Dataset: 11.1K articles from the COVID-19 Open Research Dataset (PMC Open Access subset)
All articles are made available under a Creative Commons or similar license. Specific licensing information for individual articles can be found in the PMC source and CORD-19 metadata.
More datasets: Wikipedia | CORD-19
Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
Funded by The Federal Ministry for Economic Affairs and Energy; Grant: 01MD19013D, Smart-MD Project, Digital Technologies
(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.
These have often been an intervention of last resort in the failing patient. Studies in meningitis and pneumocystis pneumonia support their role in infection control but, until recently, studies in community-acquired pneumonia were absent. The conflicting results from studies in sepsis confirmed the need for community-acquired pneumonia-specific studies, preferably randomised controlled trials. A recent double blind, placebo-controlled randomized controlled trial using 40 mg prednisolone for 7 days as the intervention found that there were no beneficial effects of adjunctive corticosteroids in patients hospitalized with community-acquired pneumonia. Other outcomes of the study showed that clinical cure was equal in both groups at Day 7. A similar study using dexamethasone for 3 days did find a reduced hospital stay of one day in the steroid-treated patients, but a large number of exclusions and lack of control for other factors limiting length of stay limited the usefulness of this study. The only other randomised controlled trial evaluating patients with community-acquired pneumonia admitted to ICU found a reduction in mortality using hydrocortisone. The small patient number and absence of any deaths in the intervention arm mean that these findings cannot be generalised unless reproduced in other studies. A role for steroids in patients with community-acquired pneumonia is yet to be proved.
There has always been a debate with regards to the value of single (B-lactam or macrolide) versus dual (B-lactam plus macrolide) antibiotic therapy – a question that has never been addressed by a good-quality randomised controlled trial.
Although there are some differences in the antibiotics recommended for first-line treatment in the Guidelines (Table 4) there is consensus that patients with more severe community-acquired pneumonia should be given dual therapy. A total of 23 studies with approximately 137,000 patients were included in a recent meta-analysis of the efficacy of macrolides in patients hospitalised with community-acquired pneumonia. Macrolide-based regimens were associated with a significant 22% reduction in mortality compared to non-macrolides.
However, this benefit did not extend to randomised controlled trials or patients that received guideline-concordant antibiotics (also found in a study of community-acquired pneumonia patients with severe sepsis). Guideline-concordance may be more important than choice of antibiotic when treating community-acquired pneumonia.
Both studies point towards the need for good adherence to hospital prescribing guidelines. A very careful study conducted in 2007 came to a verdict that the benefit of dual therapy versus single therapy cannot be reliably assessed in observational studies, since the propensity to prescribe these regimens differs markedly. Taking this into account may skew the results of previous studies comparing single and dual therapy.
A total of 5240 patients were included in an audit of adult community-acquired pneumonia management in the UK. The death rate was high at 24%. Patients treated with dual therapy had a significantly lower death rate in both moderate- and high-severity groups compared with β-lactam therapy alone.
As in other studies, the propensity to prescribe could not be corrected for. The concordance of findings with other cohort studies may suggest a real result, but randomized controlled trial results are required to confirm this.
Legionnaires’ disease is a rare cause of community-acquired pneumonia but can be associated with significant morbidity and mortality, especially amongst immunocompromised individuals. Although the evidence regarding the use of tigecycline in treating Legionnaires' disease is limited, this case report provides evidence supporting the use of tigecycline as a second-line therapeutic option in select cases where fluoroquinolone or macrolide therapy may be contraindicated.
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.
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.
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.
Legionnaires’ disease and its causative pathogen were first recognized in 1977, following a common-source outbreak of severe pneumonia involving 221 people at an American Legion convention in Philadelphia, Pennsylvania in 1976. Outbreaks and clusters of cases of Legionnaires’ disease have been associated with contaminated cooling towers, whirlpools, hospital decorative water fountains, hot spring spas, and water births.
Legionnaires’ disease can be associated with a prodromal illness with symptoms including fever, headache, myalgia, and anorexia; however, the clinical presentation of Legionnaires’ disease is often nonspecific and difficult to distinguish from other causes of community-acquired pneumonia. Blood and sputum cultures are relatively insensitive in diagnosing Legionnaires’ disease; in contrast, urine antigen testing has a sensitivity of 60%-95% and specificity greater than 99%. Urine antigen testing for Legionella only detects Legionella pneumophila serogroup 1 (Lp1) and is most sensitive for the detection of the Pontiac subtype of Lp1, which causes the majority of cases of community-acquired Legionnaires’ disease. Legionella urine antigen testing will often be positive on the first day of illness and remain positive for several weeks. Molecular testing of lower respiratory tract specimens can also be used to identify both Legionella pneumophila and Legionella species by PCR.
