Moderate Pneumonia Research Articles

本邦における HIV 感染症患者ニューモシスチス肺炎治療・ 予防目的のアトバコン使用状況と副作用 ―厚生労働省エイズ治療薬研究班 1997 年～2012 年―

Atovaquone is effective and well-tolerated for the treatment of mild or moderate Pneumocystis pneumonia (PCP) and the prevention of PCP. When atovaquone was not yet approved in Japan, it was supplied by the Clinical Study Group for AIDS Drugs, which has been supported by the Japan Health Science Foundation since 1997. We investigated the status of use and the reported side effects, since atovaquone has recently been approved and made available in Japan. We retrospectively examined the application and adverse events associated with atovaquone use between January 1997 and March 2012. During this period, there were 721 new applications, increasing over time, with the highest rate of increase observed in recent years. Fifty-seven adverse events in 39 patients were reported. Drug eruption was the most common side effect (20 cases), followed by cytopenia (11 cases), fever (10 cases), and liver dysfunction (8 cases). Two deaths were reported (one with an unknown correlation, another with no comments provided). One case of liver dysfunction attributable to atovaquone was severe. In this case, the AST and ALT levels increased to 1,921 IU/L, and 1,062 IU/L, respectively on day 4 of atovaquone administration, but these levels improved after atovaquone discontinuation. No other severe side effects were reported. This study revealed that as in other countries, few side effects caused by atovaquone were reported in Japan. Moreover, there were no side effects unique to the Japanese population. However, caution is required when administering atovaquone, because a low incidence of severe atovaquone-induced liver dysfunction has been reported.

Chest physiotherapy in paediatric patients hospitalised with community-acquired pneumonia: a randomised clinical trial

BackgroundChest physiotherapy has been used to treat children hospitalised with pneumonia with no clear scientific evidence to support a beneficial effect. The objective of the current study was to evaluate...

Prevalence and determinants of hyperglycaemia in pneumonia patients

Hyperglycaemia during pneumonia prolongs the hospitalization and increases the risks of complications and death. However, its prevalence and determinants have not been systematically assessed. This was a prospective, cross-sectional study. The material consisted of 153 hospitalized patients with pneumonia. Patients needing intensive care unit treatment were excluded. The height, weight, waist circumference, oxygen saturation, blood pressure, temperature, heart rate, and Karnofsky score were measured at admission. Blood tests included glycosylated haemoglobin A1c (gHbA1c), C-reactive protein (CRP), leukocytes, urea, and arterial blood gas analysis. Plasma glucose was measured 7 times during the first day on the ward. Hyperglycaemia was defined as a fasting glucose > 7.0 mmol/l or postprandial glucose > 11.1 mmol/l. Ninety-two patients (60%) showed hyperglycaemia. Twenty-two patients had a diagnosis of diabetes before hospitalization. Of the 131 patients without such a diagnosis, 72 (55%) showed hyperglycaemia. Of these, 67 showed fasting hyperglycaemia and 36 postprandial hyperglycaemia. In the binary logistic regression analysis, the following factors showed independent associations with the presence of hyperglycaemia: advanced age, high gHbA1c, high CRP, and high blood leukocyte level. More than half of non-diabetic patients with mild to moderate pneumonia demonstrated hyperglycaemia. The main determinants of hyperglycaemia were an abnormal pre-pneumonia glucose metabolism and the intensity of the pneumonic inflammation. Systematic screening of hyperglycaemia in all hospitalized pneumonia patients appears reasonable to identify high-risk patients.

