Severe Pneumococcal Pneumonia Research Articles

Co-infection of influenza B and Streptococcus. Authors' reply.

To the Editor—The recent report on ‘co-infection of influenza B and Streptococcus’ by Lam et al1 is very interesting. They reported “four cases infected with influenza B and streptococci that gave rise to severe pneumonia” and mentioned that “this is the second case report of severe invasive pneumococcal pneumonia secondary to influenza B infection.”1 Indeed, both influenza B and Streptococcus infections are important infectious diseases that are encountered worldwide. In fact, there are more than two previous publications reporting the concurrent infection of influenza B and Streptococcus.2,3 In the report by Aebi et al,2 three cases were document and additional four cases were presented in the report by Scaber et al.3 Hence, the claim by Lam et al1 should not be correct. Nevertheless, in all reports, the clinical features of the pneumonia were serious and sometimes fatal. As Lam et al1 suggested, physicians should increase awareness of possible concurrent infection in the present era of emerging influenza.

Methicillin-resistant Staphylococcus aureus enterocolitis sequentially complicated with septic arthritis: a case report and review of the literature

BackgroundAlthough most reports describing patients infected with methicillin-resistant Staphylococcus aureus enterocolitis have been published in Japan, this concept remains a matter of debate and diagnostic criteria have not yet been defined.Case presentationThe general status of a 74-year-old Japanese man referred to our hospital (day 1) with severe community-acquired pneumococcal pneumonia gradually improved with antibiotic therapy. Thereafter, up to 4 L/day of acute watery diarrhea that started on day 19 was refractory to metronidazole but responded immediately to oral vancomycin. Gram staining stool samples was positive for abundant fecal leukocytes from which dominant methicillin-resistant Staphylococcus aureus (104 CFU/mL) were isolated, suggesting methicillin-resistant Staphylococcus aureus enterocolitis. High fever with methicillin-resistant Staphylococcus aureus bacteremia was evident at day 30, and suppurative right hip arthritis developed around day 71. All methicillin-resistant Staphylococcus aureus strains isolated from stools, blood and aspirated synovial fluid separated in the same manner on pulsed-field gel electrophoresis, as well as two other strains isolated from sputum, belonged to the same clone as sequence type (ST) 764 (complex clonal 5), and carried SCCmec type II.ConclusionThe clinical, microbiological and molecular biological findings of this patient indicated methicillin-resistant Staphylococcus aureus enterocolitis that led to septic methicillin-resistant Staphylococcus aureus arthritis.

Uncommon cause of severe pneumonia: co-infection of influenza B and Streptococcus

Influenza and pneumococcus co-infection can cause severe morbidity and mortality. Usually, this entails influenza A, while infection by influenza B is rarely serious. The literature describes influenza A epidemics leading to prolific loss of lives, notably the 1918 epidemic was blamed for the deaths of 40 to 50 million people. In this report, four patients were infected by influenza B during the influenza epidemic of 2011/12 in Hong Kong. All of them were previously healthy and had no chronic diseases; they were admitted to the hospital due to influenza-like symptoms. They rapidly deteriorated with multi-organ failure, and were subsequently diagnosed to be infected with influenza B and streptococci that gave rise to severe pneumonia. Three of them were infected with Streptococcus pneumoniae and one with Streptococcus pyogenes. All of them had leukopenia, septic shock, and acute kidney injury; two of whom died despite aggressive antibiotic treatment and organ support in the intensive care unit. According to the literature, this is the second case report of severe invasive pneumococcal pneumonia secondary to influenza B infection.

Adjunctive Corticosteroid Therapy Improves Lung Immunopathology and Survival During Severe Secondary Pneumococcal Pneumonia in Mice

Secondary bacterial pneumonia is a significant cause of morbidity and mortality during influenza, despite routine use of standard antibiotics. Antibiotic-induced immunopathology associated with bacterial cell wall lysis has been suggested to contribute to these poor outcomes. Using Streptococcus pneumoniae in a well-established murine model of secondary bacterial pneumonia (SBP) following influenza, we stratified disease severity based on pneumococcal load in the lungs via in vivo bioluminescence imaging. Ampicillin treatment cured mice with mild pneumonia but was ineffective against severely pneumonic mice, despite effective bacterial killing. Adjunctive dexamethasone therapy improved ampicillin-induced immunopathology and improved outcomes in mice with severe SBP. However, early dexamethasone therapy during primary influenza infection impaired lung adaptive immunity as manifest by increased viral titers, with an associated loss of its protective functions in SBP. These data support adjunctive clinical use of corticosteroids in severe cases of community-acquired pneumonia.

