Secondary Logo

Journal Logo

Review Article

The Clinical Presentation and Immunology of Viral Pneumonia and Implications for Management of Coronavirus Disease 2019

Darden, Dijoia B. MD1; Hawkins, Russell B. MD1; Larson, Shawn D. MD1; Iovine, Nicole M. MD, PhD2; Prough, Donald S. MD3; Efron, Philip A. MD1

Author Information
Critical Care Explorations: April 2020 - Volume 2 - Issue 4 - p e0109
doi: 10.1097/CCE.0000000000000109
  • Open
  • COVID-19


Pneumonia is the leading infectious cause of hospitalization among adults and children in the United States (1). According to the World Health Organization (WHO), lower respiratory tract infection is among the top causes of death globally (2). The Centers for Disease Control and Prevention (CDC) Etiology of Pneumonia in the Community study estimated prevalence of pneumonia-related hospitalizations among adults older than 50 to be 4–25 times higher than those 18 to 49 years old (3).

Viral infections are the leading cause of community-acquired pneumonia (CAP) and are an important source of morbidity and mortality. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered virus causing coronavirus disease 2019 (COVID-19) that is responsible for an emerging pandemic. Given the rapid spread of this virus and its association with severe pulmonary disease, the purpose of this review is to provide an overview of the presentation and immunology of viral pneumonia, principles of early management, and application to COVID-19.


According to the CDC, the prevalence of CAP is highest among adults 65 to 79 years old (4). Hospitalization among adults is highest in elderly patients (≥ 65 yr) and those with preexisting obstructive lung disease or other cardiopulmonary disorders (4,5). The most common cause of community- or hospital-acquired pneumonia in adults is viral with the most frequently detected pathogen being human rhinovirus, followed by influenza (9–15% and 4–6%, respectively) (4–8). Other commonly detected causes of viral pneumonia include adenovirus, conventional coronaviruses, human metapneumovirus (HMPV), respiratory syncytial virus (RSV), and parainfluenza. The prevalence of viral respiratory illness is temporal in North America, with peaks of influenza, HMPV, and RSV normally seen in the winter months (Table 1) (1).

Table 1.
Table 1.:
Characteristics of Common Respiratory Viruses

The clinical presentation of viral pneumonia does not differentiate between the specific viral causes of respiratory infection. The common clinical presentation of acute viral respiratory infection includes cough, dyspnea, fever, and pleuritic chest pain. Viral etiologies of lower respiratory infection are less likely to cause sputum production, and if present, tends to be watery or scant. In contrast, sputum production tends to be mucopurulent when due to bacterial pneumonia (8,9). Clinical signs of viral respiratory illness include fever, rales (crackles) on auscultation, hypoxemia, and tachycardia. These four signs together have a positive predictive value of 57.1%, with fever as the strongest clinically predictive sign of a viral respiratory infection versus that of bacterial etiology (10). Typically, patients with viral pneumonia also will present with a normal leukocyte count and bilateral pulmonary infiltrates on chest radiograph (9). Severe viral pneumonia can manifest as sepsis and respiratory distress requiring intensive care (11). In many moderate to severe cases of pneumonia, hypoxemia occurs from impaired alveolar gas exchange (12), often necessitating mechanical ventilation.

Biopsies in pneumonia are not routinely performed due to the lack of diagnostic, prognostic, and treatment value. However, since influenza has caused the most viral respiratory epidemics to date, a number of studies have examined infected patient’s lung biopsy specimens (13). Biopsies obtained during influenza infection reveal a wide range of pathologies, including alveolar edema and exudate, interstitial inflammatory infiltration, and ulceration of bronchial mucosa to type II cell metaplasia (14,15). In autopsy specimens from H1N1 influenza patients, the respiratory tract exhibited tracheitis, bronchitis, diffuse hemorrhagic alveolar damage, and inflammatory infiltration of alveolar ducts and alveoli (16,17).