Porcine reproductive and respiratory syndrome virus induces pronounced immune modulatory responses at mucosal tissues in the parental vaccine strain VR2332 infected pigs

Porcine reproductive and respiratory syndrome (PRRS) is a chronic viral disease of pigs caused by PRRS virus (PRRSV). The PRRSV VR2332 is the prototype North American parental strain commonly used in the preparation of vaccines. Goal of this study was to understand missing information on VR2332 induced immune modulation at the lungs and lymphoid tissues, the sites of PRRSV replication. Pigs were infected intranasally and samples collected at post-infection day (PID) 15, 30, and 60. Microscopically, lungs had moderate interstitial pneumonia, and the virus was detected in all the tested tissues. Peak antibody response and the cytokine IFN-γ secretion were detected at PID 30, with increased TGF-β until PID 60. Population of CD8+, CD4+, and CD4+CD8+T cells, Natural killer (NK) cells, and γδ T cells in the lungs and lymphoid tissues were significantly modulated favoring PRRSV persistence. The NK cell-mediated cytotoxicity was significantly reduced in infected pigs. In addition, increased population of immunosuppressive T-regulatory cells (Tregs) and associated cytokines were also observed in VR2332 strain infected pigs.

Features of community-acquired pneumonia treatment with 3rd generation cephalosporins in combination with azithromycin and as monotherapy

Aim. To refine the indications for oral administration of a combination of 3rd generation cephalosporins together with azithromycin and also as monotherapy in patients with moderate and severe community-acquired pneumonia. Methods. A questionnaire was developed to evaluate the clinical and laboratory data on the 1st, 3rd, 5th, 7th and 10-14th days of treatment. The patients were included in the study if clinical signs of pneumonia were present, the disease occurred outside a hospital, and if there was radiological verification of lung tissue infiltration. The study included 77 patients (32 women and 45 men) aged 16 to 84 years. In 56 patients (73%) pneumonia had signs of a moderate course, in 21 (27%) - a severe course. Results. As a result of treatment the number of patients without shortness of breath significantly increased. The difference in comparison with the time of hospitalization was statistically significant starting from day 7 of treatment in patients treated with ceftriaxone and azithromycin (31 and 69%, p 0.05). Intergroup differences also became significant on the same time since treatment initiation (43% of patients on monotherapy, p 0.05). The increase in the proportion of patients without shortness of breath, receiving only ceftriaxone in comparison with the beginning of treatment became significant only by the 10th day (18 and 54%, p 0.05). Conclusion. A combination antibiotic therapy is indicated for patients with a severe course of disease and clinically significant dyspnea, as well as for women with a moderate community-acquired pneumonia with a productive cough. No significant differences in the safety and tolerability of the studied variants of treatment options have been revealed.

Abstract LB-264: Axitinib improves radiotherapy for murine xenograft lung tumors

Abstract Biological agents are currently being tested to improve the outcome of chemo-radiotherapy for locally advanced non-small cell lung cancer (NSCLC). The anti-angiogenic drug axitinib (AG-013736, Pfizer), is a small molecule receptor tyrosine kinase (RTKs) inhibitor. Axitinib selectively targets VEGF receptors 1, 2 and 3 (VEGFR), has a high potency for VEGFR-2 and inhibits the signal transduction induced by VEGF binding to VEGFR. Axitinib used in a phase II trial for advanced NSCLC demonstrated a promising one-year survival rate with manageable toxicities. We have tested the combination of axitinib with radiotherapy in a pre-clinical model of orthotopic A549 model of human lung carcinoma xenografts in nude mice. Mice-bearing established A549 lung tumor nodules were treated orally and daily with axitinib at 25mg/kg/day concomitant with daily fractionated radiation for 5 consecutive days. Radiation was administered to the left lung at a dose 2 Gy per day and then, axitinib treatment was continued for 5 days per week for 4 more weeks. A mild decrease in overall weight was observed in mice treated with axitinib or axitinib and radiation indicating that axitinib was safe and well tolerated, probably as a result of its short-half life (2-5h). No systemic effect on the vasculature of other organs including the heart, kidney and liver was observed by histology. Axitinib caused decreased tumor cellularity in lung nodules associated with a heavy infiltration of inflammatory cells. Mice treated with axitinib and radiation had a significant decrease in the size and number of lung tumor nodules which contained degenerating giant tumor cells and inflammatory infiltrates. Morphometric measurements of tumor nodules confirmed that the size of tumor nodules was significantly smaller in the irradiated left lung and was further reduced by combination with axitinib compared to that of mice treated with single modality (p<0.05). Ki-67 staining showed a marked decrease in the number of proliferating tumor cells. In the surrounding lung tissue, scattered intra-alveolar hemorrhage was estimated to cover 10 to 20% of the lung surface in treated mice but it was comparable to that observed in untreated mice. Axitinib caused mild chronic interstitial pneumonia and combined axitinib and radiation treatment was associated with moderate interstitial pneumonia. In independent experiments, treatment of lung tumors with a single dose of radiation (10 Gy) administered to the lungs and 10 weeks of axitinib showed a complete inhibition of tumor growth in the lungs. Histology showed the presence of distinctive lymphohistiocytic nodules with no detectable viable tumor cells. This treatment was well tolerated with minimal weight loss. These findings suggest a potential novel approach for the treatment of locally advanced NSCLC by combining radiotherapy with the anti-angiogenic drug axitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-264. doi:1538-7445.AM2012-LB-264

