Empiric use of antibiotics remains as cornerstone of treating pneumonia in the absence of effective point-of-care diagnostics for differentiating bacterial from viral infection. Many children who have viral pneumonia will continue to receive antibiotics without benefit. Early reliable detection of viral pneumonia, or early exclusion of bacterial pneumonia, could reduce unnecessary antibiotic therapy, thereby mitigating the risk of emerging antibiotic resistance. While we have been unable to identify a single biomarker or clinical feature that could be used to confidently distinguish bacterial from viral pneumonia, our findings suggest there may be utility in more sophisticated algorithms that integrate a number of clinical, microbiological, inflammatory biomarker, or radiological factors to improve pneumonia diagnostics and better targeting therapies.

Before admission, 31 of the 53 patients with viral pneumonia had received antibiotics. Eleven patients showed early treatment failure with a worsened condition. The other 20 patients showed both early and late treatment failure. Two of these 20 patients received effective corticosteroid therapy before admission. The condition of the other 18 patients became worse after antibiotic treatment. The remaining 22 patients had not received antibiotics or corticosteroids before admission, but they were referred to our hospital after their condition worsened. None of these patients had received neuraminidase inhibitors (NIs) before admission.

After admission, 46 of these 53 patients received antibiotics with β-lactams plus macrolides (n=22, 41.5%), fluoroquinolones with or without other antibiotics (n=16, 30.2%), and others (n=8, 15.1%). Antibiotics were not administered to 7 patients after admission because antibiotic treatment administered by their local physicians had failed.

Six of 13 patients with influenza-associated pneumonia received NIs (from the 5th to 23rd day from the onset of initial symptoms). In three of these 6 patients, both NIs and corticosteroids were started simultaneously, and these patients improved. In 4 of the 6 patients, NIs were started without corticosteroids (from the 5th, 8th, and 11th day after the onset of symptoms). NIs were effective in 2 of 3 patients. In the other patient, however, NI was administered from the 11th day after onset, but the patient showed early treatment failure and was switched to corticosteroid therapy from the 14th day, which was effective. In 7 patients who did not receive NIs, 6 received corticosteroid therapy (which was effective) from the 11th, 19th, 22nd, 23rd, 25th, and 47th day, respectively, after the onset of symptoms. The pulmonary shadows of the two other patients who did not receive corticosteroids or NIs improved spontaneously during follow-up. Among the 40 patients suffering from viral pneumonia due to non-influenza viruses, corticosteroids with antibiotics were administered to 21 patients from a median of 15 (range, 6-45) days after the onset of symptoms. Two of these patients died. Corticosteroid therapy was effective in one of these patients; however, this patient experienced repeated episodes of aspiration pneumonia causing their condition to deteriorate until their death. The other patient showed early and late treatment failure with corticosteroid therapy, causing the progressive deterioration of the patient's condition until their death. The other 19 patients received antibiotics without corticosteroids and all survived.

We described favorable clinical outcomes to antiviral therapy with cidofovir in non-immunocompromised adult patients with severe AdV pneumonia. Our data suggest that early administration of cidofovir in the course of treatment for respiratory failure as a result of AdV pneumonia in non-immunocompromised patients could be a treatment strategy worth considering, especially in cases of HAdV-55 infection.

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2466/14/144/prepub

Corticosteroids could increase mortality in patients with influenza pneumonia. Randomized controlled studies are needed to further verify this conclusion.

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2334/13/434/prepub

The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included hospital length-of-stay (LOS), intensive care unit (ICU) admission, and readmission rates at 30, 90, and 180 days after the index hospitalization.

We obtained written informed consent from a parent or a caregiver of the participating children before enrolling them into the study. The study protocol was reviewed and approved by the institutional review boards (IRB; named as Research Review Committee and Ethical Review Committee) of icddr,b. CDC relied on icddr,b’s IRB review.

Antibiotics constitute the first-line therapy for bacterial pneumonia. To complement current clinical practice, secondary bacterial pneumonia-infected mice were treated with anti-cANGPTL4 MAb and moxifloxacin, a commonly used antibiotic effective against respiratory infections. The combined treatment significantly prolonged the median survival time of infected mice (80%) compared to zero survival of mice receiving the control IgG treatment or moxifloxacin alone (Fig. 4A; see Fig. S3A in the supplemental material). Moreover, this combined treatment better protected alveolar integrity and reduced residual fluid in the alveolar spaces, thus indicating its efficacy in ameliorating lung edema, diminishing tissue damage, and prolonging survival time (Fig. 4B; Fig. S3B and C). As indicated in Fig. 4B and quantified in Fig. S3C, Flu+S3 superinfection destroyed the alveolar structures and caused severe edema in the lungs of infected wild-type mice. Antibiotic treatment alone protected the alveolar structures but could not clear the edema and infiltration of immune cells. Although the anti-cANGPTL4 or antipneumolysin antibody treatments alone improved lung tissue integrity and reduced edema, these improvements were not as significant as those observed when using a combined treatment with antibiotics and anti-cANGPTL4 MAb or with anti-cANGPTL4 and antipneumolysin antibodies (Fig. 4B; Fig. S3C). The efficacy of a combined approach was further confirmed by marked improvements in the mouse survival rate and lung tissue integrity in treatment groups of wild-type mice receiving antibiotics, anti-cANGPTL4, and antipneumolysin MAb. Similar trends were observed in ANGPTL4−/− mice receiving antibiotic and antipneumolysin treatment (Fig. S3).

