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.

Management of NP relies upon expert opinion, and results of retrospective observational studies from mainly single centers, as to date no randomized-controlled trials comparing different treatments have been performed. A multi-disciplinary team of pediatric respiratory physicians, intensivists, thoracic surgeons, and infectious diseases experts is often required. The overarching aims are to control and ultimately reverse the pathobiologic changes associated with NP. These include providing supplemental oxygen to relieve hypoxia, ensuring adequate analgesia to reduce pleuritic pain and improve ventilation, administering prolonged antibiotic therapy, and decreasing any mass effect or intrathoracic pressure by draining gas and/or intrapleural fluid [50, 80, 81, 86, 96]. Correcting fluid and electrolyte abnormalities and attention to nutrition, including managing hypoalbuminemia, is also important. Some children will require circulatory and ventilation support, while occasionally extracorporeal membrane oxygenation (ECMO) is used in those with refractory hypoxemic respiratory failure [19, 23, 28]. Severely ill children with suspected or proven S. aureus or S. pyogenes infection—especially with bilateral lung involvement, pulmonary hemorrhage, or impaired circulation—may also benefit from high-dose intravenous (IV) immunoglobulin infusion (2 g/kg), which is repeated after 48 h if there is no improvement [66, 97].

A prolonged course of IV antibiotics is the cornerstone of therapy. The initial choice of antibiotics in otherwise healthy, fully immunized children should be the same as for empyema and cover gram positive organisms, especially pneumococci, S. aureus and S. pyogenes, taking into account local epidemiologic and microbiologic data. Consequently, the recommended first-line treatment of IV penicillin or ampicillin for children hospitalized with severe but uncomplicated CAP [98, 99] will need broadening to include beta-lactam anti-staphylococcal antibiotics, such as oxacillin or flucloxacillin [28, 33]. Treatment can then be tailored according to microbiological results, although these may only be positive in 8–55% of cases (Table 1). When suspicion of MRSA is high (eg. local prevalence >10%, ethnicity, recent personal or household history of skin infections) or if it is confirmed by culture, antibiotics should be directed against this specific pathogen. Importantly, vancomycin penetrates poorly into lung parenchyma and treatment failures can occur in up to 20% of MRSA pneumonia when used as monotherapy. Thus, until MRSA is confirmed, a beta-lactam anti-staphylococcal antibiotic should be part of the treatment regimen. While high-level evidence is lacking, the addition of agents such as linezolid, clindamycin, or rifampicin capable of inhibiting protein synthesis (including toxin production) may result in better outcomes for those with S. aureus or S. pyogenes infections [21, 99]. When NP complicating an M. pneumoniae infection is suspected, a macrolide such as IV clarithromycin or azithromycin is added. However, these agents should not invariably replace antibiotics active against pneumococci and S. aureus, given the high rates of mixed infection associated with M. pneumoniae pneumonia, frequent negative microbiology results in patients with NP, and increasing levels of macrolide resistance in respiratory bacterial pathogens. Finally, the initial empiric antibiotic therapy may need to provide extended gram negative coverage by including a third or fourth generation cephalosporin if the child is unimmunized against H. influenzae type b (Hib), immunocompromized, or if the infection was hospital-acquired.

The optimal duration for antibiotic treatment of NP is unknown. The median length of antibiotic courses in case series listed in Table 1 range from 13 to 42 days, with 3 of the 5 studies providing these data reporting a median antibiotic course duration of 28 days [28, 33, 36]. Switching from IV to oral antibiotics is appropriate once the child is afebrile for at least 24 h and no longer showing signs of sepsis, their respiratory distress is resolving, enteral feeds are being tolerated, and inflammatory markers are declining. At this point antibiotics are continued for at least another 10–14 days, a recommendation that aligns with consensus guidelines for PPE and empyema complicating pediatric CAP [86, 99].

(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.

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.

Knowing which patients with LRTIs to treat and not to treat is challenging to determine, and physicians often err on the side of caution and prescribe antibiotics, given the high mortality rates of some bacterial LRTIs often without diagnostic results. Most patients are then empirically treated with antibiotics to pre-emptively avoid severe complications from bacterial LRTIs.

Improved diagnosis of the etiology of these infections would enable targeted therapy, leading to an overall more judicious use of antibiotics, which would likely decrease the rate of antimicrobial drug resistance as well as the safety impact of inappropriate treatment modalities on the patient. Due to the improper treatment of LRTIs, some infected patients may not be treated adequately because the responsible bacterium (such as S. pneumoniae, methicillin-resistant S. aureus and Gram-negative bacilli) is resistant to available antibiotics, leaving physicians without a weapon to combat the illness. The prudent use of available antibiotics in patients and animals, giving them only when needed, with the correct diagnosis and etiologic understanding, and in the correct dosage, dose intervals and duration is imperative. Antimicrobial stewardship is based on this premise. Over 262 million courses of outpatient antibiotic therapy were prescribed in 2011 with half of those antibiotics being unnecessary. The most inappropriate use is for acute respiratory infections, including acute bronchitis. Further research into rapid, patient-friendly, inexpensive, and accessible diagnostic modalities to appropriately characterize LRTIs as bacterial versus viral versus other is necessary to harness antibiotic use. In addition, determination of the causative bacterial pathogen will further antibiotic stewardship programs, lowering the risk of propagating resistance and unwanted adverse events including the development of C. difficile. The advancements noted above are certainly moving in the right direction to understanding the etiology of pneumonia in a rapid manner, but development still continues for even faster, more comprehensive testing.

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).