Evaluation of TREM1 Gene Expression in Circulating Polymorphonuclear Leukocytes and Its Inverse Correlation with the Severity of Pathophysiological Conditions in Patients with Acute Bacterial Infections

During bacterial infection, activated polymorphonuclear leukocytes (PMNs) often cause inflammation and organ dysfunction in severely ill patients. Gene expression was analyzed in circulating PMNs isolated from these patients to determine the distinct expression profile. We focused on immunomodulatory genes, such as those for pattern recognition receptors, inflammatory cytokines, PMN surface antigens, and myeloid cell receptors in PMNs. Gene expression in 23 patients (12 with pneumonia and 11 with sepsis) were analyzed using quantitative real-time polymerase chain reaction. The mRNA levels of TLR2 (20/23 cases) and CD14 (18/23 cases) were upregulated in the PMNs of patients when compared with healthy subjects. The mRNA expression levels of TLR4 (16/23 cases) and IL6 (16/23 cases) were downregulated in patients' PMNs, and of TNFA (16/23 cases) were upregulated in these cells. Although mRNA levels of IL8RA (15/23 cases) were downregulated in PMNs, MAC-1 mRNA levels (14/23 cases) were upregulated in the same cells. Copies of the TREM1 transcript were 0.7- to 2.1-fold higher in patients with moderate pneumonia than in the healthy subjects; the average fold change was 1.1. The mRNA levels were 0.3-fold lower in the patients with severe pneumonia and sepsis than in the healthy subjects. In conclusion, the downregulation of TREM1 expression in PMNs is associated with the severity of the pathophysiological conditions and may be used as a surrogate marker of acute bacterial infections.

Renal transplant with bronchiolitis obliterans organizing pneumonia (BOOP) attributable to tacrolimus and herpes simplex virus (HSV) pneumonia