Next, we performed transcriptomic analysis of the lung tissues to elucidate the detailed host response factors to secondary pneumococcal pneumonia during the various treatment modalities (Fig. 4C). Compared with antibiotic treatment alone, our analysis indicated that the anti-cANGPTL4 MAb treatment combined with an antibiotic notably improved the immune responses against bacterial infection as well as coagulation function, thus attenuating intra-alveolar hemorrhage and edema in the lungs of secondary bacterial pneumonia-infected mice. For example, this combination treatment yielded a 3-fold increase in activation of the coagulation system pathway compared to MAb treatment alone (Fig. 4C).

This is a retrospective and observational study in which data from children and adolescents under 18 years of age, visited to one of the 117 Emergency Departments (EDs) in Korea between 1 January 2007 and 31 December 2014 were analyzed. The data were obtained from the National Emergency Department Information System (NEDIS) for children and adolescents under 18 years of age. The patients with diagnosis codes for CAP, based on International Classification of Disease, 10th revision diagnostic codes (Table 1) which was provided at the time of discharge from ED or after hospitalization were selected to identify eligible cases.

Categorical data was performed chi-square test, depending on age. Annual and seasonal distribution of ED visits were described by the number and % of total. The tau values were calculated using the Mann-Kendall method to analyze increasing or decreasing trends. Monthly incidence rate of diseases from data in 2008–2014 were decomposed and plotted into three components of trend, seasonality and remainder using LOESS procedure. Analyzes were performed using SAS ver. 9.4 (SAS Institute Inc., Cary, NC, USA), with a P value≤0.05 deemed significant.

Institutional Review Boards waived deliberation of this study.

The clinical responses to treatment in each patient are shown in Figs 2 and 3. Fig 2 shows the clinical responses of patients 1–3, who needed vasopressors and mechanical ventilation due to septic shock and severe respiratory failure. In patient 1, after cidofovir administration, blood pressure stabilized after approximately 4 days, and tachypnea, tachycardia, and fever improved within 5 days. Oxygenation completely improved within 14 days (Fig 2A). In patient 2, blood pressure stabilized after approximately 2 days, and tachypnea, tachycardia, and fever improved within 4 days. Oxygenation completely improved within 8 days of cidofovir administration (Fig 2B). In patient 3, blood pressure stabilized after approximately 4 days, and tachypnea, tachycardia, and fever within 7 days. Oxygenation completely improved within 9 days of cidofovir administration (Fig 2C).

Fig 3 shows the clinical responses of patients 4–7. In patient 4, tachypnea, tachycardia, and fever improved within 3 days, and oxygenation completely improved within 5 days, of cidofovir administration (Fig 3A). In patient 5, tachypnea, tachycardia, and fever improved in 3 days, and oxygenation completely improved within 12 days, of cidofovir administration (Fig 3B). In patient 6, tachypnea, tachycardia, and fever improved in 2 days, and oxygenation completely improved within 2 days, of cidofovir administration (Fig 3C). In patient 7, tachypnea, tachycardia, and fever improved in 2 days, and oxygenation completely improved within 6 days, of cidofovir administration (Fig 3D).

Case management of pneumonia is a strategy by which severity of disease is classified as severe or non-severe. All children receive early, appropriate oral antibiotics, and severe cases are referred for parenteral antibiotics. When implemented in high-burden areas before the availability of conjugate vaccines, case management as part of Integrated Management of Childhood Illness was associated with a 27% decrease in overall child mortality, and 42% decrease in pneumonia-specific mortality. However the predominance of viral causes of pneumonia and low case fatality have prompted concern about overuse of antibiotics. Several randomized controlled trials comparing oral antibiotics to placebo for non-severe pneumonia have been performed [75–77] and others are ongoing. In two studies, performed in Denmark and in India, outcomes of antibiotic and placebo treatments were equivalent [76, 77]. In the third study, in Pakistan, there was a non-significant 24% vs. 20% rate of failure in the placebo group, which was deemed to be non-equivalent to the antibiotic group. Furthermore, because WHO-classified non-severe pneumonia and bronchiolitis might be considered within a spectrum of lower respiratory disease, many children with clinical pneumonia could actually have viral bronchiolitis, for which antibiotics are not beneficial. This has been reflected in British and Spanish national pneumonia guidelines, which do not recommend routine antibiotic treatment for children younger than 2 years with evidence of pneumococcal conjugate vaccination who present with non-severe pneumonia. The United States’ national guidelines recommend withholding antibiotics in children up to age 5 years presenting with non-severe pneumonia. However, given the high mortality from pneumonia in low- and middle-income countries, the lack of easy access to care, and the high prevalence of risk factors for severe disease, revised World Health Organization pneumonia guidelines still recommend antibiotic treatment for all children who meet the WHO pneumonia case definitions.