Prevotella intermedia Induces Severe Bacteremic Pneumococcal Pneumonia in Mice with Upregulated Platelet-Activating Factor Receptor Expression

Streptococcus pneumoniae is the leading cause of respiratory infection worldwide. Although oral hygiene has been considered a risk factor for developing pneumonia, the relationship between oral bacteria and pneumococcal infection is unknown. In this study, we examined the synergic effects of Prevotella intermedia, a major periodontopathic bacterium, on pneumococcal pneumonia. The synergic effects of the supernatant of P. intermedia (PiSup) on pneumococcal pneumonia were investigated in mice, and the stimulation of pneumococcal adhesion to human alveolar (A549) cells by PiSup was assessed. The effects of PiSup on platelet-activating factor receptor (PAFR) transcript levels in vitro and in vivo were analyzed by quantitative real-time PCR, and the differences between the effects of pneumococcal infection induced by various periodontopathic bacterial species were verified in mice. Mice inoculated with S. pneumoniae plus PiSup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, spleen, and blood, and higher inflammatory cytokine levels in the bronchoalveolar lavage fluid (macrophage inflammatory protein 2 and tumor necrosis factor alpha) than those infected without PiSup. In A549 cells, PiSup increased pneumococcal adhesion and PAFR transcript levels. PiSup also increased lung PAFR transcript levels in mice. Similar effects were not observed in the supernatants of Porphyromonas gingivalis or Fusobacterium nucleatum. Thus, P. intermedia has the potential to induce severe bacteremic pneumococcal pneumonia with enhanced pneumococcal adhesion to lower airway cells.

P3 Prevotella intermedia induce severe bacteremic pneumococcal pneumonia in murine with up-regulating platelet-activating factor receptor

P3 Prevotella intermedia induce severe bacteremic pneumococcal pneumonia in murine with up-regulating platelet-activating factor receptor

Krueppel-like Factor 4 terminates Streptococcus pneumonia-dependent IL-8 release and induces IL-10 expression in human Lung Epithelial Cells

Objective: Streptococcus pneumoniae is the most common cause of community-acquired pneumonia throughout the world. The release of potent pro-inflammatory mediators is not only central for mounting an efficient host response, it always bears the risk of deleterious excessive tissue damaging inflammation. This is highlighted in severe pneumococcal pneumonia, in which the delicate balance among a robust inflammatory response to kill pneumococci and loss of organ function determines outcome of disease.

TLR9- and Src-dependent expression of Krueppel-like factor 4 controls interleukin-10 expression in pneumonia

The release of potent pro-inflammatory mediators is crucial to mounting an efficient host response during infection. However, excessive inflammation may lead to deleterious tissue damage. This is highlighted in severe pneumococcal pneumonia, in which the delicate balance between a robust inflammatory response necessary to kill pneumococci and the loss of organ function determines the outcome of the disease. We assessed the regulation of the potent anti-inflammatory cytokine interleukin (IL)-10 in pneumococcal infection via Western blot, ELISA and chromatin immunoprecipitation analysis. Streptococcus pneumoniae induced IL-10 expression in mouse lungs and human lung epithelial cells. Pneumococcal infection resulted in a strong induction of Krueppel-like factor (KLF)4 expression in vivo and in vitro. The induction of both IL-10 and KLF4 is mediated by a pathway involving bacterial DNA, Toll-like receptor (TLR)9, MyD88 and Src kinase. KLF4 is recruited to the il10 promoter, and small-interfering RNA-mediated knockdown of KLF4 expression blocked IL-10 expression during pneumococcal infection. In conclusion, KLF4 is induced in a bacterial DNA-TLR9-Src-dependent manner and regulates IL-10 expression, linking the detection of bacterial DNA by TLR9 to the control of an inflammatory response.