In consequence of the diagnostic uncertainty for M. pneumoniae infections, the British Thoracic Society guidelines suggest empiric macrolide treatment at any age if there is no response to first-line β-lactam antibiotics or in the case of very severe disease (Harris et al., 2011). The lack of a cell wall makes M. pneumoniae resistant to cell wall synthesis inhibitors such as β-lactam antibiotics. The antibiotics with the best minimum inhibitory concentration values against M. pneumoniae include macrolides, tetracyclines, and fluoroquinolones (Waites and Talkington, 2004). Although the latter two have a good in vitro inhibitory effect against M. pneumoniae, tetracyclines may cause teeth discoloration (Waites and Talkington, 2004) and fluoroquinolones may affect the developing cartilage in young children (Adefurin et al., 2011). Thus, they are not recommended by current guidelines in young children; the age limit for tetracyclines is ≥8 years, while that of fluoroquinolones is adolescence with skeletal maturity (Bradley et al., 2011). The occurrence of arthropathy due to fluoroquinolones, however, is uncertain, and all musculoskeletal adverse effects reported in the literature had been reversible following withdrawal of treatment (Adefurin et al., 2011). The protein synthesis inhibitors of the macrolide class have a more favorable side effect profile and are therefore the first-line antibiotics for M. pneumoniae infections in children (Bradley et al., 2011).

Although antibiotics are effective against M. pneumoniae in vitro (Bebear et al., 2011), there is lack of evidence on their in vivo efficacy. Observational data indicated that children with CAP due to M. pneumoniae have a shorter duration of symptoms and fewer relapses when treated with an antimicrobial agent active against M pneumoniae (McCracken, 1986; Waites and Talkington, 2004). A recent Cochrane review evaluated seven studies on the effectiveness of antibiotic treatment for M. pneumoniae lower respiratory tract infections in children (Gardiner et al., 2015). However, the diagnostic criteria, the type and duration of treatment, inclusion criteria, and outcome measures differed significantly, making it difficult to draw any specific conclusions, although one trial suggested that macrolides may be efficacious in some cases (Esposito et al., 2005). It is clear that studies on the efficacy of antibiotics rely on a correct diagnosis of M. pneumoniae infections. Given the aforementioned shortcomings of current diagnostic tests, conclusions on the efficacy of antibiotic treatment will have to be re-examined.

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.

Pneumococcus is an important pathogen in childhood [1–3]. Invasive pneumococcal disease refers to unlocalised bacteremia, pneumonia, or meningitis. Despite the availability of effective vaccines, new serotypes continue to evolve [1–3]. The Hong Kong Government introduced the 7-valent polysaccharide vaccine in September 2009. In 2010, the vaccine was changed to the 10-valent vaccine and in 2011 recommendation was made to switch to a 13-valent vaccine. Locally, the coverage of the 7-valent or 10-valent and 13-valent vaccines was 65% and 90%, respectively. The parents reported that the child received one prior dose of 7-valent vaccine before 3 years of age in early 2010. It is possible that 19A was a commonly circulating strain before the introduction of the 10-valent or 13-valent vaccines. The 13-valent vaccine should stop circulation of 19A when the program is fully implemented.

History of immunization with the 7-valent vaccine is not a guaranteed prevention against pneumococcal infection in children [1–3]. Evolving serotypes associated with severe lobar pneumonia, pleural effusion, and PICU admission despite prior immunization have been previously reported locally.

Evidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery. Amoxicillin should be used as first-line therapy for previously healthy, appropriately immunized infants and preschool-aged children with mild to moderate CAP suspected to be of bacterial origin. Amoxicillin provides appropriate coverage for S. pneumoniae, the most prominent invasive bacterial pathogen. Macrolide antibiotics should be prescribed for treatment of children (primarily school-aged children and adolescents) evaluated in an outpatient setting with findings compatible with CAP caused by atypical pathogens. Laboratory testing for M. pneumoniae should be performed if available in a clinically relevant time frame. Ampicillin or penicillin G should be administered to the fully immunized infant or school-aged child admitted to a hospital ward with CAP when local epidemiologic data document lack of substantial high-level penicillin resistance for invasive S. pneumoniae. Empiric therapy with a third-generation parenteral cephalosporin (ceftriaxone or cefotaxime) should be prescribed for hospitalized infants and children who are not fully immunized, in regions where local epidemiology of invasive pneumococcal strains documents high-level penicillin resistance, or for infants and children with life-threatening infection, including empyema. Empiric combination therapy with a macrolide (oral or parenteral), in addition to a beta-lactam antibiotic, should be prescribed for the hospitalized child for whom M. pneumonia and C. pneumoniae are significant considerations; diagnostic testing should be performed if available in a clinically relevant time frame. Accordingly, earlier initiation of antibiotics might have increased the chances of survival in this child.

Antibiotic resistance has also developed in Hong Kong [1, 2]. The serotype 19A is especially virulent and may be difficult to isolate in patients who have already been started on antibiotics. The pathogen has been reported to be associated with the hemolytic uremic syndrome [6–11]. Penicillin can be used in sensitive pneumococcus [1, 2]. In patient with pneumonia not responding satisfactory initially, more invasive investigative/therapeutic management including a pleural drain for biologic specimen is indicated to guide management. Local antimicrobial sensitivity in PICU patients has been reported [1, 2]. The pathogen was sensitive to penicillin and cefotaxime in this case. In patients not responding satisfactorily with initial antibiotics but with known penicillin sensitivity, a higher dose of penicillin should be tried.

Coinfections by viral and bacterial agents in critically ill patients have been reported [12–15]. Mycoplasma pneumoniae usually affects older children and a clinical entity of atypical pneumonia or “walking” pneumonia. Metapneumovirus usually causes co-infection. Occasionally, both pathogens can cause severe acute respiratory symptoms just like SARS (severe acute respiratory syndrome).

