key: cord-1056540-9wsqtww7 authors: Stefanidis, Konstantinos; Konstantelloy, Elissavet; Yusuf, Gibran Timothy; Oikonomou, Anastasia; Tavernaraki, Kyriaki; Karakitsos, Dimitrios; Loukides, Stylianos; Vlahos, Ioannis title: Radiological, epidemiological and clinical patterns of pulmonary viral infections date: 2021-01-14 journal: Eur J Radiol DOI: 10.1016/j.ejrad.2021.109548 sha: c3970cc10596a71cc8b801f74a96c9adb1f296c3 doc_id: 1056540 cord_uid: 9wsqtww7 Respiratory viruses are the most common causes of acute respiratory infections. However, identification of the underlying viral pathogen may not always be easy. Clinical presentations of respiratory viral infections usually overlap and may mimic those of diseases caused by bacteria. However, certain imaging morphologic patterns may suggest a particular viral pathogen as the cause of the infection. Although definitive diagnosis cannot be made on the basis of clinical or imaging features alone, the use of a combination of clinical and radiographic findings can substantially improve the accuracy of diagnosis. The purpose of this review is to present the clinical, epidemiological and radiological patterns of lower respiratory tract viral pathogens providing a comprehensive approach for their diagnosis and identification in hospitals and community outbreaks. The emergence of the novel Coronavirus disease in December 2019 in Wuhan (Hubei, China) , caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) and the ongoing pandemic as a result of the viral spread, have once more drawn physicians' attention to respiratory viruses and have reemphasized the role of viral pathogens as cause of severe pneumonia. Throughout human history, outbreaks of respiratory diseases due to viruses have commonly been reported. Epidemics of smallpox in the Roman Empire and Japan during the first century AD are among the first known outbreaks of viral diseases [1, 2] . Since then, multiple epidemics caused by other viruses have been recorded. Influenza type A virus pandemic (H1N1 subtype), known as the "Spanish flu", was the most devastating leading to approximately 100,000,000 deaths worldwide from 1918 to 1920 [3] . During the 21st century new viral outbreaks were reported: SARS that [3] . In 2012 another coronavirus strain ("Middle East respiratory syndrome -MERS coronavirus") emerged and has been responsible for some hundreds of deaths so far [3] [4] [5] . The fatal burden of viral outbreaks throughout human history, as well as the fact that new respiratory viruses have been discovered during the past decade, highlight the pathogenic role of viruses in respiratory disease, including community acquired J o u r n a l P r e -p r o o f pneumonia (CAP). Diagnosis of viral pneumonia depends on clinical criteria, epidemiological factors (e.g. presence of viral epidemics in the community and seasonality of viral pathogens) and laboratory findings, including molecular detection techniques [6] . However, imaging plays a significant role in patient management, as it is necessary for determining the severity and extension of the infection. Accurate and early diagnosis of the various viral pathogens through a multimodality approach is crucial, as specific therapies are available against certain viruses. In this article, we review concurrently the epidemiological, clinical and radiological features of pathogens causing viral pneumonia. It is estimated that viruses are responsible for 15% to 56% of CAP in hospitalized immunocompetent patients, either by themselves or as co-pathogens with bacteria [7] [8] [9] [10] . The variability of the reported proportion of viral pneumonias from various studies may be explained by differences in study populations and the testing rigor for viruses. Moreover, even when viral testing is undertaken, the true incidence of viral pneumonias remains unclear and probably underestimated as upper respiratory sampling (nasal swab, nasopharyngeal swab) is most commonly performed compared to the most sensitive but less easy lower respiratory sampling [bronchoalveolar lavage (BAL) fluid, tracheal aspirates, induced sputum], [7] [8] [9] [10] . Regardless of viral testing accuracy, immunocompromised patients, especially those who have undergone hematopoietic stem cell or solid organ transplantation or patients under chemotherapy for leukaemia, demonstrate a significantly higher incidence of viral pneumonias [11] . In this population viral pneumonias are typically more severe and associated with higher mortality rates, compared to healthy subjects [11] . Additionally, it has been J o u r n a l P r e -p r o o f shown that the incidence of lower respiratory infections is higher in the very young and the elderly [12] . Consequently, in order to narrow the differential diagnosis