Preferred therapies for immunocompromised patients with Legionnaires’ disease include levofloxacin and azithromycin. Tigecycline is a third generation, intravenous glycylcycline and minocycline derivative that inhibits bacterial protein synthesis by binding to bacterial 30S ribosomal subunits. Prior in vitro and animal model studies have shown that tigecycline achieves high intracellular concentrations. However, demonstrated clinical effectiveness of tigecycline in the treatment of community-acquired pneumonia in humans with Legionnaires’ disease remains limited.
Two prior case reports describe successful use of tigecycline in the treatment of immunocompromised patients with legionellosis; however, fluoroquinolones were used as initial therapy in both of these cases and tigecycline was later added to their antimicrobial regimen. A recently published case series describes eight patients with Legionnaires’ disease who were switched to tigecycline, often due to worsening sepsis and/or respiratory status, following initial exposure to macrolide and/or fluoroquinolone therapy (median of three days). All but one of these eight patients received combination therapy with tigecycline plus either levofloxacin or azithromycin as part of their treatment regimen once tigecycline was added. Furthermore, the one patient in this case series who received 14 days of tigecycline monotherapy had received eight days of azithromycin prior to switching therapy. Thus, it is difficult to ascertain whether clinical improvement in these cases was due to the addition of tigecycline or post-antibiotic effect and delayed response from fluoroquinolone/macrolide therapy.
Integrated results from two randomized controlled trials showed comparable cure rates between tigecycline and levofloxacin in the treatment of hospitalized patients with community-acquired pneumonia, of which a small proportion were diagnosed with Legionnaires’ disease in each treatment arm. While the integrated results of these two randomized controlled trials support the early use of tigecycline as empiric treatment of community-acquired pneumonia, one of these trials permitted switching to oral levofloxacin following at least three days of intravenous therapy if evidence of clinical improvement.
Current evidence, albeit limited, suggests that tigecycline may be added as combination therapy in severe cases of Legionnaires’ disease. This case, however, demonstrates that tigecycline can be effective as a second-line treatment option for Legionnaires’ disease in the setting of allergies to traditional mainstays of therapy. In 2013, the Food and Drug Administration (FDA) approved a new boxed warning about the higher risk of death among patients receiving tigecycline compared with other antibiotics, particularly apparent for hospital-acquired pneumonia and ventilator-associated pneumonia. While both the FDA and Health Canada have approved tigecycline for treatment of community-acquired bacterial pneumonia, complicated skin and soft tissue infections, and complicated intra-abdominal infections, its use should be reserved for situations when alternative treatments are not suitable.
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. 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.
The need for informed consent was waived in view of the observational nature of the study with no interventions performed. The protocol and standardized clinical form, including the waiver of informed consent, were approved by the Asan Medical Center Institutional Review Board (IRB number: 2010-0079).
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 physician suspected the patient of having atypical pathogens when they had persistent or deteriorating symptoms or signs despite treatment with appropriate empirical antibiotics for 2–3 days. Thus, we compared the clinicolaboratory findings between Adv and Non-Adv group patients who were unresponsive to the initial antibiotics treatment (Table 4). The number of patients who did not a response to initial antibiotics treatment was 47 and 50 in the Adv and Non-Adv groups, respectively. The percentage of patients having leukocytosis and monocytopenia was higher in the Adv patients, although there was no significant difference in white blood cell and platelet counts between the two groups. Leukopenia and thrombocytopenia, which were a showed a significant difference in all study patients, showed no difference in patients with unresponsiveness to initial antibiotics treatment (P = 0.720, P = 0.733, respectively).
A greater number of Adv group patients exhibited no response to antipyretic treatment compared with the Non-Adv group patients (25.5% vs. 10.0%, P = 0.045) as well as the number of patients to reach over 40 °C and 39 to 40 °C (P = 0.003). In addition, the Adv group patients had a higher mean temperature at admission than the Non-Adv group patients (37.8 ± 0.3 vs. 37.3 ± 0.2, P = 0.005).