BackgroundSolid organ transplants (SOTs) may be complicated by a wide variety of infectious and noninfectious pulmonary disorders. Transplant patients receive immunosuppressive drugs to prevent rejection, but these drugs also predispose them to infection. Because immunosuppressive therapy impairs T-lymphocyte function, ie, cell-mediated immunity, such therapy, not surprisingly, predisposes patients to intracellular pulmonary pathogens. Community-acquired pneumonia (CAP) in patients with SOT usually involves one of the common typical or atypical bacterial CAP pathogens infecting immunocompetent hosts. The most frequent intracellular CAP pathogens in SOTs during immunosuppressive therapy are viral, eg, cytomegalovirus (CMV), respiratory syncytial virus (RSV), and herpes simplex virus (HSV). In addition, intracellular fungal pathogens are also common in patients with SOTs during immunosuppressive therapy, eg, Pneumocystis (carinii) jiroveci pneumonia (PCP). In addition, a variety of noninfectious disorders are not uncommon in patients with SOTs, including bronchiolitis obliterans organizing pneumonia (BOOP). Bronchiolitis obliterans organizing pneumonia may be associated with a variety of infectious agents, or may be attributable to drugs, including some immunosuppressive agents. MethodsThe clinical approach to CAP in patients with SOTs may be based on the appearance of the chest x-ray (CXR) or chest computed tomography scan, combined with the degree of hypoxemia (ie, the A-a gradient). Patients with SOTs and with a normal or nearly normal CXR and a high degree of hypoxemia (A-a gradient, >35) most often have an early viral pneumonia, eg, CMV or early PCP. If the CXR reveals bilateral patchy interstitial infiltrates and severe hypoxemia, the differential diagnosis is limited to moderate or severe viral pneumonia or PCP. Patients with SOTs and presenting with diffuse infiltrates and mild to moderate hypoxemia (A-a gradient, <35) are usually prone to noninfectious disorders, eg, congestive heart failure, pulmonary embolism, or drug-induced pneumonias. In patients with SOTs and CAP with focal or lobar infiltrates, the distribution of pathogens is the same as in immunocompetent hosts, ie, either a bacterial or atypical CAP pathogen. Case Report and ConclusionA renal transplant patient developed bilateral patchy interstitial infiltrates with severe hypoxemia during hospitalization. The most likely differential diagnostic possibilities included PCP and BOOP. Bronchoalveolar lavage was performed to rule out PCP, and indicated cytopathic effects diagnostic of HSV pneumonia. Lung biopsy pathology confirmed the diagnosis of BOOP. In reviewing the patient’s medications, we surmised that tacrolimus may have caused BOOP. The tacrolimus was discontinued, and the patient received acyclovir for HSV pneumonia.

Role of a Tissue Factor Pathway Inhibitor, the Plasma Proteinase ADAMTS-13 and its Inhibitor in the Pathogenesis of Acute Respiratory Distress Syndrome in A/H1N1 Influenza

Objective: to study the role of a tissue factor pathway inhibitor (TFPI), the metalloproteinase ADAMTS-13, and its inhibitor in the pathogenesis of acute respiratory distress syndrome (ARDS) in A/H1N1 influenza. Subjects and methods. The study enrolled 52 patients of both sexes aged 19 to 40 years with different clinical forms of A/H1N1 influenza, of whom 14 patients developed Stages I-II ARDS in the presence of pneumonia. An enzyme immunoassay was used to estimate the concentrations of TFPI, ADAMTS-13, and its inhibitor, the antibodies of the IgG class. Results. The level of TFPI increased in parallel with the progression of the disease, its highest concentration was found in patients with ARDS-complicated influenza pneumonia. There was a higher relative activity of ADAMTS-13 in patients with moderate pneumonia while this enzyme was relatively deficient in those with ARDS-complicated pneumonia. Conclusion. Relative ADAMTS-13 deficiency is one of the triggers of ARDS in severe forms of pneumonia in the presence of A/H1N1 influenza. The high level of TFPI may predict the development of respiratory distress syndrome in pneumonia in the presence of influenza infection. Key words: A/H1N1 influenza, respiratory distress syndrome, tissue factor pathway inhibitor, ADAMTS-13.

Reducing Occurrence and Severity of Pneumonia Due to Pandemic H1N1 2009 by Early Oseltamivir Administration: A Retrospective Study in Mexico