The host response to severe viral lung infection occurs secondary to immune dysregulation leading to lung injury and the systemic inflammatory response. There have been many studies on the immunologic changes associated with influenza A virus (IAV). However, little is known about other respiratory viral illnesses in adults. Therefore, much of our discussion on the immunology of viral pneumonia will focus on IAV studies.


During a respiratory infection, airway epithelial cells, natural killer (NK), and CD8 T-cells release interferon-gamma (INF-γ) to limit viral replication (18,19). There is additional release of interleukin (IL)–6 and IL-8, important mediators of tissue damage and associated with disease progression, respectively (20). High levels of IL-17, tumor necrosis factor (TNF)–α, INF-γ, and IL-4 have been found in postmortem human lung tissue after severe IAV (21).

Although there seems to be a difference in cytokine response based on the cause of respiratory infection, there are mixed results in the utility of plasma cytokine levels for prediction of pneumonia etiology (22,23). In a recent single-center study, differences in admission plasma levels of IL-6, IL-10, IL-17A, and INF-γ were observed between different etiologies of CAP, with INF-γ most elevated in viral CAP (24). Conversely, a similar study demonstrated, admission plasma cytokine levels were not statistically different based on etiology (bacterial vs viral vs mixed bacterial-viral vs unknown etiology) (25). Other studies noted that serum transforming growth factor-beta (TGF-β) levels predicted viral pneumonia, as opposed to other etiologies of CAP, where TGF-β had negative correlations with the Sequential Organ Failure Assessment score in patients that progressed to sepsis (26,27). Therefore, although the specific cytokine profile elicited by particular viruses is unknown, it is clear that, as with most etiologies of sepsis, an elevation of both pro- and anti-inflammatory cytokines are responsible for the host septic and systemic inflammatory response syndrome response in all severe viral cases of pneumonia (23,28–30).

Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns

As with many other responses to infection, it is pertinent to recognize the role of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in viral respiratory infection. Pattern recognition receptors on respiratory epithelial cells, such as Toll-like receptors (TLRs), detect evolutionarily conserved microbial ligands, or PAMPs (31,32). Viral PAMPs are typically viral envelope proteins or nucleic acids motifs within the DNA or RNA genomes of the virus, which are critical for structure and function (33). The recognition of viral PAMPs leads to transcription and release of type I interferons (33) which effect decreased expression of viral proteins and replication, enhance antigen presentation and NK cell function, and augment adaptive immune responses. Additional recognition of host cell constituents from damaged or dying cells, recognized as DAMPs, are thought to control the magnitude of the immune response (34–36). Together, PAMPs and DAMPs play a major role in the initiation of both the innate and adaptive immune response to viral lung infection (31,35,37–40).

Increased Susceptibility to Secondary Bacterial Infection/Ventilator-Associated Pneumonia

Viruses can be the primary cause of pneumonia, present in conjunction with bacterial pneumonia, and/or contribute to increased susceptibility to secondary bacterial infection. In addition to influenza, other viruses, such as rhinovirus, can cause severe pneumonia requiring mechanical ventilation, however, this usually occurs in the elderly and immunocompromised (8,41). Severe pneumonia associated with noninfluenza viruses is also significantly associated with bacterial coinfection (8,42–44), most commonly due to Staphylococcus aureus, Streptococcus pneumoniae, or Haemophilus influenzae (45,46).

A pattern of dysregulated inflammation caused by viral respiratory infection leads to this increased susceptibility to secondary bacterial pneumonia or coinfection. Most research on viral-bacterial respiratory coinfection has been focused on elucidating the pathophysiology of influenza viruses given its high propensity to cause pandemics and higher mortality when compared with the other viruses (13). Influenza A causes a reduction in murine alveolar macrophages and dysregulation of remaining macrophages and neutrophils, one of the body’s primary defense mechanisms against bacterial pathogens (47–49). Additionally, prior infection with influenza virus attenuates bacterial induced release of IL-17 leading to decreased innate T cell-mediated bacterial clearance (49). Replication of IAV in respiratory epithelium impairs mucociliary clearance, allowing for increased bacterial colonization (34,50,51). Additionally, there is evidence of sustained desensitization of TLR ligands following viral infection, leading to decreased chemokine release and nuclear factor kappa B activation in macrophages (52,53). This in turn results in attenuated neutrophil recruitment, further decreasing the ability to reduce bacterial load in secondary bacterial infection (52,53).