of the various pathogens in a case of pneumonia, it is important not only to consider patient characteristics (immune state, age, co-morbidities), but also a patient's travel and epidemiological factors (e.g. seasonality of viral infections, current epidemics). Seasonality is one of the defining characteristics of viral respiratory infections, although the aetiology for this observation is not fully elucidated [13, 14] . Various epidemiological studies have shown that the frequency of respiratory infections increases rapidly in the autumn, remains high throughout the winter and decreases in the spring in temperate regions of the northern hemisphere (Table 1) [13, 14] . A combination of factors seems to be responsible for the seasonality of viral infections: increased viral survival due to low environmental humidity and temperature during winter, diminished daylight and vitamin D deficiency resulting in wintertime relative immunosuppression, rapid spreading of the viruses because of increased people crowding and school opening during autumn and winter [15] [16] [17] [18] [19] . In tropical areas, most viral infections arise during the rainy season [20] . The clinical presentation of viral pneumonias is variable, depending on the causative organism and the immune status and comorbidities of the host (Table 2 ). Viral pneumonias present in a much more severe form in immunocompromised patients, the elderly or those of very young age [12] . Institutionalization and cardiac comorbidities seem to be additional risk factors [8] . J o u r n a l P r e -p r o o f Viral pneumonias in general have similar clinical symptoms (cough, shortness of breath, increased sputum, chest pain) and signs (fever, tachycardia, tachypnoea, hypoxia) with bacterial pneumonias [6] . However, some clinical features are noted more often in viral infections, such as cough and myalgia [7, 21] . Features such as rhinitis, conjunctivitis and pharyngitis are also usual clinical manifestations of viral pneumonias. Moreover, as compared to bacterial pneumonia, in viral pneumonitis leucocytosis is less frequently seen and procalcitonin levels are lower [6] . It is clinically recognized that radiological findings may contribute to the differentiation of viral from bacterial pneumonias. Ruuskanen et al. have proposed a set of combined clinical, radiological, epidemiological and laboratory criteria that may predict viral aetiology of pneumonia in patients [6] . Nonetheless, predicting the viral aetiology from clinical, laboratory or radiological parameters remains imprecise. In the absence of isolation of a viral pathogen, there is no clinico-radiological gold standard for differentiating the aetiology of pneumonia [22] . Differential diagnosis is rendered even more challenging by the fact that viral The detection of virus or specific viral antigens in respiratory tract samples has traditionally been done by culture and immunofluorescence microscopy. Additionally, antibody seroconversion during the clinical course of the disease, has also been performed for years [28] . Improvements in molecular detection techniques, particularly real time techniques such as reverse transcription polymerase chain reaction (RT-PCR), have enabled assessment of the proportion of CAP caused by specific organisms, and viruses as a whole. In particular, the advent of fast and reliable viral genome sequencing using PCR has facilitated the detection of many viral causes of pneumonia, some of which were previously unknown such as human metapneumovirus [29] . PCR techniques are reported to be 2-5 times more sensitive than conventional methods for the detection of respiratory viruses [30] . Clinical specimens that are suitable for diagnosis of viral pneumonia include, in order of preference: lung tissue and BAL fluid, nasopharyngeal wash samples, nasopharyngeal swabs and sputum. Lung tissue and BAL are often unavailable because of their invasive nature, but nevertheless are very useful in immunocompromised and critically ill patients, in whom a specific diagnosis is necessary and co-infections are common [31] . Improvements in imaging technology, in particular the availability of high-resolution CT, coupled with the growing number of detectable pathogenic organisms in atypical pneumonia, provide both opportunities and challenges for the radiologist. J o u r n a l P r e -p r o o f Chest x-ray is the first screening tool for the detection of an active infective process. However, it has been shown that it is of limited value predicting aetiology of lower respiratory tract infection as it is frequently non-specific, demonstrating normal or subtle findings [32] . CT imaging provides further detailed information with different patterns (Table 3) . However, the significant overlap