Use of supplemental oxygen is life-saving, but this is not universally available in low- and middle-income countries; it is estimated that use of supplemental oxygen systems could reduce mortality of children with hypoxic pneumonia by 20%. Identifying systems capacity to increase availability of oxygen in health facilities, and identifying barriers to further implementation are among the top 15 priorities for future childhood pneumonia research. However, up to 81% of pneumonia deaths in 2010 occurred outside health facilities, so there are major challenges with access to health services and health-seeking behavior of vulnerable populations. Identifying and changing the barriers to accessing health care is an important area with the potential to impact the survival and health of the most vulnerable children.

The treatment and clinical outcomes between the severe and non-severe groups are compared in Table3. There were no significant differences in antimicrobial therapy, intensive care units, hemodialysis, and mechanical ventilation between the two groups. All patients from the two groups received the appropriate antibiotic therapy for pneumococcal pneumonia based on the antimicrobial susceptibility results. Twenty-three (12·0%) patients received antibiotics for pneumococcal pneumonia prior to arriving at this hospital, which was not significantly different between the case and the control groups (14 [14·1%] vs. 9 [9·8%], respectively; P = 0·355). The resistance rates of the pneumococcal isolates to penicillin and levofloxacin were significantly higher in the case group than in the control group (Table4).

The all-cause in-hospital mortality rate and pneumonia-related mortality rate were 8·4% and 6·3%, respectively. The median length of hospital stay for inpatients was 8 days (IQR, 4–18). Patients with severe pneumococcal pneumonia showed higher pneumonia-related mortality and longer hospital stays than patients with non-severe pneumococcal pneumonia (Table3).

This research was submitted to our university institutional review board and was

approved. The IRBNet ID is 1083099-2.

This study highlights the potential benefits of improved diagnostics for respiratory viruses, primarily the potential for decreased antibacterial exposure and thus decreased selective pressure for resistant bacterial isolates. Antibacterial exposure applies selective pressure and promotes colonization/infection by resistant organisms including MRSA and VRE [40, 41]. Halting this process is essential to maintain effective therapeutic options in the future and may be aided by discontinuation of antibacterials in cases of viral pneumonia. In our study, patients with viral pneumonia exposed to long-course antibacterials had more occurrences of subsequent infection or colonization with MDRO isolates. In contrast, the number of patients with subsequent MDRO infection or colonization was not different between groups although this may be due to the small number of patients in each group. No differences in clinical outcomes, including in-hospital mortality and readmission rates, were observed between patient groups. In the setting of viral pneumonia and no coinfecting bacterial pathogens, discontinuation of antibacterials is reasonable in many if not most cases, and may allow for decreased overall antibacterial use. Enhanced diagnostic technologies can potentially be incorporated into antimicrobial stewardship practices to allow for de-escalation of unnecessary antibacterials. These findings warrant further investigation to determine the applicability of an antibacterial de-escalation approach in the setting of viral pneumonia.