In-house real-time RT-PCRs were performed according to hospital laboratory standard operating procedures for the qualitative detection of human Metapneumovirus (hMPV) RNA and of Mycoplasma pneumoniae (MP). The target of amplification for hMPV was the nucleoprotein gene (N gene) with primer sequences and method as described by Hopkins et al. and 45 cycles were run on real-time PCR (ABI prism 7900 HT FAST). Positive and negative controls were included, and a Ct value of ≤37 was considered positive. The target of amplification for MP was the ADP-ribosylating toxin gene encoding the CARDS (community-acquired respiratory distress syndrome) toxin using primer pairs and method as described by Winchell et al.. Both internal DNA control and a positive and negative control were included in the reaction run. A Ct value ≤34 was considered positive.

It is difficult to ascertain if Metapneumovirus and Mycoplasma had contributed to this fatal illness. These pathogens were detected in the tracheal and the nasopharyngeal aspirates but not in the postmortem lung tissue cultures. Unlike the nasopharynx, the presence of any pathogens in the tracheal aspirates represents infection in the lower respiratory tract rather than carriage in the upper airway. Both pathogens are known to cause pneumonia on their own and both are not commonly carried by healthy young persons [5, 13, 19–22]. These facts support the argument that they were copathogens with pneumococcus which was found in pleural fluid, tracheal aspirates, and blood. In conclusion, the simultaneous isolations of 3 respiratory viral and bacterial pathogens have not been reported in our locality and may contribute to the fatal outcome of this unfortunate child.

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.

Several clinical trials of antibiotics for CAP are registered on ClinTrialsGov.

A study in Beijing Children’s Hospital (NCT02775968) is investigating the population pharmacokinetics of cephalosporins and macrolide antibiotics for CAP in children, aiming to correlate it with treatment effectiveness and the incidence of adverse effects. The study commenced in August 2016 with an estimated enrollment of 750 children and a completion date of October 2022.

A phase 2/3, randomised, open-label, active control, multi-centre study (NCT02605122) to assess the safety and efficacy of solithromycin in children and adolescents with CAP is being conducted under the sponsorship of Cempra Inc.. Solithromycin will be compared with the standard of care for an estimated enrollment of 400 patients. The study commenced in March 2016 with an estimated completion date of January 2018.

A Canadian randomised, controlled, double-blind, non-inferiority clinical trial (NCT02380352) will determine whether 5 days of high-dose amoxicillin leads to comparable rates of early clinical cure compared with 10 days of high-dose amoxicillin for previously healthy children with mild CAP. In the experimental arm, patients will be given 5 days of amoxicillin 90 mg/kg/day in three divided doses, followed by 5 days placebo three times a day. The active comparator arm will be given 5 days amoxicillin 90 mg/kg/day in three divided doses, followed by alternate formulation 5 days amoxicillin 90 mg/kg/day in three divided doses. The estimated enrollment for the study is 270 patients and it commenced in March 2016 with a completion date of May 2018.

The National Institute of Allergy and Infectious Diseases (NIAID) is sponsoring a multi-centre, randomised, double-blind, placebo-controlled, superiority clinical trial (NCT02891915) to test the effectiveness of short (5-day) vs standard (10-day) course therapy in children diagnosed with CAP and initially treated in outpatient clinics, urgent care facilities and emergency departments. The primary objective is to compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) in children with CAP aged 6–71 months assigned to a strategy of short course (5 days) vs standard course (10 days) outpatient β-lactam therapy at Outcome Assessment Visit 1 (Study Day 8 ± 2 days). The study commenced in October 2016 and the completion date is March 2019 with an estimated enrollment of 400 patients.

A Malaysian trial (NCT02258763) in children hospitalised with pneumonia is being conducted to determine whether an extended duration of oral antibiotics (10 days) is better for improving clinical outcomes than a shorter duration (3 days) of antibiotics. Patients in the experimental arm will receive amoxicillin-clavulanate 22.5 mg/kg/dose bd for 10 days, while the comparator arm will receive amoxicillin-clavulanate 22.5 mg/kg/bd for 3 days followed by another 7 days of placebo given at the same dose and frequency. The study began in November 2014, aiming to enrol 300 patients, and the estimated completion date is December 2018.

Two clinical trials investigating amoxicillin in childhood pneumonia are being conducted in Malawi. In a trial (NCT02760420) sponsored by Save the Children, the effectiveness of no antibiotic treatment for fast-breathing CAP is being compared with amoxicillin therapy. Patients in the placebo arm will be given 250 mg of placebo (dispersible tablet) in two divided doses based on age bands (500 mg/day for children 2–12 months, 1000 mg/day for children 12 months to 3 years, and 1500 mg/day for children 3–5 years of age). The active comparator arm will receive 3 days of 250 mg amoxicillin, dispersible tablet (DT) in two divided doses based on age bands (500 mg/day for children 2–12 months, 1000 mg/day for children 12 months to 3 years, and 1500 mg/day for children 3–5 years). The estimated enrollment is 2000 patients with the study running from June 2016 to September 2018.

In the same setting, another trial (NCT02678195) will compare 3 vs 5 days of treatment for chest-indrawing pneumonia. The experimental arm will receive 3 days of amoxicillin and 2 days of placebo while the comparator arm will receive 5 days of amoxicillin. The study aimed to run from March 2016 to August 2018 with an estimated enrollment of 2000 patients.

A one-arm safety intervention (NCT02878031) in Nigeria will evaluate the role of community management of chest-indrawing pneumonia with oral amoxicillin. The primary objective is to assess whether community health workers can safely and appropriately manage chest-indrawing pneumonia in children aged 2–59 months and refer children with danger signs. The aim was to include approximately 308 children aged 2–59 months with chest-indrawing pneumonia and the study was conducted between October 2016 and July 2017.