of imaging features between pathogens limits the identification of specific causative organisms. Specifically, coinfection with multiple viral and bacterial pathogens, estimated in several studies to occur in around 15% of the cases, can further complicate diagnosis [7, 33] . Influenza virus belongs to the orthomyxovirus family of RNA viruses. There are three groups of influenza viruses (A, B and C) of which type A virus is the most virulent and can easily mutate [34] . In temperate climates, epidemics are seen almost exclusively in the winter months (generally November to April in the Northern hemisphere and May to September in the Southern hemisphere), whereas in tropical areas, influenza infection is reported throughout the year [13, 14] . Influenza can cause a spectrum of clinical disease ranging from relatively mild upper respiratory tract infection with flu-like symptoms, to fulminant and overwhelming pneumonia which occurs particularly in the elderly and immunocompromised. Histopathologic studies have showed that severe influenza is characterized by necrotizing bronchitis, capillary and small-vessel thrombosis, interstitial oedema and inflammatory infiltrates, the formation of hyaline membranes, haemorrhage, as well as diffuse alveolar damage (DAD) [35] . Paralleling the histopathological picture, there is a broad range of reported imaging appearances in influenza pneumonia. Findings at initial chest x-ray in patients with H1N1 influenza include central or peripheral ground glass opacities and consolidation with a patchy or nodular appearance [36] (Fig 1, 2 ). Aviram et al have showed that the initial chest radiographic findings have also a prognostic role predicting clinical outcome. Specifically, there is association of multizonal and bilateral peripheral opacities with progression to respiratory failure requiring mechanical ventilation and poor clinical outcome [36] . A normal CT scan is seen in approximately half of patients with proven influenza virus disease [37] . In those with abnormal findings, ground glass opacities, multifocal consolidation or a combination of ground glass opacity and consolidation is the commonest pattern. A predominant peribronchovascular and subpleural distribution, has been described, resembling organizing pneumonia [37] . Interlobular septal thickening and centrilobular nodules are also common findings [38] [39] [40] . Bilateral patchy consolidation, ill-defined small nodules, and patchy ground glass opacities associated with the areas of consolidation have been reported in patients with underlying hematologic malignancy [41] . The human parainfluenza virus (PIV) belongs to the Paramyxoviridae family and is separated into 4 types accounting for 2-4% of CAP cases in adults [42, 43] . Type 3 is the most common form and related to acute illness in immunocompromised patients [44, 45] . Epidemiological data demonstrate distinct seasonality for all four types with type 3 more prevalent in the spring and summer [13, 14] . PIV can cause upper tract respiratory infections (rhinitis, pharyngitis, laryngitis), as well as more severe The radiographic appearance of PIV infections is not specific and includes opacities and nodules. The virus presents with a predominantly airway-centric pattern of disease on CT [46] . Findings include ground glass opacities, consolidation, tree-inbud nodules and bronchial wall thickening [34, [44] [45] [46] (Fig 3) . PIV infections appear to affect the lower lobes more which may assist differentiation from other viral infections such as influenza and RSV [34] . Respiratory syncytial virus (RSV) is classified in the Pneumovirus genus of the Paramyxoviridae family. Although RSV is the most frequent viral pathogen causing lower respiratory tract infection in infants, it is now recognized as a significant pathogen especially in immunocompromised adults particularly with a haematological or autoimmune primary disease [47] [48] [49] . Similar to the influenza viruses, RSV causes outbreaks of respiratory illness in the late fall, winter or spring [13, 14] . In infants and children, RSV infection is usually associated with upper respiratory tract illness manifestations. In immunosuppressed adults, RSV infection manifests with severe lower respiratory tract complications which can result in serious morbidity and significant mortality. Whimbey and Ghosh evaluated the role of community respiratory viral infections in hospitalized adult bone marrow transplant recipients and found an incidence of RSV pneumonia of 9.2% with a mortality rate of 60% [50] . The histopathology of RSV bronchiolitis is most commonly described as plugging or occlusion of bronchiolar airway lumens by sloughed necrotic and irregular epithelium, combined with peribronchiolar infiltration