Genomic/Transcriptomic Changes Associated With Viral Pneumonia

Although CAP remains a significant source of morbidity and mortality, very little work has been done establishing genomic, epigenetic, or transcriptomic changes specifically associated with viral pneumonia (54). In particular, no clear polymorphism definitively raises the risk of viral pneumonia, limiting personalized medicine for predictive models. In one of the few studies of transcriptomics in viral pneumonia, microarray analysis and Ingenuity Pathway Analysis (Qiagen, Redwood City, CA) was performed on 19 critically ill patients with 2009 H1N1 influenza A pneumonia. The most severely ill group of 12 patients demonstrated impaired expression of numerous genes participating in adaptive immune responses (e.g., diminished antigen presentation, B-cell development, T-helper cell differentiation, and apoptosis), suggesting impaired adaptive immunity in severe viral pneumonia (55). In terms of epigenetics, many postulate that long-term epigenetic changes following severe pneumonia are responsible an increased likelihood of later infections and death, although specific epigenetic changes are yet to be identified (54).


Natural infection with viral causes of pneumonia does not induce long-term protective immunity due to an evolutionary advantage allowing viruses to evade host immune defenses via antigenic shift and drift. Antigenic drift occurs with small point mutations in the viral genome leading to minor changes in key viral epitopes, while antigenic shift is a major change in a key gene leading to a complete exchange of a key epitope (56). Antigenic shift often leads to influenza epidemics secondary to vaccine strain-circulating strain mismatches. Antigenic shift is the molecular mechanism by which novel influenza strains emerge and is the cause of pandemics such as the 2009 H1N1 pandemic (57–61).

Influenza vaccines rely on conserved antigens such as ectodomain of influenza M2 protein, M2e, or hemagglutinin stalk domains. Hemagglutinin globular head specific antibodies confer immunity since it interferes with virus attachment to host cell receptors; however, they are also one of the most variable viral antigens (56). Additional adjuvants are important in vaccine formulations to induce desired immune responses that would not be triggered with the antigen alone (62). The need for adjuvants in vaccinations confers an additional important role for DAMPs and PAMPs in viral immunity. One recent study used PAMP TLR9 agonist and commonly used pharmaceutical additive to induce the release of DAMPs to improve immunogenic response to the seasonal influenza vaccine (63).

Prevention of viral pneumonia is mainly limited to influenza vaccines since the formalin-inactivated RSV vaccine in the 1960s failed secondary to adverse events (64). However, oral adenovirus vaccination has been used in military populations with 100-fold reduction of respiratory illnesses (65,66). Production of this vaccine was stopped in 1999 but was reintroduced in 2011, leading to a dramatic and sustained decrease of acute respiratory distress outbreaks among U.S. Army trainees (67,68).

Additionally, there is still ongoing work to develop a vaccine to prevent RSV infection. Recently, one study reported protective immunity against RSV with a molecularly adjuvanted adenovirus serotype 5 based RSV oral vaccine in a rat model (69). However, two recent randomized control failed to establish an effect of anti-RSV monoclonal antibodies and recurrent wheeze of early childhood or asthma (70–73).


Clinical Presentation

Since the COVID-19 caused by the novel coronavirus known as SARS-CoV-2 began its rapid spread in Wuhan, China, in November 2019, researchers have responded swiftly to help thwart the pandemic by quickly establishing studies to better understand the virus. SARS-CoV-2 is a novel beta-coronavirus that likely originated in bats. The virus uses a glycosylated spike protein to bind to and enter the human host cell predominantly via angiotensin-converting enzyme 2 receptors that are highly expressed in type 2 alveolar cells (74).