BackgroundAnti-viral treatment has been used to treat severe or progressive illness due to pandemic H1N1 2009. A main cause of severe illness in pandemic H1N1 2009 is viral pneumonia; however, it is unclear how effective antiviral treatment is against pneumonia when administered >48 hours after symptom onset. Therefore, we aimed to determine how time from symptom onset to antiviral administration affected the effectiveness of antiviral treatment against pneumonia due to pandemic (H1N1) 2009.Methods/Principal FindingsA retrospective medical chart review of 442 patients was conducted in a hospital in Mexico. Subjects had tested positive for pandemic H1N1 2009 virus by real-time reverse-transcriptase-polymerase-chain-reaction and were administered oseltamivir. Median time from symptom onset to oseltamivir administration was 5.0 days (range, 0–43). 442 subjects, 71 (16.1%) had severe pneumonia which required mechanical ventilation, 191 (43.2%) had mild to moderate pneumonia, and 180 (40%) did not have pneumonia. Subjects were divided into four groups based on time to oseltamivir administration: ≤2, 3–7, 8–14, and >14 days. Severity of respiratory features was associated with time to treatment, and multivariate analysis indicated that time to oseltamivir administration was associated with severity of respiratory features. A proportional odds model indicated that 50% probability for occurrence of pneumonia of any severity and that of severe pneumonia in patients who would develop pneumonia reached at approximately 3.4 and 21 days, respectively, after symptom onset. Patients with a shorter time to oseltamivir administration were discharged earlier from the hospital.ConclusionsEarlier initiation of oseltamivir administration after symptom onset significantly reduced occurrence and severity of pneumonia and shortened hospitalization due to pandemic H1N1 2009. Even when administered >48 hours after symptom onset, oseltamivir showed considerable potential for reducing pneumonia. Application of these results would benefit patients affected by future influenza pandemics.

Pathogenesis of Influenza A/H5N1 Virus Infection in Ferrets Differs between Intranasal and Intratracheal Routes of Inoculation

Most patients infected with highly pathogenic avian influenza A/H5N1 virus develop severe pneumonia resulting in acute respiratory distress syndrome, with extrarespiratory disease as an uncommon complication. Intranasal inoculation of ferrets with influenza A/H5N1 virus causes lesions in both the respiratory tract and extrarespiratory organs (primarily brain). However, the route of spread to extrarespiratory organs and the relative contribution of extrarespiratory disease to pathogenicity are largely unknown. In the present study, we characterized lesions in the respiratory tract and central nervous system (CNS) of ferrets (n = 8) inoculated intranasally with influenza virus A/Indonesia/5/2005 (H5N1). By 7 days after inoculation, only 3 of 8 ferrets had a mild or moderate bronchointerstitial pneumonia. In contrast, all 8 ferrets had moderate or severe CNS lesions, characterized by meningoencephalitis, choroiditis, and ependymitis, and centered on tissues adjoining the cerebrospinal fluid. These findings indicate that influenza A/H5N1 virus spread directly from nasal cavity to brain, and that CNS lesions contributed more than pulmonary lesions to the pathogenicity of influenza A/H5N1 virus infection in ferrets. In comparison, intratracheal inoculation of ferrets with the same virus reproducibly caused severe bronchointerstitial pneumonia. The method of virus inoculation requires careful consideration in the design of ferret experiments as a model for influenza A/H5N1 in humans.

Pulmonary trematodosis (Pharyngostomoides sp.) in a juvenile raccoon (Procyon lotor)

A lethargic, wild, juvenile raccoon died and was subsequently presented for necropsy. The lungs had widely disseminated, finely granular, yellow-tan foci with moderate pulmonary, as well as, thoracic lymphadenopathy. Histopathology revealed numerous cross-sections of larval trematodes morphologically consistent with diplostomid mesocercariae and metacercariae as well as moderate alveolointerstitial pneumonia with a mixed population of eosinophils, macrophages, lymphocytes, and plasma cells. The presence of larval trematodes within lymphatics in multiple organs indicates a route of fluke migration. Live specimens of mesocercariae and metacercariae recovered from refrigerated lung tissue after 7 days were identified as Pharyngostomoides sp., an intestinal diplostomid parasite (trematode) of raccoons and other mammals that is similar in appearance and life cycle to Alaria spp.