Antibiotic strategy in severe community-acquired pneumococcal pneumonia

ObjectiveThe authors had for aim to make an inventory of antibiotic treatment for severe community-acquired Streptococcus pneumoniae pneumonia and compare local practices to the local and national guidelines. Patients and methodAn audit was conducted retrospectively in the Versailles hospital ICU between January 2006 and April 2009. Forty patients were included. ResultsNinety-three percent had major risk factors for pneumonia. Ninety-eight percent were treated, with the usual empirical treatment (69%) or treatment active against Pseudomonas aeruginosa (31%). Eighty-five percent of empirical treatment complied with the French national guidelines issued by the SPILF and 49% with the local ICU protocol, more restrictive for the choice of the agent and dose. Early de-escalation to amoxicillin was applied to 41% of patients after obtaining results for pneumococcal and Legionella antigen and results of respiratory sample direct examination. For all patients, empirical treatment was reassessed according to culture results: 81% were prescribed amoxicillin. Evaluation showed that 92% of treatment complied with SPILF guidelines and 65% with the local ICU protocol that required adaptation of amoxicillin doses according to MICs; adaptation to severity and BMI was necessary for ten patients. Mortality remained high, at 37%, despite using antibiotics still effective against S. pneumoniae. ConclusionsThis survey revealed a satisfactory adhesion to recommendations and prompt responsiveness of the team for adjustment of antibiotic therapy. The audit allowed updating the local ICU protocol.

Ventilator-induced lung injury in severe pneumococcal pneumonia: protection by Adrenomedullin

Ventilator-induced lung injury (VILI) contributes to mortality in ARDS. Particularly preinjured lungs may be susceptible to VILI despite lung protective ventilation. We previously observed protection against VILI by therapeutic use of the endogenous peptide Adrenomedullin (AM) in addition to lung protective ventilation in mice. The current study analyzed the impact of mechanical ventilation (MV) on lung injury, pulmonary and systemic inflammation and bacterial burden in established pneumonia. Further, AM was used therapeutically to limit VILI in a clinically relevant murine model.

Incidence and Cinical Characteristics of Severe Community-Acquired Pneumococcal Pneumonia: Comparisons with Non-Pneumoccocal Pathogens

ëª©ì : ì¤‘ì¦ì§€ì—­ì‚¬íšŒíšë“íë ´(severe CAP or SCAP)에 대한 국내 연구는 많지 않았으며 특히 가장 흔한 원인 ê· ì¸ íë ´êµ¬ê· ì— 의한 중증지역사회획득 íë ´(pneumococcal SCAP or P-SCAP)에 대한 연구는 매우 부족한 ì‹¤ì •ì´ë‹¤. 방법: 2007ë „ 1월부터 2008ë „ 12월까지 한림대학교 성심병원 내과에 ìž ì›í•œ 18세 이상의 성인 환자들 중 2007 Infectious Disease Society of America/American Thoracic Society (IDSA/ATS) criteria에 따른 SCAP의 ì •ì˜ë¥¼ 만족 하는 환자를 대상으로 í›„í–¥ì  의무기록 분석을 시행하였다. ê²°ê³¼: 연구 기간 동안 총 94ëª ì˜ SCAP 환자가 ì„ ì •ë˜ì—ˆë‹¤. 환자의 í‰ê· ì—°ë ¹ì€ 73.5 ± 14.3ì„¸ì˜€ê³ , 이 중 남자가 70ëª ì´ì—ˆë‹¤. ì „ì²´ SCAP 환자 중 P-SCAP가 23ëª (24.5%), non-P-SCAP가 17ëª ì´ì—ˆìœ¼ë©°(Pseudomonas aeruginosa, 4 [4.3%]; Staphylococcus aureus, 4 [4.3%]), 54ëª (57.4%)에서는 ê· ì´ ë™ì •ë˜ì§€ 않았다. ìž ì› 당시 패혈성 쇽의 ë°œìƒë¥ ë° PSI ì ìˆ˜ëŠ” P-SCAP 환자군에서 non-P-SCAP 및 ê· ì´ ë™ì •ë˜ì§€ 않은 SCAP 환자군(SCAP with no organism identified)에 비하여 낮게 확인되었다(p= 0.023 and p= 0.007). 또한 P-SCAP 환자군에서 non-P- SCAP 환자군에 비하여 낮은 치료 실패율(p= 0.048)을 ë³´ì˜€ê³ , ë³‘ì›ì‚¬ë§ë¥ ë° 30일 ì‚¬ë§ë¥ ë„ 낮은 경향을 보였다. 30ì¼ì‚¬ë§ë¥ ê³¼ ê´€ë ¨ëœ 다변량분석에서는 ì¢ ì–‘ì˜ ê¸°ì™•ë ¥ì´ 가장 ê°•ë ¥í•œ 예후인자로 확인되었다(odds ratio = 9.068; 95% confidence interval = 1.856-44.309). ê²°ë¡ : P-SCAP은 ì „ì²´ SCAP 환자 중 24.5%를 차지하여 SCAP의 가장 흔한 ì›ì¸ê· ìœ¼ë¡œ 확인되었다. P-SCAP 환자에서 non-P-SCAP 환자에 비하여 낮은 중증도를 ë³´ì˜€ê³ ì¢€ 더 양호한 예후를 갖는 경향을 보였다. 중심 단어: íë ´êµ¬ê· ; 중환자실; íë ´