Because the severity of pneumonia and ARDS may be dependent on the amount of substances that are toxic to respiratory cells, the first target of early treatment for ARDS is to reduce the toxic substances as soon as possible. Early antimicrobial therapy, such as the provision of antibiotics and antivirals, for pathogen-induced pneumonia is critical to reduce the number of pathogens and pathogen-originated substances, thereby inducing early recovery from the disease. Antibiotic treatment is recommended as soon as possible when bacterial infection is suspected. On the other hand, the use of antibiotics is not always successful in patients with community-acquired pneumonia (CAP). Some patients with bacterial pneumonia can experience complications such as lung abscess, empyema, pulmonary gangrene, and necrotizing pneumonia. Pneumonia has remained one of the most common causes of mortality in young children under five years of age in the developing world throughout the antibiotic era. Furthermore, early treatment with antibiotics for young children with suspected pneumonia diagnosed by the clinical criteria of the World Health Organization has been shown not to reduce referral rates to hospitals or to prevent treatment failure, suggesting that most of these patients are affected by other non-bacterial respiratory pathogens. Some pneumonia patients with CAP in developed countries, especially elderly patients with underlying diseases, experience treatment failure with a high mortality of 15%–20%, despite early application of antimicrobials. Some pneumonia patients with septic conditions show transient deterioration of clinical symptoms following antibiotic treatment. This may be caused by a cytokine storm, characterized by extensive immune cell activation against large amounts of substances produced during the process of bacterial death. Antibiotic treatment may induce rapid defervescence for patients with M. pneumoniae pneumonia, but some patients show progressive pneumonia despite early treatment with adequate antibiotics. Necrotizing pneumonia is a unique type of lobar pneumonia caused by pneumococci and other pathogens. Patients with necrotizing pneumonia show a protracted clinical course with prolonged fever, despite treatment with an adequate dose of antibiotics. Clinical course and computed tomography findings are relatively similar among patients affected with different pathogens, suggesting a common pathogenesis of the disease, such as ischemic lung injury caused by blood vessel occlusion from the insults of bacterial infection. Similar findings are observed in respiratory virus infections. In influenza virus infection, patients receiving early antiviral treatment such as oseltamivir may show more rapid defervescence than patients without early antiviral treatment. Some patients, however, are shown to be rapidly progressive to ARDS despite early antiviral treatment. These findings suggest that antimicrobials may have limitations in some ARDS patients with infection-related conditions.

Because abnormal immune reaction of the host against infectious insults, such as cytokine storm, is a suggested part of the immunopathogenesis of ARDS, early management of this type of immune disturbance may be critical in preventing the progression of the disease. Excessive substances from various insults react to a type of organ-specific tissue cells and induce corresponding excessive responses of immune cells, which may be responsible for damage to the same organ-specific cells, manifesting similar clinical and pathological findings. In order to reduce abnormal immune reactions, immune modulators, especially corticosteroids, have been used for pneumonia or ARDS. Although numerous studies, including studies regarding influenza pneumonia, have been conducted on corticosteroid effects in patients with severe pneumonia or ARDS, the results remain controversial. The cause of this controversy, however, may be that the timing of therapy, the dose of initial steroids, schedules of treatment, and patient selection are different across existing studies. Recently, well-randomized case-control studies have reported that early corticosteroid treatment with antibiotics within 24–36 h after admission is helpful for reducing treatment failure and morbidity in adult patients with severe CAP. Considering the immunopathogenesis of pneumonia and ARDS suggested in this article, earlier treatment (i.e., intervention as soon as possible) in fact stands to show better outcomes. We have also observed that early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin (IVIG)) with antibiotics or antivirals may halt the progression of pneumonia and induce rapid recovery of pulmonary lesions in patients with M. pneumoniae or influenza virus infections. In the 2009 influenza pandemic, we observed that extensive pneumonic consolidations that had developed rapidly within 48 h after fever onset resolved dramatically within 24 h after corticosteroids and/or IVIG treatment. This finding suggests that there is a critical period for reversible pathologic states, which can be induced by early immune modulators. Acute bronchiolitis is a self-limiting lower respiratory tract infection in infancy, which is caused by various respiratory pathogens, including respiratory syncytial viruses, rhinoviruses, and M. pneumoniae. However, some severely affected patients show severe respiratory distress and complications, including respiratory failure with mechanical ventilation and subsequent bronchiolitis obliterans. Also, the effects of corticosteroid treatment for patients with acute bronchiolitis remain controversial despite a great deal of existing studies. We have applied the same treatment modality for patients with severe acute bronchiolitis, as well as for severe M. pneumoniae and influenza pneumonia, which consist of early, short-term, high-dose and rapid tapering of corticosteroids. For severe bronchiolitis patients with respiratory distress in need of oxygen supply at the time of presentation or during hospitalization, we have used intravenous methylprednisolone (5–10 mg/kg/day, as initial dose), regardless of patient age and causal viruses. During the past decade at our institution, we experienced no patient who progressed to a state needing the intensive care unit (ICU) and mechanical ventilation or to respiratory complications among over 1200 patients (unpublished observation).