and submucosal oedema [51] . In children, chest x-ray may be normal or abnormal with features of central airspace opacification and peribronchial thickening [52, 53] . In adults and elderly patients, chest x-ray generally does not distinguish RSV pneumonia from bacterial infection and most commonly demonstrate bilateral alveolar opacities but may also show interstitial changes [54] . On CT, RSV pneumonia typically shows an airway-centric pattern of disease, with ground glass opacities, nodules, small focal areas of consolidation and bronchial wall thickening [47, 48, 55] (Fig 4) . Especially during the early phase, the CT findings may be more characteristic with nodules and tree-in-bud opacities [55] . When nodules are present, a peripheral halo of ground-glass is common (70%) and may assist in narrowing the differential diagnosis [55] . Rhinovirus (RV) is encountered in the RNA Enterovirus genus in the Picornaviridae. RV is a major pathogen of respiratory infection detected in 18%-26% of paediatric patients and in 2%-17% of adult patients with CAP [56, 57] . RVs infections are reported to be more prevalent in the early fall and late spring [13, 14, 58] . It can cause a wide spectrum of upper and lower respiratory tract manifestations, varying from mild episodes of coryza, scratchy throat, rhinorrhoea, pharyngitis and bronchitis to pneumonia or bronchiolitis frequently associated with exacerbation of asthma and chronic obstructive pulmonary disease [59, 60] . The histological findings mirror the radiological appearances. RV by itself does not destroy the airway epithelial barrier with no cytopathic effect on the respiratory epithelium. However, it can cause disruption of the epithelial barrier, which leads to increased vascular permeability and mucous secretion [61] . Therefore, while normal or almost normal appearances can be found in mild disease, in patients with severe J o u r n a l P r e -p r o o f rhinovirus pneumonia, a peribronchial and interstitial pattern with ground glass opacity is most commonly noted [62] (Fig 5) . Human metapneumovirus (hMPV), first discovered in 2001, is a paramyxovirus that has emerged as an important worldwide cause of lower respiratory tract infections [29] . It is molecularly similar to RSV and parainfluenza virus and shows similar seasonality of outbreaks in winter and spring [13, 14] . It most commonly causes upper and lower respiratory tract infections in children, but can also cause pneumonia in adults, particularly in the elderly with cardiopulmonary disease, as well as in immunocompromised populations. In adults, hMPV typically accounts for 2-5% of CAP, although this percentage can be much higher in hospitalized patients during years with larger outbreaks [42, 63-65]. The histological patterns in hMPV pneumonia reflect the radiological appearances and include necrotizing bronchiolitis that evolves to chronic bronchiolitis, acute or organizing DAD and alveolar haemorrhage [65] . Accordingly, bronchial wall thickening, GGOs, and ill-defined centrilobular nodules were the commonest CT findings for hMPV pneumonia in the largest retrospective study of 251 patients with confirmed hMPV and without other pathogen identified [66] (Fig 6) . Macronodules and consolidation were observed in <50% of patients [66] . In a small study of 10 patients with hMPV pneumonia, the CT findings demonstrated a more asymmetric distribution compared to RSV-pneumonia which presents with more symmetrical involvement [67]. Coronoviruses are enveloped single-stranded RNA viruses member of the Betacoronavirus genus belonging to the Coronaviridae family. Several strains cause respiratory infections, including the common cold during winter months, but outbreaks throughout the year have been reported [13, 14] . and MERS may overlap. The initial chest x-ray will be abnormal in up to 80% of patients with SARS and 83% of patients with MERS [70] . The initial radiographic appearance in SARS frequently shows ill-defined peripherally distributed areas of airspace opacification in the lower lung zones. The majority of patients will show progressive multifocal consolidation over a course of 6-12 days. CT frequently shows patchy areas of ground glass opacity and consolidation (Fig 7) . The presence of bilateral confluent diffuse airspace opacities, similar to the findings of ARDS, involvement of four or more lung zones, bilateral lung involvement, and progressive worsening of airspace consolidation on chest imaging more than 12 days after symptom onset, despite treatment, are associated with unfavourable outcomes [70] . The radiographic appearance in patients with MERS will show most commonly multifocal airspace opacities in the lower lung zones. MERS pneumonia at CT typically demonstrates bibasilar