In a double blind efficacy study entitled RETAPP (NCT02372461), investigators based at Aga Khan University, Karachi compared standard amoxicillin treatment with placebo in poor urban slum settings in South Asia. The study ran from November 2014 to July 2017 with an enrolment of 2500 patients.

Investigators in the United Kingdom are initiating a multi-centre, randomised, double-blind placebo-controlled 2 × 2 factorial non-inferiority trial of amoxicillin dosage and duration in paediatric CAP (CAP-IT) (ISRCTN76888927). The efficacy, safety and impact on antimicrobial resistance related to the duration and dosage of amoxicillin will be assessed in children aged 1–5 years presenting to the Emergency Room or Paediatric Assessment Unit with a clinical diagnosis of CAP in whom the decision has been made to treat with antibiotics. Participants will be randomised to four treatment groups: shorter course and lower dose (3 days of 35–50 mg/kg/day), longer course and lower dose (7 days of 35–50 mg/kg/day), shorter course and higher dose (3 days of 70–90 mg/kg/day), and longer course and higher dose (7 days of 70–90 mg/kg/day). They expect to recruit 2400 over the 2 years from March 2016 to May 2018.

Ceftaroline fosamil is a broadspectrum cephalosporin antibiotic with activity against many bacteria, including S. pneumoniae (both penicillin-non-susceptible and multi-drug-resistant strains) and S. aureus (including methicillin-resistant S. aureus). In a phase 2/3 study (NCT01530763), 160 paediatric patients hospitalised with CAP received either intravenous ceftaroline fosamil or ceftriaxone in a randomised, active-controlled, observer-blinded clinical trial. The effectiveness of ceftaroline fosamil was similar to that of ceftriaxone, with high clinical cure rates at test of cure in the modified intention-to-treat population (94/107; 88% and 32/36; 89%, respectively). Three documented S. aureus infections were successfully treated in the ceftaroline group, including one caused by methicillin-resistant S. aureus. In the phase 4 study (NCT01669980), the safety and effectiveness of ceftaroline fosamil in children was evaluated in a multi-centre, randomised, observer-blinded, active-controlled trial[24]. Ceftaroline fosamil was compared with intravenous ceftriaxone plus vancomycin in patients aged between 2 months and 17 years with complicated CAP. Clinical response rates in the modified intention-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. Ceftaroline fosamil was well tolerated and the clinical response rates were similar to that of ceftriaxone plus vancomycin.

Antibiotics treat LRTIs with a bacterial etiology. With the potential for antibiotic-resistant bacteria as well as sequelae from the use of unnecessary antibiotics including Clostridioides difficile infection, defining the etiology of the LRTI is imperative for appropriate patient treatment. Currently, there are few diagnostic tools to adequately do this in a time-efficient manner at the point of care.

Clinical assessment does not typically decipher between bacterial, viral or both as an etiology for LRTIs. Therefore, diagnostic tools are essential for empiric treatment. Currently, these tools include the use of C-reactive protein, procalcitonin, and/or other combinations.

Briefly, C-reactive protein (CRP) is an acute phase reactant synthesized by the liver in response to cytokines, such as interleukin-6, released by macrophages and adipocytes in response to inflammatory conditions from bacterial infections. Consortia have developed interpretative cut-offs for CRP levels to assist physicians with antibiotic prescribing. CRP levels ≤ 20 mg/L indicate a self-limited LRTI for which antibiotics are not needed, and CRP ≥ 100 mg/L indicate severe infection for which antibiotics should be prescribed. CRP levels between 21 and 99 mg/L are more challenging to interpret and must include further clinical assessment (Table 1).

Although rapid tests for CRP are used in point-of-care settings, the use of CRP has been controversial. A Cochrane review of trials conducted throughout Europe and Russia determined that CRP levels may reduce the use of antibiotics but the results did not affect patient outcomes, and suggested that increased hospitalization due to CRP evaluation may occur. Although Andreeva et al. reports a decrease of 36% in antibiotic prescribing with the evaluation of CRP, the authors discuss multiple studies that have not resulted in such changes. Therefore, the utility of CRP levels remains specific to individual treatment settings, and the measurement of CRP is not a substitute for clinical assessment and follow-up, which remain main-stays in the assessment of LRTIs.