Epidemiology and outcome of severe pneumococcal pneumonia admitted to intensive care unit: a multicenter study

IntroductionCommunity-acquired pneumonia (CAP) account for a high proportion of ICU admissions, with Streptococcus pneumoniae being the main pathogen responsible for these infections. However, little is known on the clinical features and outcomes of ICU patients with pneumococcal pneumonia. The aims of this study were to provide epidemiological data and to determine risk factors of mortality in patients admitted to ICU for severe S. pneumoniae CAP.MethodsWe performed a retrospective review of two prospectively-acquired multicentre ICU databases (2001-2008). Patients admitted for management of severe pneumococcal CAP were enrolled if they met the 2001 American Thoracic Society criteria for severe pneumonia, had life-threatening organ failure and had a positive microbiological sample for S. pneumoniae. Patients with bronchitis, aspiration pneumonia or with non-pulmonary pneumococcal infections were excluded.ResultsTwo hundred and twenty two patients were included, with a median SAPS II score reaching 47 [36-64]. Acute respiratory failure (n = 154) and septic shock (n = 54) were their most frequent causes of ICU admission. Septic shock occurred in 170 patients (77%) and mechanical ventilation was required in 186 patients (84%); renal replacement therapy was initiated in 70 patients (32%). Bacteraemia was diagnosed in 101 patients. The prevalence of S. pneumoniae strains with decreased susceptibility to penicillin was 39.7%. Although antibiotherapy was adequate in 92.3% of cases, hospital mortality reached 28.8%. In multivariate analysis, independent risk factors for mortality were age (OR 1.05 (95% CI: 1.02-1.08)), male sex (OR 2.83 (95% CI: 1.16-6.91)) and renal replacement therapy (OR 3.78 (95% CI: 1.71-8.36)). Co-morbidities, macrolide administration, concomitant bacteremia or penicillin susceptibility did not influence outcome.ConclusionsIn ICU, mortality of pneumococcal CAP remains high despite adequate antimicrobial treatment. Baseline demographic data and renal replacement therapy have a major impact on adverse outcome.

Ventilator-induced lung injury in severe pneumococcal pneumonia: protection by Adrenomedullin

Introduction: Ventilator-induced lung injury (VILI) contributes to mortality in ARDS. Particularly preinjured lungs may be susceptible to VILI despite lung protective ventilation. We previously observed protection against VILI by therapeutic use of the endogenous peptide Adrenomedullin (AM) in addition to lung protective ventilation in mice. The current study analyzed the impact of mechanical ventilation (MV) on lung injury, pulmonary and systemic inflammation and bacterial burden in established pneumonia. Further, AM was used therapeutically to limit VILI in a clinically relevant murine model.

Increase of Apoptosis in a Murine Model for Severe Pneumococcal Pneumonia during Influenza A Virus Infection

The mechanisms of severe pneumonia caused by co-infection of bacteria and influenza A virus (IAV) have not been fully elucidated. We examined apoptosis and inflammatory responses in a murine model for pneumococcal pneumonia during IAV infection. Inflammation, respiratory epithelium apoptosis, and inflammatory-cell infiltration increased in a time dependent manner in the lungs of mice co-infected with Streptococcus pneumoniae and IAV, in comparison with those infected with either S. pneumoniae or IAV. According to appearance of terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cells, caspases-3 and -8 were activated 24 h after S. pneumoniae infection, and caspase-3 activation decreased after 48 h, whereas inflammatory cytokine levels continued to increase in co-infected mice. In contrast, in mice infected with either IAV or S. pneumoniae, apoptosis and activation of factors related to caspase-3 peaked at 48 h. Furthermore, Fas-associated death domain was significantly expressed in the lungs of co-infected mice 24 h after S. pneumoniae infection. These data suggest that early onset of apoptosis and its related factors play important roles in fulminant pneumonia resulting from bacterial pneumonia complicated by co-infection with influenza virus.