peripheral predominant ground glass opacities; J o u r n a l P r e -p r o o f however, isolated consolidation, interlobular septal thickening, and pleural effusion are not uncommon, observed in 20-33% of MERS pneumonia [71] . In Transmission seems to be similar to that of other coronaviruses [72] . Patients are infectious for up to two days before the onset of symptoms and remain so for 10 days after symptoms onset in mild to moderate disease and for up to 20 days in severe Covid-19 illness [3] . This relatively long infectious period in addition to the fact that many patients may be completely asymptomatic plays an important role in the rapid transmission of the virus. The predominant laboratory abnormalities include the elevation of inflammatory markers, such as C-reactive protein, lactate dehydrogenase, and the erythrocyte sedimentation rate. Additionally, lymphopenia is consistently present in more than 40% of patients [73] . pneumonia are similar to those described in SARS-CoV-1 and MERS-CoV with similarities in the pathogenesis and the mechanisms of tissue damage and inflammatory response [75] . In the very early course of the disease imaging findings may be normal. The chest xray is typically the first-line imaging modality; however, it is of limited sensitivity and may be normal in the early phase. Chest x-rays can be useful in the follow-up of hospitalized patients monitoring the progression or regression of the disease. In those Covid-19 cases requiring hospitalization, an abnormal chest x-ray has been reported in 69% of the cases at the initial time of admission, and 80% had radiographic abnormalities sometime during hospitalization [76] . Chest radiographic abnormalities include ground-glass opacities, coarse horizontal linear opacities, and consolidation [73, 76] . These are more likely to be peripheral and in the lower zones, but the whole lung can be involved (Fig 8a-c) . CT is more sensitive than chest x-ray and shows characteristic imaging patterns in the different stages of the disease [77] [78] [79] . In the early stage (0-4 days) the CT imaging findings may be normal or show ground-glass opacities which is the most common finding and has been suggested as the hallmark of Covid-19. Distribution is usually multifocal, bilateral peripheral and posterior (Fig 9a, b) . The presence of typically nodular (round or oval) ground glass opacities (Fig 10) may suggest the diagnosis and should alert the radiologist to the possibility of Covid-19 infection [80, 81] . Another typical finding described in the affected area of ground-glass opacification is pulmonary vascular enlargement which plays a potential diagnostic role for Covid-19. Bai and colleagues have shown that the CT regional pulmonary vascular enlargement was significantly associated with Covid-19 [82] . In the progressive stage (5-8 days), J o u r n a l P r e -p r o o f the typical appearance is increased ground glass opacification often combined with thickened interlobular and intralobular lines (crazy paving pattern) (Fig 11 a) . Areas of consolidation is the most common finding in the peak stage (9-13 days). Atypical findings include mediastinal lymphadenopathy and pleural effusions [75] . In the absorption stage (>14 days) traction bronchiectasis and fibrotic bands can be seen (Fig 11b) with complete or almost complete resolution of abnormalities at one month or beyond. Different studies have also shown the potential role of CT in predicting the severity of the disease [83, 84] . A CT severity score estimating of the percentage of Covid-19 lung involvement by visual assessment can help identify patients with severe forms of Covid-19 and better triage patients [83, 84] . Adenovirus is a double-stranded DNA virus. Adenovirus pneumonia is rare in healthy individuals [85] , while occurs commonly in immunocompromised hosts including patients who have received organ and bone marrow transplants [86, 87] . Adenovirus infections can occur throughout the year. Outbreaks of adenovirusassociated respiratory disease have been more common in the late winter, spring, and early summer [13, 14] . Clinically, respiratory involvement in non-severe adenovirus infection includes a spectrum of upper and lower respiratory tract manifestations such as rhinitis and conjunctivitis, pharyngitis, tracheitis and bronchitis. In mild disease, findings of interstitial inflammatory cell inflammation are present while in severe pneumonia, haemorrhage and DAD are the predominant histological patterns. Chest x-ray J o u r n a l P r e -p r o o f findings may be normal in the early phase and show bilateral or unilateral parenchymal opacities with infective progression. The most common finding on CT is consolidation with or without ground glass opacity with subpleural