The clinical presentation of COVID-19 can be indistinguishable from other viral causes of pneumonia and include fever (83–98%), dry cough (76–82%), and fatigue or myalgia (11–44%) (74,75). The median age of confirmed COVID-19 cases is in the 6th decade of life with a slight male predominance. Twenty-five percent of patients have severe symptoms requiring intensive care treatment of which 10% develop respiratory failure requiring mechanical ventilation. Chest radiograph imaging of these patients reveals bilateral patchy infiltrates and CT imaging shows ground-glass infiltrates. Patients typically present with laboratory findings of prolonged prothrombin time, elevated lactate dehydrogenase, and lymphopenia (70% of patients) (76). However, it is unclear if the lymphopenia is related to direct cytotoxic effect of the virus or underlying chronic conditions (77,78).

There are limited publications on the autopsy results of patients who have died from COVID-19. However, pathologic samples show hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and multinucleated giant cells. There are also high levels of pro-inflammatory cytokines, such as IL-2 and TNF-α. As with other causes of severe viral pneumonia, a “cytokine storm” occurs which also contributes to the high morbidity and mortality (79,80).

Principles of Early Management

The most important aspect of early management of viral spread has been early isolation of those presenting with concerning symptoms, history, and high likelihood of exposure to prevent spread of the disease to those in immunocompromised states, the elderly, and/or those with comorbid conditions. A chest radiograph along with throat and mid-turbinate nasal swabs for respiratory viral panel (reverse transcriptase-polymerase chain reaction) are needed for proper diagnosis of COVID-19. Among hospitalized patients, negative pressure rooms and airborne-droplet-contact precautions are important for prevention and further spread between patients and hospital care-workers (81).

Currently, there is no approved drug or vaccination for the treatment or prevention of SARS-CoV-2 viral pneumonia. There are many trials underway attempting to attenuate the disease with remdesivir, IL-6 receptor blockers, IL-7, and antiretrovirals such as lopinavir-ritonavir (82). The New England Journal of Medicine recently published a randomized controlled trial evaluating the efficacy of lopinavir-ritonavir versus standard care alone in the treatment of adult hospitalized patients with severe COVID-19. There were no differences in hospital mortality, time to clinical improvement, or viral RNA levels. Although the median time to improvement was 1 day shorter with lopinavir-ritonavir on intention-to-treat analysis, 14% of patients had adverse events requiring treatment discontinuation. Therefore, it was concluded that there was no benefit observed with lopinavir-ritonavir treatment versus standard treatment of severe COVID-19 patients (83). Historically, hydroxychloroquine, an anti-malarial and anti-inflammatory agent, has shown some promise in reducing mortality from SARS and, therefore, is currently being studied for COVID-19 (84). In one very limited study from France (n = 20 per group, nonrandomized), hydroxychloroquine was associated with reduced viral load and reduced duration of viral detection which was further attenuated by the addition of azithromycin (85).

Research is already underway to create a vaccine to protect against SARS-CoV-2. Taking advantage of the similarities in structure between SARS-CoV (responsible for the 2003 SARS epidemic) and SARS-CoV-2 (responsible for COVID-19), studies have mapped several epitopes to be targeted for a potential vaccine (86,87). WHO estimates an approximately 18-month timeframe for COVID-19 vaccine availability.

Until such time that effective therapies and vaccines become available, public health efforts should continue to focus on mitigating the spread of SARS-CoV-2 through well-established infection control strategies (88). This can be aided in the hospital with admission of SARS-CoV-2 positive patients into negative pressure rooms with contact precaution protocols requiring personal protective equipment such as gowns, gloves, fit-tested N95 respirators, and face shields. Additionally, rules limiting the people entering the isolation room and requiring logging of healthcare workers involved in COVID-19 patient care should be followed to effectively monitor patient contact and limit spread. All equipment (monitors, etc.) in the isolation room should be designated for the case patient only. Physicians should limit potential spread by recognizing any necessary aerosol-generating procedures and preparing accordingly (e.g., for intubation using controlled measures including paralytics, video laryngoscopy, N95 masks). Although fomites are suspected as the main source of transmission, there is also possible fecal-oral transmission; therefore, hand washing is a mainstay of control/prevention (89).