For HAP/VAP, Infectious Diseases Society of America (IDSA) has indicated that clinical criteria alone, rather than using CRP is preferred, since CRP results did not reproducibly determine whether VAP was bacterial, leaving clinicians to rely on clinical assessment alone. Procalcitonin (PCT) is another acute phase reactant associated with bacterial infections. PCT increases within 2–4 h of infection, peaking at 24–48 h. PCT is used to assist in the diagnosis of sepsis and has since been used for LRTIs and post-operative infections. Like CRP, its use has been targeted to ensure appropriate antibiotic use (Table 1). Typically, PCT is produced by parafollicular cells of the thyroid and by the neuroendocrine cells of the lung and the intestine in small quantities and is a precursor to calcitonin which regulates calcium and phosphate in the blood, but bacterial endokines and cytotoxins stimulate its production early in the disease process. Evidence has shown that PCT is a useful method in guiding the initiation and duration of antibiotic treatment for LRTIs. A meta-analysis of 32 randomized studies with a majority of patients with acute LRTIs showed that PCT testing lowered mortality (decrease of 1.4%), antibiotic consumption (2.4 day mean reduction in exposure), and antibiotic-related adverse events (decrease of 5.8%). Briel et al. evaluated 458 patients whom the physician thought needed antibiotics for a respiratory tract infection. Patients were randomized to PCT-guided approach to antibiotic therapy or to a standard approach. The antibiotic prescription rate was 72% lower in those who had procalcitonin-guided antibiotic use without any impact on patient outcome. However, Huang et al. conducted a study in 14 hospitals in the United States and among 1656 patients observed no significant difference between the PCT group and the usual-care group in antibiotic days (mean, 4.2 and 4.3 days, respectively) or the proportion of patients with adverse outcomes (11.7% and 13.1%, respectively). The bioMérieux’s VIDAS® BRAHMS PCT™ test has been developed and was approved by FDA in 2017 to differentiate bacterial from viral infections and ultimately whether antibiotics are needed for pneumonia (Table 1). An ongoing study (Targeted Reduction of Antibiotics using Procalcitonin; TRAP-LRTI) is evaluating outpatient adults with suspected LRTIs and low procalcitonin levels. Low blood levels of PCT (≤0.25 ng/mL) using bioMérieux’s VIDAS® BRAHMS PCT™ test, which produces results within 20 min, is being used as an inclusion criterion, and then patients will be randomized to either azithromycin for 5 days or placebo. At Day 5, patients will be evaluated for improvement in symptoms with additional follow-up to 28 days after randomization. The study will evaluate the recovery of patients given azithromycin versus placebo, and whether a low PCT level can be used to avoid antibiotic therapy. The study will be completed in 2020, and it will add evidence to the utility of point-of-care PCT testing for patients with symptoms of LRTI in the outpatient setting.

Using host biomarkers in conjunction has also been studied and found to have high sensitivity and specificity for bacterial LRTIs. A point-of-care test of CRP and Myxovirus resistance protein A (MxA) was used in 54 patients with pharyngitis or LRTIs to determine the etiology of the infection. This combination characterized 80% (16/20) with bacterial infection, 70% (7/10) with viral infection, along with 92% (22/24) negative for a bacterial or viral infection. However, this study was small, and further confirmation of this point of care test is needed. Another host-protein signature assay combines the results of tumor necrosis-factor related apoptosis-inducing ligand (TRAIL), interleukin-10, and CRP and produces a score of 0–100 using the ImmunoXpert™ software. ImmunoXpert™ scores of <35 indicate nonbacterial etiology, whereas scores of ≥65 predict bacterial infections including mixed viral/bacterial co-infections. This assay has a sensitivity of 93% with a 91–94% specificity. The use of this assay was superior to using the biomarkers individually, so development is continuing for a point-of-care platform to provide results within 15 min.

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).

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.

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.

Among the 93 patients, 81 (87.1%) initially received antibiotic therapy: 63 (69.3%) antibiotic combinations (AC), and 18 (19.4%) a single antibiotic. AC were administered for a median duration of 48 h (IQR, 24–116), and were secondarily switched in 48 (76.2%) cases and discontinued in 15 (23.8%). AC were third-generation cephalosporin and macrolides in 55 patients (87.3%), aminopenicillin and macrolides in three patients and third-generation cephalosporin and fluoroquinolone in four patients. An AC was maintained in 10 (19.2%) cases, with aminopenicillin–spiramycin in six and quinolones plus spyramicin or rifampicin in four. Thirty-eight (60.3%) patients were switched to a single antibiotic as amoxicillin-clavulanate in 12 (31.5%), third-generation cephalosporin in eight, amoxicillin in seven, spiramycin in six, levofloxacin in three, and piperacillin-tazobactam and doxycycline each in one.

Single antibiotics initially prescribed were amoxicillin-clavulanate in nine patients (50%), amoxicillin in five, or third-generation cephalosporin in four. This antibiotic was maintained throughout treatment in 14 cases and switched to oral amoxicillin-clavulanate in four cases, with no discontinuation in the 48 first hours of treatment.

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.

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

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

A prospective, observational study of the cytokine profile and genetic determinants of invasive pneumococcal disease (children presenting with pneumonia or meningitis) was undertaken at Queen Elizabeth Central Hospital (QECH), Blantyre, between 1st April 2004 and 30th October 2006. The details of the study participants and recruitment procedures have been previously reported,,. All children screened for inclusion in the present study had a clinical diagnosis of pneumonia only, and only those with radiologically confirmed pneumonia with focal, segmental or lobar pneumonia were enrolled. Routine immunisation during the period of this study included neonatal BCG, DPT-Hep B and Hib conjugate vaccine at 6, 10 and 14 weeks. Hib vaccine was introduced in Malawi in 2002 and pneumococcal conjugate vaccine was not available throughout the study period.

Clinical data collected on enrolment to the study following written informed consent included prior or current treatment with antibiotics or antimalarials. Chest radiographs were performed on admission and only children with focal, lobar or segmental consolidation were recruited. Arterial oxygen saturation (SpO2) when breathing air was measured with pulse oximetry and monitored regularly along with vital signs throughout the hospital stay by nursing staff according to research ward protocols. Urine was not tested for antibiotic activity. All children were reviewed by the study clinicians at least twice per day.

Blood (1–2 ml) was taken for culture prior to commencement of antibiotics and cultured using the BacT/Alert 3D automated system (BioMerieux, France). All isolates were identified using standard diagnostic techniques and antibiotic susceptibility was tested using the Kirby-Bauer disk diffusion method. HIV testing was done following a separate written informed consent with pre- and post-test counselling provided by a trained nurse counsellor, for those who accepted testing. HIV status was determined in all patients. In children ≥18 months, HIV status was assessed using at least two of the following tests; Unigold (Trinity Biotech, Ireland), Serocard (Trinity Biotech, Wicklow, Ireland), or Determine-HIV (Abbott Laboratories, Illinois, USA). In children under 18 months, and those with discordant antibody tests, HIV status was determined using Amplicor HIV-1 DNA (Roche Diagnostics, USA).