and peribronchovascular predisposition as shown in a study of 104 immunocompetent patients with adenovirus pneumonia [88] . Less often septal thickening and nodules may also be present [88, 89] . As severe adenovirus pneumonia may manifest as focal consolidation, adenovirus is the only virus known to cause focal or lobar consolidation resembling bacterial pneumonia [88, 90] (Fig 12) . Herpes simplex virus (HSV) includes two types, HSV-1 and HSV-2 and belongs to the alphaherpesvirus subfamily of herpesviruses, sharing the same basic structural features. No seasonality has been demonstrated for HSV-1 infection but case clusters are reported sporadically throughout the year [13, 14] . HSV-1 is the type most commonly associated with respiratory infection. Interestingly, isolation of HSV in lower respiratory tract secretions has been reported in patients with ARDS and in mechanically ventilated patients in general and this has been associated with poor prognosis [91, 92] . The histopathological pattern of HSV pulmonary infection is of DAD consisting of interstitial lymphocytic infiltration, alveolar haemorrhage and hyaline membrane formation [93]. Radiographic findings include lung air-space opacification, predominantly with focal or more extensive bilateral distribution [94] . The most common CT patterns of pulmonary abnormalities identified in HSV pneumonia are areas of diffuse or multifocal ground glass opacity, multifocal peribronchial consolidations and interlobular septal thickening [95, 96] . the Herpesviridae family that typically causes outbreaks of a highly contagious childhood disease (Varicella -"chickenpox") in late winter and early spring months in temperate regions [13, 14] . The diagnosis of varicella infection usually can be established on the basis of clinical findings (rash, pulmonary symptoms, and history of contact with a patient with chickenpox). Clinical manifestations of VZV pneumonia are non-specific and include fever, cough, dyspnoea, pleuritic chest pain and haemoptysis. Histologic features of pneumonitis associated with chickenpox and zoster include an interstitial mononuclear inflammatory infiltrate associated with features of DAD including intraalveolar proteinaceous exudate, hyaline membrane formation, and type II cell hyperplasia. Chest radiographic findings of varicella-zoster virus pneumonia consist of multiple scattered 5-10-mm ill-defined nodules that may be confluent (Fig 13a, b) . The nodules may persist for several months and can calcify and persist as numerous, welldefined, randomly scattered, 2-3 mm dense calcifications. CT findings of varicellazoster pneumonia include nodules, nodules with surrounding ground-glass attenuation (halo sign), patchy ground glass opacities and coalescence of nodules; the disappearance of these features on CT corresponds to healing of skin lesion in patients after antiviral chemotherapy [97] . Similarly, to the radiographic appearances, nodules may calcify and persist as well-defined, randomly scattered, 2-3 mm densely calcified nodules (Fig 13c) . The chest x-ray appearance may be unremarkable in the early phase with features of interstitial oedema with the progression of the infection [107] . The CT features consist of extensive bilateral ground glass opacity with mid and lower zone predominance, a few slightly thickened interlobular septa and poorly defined small nodules, bronchial wall thickening and small bilateral pleural effusions [108] . Viral pathogens are responsible for a significant cause of death worldwide in healthy and immunocompromised hosts. Although our knowledge of the different organisms has increased over the last decades, the diagnosis still strongly relies on clinical suspicion. However, combining imaging findings with relevant clinical and epidemiological features can enable radiologists and clinicians to significantly narrow the differential diagnosis. Radiological findings can influence early treatment decisions, before the results of molecular tests are available guiding clinical management and improving patient outcomes. 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Chest x-ray and magnified view shows left upper lobe patchy increased air-space opacification (arrows). 1c. Coronal CT image confirms the left upper lobe ground glass opacity and further multifocal ground glass 45-year-old male patient with confirmed influenza pneumonia. 2a, b. Axial CT images show multifocal patchy ground glass opacities (arrows) 54-year-old woman with fever and cough. Parainfluenza was the only pathogen recovered from respiratory secretions. 3a. Chest x-ray shows reticulonodular opacities in the right lower zone (arrows). 3b. Transverse thin section CT scan confirms the The authors have no conflicts of interest to declare.