Lymphopenia may be characteristic of severe pneumonia patients infected with respiratory pathogens, including influenza viruses, corona viruses, the measles virus, and M. pneumoniae. The severity of lymphopenia is correlated with the severity of lung injury. The autopsy findings of severe ARDS patients and experimental animals infected with influenza viruses show lymphocyte depletion of whole lymphoid tissues. This finding, together with lymphocyte predominance in early lung lesions, suggests that immune cells (including T cells) may control the substances from pathogens and/or injured host cells. It is possible that there is a limitation on the numerical capacity of the host immune system on mobilizing immune cells against these relentless substances to counter extensive lung cell injury in immune-competent patients. Patients with underlying diseases, malnutrition or immune-deficient states may have a limited repertoire of immune cells. Furthermore, severe pneumonia or ARDS from a viral infection tends to induce subsequent bacterial infections in patients, which adds to the workload of immune cells. However, prolonged high-dose corticosteroid therapy or immune-suppressants in advanced ARDS patients may suppress all working immune cells, including specific T cells and B cells that may control etiologic substances. Therefore, early management of conditions with ARDS potential may be crucial at the stage of hyperimmune reaction, possibly performed by non-specific adaptive immune cells. During any respiratory insult event, it is proposed that patients who have acute onset respiratory distress, such as dyspnea with or without wheezing, should be treated as soon as possible with an early and adequate dosage of systemic immune modulators (corticosteroids and/or IVIG). The rationale for this recommendation may be the same as the rationale behind the recommendations for early antibiotics and antivirals, since there may be a critical stage of lung cell injury due to hyperimmune reactions of the host. The corticosteroid dose could be tapered rapidly for normally acting immune cells, especially for specific immune cells, which may appear within several days to a week from the time of insult.

Corticosteroids have multi-potent immune-modulatory and anti-inflammatory modes of action on almost all human diseases, including infectious diseases, allergic diseases, malignances, and rheumatic diseases. Although the entire mode of action of corticosteroids is unknown, corticosteroids may act on hyperactive immune cells that are needed for disease control. In the case of hyperactivity, however, these immune cells may overproduce immune substances such as proinflammatory cytokines. The immune cells affected by corticosteroids, especially non-specific immature T cells, B cells, and eosinophils, may be rapidly eliminated by apoptosis. Intravenous immunoglobulin (IVIG) is an alternative immune-modulator, and indications for high-dose IVIG have been extended for immune-mediated diseases, including Kawasaki disease and other diseases. It has been reported that IVIG shows beneficial effects on pulmonary lesions in influenza pneumonia and M. pneumoniae pneumonia. Precise mechanisms of the immune-modulatory and anti-inflammatory effects of IVIG on immune-mediated diseases are also unknown, but IVIG may act on hyperimmune reactions of hosts via the binding to receptors of immune cells, etiologic substances including PPs, or other proteins that are involved in inflammatory pathways. Because corticosteroids (i.e., hydrocortisone) and IVIG (i.e., serum IgG) can be regarded as host-origin immune controllers in vivo, it is possible that a host immune system cannot produce them in adequate doses within the short duration of exposure to acute extensive substances from infectious insults. Thus, for patients with ARDS or other acute whole organ-specific diseases with lymphopenia, early systemic immune-modulator treatment before the occurrence of diffuse organ-specific cell injury may be critical, especially in previously healthy immune-competent patients. It is possible that an early and adequate dose of immune modulators can mitigate rapid disease progression, and reduce morbidity, and possibly prevent irreversible total organ destruction.

Although eventual recovery from ARDS is dependent on the immune status of a patient, other aspects of supportive care, especially lung preventive ventilation therapy, are important. The protective lung ventilation strategies (low tidal volume or limited driving pressure strategy) are currently accepted as major ways to improve the mortality of ARDS, and the main purpose of protective ventilation is to minimize the lung cell injury and avoid the further release of inflammatory mediators from the mechanically injured lung cells. Other therapeutic modalities, such as extracorporeal membrane oxygenation (ECMO), nutritional support, and other anti-inflammatory therapies, are also important during the delicate period in which immune cells are combating the insults from ARDS.

Several previous studies have revealed potential morbidity from bacterial pneumonia

in patients with respiratory syncytial virus (RSV). RSV infection may increase the

risk for pneumococcal pneumonia.1 RSV increases the virulence of streptococcal pneumonia by binding to

penicillin-binding protein 1a. Coinfection with RSV and Streptococcus

pneumoniae is associated with severe and often fatal pneumonia.2 Physicians must be mindful of the potential for secondary bacterial pneumonia

in viral bronchiolitis so that it can be promptly treated.

As pediatricians, we follow the guidelines published by the American Academy of

Pediatrics. The 2014 guidelines dealing with evaluation and management of viral

bronchiolitis promote supportive care, and note that routine radiographic or

laboratory studies are not necessary.3 While these guidelines are paramount to treating viral illness, it is

imperative that the physician recognizes at what point further investigation is

warranted. Missing a secondary pneumonia could result in delay in antibiotic

treatment, transfer to the pediatric intensive care unit (PICU), or intubation.