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.

The PRISTINE study is the first exploratory clinical trial in humans to determine the feasibility of adding rifampicin to standard treatment with β-lactams for patients with community-acquired pneumococcal pneumonia. The rifampicin is added to reduce the release of bacterial compounds within the first hours of therapy and thereby attenuate the inflammatory response. In this initial small group, the β-lactam antibiotic with additional non-lytic rifampicin antibiotic versus lytic β-lactam antibiotic only treatment for pneumococcal pneumonia did not reveal differences in the blood concentrations of various inflammatory biomarkers, nor in the clinical response to treatment.

The strengths of our study are the high percentage of pneumococcal infections included, the frequent sequential measurement of a spectrum of biomarkers in the first 48 h to assess our hypothesis and the complete biomarker profile used to evaluate specific inflammatory responses. Initially, we included only patients with a high severity score (CURB-65 ≥ 2) as the percentage of pneumococcal infection is highest in this group and the high severity would best contrast with the possible effects. After inclusion of the eighth study patient, we extended our inclusion criteria to patients having a specific risk factor for pneumococcal pneumonia to speed up inclusions.17 We applied extensive testing for pneumococcal infection to ensure the identification of all patients with pneumococcal pneumonia.23 We were able to confirm a pneumococcal infection in 41% of patients. This percentage is higher than in comparable hospital and intensive care studies with community-acquired pneumonia.11,26,27

In vitro studies and animal models have demonstrated differences in LTA release and inflammatory responses within hours in lytic versus non-lytic antibiotic treatment of S. pneumoniae.12,28,29 Although extensive sampling is a challenge in human trials, it is essential for the testing of our hypothesis. Therefore, the large number of sequential samples that we collected is an important strength of our study. With the extensive sampling, we detected that the expression of CCL5 was significantly different between pneumococcal pneumonia versus non-pneumococcal pneumonia 24 h after the start of treatment. CCL5 is known to be upregulated in pneumococcal infection and to be an essential chemokine in pneumococcal adaptive immunity.30 Our finding needs to be validated in a larger cohort of pneumonia patients.

A weakness of our pilot trial is the small sample size; this is in line with the exploratory character of our study. As we anticipated that the LTA and biomarker responses induced by β-lactam treatment would be spread across a broad range, we included more patients with rifampicin added to β-lactam treatment than β-lactam treatment only and randomized at a 2:1 ratio. With only four patients with pneumococcal pneumonia treated with β-lactam therapy only, this assumption was imperfect and the small group hindered comparisons. For example, in the analyses of biomarkers for inflammation, at the start of treatment, the PCT value seemed higher in the β-lactam group, while those of CRP and MR-proADM were higher in the rifampicin group. Since only three samples (one sample was missing) were available in the β-lactam group, the interpretation of these findings is difficult.

We could not detect LTA in plasma nor its direct inflammatory response via TLR2. LTA cell wall components should bind TLR2 and induce the release of a broad range of pro-inflammatory cytokines leading to neutrophil-mediated lung damage, and, with that, morbidity and mortality.31,32 Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, with a median number of only one infected lung lobe, representing relatively limited pneumococcal load, the LTA plasma concentration could be too low to mount a response via TLR2 in vitro (see the Supplementary data), but may nonetheless have an effect in vivo.

LTA release may also have been delayed by quinolone treatment.14,29 Ciprofloxacin was frequently co-administered in our cohort. Delayed LTA release may have decreased the potential difference in inflammatory responses between the two treatment groups.

Finally, another reason for the absence of detectable LTA in our samples could be the serotypes causing pneumococcal pneumonia. Different pneumococcal isolates have different lytic effects.33 In an experimental meningitis model in rabbits, serotype 23F caused more LTA release and inflammation than pneumococcal serotype 3.34 In our study, only one patient had a pneumococcal pneumonia with serotype 23F versus four patients with serotype 3.

In contrast to LTA in plasma, LTA can be detected at the site of infection in humans (see the Supplementary data). For example, in liquor of patients with pneumococcal meningitis, LTA is detectable until 15 days after the start of treatment.35 It is not possible to puncture the infected lung lobe for repeated measurements in critically ill human patients. Therefore, human studies to determine the LTA load in the lung during pneumonia have not been performed.

Previous in vitro and animal studies have shown vast differences in LTA release and inflammatory response between lytic versus non-lytic antibiotic treatment. The potential clinical benefit of decreased LTA release and inflammatory response in patients with pneumococcal pneumonia might be substantial. Restrepo et al.36 demonstrated that patients with community-acquired pneumonia who were immediately transferred to the ICU from the emergency department were better off than patients who were initially treated on wards and thereafter transferred to the ICU. This secondary deterioration could be caused by inflammation due to LTA release after the start of treatment.

A large randomized trial of patients with Gram-positive Staphylococcus aureus bacteraemia showed no adjunctive clinical benefit of rifampicin over standard (most often flucloxacillin) antibiotic treatment.37 Long-term endpoints in that trial were used, making comparison with our short-term outcome measures difficult.

Strategies to dampen the inflammatory response in pneumonia have so far primarily focused on corticosteroids. Corticosteroid therapy has been demonstrated to result in shorter times to clinical stability and limited shortening of hospital stays in patients with non-severe community-acquired pneumonia. Some studies in adults with severe disease have shown a reduction in mortality. The quality of these studies is moderate. In all studies, corticosteroid therapy increased the risk of hyperglycemia.38 Therefore, corticosteroids are not included in current treatment guidelines.7,8

Alternative therapeutic options should be explored to attenuate the inflammation.