Severe pneumococcal community-acquired pneumonia admitted to medical Tunisian ICU

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP). There are no available data about this disease in Tunisian intensive care patients. The objective of this study is to describe the clinical and microbiological features of pneumococcal CAP and determine the prognostic factors. This is a retrospective cohort study of all pneumococcal CAP cases hospitalized in the medical intensive care unit (ICU) of Hospital A. Mami of Ariana (Tunisia) between January 1999 and August 2008. Included were 132 patients (mean age, 49.5 years; 82.6% males); 30 patients had received antimicrobial treatment before hospital admission. The mean of the Simplified Acute Physiology Score II was 32.9. All patients had an acute respiratory failure; 34 patients (25.8%) had pneumococcal bacteremic CAP. Among the isolated strains, 125 antimicrobial susceptibility tests were performed. The use of the new Clinical and Laboratory Standards Institute breakpoints for susceptibility when testing penicillin against S. pneumoniae showed that all isolated strains were susceptible to penicillin. The mortality rate was 25%. The need of mechanical ventilation at admission [odds ratio (OR), 3.4; 95% confidence interval (CI), 1.67–6.94; P = 0.001), Sepsis-related Organ Failure Assessment (SOFA) score at admission ≥4 (OR, 3.1; 95% CI, 1.56–6.13; P = 0.001), and serum creatinine at admission ≥102 μmol/l (OR, 1.8; 95% CI, 1.02–3.17; P = 0.043) were independent factors related to ICU mortality. In conclusion, pneumococcal CAP requiring hospitalization in the ICU is associated with high mortality. All isolated stains were susceptible to penicillin.

A new urinary antigen test score correlates with severity of pneumococcal pneumonia in children

Streptococcus pneumoniae is the most common bacterial cause of community-acquired pneumonia in children. This study was designed to determine whether a newly designed urinary antigen test score correlated with severity of pneumococcal pneumonia in children. We recruited 119 children hospitalized with pneumonia diagnosed by positive urinary pneumococcal antigen test at the National Cheng Kung University Hospital from 2002 through 2007. The urinary antigen reactivity score was determined by the rate of the reaction time and intensity of the pneumococcal antigen-antibody band. The children were stratified into three groups according to total score: group I, 8; group II, 5-7; and group III, 2-4. Disease severity was based on clinical presentation and radiological and laboratory findings. Patients in group I had significantly more respiratory distress (p=0.01), oxygen desaturation (p=0.04), febrile days (p=0.03), pulmonary complications (p=0.01), and bacteremia (p=0.01), greater requirement for intensive care (p=0.004), longer hospital stays (p<0.001), and lower white blood cell counts (p=0.01) than patients in group II or III. A new urinary pneumococcal antigen test score correlated well with the severity of pneumococcal pneumonia in children. It might provide helpful diagnostic and prognostic information.

Cathepsin G and neutrophil elastase play critical and nonredundant roles in lung-protective immunity against Streptococcus pneumoniae in mice.

Neutrophil serine proteases cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3) have recently been shown to contribute to killing of Streptococcus pneumoniae in vitro. However, their relevance in lung-protective immunity against different serotypes of S. pneumoniae in vivo has not been determined so far. Here, we examined the effect of CG and CG/NE deficiency on the lung host defense against S. pneumoniae in mice. Despite similar neutrophil recruitment, both CG knockout (KO) mice and CG/NE double-KO mice infected with focal pneumonia-inducing serotype 19 S. pneumoniae demonstrated a severely impaired bacterial clearance, which was accompanied by lack of CG and NE but not PR3 proteolytic activity in recruited neutrophils, as determined using fluorescence resonance energy transfer (FRET) substrates. Moreover, both CG and CG/NE KO mice but not wild-type mice responded with increased lung permeability to infection with S. pneumoniae, resulting in severe respiratory distress and progressive mortality. Both neutrophil depletion and ablation of hematopoietic CG/NE in bone marrow chimeras abolished intra-alveolar CG and NE immunoreactivity and led to bacterial outgrowth in the lungs of mice, thereby identifying recruited neutrophils as the primary cellular source of intra-alveolar CG and NE. This is the first study showing a contribution of neutrophil-derived neutral serine proteases CG and NE to lung-protective immunity against focal pneumonia-inducing serotype 19 S. pneumoniae in mice. These data may be important for the development of novel intervention strategies to improve lung-protective immune mechanisms in critically ill patients suffering from severe pneumococcal pneumonia.