Following a respiratory season at our institution, we noted that children with viral

illness who also had a fever tended to have a worse clinical course versus afebrile

patients. We hypothesized that fever may be a marker for secondary bacterial

pneumonia in patients with viral bronchiolitis. Fever is defined as temperature

≥100.4°F. If a patient developed a fever and the workup showed pneumonia, then

antibiotics could be started quickly rather than waiting until after worsening of

the patient’s clinical condition. Our hypothesis is based on the following anecdotal

evidence from our practice:

Our objective is to investigate whether children with viral bronchiolitis with fever

are more likely to have a diagnosis of secondary bacterial pneumonia than their

counterparts without fever.

The following combination therapies may be performed. Anti-pneumococcal, anti-pseudomonal β-lactams, such as cefepime, piperacillin/tazobactam, imipenem, and meropenem may be used.

(a) Anti-pneumococcal, anti-pseudomonal β-lactam + ciprofloxacin or levofloxacin

(b) Anti-pneumococcal, anti-pseudomonal β-lactam + aminoglycoside + azithromycin

(c) Anti-pneumococcal, anti-pseudomonal β-lactam + aminoglycoside + anti-pneumococcal fluoroquinolone (gemifloxacin, levofloxacin, moxifloxacin)

The risk factors of P. aeruginosa infection include alcohol consumption, structural lung diseases such as bronchodilation, frequent use of steroids due to acute worsening of chronic obstructive pulmonary disease, and use of antibiotics in the last three months. If there is a possibility that a patient has pneumonia caused by P. aeruginosa, antibiotics that are effective against and highly sensitive to S. pneumoniae must be selected. Examples of these antibiotics include cefepime, piperacillin/tazobactam, imipenem, and meropenem. In a prospective observational study, gram-negative bacillus infections including those caused by P. aeruginosa were associated with high mortality rates. In a multi-institutional study conducted in Asian, gram-negative bacilli accounted for 10.1% of all cases of deaths, were the most common causative bacteria of severe pneumonia, and were a risk factor of death. Of these bacteria, P. aeruginosa may exhibit various levels of antibiotic resistance. Therefore, more than two empirical combination therapies are needed against these bacteria, and it is recommended to readjust the antibiotic selection once the bacteria are isolated and their susceptibility results are obtained.

This study compared a cohort of 174 patients with viral pneumonia and mixed viral–bacterial infection based on exposure to continued empiric antibacterials after respiratory virus identification. More of the subsequent infecting or colonizing bacterial isolates from the group with pure viral pneumonia who received continued long-course antibacterials were defined as MDROs compared with the short-course group (P = 0.027). These findings suggest that more prolonged exposure to broad-spectrum antibacterials in patients with viral pneumonia may have promoted resistance in these patients.

No benefit of continued empiric antibacterials for patients with pure viral pneumonia was seen in this study. The risk of bacterial coinfection in the setting of viral pneumonia, especially with influenza, creates a challenging situation for clinicians. The potential detrimental impact of not treating a bacterial pathogen weighs heavily on the decision process and downstream effects of such therapies may be disregarded. Our findings of similar clinical outcomes between patients with pure viral pneumonia who received long-course antibacterials after virus recognition and those who did not may suggest opportunity for de-escalation of empiric antibacterial therapy when viral pneumonia is identified.

A previous randomized controlled trial by Oosterheert et al. evaluated implementation of real-time PCR rapid diagnostics for respiratory pathogen identification. They found increased diagnostic yield with the assay but no difference in antibiotic use, and hypothesized that reluctance to change treatment based on testing results may have inhibited cost-effectiveness from being demonstrated. In our study, systemic antibacterials were discontinued following identification of a respiratory virus by RVP for several patients; however, whether virus identification directly led to discontinuation of antibacterials cannot be determined. The willingness of prescribers to de-escalate and stop antibacterials in this setting may suggest increased recognition of the role of viral pathogens in pneumonia. Additionally, the expanded panel of viruses detected may have factored into how results were perceived, as prescribers may have been more likely to attribute pneumonia to newly detectable viruses such as human metapneumovirus. However, it is not possible to definitively determine the rationale for stopping antibacterial therapy.

Timely antibiotic administration is crucial for treating hospitalized patients with suspected pneumonia. Antimicrobial de-escalation attempts to balance the use of these essential drugs up front with the emergence of resistance. The optimal strategy for de-escalation of antibacterials in the setting of viral pneumonia without an identified bacterial coinfection is unclear. Our study found no difference in clinical outcomes based on antibiotic duration of therapy in patients with viral pneumonia despite significantly different total antibacterial exposure (DOT/1000PD) between groups. Byington et al. found previously that improved diagnostic technologies enhancing detection of respiratory viruses decreased antibacterial use at a children’s hospital. The authors concluded that improved diagnostics are an important tool in decreasing unnecessary antibacterial prescribing. Our study similarly illustrated the potential impact of respiratory virus diagnostics on antibacterial use in an adult population.