CD4+/CD8+ T lymphocytes imbalance in children with severe 2009 pandemic influenza A (H1N1) pneumonia

PurposeThis study was conducted to investigate the immune responses of children with moderate and severe novel influenza A virus (H1N1) pneumonia, and to compare their clinical and immunological findings with those of control subjects.MethodsThirty-two admitted patients with H1N1 pneumonia were enrolled in the study. The clinical profiles, humoral and cell-mediated immune responses of the 16 H1N1 pneumonia patients who were admitted to the pediatric intensive care unit (severe pneumonia group), 16 H1N1 pneumonia patients admitted to the pediatric general ward (moderate pneumonia group) and 13 control subjects (control group) were measured.ResultsTotal lymphocyte counts were significantly lower in patients with H1N1 pneumonia than in the control group (P=0.02). The number of CD4+ T lymphocytes was significantly lower in the severe pneumonia group (411.5±253.5/µL) than in the moderate pneumonia (644.9±291.1/µL, P=0.04) and control (902.5±461.2/µL, P=0.01) groups. However, the number of CD8+ T lymphocytes was significantly higher in the severe pneumonia group (684.2±420.8/µL) than in the moderate pneumonia (319.7±176.6/µL, P=0.02) and control (407.2±309.3/µL, P=0.03) groups. The CD4+/CD8+ T lymphocytes ratio was significantly lower in the severe pneumonia group (0.86±0.24) than in the moderate pneumonia (1.57±0.41, P=0.01) and control (1.61±0.49, P=0.01) groups. The serum levels of IgG, IgM and IgE were significantly higher in the severe pneumonia group than in the 2 other groups.ConclusionThe results of this study suggest that increased humoral immune responses and the differences in the CD4+ and CD8+ T lymphocyte profiles, and imbalance of their ratios may be related to the severity of H1N1 pneumonia in children.

Clinical efficacy of carbapenems on hospital-acquired pneumonia in accordance with the Japanese Respiratory Society Guidelines for management of HAP

Hospital-acquired pneumonia (HAP) is the second most common cause of hospital-acquired infection and is the leading cause of death. In 2002, the Japanese Respiratory Society (JRS) published guidelines for the diagnosis and treatment of HAP (JRS GL 2002). In these guidelines, treatment with carbapenems is recommended for all disease types of HAP, excluding cases of mild or moderate pneumonia with no risk factors, and cases with early-onset ventilation-acquired pneumonia. To evaluate the efficacy of carbapenems on HAP in accordance with JRS GL 2002, we conducted a prospective study of HAP patients treated with carbapenems based on JRS GL 2002. The results of this study were also analyzed based on the revised guidelines published in June 2008 (JRS GL 2008), and the validity of the new guidelines was examined. Of the 33 subjects, 19 were judged as responders to the treatment, corresponding to a response rate of 57.6%. There were 3 deaths, corresponding to a mortality rate of 9.1%. The efficacy of carbapenems for the treatment of HAP based on JRS GL 2002 was confirmed. The severity rating system in JRS GL 2002 has a tendency to overestimate the severity of the cases and may lead to overtreatment in some cases. On the other hand, the severity rating system by JRS GL 2008 seemed to be more accurate and closely correlated with the efficacy of the treatment. It is suggested that JRS GL 2008 is more useful in clinical practice for accurately judging the severity of the disease and initiating appropriate subsequent antibiotic therapy.