In vivo efficacy of KRP-109, a novel elastase inhibitor, in a murine model of severe pneumococcal pneumonia

KRP-109 is a novel specific inhibitor of neutrophil elastase (NE). Various studies suggest that NE inhibitors reduce lung injury associated with systemic inflammatory response syndrome (SIRS). In this study, the efficacy of KRP-109 was examined using a murine model of severe pneumonia induced by Streptococcus pneumoniae ( S. pneumoniae). Female mice (CBA/J, aged 5 weeks) were inoculated intranasally with penicillin-susceptible S. pneumoniae (ATCC49619 strain, 2.5 × 10 8 CFU/mouse). KRP-109 (30 or 50 mg/kg) or physiological saline as a control was administered intraperitoneally every 8 h beginning at 8 h after inoculation, and survival rate was evaluated over 7 days. Histopathological and bacteriological analyses of the lung, and bronchoalveolar lavage were performed at 48 h post-infection. The mice treated with KRP-109 (KRP-109 mice) tended to have higher survival rate than those given saline. The lung tissues of the KRP-109 mice had few neutrophils in the alveolar walls and less inflammation. Furthermore, KRP-109 decreased significantly total cell and neutrophil counts, and cytokine levels (interleukin 1β and macrophage inflammatory protein 2) in bronchoalveolar lavage fluid. Viable bacterial numbers in lung were not influenced by treatment of KRP-109. The present results indicate that KRP-109 reduces lung inflammation in a murine model, and that KRP-109 may be useful for the treatment of patients with severe pneumonia.

Severe pneumococcal pneumonia: impact of new quinolones on prognosis

BackgroundMost guidelines have been proposing, for more than 15 years, a β-lactam combined with either a quinolone or a macrolide as empirical, first-line therapy of severe community acquired pneumonia (CAP) requiring ICU admission. Our goal was to evaluate the outcome of patients with severe CAP, focusing on the impact of new rather than old fluoroquinolones combined with β-lactam in the empirical antimicrobial treatments.MethodsRetrospective study of consecutive patients admitted in a 16-bed general intensive care unit (ICU), between January 1996 and January 2009, for severe (Pneumonia Severity Index > or = 4) community-acquired pneumonia due to non penicillin-resistant Streptococcus pneumoniae and treated with a β-lactam combined with a fluoroquinolone.ResultsWe included 70 patients of whom 38 received a β-lactam combined with ofloxacin or ciprofloxacin and 32 combined with levofloxacin. Twenty six patients (37.1%) died in the ICU. Three independent factors associated with decreased survival in ICU were identified: septic shock on ICU admission (AOR = 10.6; 95% CI 2.87-39.3; p = 0.0004), age > 70 yrs. (AOR = 4.88; 95% CI 1.41-16.9; p = 0.01) and initial treatment with a β-lactam combined with ofloxacin or ciprofloxacin (AOR = 4.1; 95% CI 1.13-15.13; p = 0.03).ConclusionOur results suggest that, when combined to a β-lactam, levofloxacin is associated with lower mortality than ofloxacin or ciprofloxacin in severe pneumococcal community-acquired pneumonia.

Cathepsin G and neutrophil elastase play critical and non-redundant roles in lung protective immunity against S. pneumoniae in mice

Neutrophil serine proteases cathepsin G (CtsG), neutrophil elastase (NE) and proteinase-3 (PR3) have recently been shown to contribute to killing of Streptococcus pneumoniae in vitro. However, their relevance in lung protective immunity against different serotypes of S. pneumoniae in vivo has not been determined so far. We here infected CtsG-deficient mice and CtsG/NE deficient mice with two serotypes of S. pneumoniae exhibiting different virulence profiles. Despite similar neutrophil recruitment, both CtsG KO mice and, even more accentuated, CtsG/NE KO mice infected with serotype 19 S. pneumoniae demonstrated a severely impaired bacterial clearance, which was accompanied by lack of CtsG and NE but not PR-3 proteolytic activity in recruited neutrophils, as determined by FRET analysis. Moreover, both CtsG and CtsG/NE KO mice but not wild-type mice responded with increased lung permeability to infection with S. pneumoniae, resulting in severe respiratory distress and progressive mortality. On the other hand, CtsG/NE deficient mice demonstrated a similar mortality after infection with highly invasive serotype 2 S. pneumoniae as compared to wild-type mice. This is the first study to show a differenzial contribution of neutral serine proteases CtsG and NE to regulate lung protective immunity against focal pneumonia-inducing serotype 19 but not sepsis-inducing serotype 2 S. pneumoniae in mice. These data may be important for the development of novel intervention strategies to improve lung protective immune mechanisms in critically ill patients suffering from severe pneumococcal pneumonia.