Although viral pneumonia is common, the specific inflammatory and immunosuppressive effects it has on the host is still largely unknown. COVID-19 has brought viral pneumonia and subsequent host pathology to the forefront of medical care and research. SARS-CoV-2 spread worldwide in a matter of months to cause a pandemic not seen since influenza in 1918. Our highly interconnected global society creates ample opportunity for the rapid spread of novel viruses. Since these types of viral pandemics have occurred multiple times historically (e.g., influenza in 1918, Middle East respiratory syndrome in 2014, and SARS in 2004) and will continue to occur in the future, research into immunomodulative therapies for patients afflicted with viral pneumonia will be a key aspect to improving outcomes after viral pneumonia. A personalized approach, taking into account differences in the biology of individuals and the pathophysiology of different viruses, will also be required to make significant progress in the treatment of these patients.


1. Pfuntner A, Wier LM, Stocks C. Most Frequent Conditions in U.S. Hospitals, 2011: Statistical Brief #162. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. 2006, Rockville, MD: Agency for Healthcare Research and Quality (US). Available at: Accessed March 27, 2020
2. World Health Organization: The Top 10 Causes of Death. 2018. Available at: Accessed March 23, 2020
3. Jain S, Self WH, Wunderink RG, et al.; CDC EPIC Study Team. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med. 2015; 373:415–427
4. Jain S. Epidemiology of viral pneumonia. Clin Chest Med. 2017; 38:1–9
5. Shorr AF, Zilberberg MD, Micek ST, et al. Viruses are prevalent in non-ventilated hospital-acquired pneumonia. Respir Med. 2017; 122:76–80
6. Alimi Y, Lim WS, Lansbury L, et al. Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe. J Clin Virol. 2017; 95:26–35
7. Burk M, El-Kersh K, Saad M, et al. Viral infection in community-acquired pneumonia: A systematic review and meta-analysis. Eur Respir Rev. 2016; 25:178–188
8. Choi SH, Huh JW, Hong SB, et al. Clinical characteristics and outcomes of severe rhinovirus-associated pneumonia identified by bronchoscopic bronchoalveolar lavage in adults: Comparison with severe influenza virus-associated pneumonia. J Clin Virol. 2015; 62:41–47
9. Johnstone J, Majumdar SR, Fox JD, et al. Viral infection in adults hospitalized with community-acquired pneumonia: Prevalence, pathogens, and presentation. Chest. 2008; 134:1141–1148
10. Moore M, Stuart B, Little P, et al. Predictors of pneumonia in lower respiratory tract infections: 3C prospective cough complication cohort study. Eur Respir J. 2017; 50:1700434
11. Shorr AF, Fisher K, Micek ST, et al. The burden of viruses in pneumonia associated with acute respiratory failure: An underappreciated issue. Chest. 2018; 154:84–90
12. Dunham-Snary KJ, Wu D, Sykes EA, et al. Hypoxic pulmonary vasoconstriction: From molecular mechanisms to medicine. Chest. 2017; 151:181–192
13. Paules C, Subbarao K. Influenza. Lancet. 2017; 390:697–708
14. Kalil AC, Thomas PG. Influenza virus-related critical illness: Pathophysiology and epidemiology. Crit Care. 2019; 23:258
15. Yeldandi AV, Colby TV. Pathologic features of lung biopsy specimens from influenza pneumonia cases. Hum Pathol. 1994; 25:47–53
16. Guarner J, Shieh WJ, Dawson J, et al. Immunohistochemical and in situ hybridization studies of influenza A virus infection in human lungs. Am J Clin Pathol. 2000; 114:227–233
17. Martin CM, Kunin CM, Gottlieb LS, et al. Asian influenza A in Boston, 1957-1958. I. Observations in thirty-two influenza-associated fatal cases. AMA Arch Intern Med. 1959; 103:515–531
18. Percopo CM, Dyer KD, Ochkur SI, et al. Activated mouse eosinophils protect against lethal respiratory virus infection. Blood. 2014; 123:743–752