Use of the ‘CURB 65’ score in hospital practice

The 'CURB 65' score is a simple well-validated tool for the assessment of severity in community acquired pneumonia (CAP). Whether it is used routinely is unknown. The aim of this study was to determine the frequency of use of the score in routine hospital practice and correlate this with clinical decision making and patient outcome. Retrospective cohort study of all patients with CAP (n=174) presenting in three winter months. Demographic and clinical outcome data were recorded and comparisons were made between those patients who had score applied on admission with those that did not. A CURB 65 score was assigned to all patients using data from the patient record, and admission decisions were compared. Only 9 (5.2%) CAP patients had the 'CURB 65' score applied at admission. The overall mortality rate was 3.4%. On applying a score to all cases retrospectively, appropriate admission decisions were made for patients with moderate or severe pneumonia and outcome was in accordance with published results. However, 23 (13%) patients age<65 with mild CAP and no comorbidities were admitted in spite of guideline recommendation for community care. These data demonstrate that clinical decision making in respect of moderate or severe CAP is the same whether or not a pneumonia severity score is applied. However, routine use of the score will identify patients with mild CAP thus potentially reducing unnecessary admission.

Pneumonia in the developed world

In this paper, we review the literature on the management of pneumonia in the developed world setting. Pneumonia is usually diagnosed on the basis of a cough, respiratory distress, a fever, and chest X-ray changes. Pneumonia affects all paediatric age groups, though the highest incidence is in the under 5s. There is a significant burden of primary and secondary care illness, although mortality is low. Inpatient admission rates for pneumonia may have increased in recent years in some regions. Pneumonia is unlikely if a child presents with solely wheeze. In routine clinical practice, a microbiological diagnosis is often not made, because current tests are insensitive. Aetiology varies with geographical location, but approximately half of cases are viral. The mainstay of management of moderate pneumonia (the commonest group presenting to secondary care) is careful assessment, and oral antibiotics, followed by early discharge when the patient shows signs of improvement. We summarise the available clinical trial data from the developed world; most of these trials are not adequately powered. Patients with moderately severe pneumonia do not require invasive investigation, but clinical judgement should be used to identify and investigate more complex cases. We discuss several pathogens that have gained importance as causal agents, including non-vaccinated strains of S. pneumoniae, Panton Valentine leucocidin S. aureus, H1N1 Influenza A and Human Bocavirus. The importance of antimicrobial resistance is considered, and we review recent data on long term effects of pneumonia in childhood. By reviewing the available literature, we demonstrate that there are clear evidence gaps, and we suggest future areas for clinical research.

Adrenal function is related to prognosis in moderate community-acquired pneumonia

The aim of our study was to prospectively examine adrenal function, including cosyntropin stimulation, and its prognostic value in patients with moderate community-acquired pneumonia (CAP). 59 consecutive adult patients hospitalised on normal wards because of CAP were enrolled. A cosyntropin stimulation test was performed and serum concentrations of C-reactive protein, procalcitonin, interleukin-6, tumour necrosis factor-α, ACTH, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) were measured. Predefined outcome parameters were clinical instability after 72 h, mortality and combined intensive care unit (ICU) admission or mortality. Critical illness-related corticosteroid insufficiency (CIRCI) occurred in six patients (10.3%). Cortisol, age-corrected DHEA, ACTH and the DHEA/DHEAS ratio were elevated in patients remaining unstable after 72 h. In multivariate analysis, cortisol (p = 0.03), ACTH (p = 0.04) and the pneumonia severity index (PSI) score (p = 0.005) independently predicted clinical instability after 72 h, and only cortisol predicted mortality (p = 0.04) and combined ICU-admission or mortality (p = 0.006). The predictive value of serum cortisol after receiver operating characteristic curve analysis equalled that of the PSI score. Patients with serum cortisol >734 nmol·L(-1) had a high probability for mortality (OR 38.3; p = 0.002). CIRCI is rare in patients with moderate CAP. Adrenal function is related to the prognosis of CAP. The diagnostic accuracy of serum cortisol equals that of the PSI score. Serum cortisol should be evaluated within clinical prediction scores on larger studies.

Investigation of pneumonia-causing pathogenic organisms in children and the usefulness of tebipenem pivoxil for their treatment.