The effects and benefits of non-lytic antibiotics for the treatment of pneumococcal infections may be easier to detect and prove in pneumococcal meningitis patients. In this group of patients with high morbidity, long-term sequelae and substantial mortality, strategies to improve outcomes are urgently needed.39 Moreover, the clinical results of our study could have been blurred by the use of antipyretics.

Higher LTA concentrations in liquor in human patients with pneumococcal meningitis are associated with worse outcome.40 In addition, in rabbits with pneumococcal meningitis, rifampicin reduces LTA release and the inflammatory response, and substantially improves survival.13 Therefore, clinical trials with non-lytic antibiotics in pneumococcal meningitis should be developed. Rifampicin would be the antibiotic of choice, since it is most effective in killing S. pneumoniae while causing the least release of LTA per killed bacterial cell.41

Unfortunately, we could not compare monotherapy of a non-lytic (rifampicin) antibiotic versus monotherapy of a lytic, β-lactam, antibiotic. This would be a highly relevant but different research question. The reasons for this are that the current Dutch guidelines for community-acquired pneumonia recommend β-lactam antibiotic (e.g. benzylpenicillin) treatment and the fact that rifampicin monotherapy may induce resistance during treatment. Therefore, it would have been unethical to withhold this first-line treatment from patients with community-acquired pneumonia. A significant difference in LTA release has been demonstrated in a rabbit model of S. pneumoniae meningitis, when comparing β-lactam monotherapy with rifampicin followed by β-lactam antibiotic therapy 6 h later.42 In the rifampicin treatment group in our study, rifampicin was frequently (56%) given before β-lactam treatment, but with a median time frame of 5 min only (IQR = −10 to 60 min). Therefore, the antimicrobial killing of S. pneumonia in both groups might be primarily caused by the β-lactam (lytic) killing effect.

In conclusion, the PRISTINE exploratory study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia; however, despite solid in vitro and experimental animal research evidence, it failed to demonstrate a difference in LTA and subsequent inflammatory response. Further studies in selected groups of patients, such as those with pneumococcal meningitis, will be necessary to confirm the hypothesis that non-lytic antibiotic treatment attenuates inflammatory response and improves clinical outcome.

The pneumococcal conjugate vaccination and Haemophilus influenzae type B conjugate vaccination have been effective tools to decrease pneumonia incidence, severity and mortality [58, 59]. However, equitable coverage and access to vaccines remains sub-optimal. By the end of 2015, Haemophilus influenzae type B conjugate vaccination had been introduced in 73 countries, with global coverage estimated at 68%. However, inequities are still apparent among regions: in the Americas coverage is estimated at 90%, while in the Western Pacific it is only 25%. By 2015, pneumococcal conjugate vaccination had been introduced into 54 countries, with global coverage of 35% for three doses of pneumococcal conjugate vaccination for infant populations. To address this issue, the WHO’s Global Vaccine Access Plan initiative was launched to make life-saving vaccines more equitably available. In addition to securing guarantees for financing of vaccines, the program objectives include building political will in low- and middle-income countries to commit to immunization as a priority, social marketing to individuals and communities, strengthening health systems and promoting relevant local research and development innovations.

Maternal vaccination to prevent disease in the youngest infants has been shown to be effective for tetanus, influenza and pertussis. Influenza vaccination during pregnancy is safe, provides reasonable maternal protection against influenza, and also protects infants for a limited period from confirmed influenza infection (vaccine efficacy 63% in Bangladesh and 50.4% in South Africa). However as antibody levels drop sharply after birth, infant protection does not persist much beyond 8 weeks. Recently respiratory syncytial virus vaccination in pregnancy has been shown to be safe and immunogenic, and a phase-3 clinical trial of efficacy at preventing respiratory syncytial virus disease in infants is under way. Within a decade, respiratory syncytial virus in infancy might be vaccine-preventable, with further decreases in pneumonia incidence, morbidity and mortality.

Improved access to health care, better nutrition and improved living conditions might contribute to further decreases in childhood pneumonia burden. The WHO Integrated Global Action Plan for diarrhea and pneumonia highlights many opportunities to protect, prevent and treat children. Breastfeeding rates can be improved by programs that combine education and counseling interventions in homes, communities and health facilities, and by promotion of baby-friendly hospitals. Improved home ventilation, cleaner cooking fuels and reduction in exposure to cigarette smoke are essential interventions to reduce the incidence and severity of pneumonia [70, 71]. Prevention of pediatric HIV is possible by providing interventions to prevent mother-to-child transmission. Early infant HIV testing and early initiation of antiretroviral therapy and cotrimoxazole prophylaxis can substantially reduce the incidence of community-acquired pneumonia among HIV-infected children. Community-based interventions reduce pneumonia mortality and have the indirect effect of improved-care-seeking behavior. If these cost-effective interventions were scaled up, it is estimated that 67% of pneumonia deaths in low- and middle-income countries could be prevented by 2025.

To the best of our knowledge, this is among the largest prospective multicenter studies regarding the microbiology of acute bronchitis. Notably, about 50% of patients with acute bronchitis and acceptable sputum had evidence of bacterial infection (typical or atypical), a higher frequency than that of viral infection. Also, the distributions of infectious etiologies differed by age and the presence of underlying chronic lung disease. Finally, mixed infections were common, and >50% of patients with viral infections also had bacterial infections.