19. Hermesh T, Moltedo B, Moran TM, et al. Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell Host Microbe. 2010; 7:343–353
20. Davey RT Jr, Lynfield R, Dwyer DE, et al.; INSIGHT FLU 002 & 003 Study Groups. The association between serum biomarkers and disease outcome in influenza A(H1N1)pdm09 virus infection: Results of two international observational cohort studies. PLoS One. 2013; 8:e57121
21. Rodriguez-Ramirez HG, Salinas-Carmona MC, Barboza-Quintana O, et al. CD206+ cell number differentiates influenza A (H1N1)pdm09 from seasonal influenza A virus in fatal cases. Mediators Inflamm. 2014; 2014:921054
22. Zobel K, Martus P, Pletz MW, et al.; CAPNETZ study group. Interleukin 6, lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk and etiologic patterns in patients with community-acquired pneumonia: Results from the German competence network CAPNETZ. BMC Pulm Med. 2012; 12:6
23. Endeman H, Meijvis SC, Rijkers GT, et al. Systemic cytokine response in patients with community-acquired pneumonia. Eur Respir J. 2011; 37:1431–1438
24. Burgmeijer EH, Duijkers R, Lutter R, et al. Plasma cytokine profile on admission related to aetiology in community-acquired pneumonia. Clin Respir J. 2019; 13:605–613
25. Siljan WW, Holter JC, Nymo SH, et al. Cytokine responses, microbial aetiology and short-term outcome in community-acquired pneumonia. Eur J Clin Invest. 2018; 48:e12865
26. Rendon A, Rendon-Ramirez EJ, Rosas-Taraco AG. Relevant cytokines in the management of community-acquired pneumonia. Curr Infect Dis Rep. 2016; 18:10
27. Rendón-Ramirez EJ, Ortiz-Stern A, Martinez-Mejia C, et al. TGF-β blood levels distinguish between influenza a (H1N1)pdm09 virus sepsis and sepsis due to other forms of community-acquired pneumonia. Viral Immunol. 2015; 28:248–254
28. Paats MS, Bergen IM, Hanselaar WE, et al. Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia. Eur Respir J. 2013; 41:1378–1385
29. Kellum JA, Kong L, Fink MP, et al.; GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis: Results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med. 2007; 167:1655–1663
30. Donnelly SC, Strieter RM, Reid PT, et al. The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome. Ann Intern Med. 1996; 125:191–196
31. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009; 227:75–86
32. Creagh EM, O’Neill LA. TLRs, NLRs and RLRs: A trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol. 2006; 27:352–357
33. Wilkins C, Gale M Jr. Recognition of viruses by cytoplasmic sensors. Curr Opin Immunol. 2010; 22:41–47
34. Yoo JK, Kim TS, Hufford MM, et al. Viral infection of the lung: Host response and sequelae. J Allergy Clin Immunol. 2013; 132:1263–1276; quiz 1277
35. Pang IK, Iwasaki A. Inflammasomes as mediators of immunity against influenza virus. Trends Immunol. 2011; 32:34–41
36. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003; 425:516–521
37. Ichinohe T, Pang IK, Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol. 2010; 11:404–410
38. Muruve DA, Pétrilli V, Zaiss AK, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008; 452:103–107
39. Koyama S, Ishii KJ, Kumar H, et al. Differential role of TLR- and RLR-signaling in the immune responses to influenza A virus infection and vaccination. J Immunol. 2007; 179:4711–4720
40. Heer AK, Shamshiev A, Donda A, et al. TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. J Immunol. 2007; 178:2182–2191
41. Jennings LC, Anderson TP, Beynon KA, et al. Incidence and characteristics of viral community-acquired pneumonia in adults. Thorax. 2008; 63:42–48
42. Abelenda-Alonso G, Rombauts A, Gudiol C, et al. Influenza and bacterial coinfection in adults with community-acquired pneumonia admitted to conventional wards: Risk factors, clinical features, and outcomes. Open Forum Infect Dis. 2020; 7:ofaa066