We investigated the usefulness of the novel oral carbapenem antibiotic tebipenem pivoxil (TBPM-PI) for treating bacterial pneumonia in children. Sputum and nasopharyngeal swabs were collected simultaneously, and causative organisms were identified by conventional bacterial culture together with exhaustive bacterial and viral identification by real-time polymerase chain reaction (PCR). The subjects were eight patients diagnosed with mild or moderate pneumonia at Sotobo Children’s Clinic Outpatient Department between October 2006 and June 2007. TBPM-PI was administered at the recommended clinical dose of 4 mg/kg b.i.d. to five patients and at a high dose of 6 mg/kg b.i.d. to three patients. Sputum was collected from all patients, and 11 strains were detected from washed sputum culture. Causative organisms were mainly Streptococcus pneumoniae (3 strains) and Haemophilus influenzae (6 strains), and nasopharyngeal swabs showed the same organisms as coughed-up sputum. Real-time PCR for individual viruses and Mycoplasma pneumoniae identified four cases of only bacterial infection, one case of M. pneumoniae coinfection, two cases of viral coinfection, and one case of both viral and M. pneumoniae coinfection. The clinical results indicated efficacy in all patients, and causative organisms were 100% eliminated. In the four patients with only bacterial infection, the average fever of 38.9°C at the start of treatment normalized the following day, showing excellent efficacy. No clinically problematic adverse events occurred, and compliance was good. We consider that these cases provide valuable insights into the identity of pathogenic organisms of pneumonia in children and the possible role of TBPM-PI in outpatient treatment.

Long-term flaxseed oil supplementation diet protects BALB/c mice against Streptococcus pneumoniae infection

Intense host immune response to infection contributes significantly to the pathology of pneumococcal pneumonia. Therefore, the regulation of host immune response is critical for the successful outcome of pneumonia in such patients. The aim of the present study was to investigate the effect of n-3 PUFA, i.e. flaxseed oil supplementation for short (4 weeks) as well as long (9 weeks) term, on the course of S. pneumoniae D39 serotype 2 infection in mice. The efficacy of flaxseed oil supplementation was investigated in terms of survival of animals and production of various inflammatory molecules (malondialdehyde, myeloperoxidase, nitric oxide) in the lung homogenate of animals. This was correlated with bacteriological and histopathological parameters. The immunomodulation was studied in terms of cytokines in the lungs following infection with Streptococcus pneumoniae. Results suggest that long-term flaxseed supplementation protected the mice against bacterial colonization of lungs with Streptococcus pneumoniae with reduced histopathological involvement of lung tissue. Moderate pneumonia was observed in supplemented, infected mice compared to severe pneumonia seen in control mice. This was accompanied by decreased inflammatory markers (malondialdehyde, myeloperoxidase, nitric oxide) as the disease progressed. In addition, difference in the levels of pro-inflammatory (TNF-alpha and IL-1beta) and anti-inflammatory (IL-10) cytokines was observed in the flaxseed fed animals. On the contrary, short-term supplementation did not show such an effect on lung colonization.

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

Pneumocystis remains an important cause of fatal pneumonia (PCP) in HIV patients and other immunocompromised hosts. Preclinical drug discovery for agents active against PCP has been hindered in large part by the lack of a continuous in vitro growth system. Since approval in 1978, the combination of the folic acid synthesis inhibitor combination trimethoprim-sulfamethoxazole has been the primary agent for prophylaxis and therapy. Short term in vitro assays using cell monolayer-based and cell free systems in combination with in vivo studies in rodent models of infection have been the mainstay of candidate screening methods. These systems and their applications are reviewed here. Most strategies have focused on testing compounds already in clinical use, such as dapsone or atovaquone, for activity against Pneumocystis alone or in combination, and as parent compounds for chemical derivation, such as pentamidine and its analogues. Other successes from the bench include primaquine-clindamycin for moderate pneumonia and the family of Beta-glucan synthase inhibitors, which hold promise for clinical use against PCP. Despite the significant obstacles for drug discovery, progress in identifying novel agents has been made with current systems and the promise of future new targets is expected with the annotation of the Pneumocystis genome.