ALI or ARDS.19,20 ALI may be a critical cause of death in patients with H5N1 infection.19,21 Like H5N1 infection, H7N9 also causes serious lung pathology. In addition, SARS-CoV infection caused ALI that may progress to life-threatening ARDS. MERS-CoV infection resulted in a more severe pneumonia than SARS-CoV infection.22
Respiratory distress is the most common cause of death in patients infected with highly pathogenic virus. In terms of therapy, lung protective ventilation is the cornerstone of supportive care.23 Extracorporeal membrane oxygenation is routinely used in many centers for the treatment of severe respiratory tract infections. However, due to few effective treatment options, ALI is often fatal for patients infected with highly pathogenic viruses. This suggests that serious lung pathology should be of particular concern.
A 36-year-old man presented with fever for 5 days (peak body temperature: 40℃) and was admitted to the Fever Clinic of the Beijing Haidian Hospital. The patient had no direct contact history with patients with COVID-19 or people from the Hubei province, but a recent travel history to Chongqing was reported. Physical examination showed fever with a body temperature of 38.5℃. Respiratory symptoms at admission included dry throat and difficulty breathing; no cough, sputum, or stuffy/runny nose was observed. Other symptoms included nausea, vomiting, and diarrhea. Laboratory examination revealed increased leukocyte (13.69 × 109/L) and neutrophil (10.42 × 109/L) counts, decreased differential count of lymphocytes (12.6%), and an elevated C-reactive protein level (155 mg/mL).
Chest CT showed emphysema in both upper lungs and diffuse ground-glass opacities in the right lower lobe, highly suggestive of viral pneumonia. In addition, the DL-based computer-aided diagnostic system also indicated a high risk of pneumonia with the infected area accounting for 8.9% of the whole lungs (Fig. 2). Subsequently, throat swab specimens were promptly collected for SARS-CoV-2 rRT-PCR. A negative result for SARS-CoV-2 was observed in the first rRT-PCR test. A second consecutive SARS-CoV-2 rRT-PCR test was conducted immediately thereafter, and a positive result was obtained. The patient was further confirmed with COVID-19 with additional positive rRT-PCR tests.