In recent placebo-controlled randomized trials, antibiotics appeared to provide minimal benefit in treating acute bronchitis [4, 5, 22]. Therefore, it is often assumed that acute bronchitis is primarily a viral disease [4, 5]. Accordingly, previous studies have usually focused on viral etiologies and did not include sputum cultures, or used only serological tests for bacteria, and may have underestimated the bacteria’s role in acute bronchitis [23–25]. Creer et al. detected bacteria and viruses in 26% and 63% of acute bronchitis patients, respectively, prompting the authors to consider bacterial infection relatively uncommon. However, they collected sputum specimens for bacterial cultures from only a portion of patients, most patients submitted swabs and nasal aspirates for viral testing, and sputum specimen adequacy was not discussed. In contrast, we collected sputum specimens from all patients for viral, typical bacterial, and atypical bacterial infection simultaneously.

Although previous studies showed that antibiotics have little benefit in treating acute bronchitis, several factors may have affected the results [4, 5, 27]. First, patients included in such studies were inhomogeneous, and a considerable proportion of them may have had only upper respiratory tract infections (URIs). It is more appropriate to evaluate antibiotic effects in a fully differentiated group of bacterial etiologies. Second, the use of the term ‘bacterial infection’ in the lower respiratory tract does not necessarily imply that there is a requirement for antibiotics. Many of these infections can be cured without antibiotics. Third, even if bacterial infections were treated using antibiotics, subjective symptoms, such as post-infectious cough or upper-airway cough syndrome, might persist. Interestingly, in a randomized controlled trial of patients with URIs, antibiotics were clinically beneficial for a subgroup whose nasopharyngeal secretions contained respiratory bacteria. Although the presence of bacterial agents does not always indicate a disease, antibiotic treatments might be beneficial in subgroups of patients with bacterial etiologies. C-reactive protein or procalcitonin levels may eventually provide an objective marker for evaluating the need for antibiotic treatment.

Recent studies have used the term “lower respiratory tract infection (LRTI)” for conditions approximating acute bronchitis. LRTI is characterized by acute cough, with at least one other lower respiratory tract symptom, including purulent sputum, dyspnea, wheezing, chest discomfort, or chest pain [1, 4, 7, 10]. In our study, we attempted to limit patient enrollment to patients with acute bronchitis; however, some URI patients might have been enrolled because of symptom overlap. This potential bias should be considered when interpreting our results. However, the cohort of 291 patients with acceptable sputum could be considered as a purer group of acute bronchitis patients. Patients with acceptable sputum had more sputum production and auscultatory abnormalities, strongly supporting the diagnosis of LRTI.

In earlier studies, viral prevalence was 9.2–61.3% and rhinovirus or influenza were most commonly detected [7, 8, 26, 32, 33]. Importantly, not all studies spanned an entire year, and some were limited to the winter influenza season [25, 33]. We enrolled patients for an entire year, but fewer were enrolled during the winter, likely because we excluded those with typical symptoms of influenza during the winter (December–February).

In our study, the most common bacterial agent was H. influenzae, followed by S. pneumoniae. Some previous studies found S. pneumoniae to be the most frequent pathogen [7, 26], while others found H. influenzae more frequently [28, 34]. However, with the detection of pneumococcal antigens in sputum or urine, or PCR on airway secretions, S. pneumoniae is found in 17–19% of LRTI cases [7, 26]. Because we only used sputum cultures to detect typical bacteria, the incidence of S. pneumoniae might have been underestimated. Interestingly, S. pneumoniae was isolated in older patients twice as commonly than in younger patients (≥60 vs. <40 years: 15.0% vs. 7.3%, p = 0.075). Therefore, pneumococcal vaccines may be beneficial in preventing acute bronchitis associated with S. pneumoniae in older patients. Additional studies are warranted.

Mixed infection occurred in 18.9% of our patients, in 22–32% of patients in previous studies of LRTI [7, 8, 26], and in 6–26% of non-immunocompromised adults with community-acquired pneumonia (CAP). The most typical combination has been viral-bacterial mixed infection [10, 35]. In our study, rhinovirus was the most common virus in mixed infections. Several studies have suggested that rhinovirus can be pathogenic for LRTI, but it is unclear whether rhinovirus triggers secondary bacterial infection [36–38]. Also, viral-bacterial mixed infections have induced more severe inflammation and disease than individual infections in CAP cases [35, 39, 40]. Clinical features and outcomes have not been studied in patients with mixed infection acute bronchitis or LRTI without pneumonia, and we found no distinct characteristics of mixed infections.

We did not exclude patients with chronic lung disease, a large proportion of the patients evaluated for cough in our clinics. In a recent review, Mohan et al. detected viruses via PCR and RT-PCR in 34.1% of patients with an acute exacerbation of COPD. The same rate (34.1%) was observed for COPD patients in our study. However, none of our COPD or asthma patients were positive for M. pneumoniae, C. pneumoniae, or B. pertussis. Despite potential methodological problems, studies using PCR also found no COPD exacerbations associated with M. pneumoniae or C. pneumoniae [42, 43]. In a previous multicenter study, we demonstrated the absence of B. pertussis in patients with chronic lung disease.

We found that the prevalences of rhinovirus, adenovirus, and M. pneumoniae with acute bronchitis were higher in young adults. This observation is consistent with prior LRTI studies. Conversely, the frequency of typical bacteria was higher in the older age group, as demonstrated in studies of CAP [45, 46]. This result suggests antibiotics may be more beneficial in older patients with acute bronchitis. Petersen et al. reported that antibiotics substantially reduced pneumonia risk after chest infection (acute bronchitis), particularly in elderly patients.

In summary, bacterial infections were identified as the etiology for about half of the 35.9% of acute bronchitis patients who had acceptable sputum. The infectious etiologies differed by age and the presence of underlying chronic lung disease. Further, mixed infection with both bacteria and viruses were common. Future research should be directed at the identification of patient groups most likely to benefit from antibiotic treatment.