C. difficile infection is a major cause of morbidity and mortality in US hospitals and has been directly linked to exposure to broad-spectrum antibiotics [35, 36]. In a cohort of hospitalized adult patients, Shiley et al. found that significantly more patients who continued to receive antibacterials after diagnosis of a viral respiratory tract infection developed C. difficile infection. One patient in our study who was treated with long-course antibacterials after identification of a respiratory virus also developed C. difficile infection. Strategies to best limit the use of unneeded antibacterials are important to curtail against the growing issues of C. difficile and resistance, and may be aided by de-escalation approaches using enhanced viral diagnostic technologies.

Limitations of this study should be noted. First, this was a small retrospective cohort study of patients at a single institution and may not be representative of all settings. It is important to note that BJH is a regional specialty referral hospital and not a community hospital. This accounts for the case mix with a high prevalence of immunosuppressed patients and the low prevalence of narrow spectrum empiric antibiotic utilization. The small number of patients meeting inclusion criteria did not allow for definitive conclusions to be made regarding group comparison as a lack of statistically significant differences being found could be due to the lack of sample size. Second, patients were determined to have viral pneumonia based on virus identification and radiographic findings but other markers of illness, such as white blood cell count and fever, were not considered and the retrospective nature of the study did not allow evaluation of what drove continuation of antibacterials in some patients but not others. Moreover, we did not attempt to identify risk factors associated with pure viral pneumonia. Third, although coinfecting bacterial pathogens were not identified in patients with pure viral pneumonia, it is impossible to prove that they were not present. Receipt of antibacterials prior to obtaining bacterial cultures could have limited the diagnostic yield of bacterial cultures in some cases and yield from bacterial cultures is not perfect. Finally, all of the viral pneumonia cases occurred in a 20-month period. Viral epidemiology during this time may not be representative of all seasons. Influenza H1N1 p2009 was the primary influenza virus identified in our study (85 %). Incidence rates of bacterial coinfection and coinfecting organisms may differ from year to year and from virus type to virus type, which may hinder application of de-escalation strategies using the results of this study.

It is not possible to directly link the development of subsequent MDRO infections/colonization and C. difficile infection seen in our study to the continued empiric antibacterials administered. All of the patients included in the cohort received antibacterials at some point during their index hospitalization and infection control measures were not directly assessed in these patients. Additionally, hospitalization itself probably increases the risk of these patients being colonized with MDROs. Use of cephalosporins and vancomycin, two of the most commonly administered empiric agents in our study, have been implicated as increasing the prevalence of VRE, the most commonly identified subsequent MDRO in this study [38, 39]. Decreasing exposure to broad-spectrum antibacterials such as third-generation and fourth-generation cephalosporins and vancomycin would be expected to lessen the incidence of VRE and other MDROs as was seen in this study, but the risk of development and transmission of resistance in the hospital cannot be completely eliminated. Antibacterials are extraordinarily important in the treatment of many hospitalized patients and their use is often warranted. Decreasing unnecessary use may help curb acquirement of resistant organism in healthcare settings but even appropriate use can lead to the development of resistance. Only through multifaceted efforts of infection control and antimicrobial stewardship can the spread of MDROs between patients, clinicians, workers, and visitors be diminished.

The last few years have seen some major advances in the management of community-acquired pneumonia. Risk stratification of patients has recently been advanced by the addition of several useful biomarkers. The issue of single versus dual antibiotic treatment remains controversial and awaits a conclusive randomized controlled trial. However, in the meantime, there is a working consensus that more severe patients should receive dual therapy.

These have often been an intervention of last resort in the failing patient. Studies in meningitis and pneumocystis pneumonia support their role in infection control but, until recently, studies in community-acquired pneumonia were absent. The conflicting results from studies in sepsis confirmed the need for community-acquired pneumonia-specific studies, preferably randomised controlled trials. A recent double blind, placebo-controlled randomized controlled trial using 40 mg prednisolone for 7 days as the intervention found that there were no beneficial effects of adjunctive corticosteroids in patients hospitalized with community-acquired pneumonia. Other outcomes of the study showed that clinical cure was equal in both groups at Day 7. A similar study using dexamethasone for 3 days did find a reduced hospital stay of one day in the steroid-treated patients, but a large number of exclusions and lack of control for other factors limiting length of stay limited the usefulness of this study. The only other randomised controlled trial evaluating patients with community-acquired pneumonia admitted to ICU found a reduction in mortality using hydrocortisone. The small patient number and absence of any deaths in the intervention arm mean that these findings cannot be generalised unless reproduced in other studies. A role for steroids in patients with community-acquired pneumonia is yet to be proved.