43. Cawcutt K, Kalil AC. Pneumonia with bacterial and viral coinfection. Curr Opin Crit Care. 2017; 23:385–390
44. Talbot TR, Poehling KA, Hartert TV, et al. Seasonality of invasive pneumococcal disease: Temporal relation to documented influenza and respiratory syncytial viral circulation. Am J Med. 2005; 118:285–291
45. Robinson KM, Kolls JK, Alcorn JF. The immunology of influenza virus-associated bacterial pneumonia. Curr Opin Immunol. 2015; 34:59–67
46. van der Sluijs KF, van der Poll T, Lutter R, et al. Bench-to-bedside review: Bacterial pneumonia with influenza - pathogenesis and clinical implications. Crit Care. 2010; 14:219
47. Damjanovic D, Lai R, Jeyanathan M, et al. Marked improvement of severe lung immunopathology by influenza-associated pneumococcal superinfection requires the control of both bacterial replication and host immune responses. Am J Pathol. 2013; 183:868–880
48. Ghoneim HE, Thomas PG, McCullers JA. Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J Immunol. 2013; 191:1250–1259
49. Kudva A, Scheller EV, Robinson KM, et al. Influenza A inhibits Th17-mediated host defense against bacterial pneumonia in mice. J Immunol. 2011; 186:1666–1674
50. Pittet LA, Hall-Stoodley L, Rutkowski MR, et al. Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae. Am J Respir Cell Mol Biol. 2010; 42:450–460
51. Plotkowski MC, Puchelle E, Beck G, et al. Adherence of type I Streptococcus pneumoniae to tracheal epithelium of mice infected with influenza A/PR8 virus. Am Rev Respir Dis. 1986; 134:1040–1044
52. Tanaka A, Nakamura S, Seki M, et al. Toll-like receptor 4 agonistic antibody promotes innate immunity against severe pneumonia induced by coinfection with influenza virus and Streptococcus pneumoniae. Clin Vaccine Immunol. 2013; 20:977–985
53. Didierlaurent A, Goulding J, Patel S, et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. J Exp Med. 2008; 205:323–329
54. Waterer GW. Community-acquired pneumonia: Genomics, epigenomics, transcriptomics, proteomics, and metabolomics. Semin Respir Crit Care Med. 2012; 33:257–265
55. Bermejo-Martin JF, Martin-Loeches I, Rello J, et al. Host adaptive immunity deficiency in severe pandemic influenza. Crit Care. 2010; 14:R167
56. Kim H, Webster RG, Webby RJ. Influenza virus: Dealing with a drifting and shifting pathogen. Viral Immunol. 2018; 31:174–183
57. Mei L, Song P, Tang Q, et al. Changes in and shortcomings of control strategies, drug stockpiles, and vaccine development during outbreaks of avian influenza A H5N1, H1N1, and H7N9 among humans. Biosci Trends. 2013; 7:64–76
58. Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013; 368:1888–1897
59. Bautista E, Chotpitayasunondh T, Gao Z, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010; 362:1708–1719
60. Cox NJ, Subbarao K. Global epidemiology of influenza: Past and present. Annu Rev Med. 2000; 51:407–421
61. Jackson ML, Chung JR, Jackson LA, et al. Influenza vaccine effectiveness in the United States during the 2015-2016 season. N Engl J Med. 2017; 377:534–543
62. Desmet CJ, Ishii KJ. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol. 2012; 12:479–491
63. Hayashi T, Momota M, Kuroda E, et al. DAMP-inducing adjuvant and PAMP adjuvants parallelly enhance protective type-2 and type-1 immune responses to influenza split vaccination. Front Immunol. 2018; 9:2619
64. Ruuskanen O, Lahti E, Jennings LC, et al. Viral pneumonia. Lancet. 2011; 377:1264–1275
65. O’Donnell FL, Taubman SB. Follow-up analysis of the incidence of acute respiratory infections among enlisted service members during their first year of military service before and after the 2011 resumption of adenovirus vaccination of basic trainees. MSMR. 2015; 22:2–7