(a) β-lactam+azithromycin or

(b) β-lactam+fluoroquinolone combination therapy is performed. The following antibiotics are recommended (in alphabetical order)

In a randomized controlled clinical trial involving patients with community-acquired pneumonia not accompanied by shock, combination therapy had no significant effects; however, the combination therapy showed better outcomes than the fluoroquinolone monotherapy for patients who were on mechanical ventilation. In another retrospective study, the β-lactam + macrolide combination therapy led to higher survival rates than the fluoroquinolone monotherapy for patients with severe pneumonia. Most patients who are admitted to an ICU experience shock, or require mechanical ventilation. Therefore, combination therapy is recommended over the fluoroquinolone monotherapy for these patients. The effectiveness of the fluoroquinolone monotherapy in pneumonia accompanied by meningitis caused by S. pneumoniae is unclear. In a recent noninferiority trial, the β-lactam + macrolide combination therapy produced better outcomes than the β-lactam monotherapy in severe pneumonia or pneumonia caused by atypical bacteria. In a prospective observational study involving patients with S. pneumoniae bacteremia, the combination therapy (β-lactam + macrolide or β-lactam + fluoroquinolone) also led to higher survival rates compared with the β-lactam monotherapy, and this result was observed not in patients with mild pneumonia, but patients with severe pneumonia. Some studies have also reported better treatment outcomes from combination therapy than from monotherapy even in patients treated with effective antibiotics. Therefore, for the empirical antibiotic treatment of patients with severe community-acquired pneumonia requiring ICU admission, combination therapy is recommended over monotherapy.

For patient descriptions, we compared RSV-positive with RSV-negative patients within two groups of patients: all ARI patients and ARI patients with pneumonia. For the assessment of predictive factors for severity, patients with severe outcomes were compared with patients with no severe outcome within 6 groups of patients: all ARI patients, RSV-positive ARI patients, RSV-negative ARI patients, and those same three groups in patients less than 2-year old. Death, stay in ICU, oxygen use and severe pneumoniae were considered as indicators for severity. However, the mortality rate was too low to be analyzed and the analyses of ICU stay and oxygen use did not provide any added-value, so ultimately severe pneumonia alone was analyzed as an indicator of severe outcome. Data were double entered into an Access database (Microsoft Corporation). Statistical analysis was performed using Statistical Package for the Social Sciences version 23.0 for Windows (SPSS Inc., Chicago, IL, USA). For comparison of categorical data, the Pearson Chi-square (χ2) test and Fisher’s exact test were used as appropriate. The ANOVA test was applied to compare continuous variables. We fitted a binary logistic regression model, including a stepwise selection procedure, to assess predictive factors for severity. The level of significance was set at p < 0.05.

Antibiotic resistance among clinical strains of S. pneumoniae underscores the urgency for alternative treatment strategies. Multimodal host- and pathogen-directed immunotherapy is a feasible option. Thus, we employed the experimental dual-infection mouse model to explore concurrent immunotherapy for secondary bacterial pneumonia. The host response protein cANGPTL4 and bacterial virulence factor pneumolysin were targeted using cognate neutralizing antibodies. The antipneumolysin antibody mitigated the pore-forming action of pneumolysin in human alveolar epithelial cells and reduced tissue damage. This effect persisted for 48 h (Fig. 4D). The concurrent antibiotic and antibody treatment significantly improved lung tissue integrity and, importantly, extended the median survival time of mice with secondary bacterial pneumonia compared to treatment with either the antibiotic or a single antibody (Fig. 4A and B). Taken together, these observations highlight that host-directed therapeutic anti-cANGPTL4 MAb can complement pathogen-directed treatment, such as conventional antibiotics or a novel antipneumolysin antibody, to enhance lung tissue integrity and augment host survival during secondary pneumococcal pneumonia. The improved tissue integrity and considerably longer median survival time suggest that a multimodal treatment approach targeting both host and pathogen factors can be highly efficacious against DRSP infection.

Pneumonia and ARDS occur in heterogeneous conditions, but the immunopathogenesis of ARDS may be similar in different conditions. The present study presents a unified immunopathogenesis of ARDS using the PHS hypothesis. This hypothesis provides compelling reasons to unify the immunopathogenesis of ARDS and gives a rationale for early treatment with systemic immune modulators for patients in the beginning stage of ARDS. The severity or chronicity of ARDS depends on the amount of etiologic substances, including PPs and pathogenic peptides, the duration of the appearance of specific immune cells, or the repertoire of specific immune cells that control the substances in the host. Therefore, early systemic immune-modulator (corticosteroids and/or IVIG) therapy, administered as soon as possible, can reduce initial aberrant immune responses elicited by non-specific immune cells. This treatment policy for severe pneumonia or early ARDS can be described as having the same rationale as early antibiotic and antiviral therapies, insofar as there is a critical early stage of immune-mediated lung injury, which can be reversed with prompt intervention.