66. Radin JM, Hawksworth AW, Blair PJ, et al. Dramatic decline of respiratory illness among US military recruits after the renewed use of adenovirus vaccines. Clin Infect Dis. 2014; 59:962–968
67. Clemmons NS, McCormic ZD, Gaydos JC, et al. Acute respiratory disease in US army trainees 3 years after reintroduction of adenovirus vaccine (1). Emerg Infect Dis. 2017; 23:95–98
68. Tucker SN, Tingley DW, Scallan CD. Oral adenoviral-based vaccines: Historical perspective and future opportunity. Expert Rev Vaccines. 2008; 7:25–31
69. Joyce C, Scallan CD, Mateo R, et al. Orally administered adenoviral-based vaccine induces respiratory mucosal memory and protection against RSV infection in cotton rats. Vaccine. 2018; 36:4265–4277
70. Scheltema NM, Nibbelke EE, Pouw J, et al. Respiratory syncytial virus prevention and asthma in healthy preterm infants: A randomised controlled trial. Lancet Respir Med. 2018; 6:257–264
71. Blanken MO, Rovers MM, Bont L; Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze. N Engl J Med. 2013; 369:782–783
72. Fainaru M, Schafer Z, Gavish D, et al. Interactions between human and carp (Cyprimus carpio) low density lipoproteins (LDL) and LDL receptors. Comp Biochem Physiol B. 1988; 91:331–338
73. Driscoll AJ, Arshad SH, Bont L, et al. Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting. Vaccine. 2020; 38:2435–2448
74. Del Rio C, Malani PN. COVID-19-new insights on a rapidly changing epidemic. JAMA. 2020. Feb 28. [online ahead of print]
75. Guan WJ, Ni ZY, Hu Y, et al.; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020. Feb 28. [online ahead of print]
76. Bermejo-Martin JF, Almansa R, Menendez R, et al. Lymphopenic community acquired pneumonia as signature of severe COVID-19 infection. J Infect. 2020. Mar 5. [online ahead of print]
77. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med. 2020. Feb 24. [online ahead of print]
78. Bermejo-Martin JF, Martin-Fernandez M, Lopez-Mestanza C, et al. Shared features of endothelial dysfunction between sepsis and its preceding risk factors (aging and chronic disease). J Clin Med. 2018; 7:400
79. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020; 38:1–9
80. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497–506
81. Marchand-Senecal X, Kozak R, Mubareka S, et al. Diagnosis and management of first case of COVID-19 in Canada: Lessons applied from SARS. Clin Infect Dis. 2020. Mar 9. [online ahead of print]
82. Chinese Clinical Trial Register: A randomized, controlled open-label trial to evaluate the efficacy and safety of lopinavir-ritonavir in hospitalized patients with novel coronavirus pneumonia (COVID-19)2020, Chengdu, Sichuan, China: Ministry of Health (China). H. ChiCTR2000029308. Available at: Accessed March 23, 2020
83. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020. Mar 18. [online ahead of print]
84. Fauci AS, Lane HC, Redfield RR. Covid-19 - navigating the uncharted. N Engl J Med. 2020; 382:1268–1269
85. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020. Mar 20. [online ahead of print]
86. Ahmed SF, Quadeer AA, McKay MR. Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies. Viruses. 2020; 12:E254
87. Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020; 94:e00127–20
88. Jiang F, Deng L, Zhang L, et al. Review of the clinical characteristics of coronavirus disease 2019 (COVID-19). J Gen Intern Med. 2020. Mar 4. [online ahead of print]
89. World Health Organization: Coronavirus Disease (COVID-19) Technical Guidance: Infection Prevention and Control/WASH. 2020. Available at: Accessed March 23, 2020

coronavirus; immunology; influenza virus; severe acute respiratory syndrome; viral pneumonia

Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.