Table 5 compares the clinicolaboratory variables between the combined Adv (cAdv), Non-Adv, and only Adv identified pathogen (OAIP) group patients. Compared to the cAdv and Non-Adv patients, more patients in the OAIP group exhibited the following characteristics: were currently smoking; had leukopenia, lymphopenia, monocytopenia, and thrombocytopenia; exhibited a longer duration of fever after symptom onset; had a higher maximal temperature at admission (over 40 °C and 39–40 °C); and exhibited no response to antipyretics at admission.
The study was performed at a medical ICU of the Asan Medical Center, a tertiary referral hospital in Seoul, Republic of Korea. This university-affiliated teaching hospital has 2700 beds and eight ICUs. During the study period, most of the adult patients with severe HAP requiring ICU care were referred to the medical ICU. The medical ICU is a closed 28-bed unit managed by five board-certified intensivists. All intensivists attend structured twice daily bedside rounds. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) was preferably performed on patients with bilateral interstitial pattern infiltration or non-resolving pneumonia, at the discretion of the physician’s judgment. The BAL protocol has been described in detail elsewhere.
In conclusion, even though some studies have reported the efficacy and effectiveness of systemic glucocorticoids in the treatment of MRMP [12–35], this is the first systematic review and meta-analysis to investigate the effectiveness of glucocorticoids in MRMP. We found that the use of glucocorticoids could shorten hospital days, shorten fever duration, and lower CRP levels after treatment.
However, these results should be interpreted cautiously, and future studies should also assess other outcomes to clarify the effect of glucocorticoids in MRMP.
All patients received empirical antibiotic treatment (Table 6) as follows: a 3rd generation cephalosporin plus azithromycin was the most common regimen (n = 243, 96.8%), followed by piperacillin/tazobactam plus respiratory quinolone (n = 5, 2.0%). The change in antibiotics treatment regimen was more frequent in the Adv group patients than in the Non-Adv patients (70.1% vs. 27.2%, P = 0.024). The duration of antibiotic treatment was not significantly different between the two groups. In our study, we did not evaluate the administration of cidofovir or adjuvant intravenous immunoglobulin (IVIG). In addition, there were no patients who received mechanical ventilation or extracorporeal membrane oxygenation support.
At admission, the mean dose of antipyretics administered was higher in the Adv group patients than in the Non-Adv group patients (5.52 vs. 4.30 g, P = 0.032), although the overall duration of antipyretics was not significantly different between the two groups. In this study, we identified adverse events after antipyretics administration, such as hypotension, gastrointestinal trouble, skin rash, and elevated liver enzyme, which were commonly observed in the Adv group patients (P = 0.005).
The time to overall clinical stabilization from admission was significantly longer in the Adv group patients than in the Non-Adv group patients (4.3 ± 2.8 d vs. 2.9 ± 1.8 d, P = 0.034). In addition, the length of hospital was not significantly different between the two groups, and no patient died in our study.
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.
The pre-publication history for this paper can be accessed here:
The detection of a viral pathogen led to changes in the management of the disease in 23 (33.3%) patients. Twelve patients received antiviral therapy such as oseltamivir and ribavirin, and empirical antiviral therapy was continued or extended in 4 patients. The use of immunosuppressive agents, including steroids, was decreased or stopped in 3 patients. In some patients, antibiotics (n = 2) or antiviral agents (n = 1) were discontinued because bacterial pathogen was no longer suspected, or the detected virus had no effective antiviral agent (Table 4).
The clinical outcomes, such as the length of hospital stay, length of ICU stay, and in-hospital mortality, were compared according to changes in management. However, the differences were not statistically significant (S2 Table).
Low-dose systemic corticosteroids may be used for septic shock related to severe influenza since evidence from RCTs suggests that corticosteroids may be associated with delayed clearance of viruses [21–23] and invasive fungal infections. Case control studies and a RCT suggested that plasma and hyperimmune globulin have demonstrated favorable responses in patients with severe avian influenza A (H5N1) and H1N1pdm09 infection compared with controls [27, 28, 198]. Further evaluation of novel treatments with RCTs is needed.
Two new neuraminidase inhibitors have recently been described: peramivir and laninamivir octanoate. Peramivir, which can be given as a single intravenous dose, was authorized for a short period by the US Food and Drug Administration (FDA) for emergent intravenous use in hospitalized patients with the 2009 H1N1 pandemic influenza virus. Laninamivir is given as a single inhaled dose for the treatment of seasonal influenza in adults and may also treat oseltamivir-resistant virus. In addition, new therapeutics for the treatment of influenza A virus infections are under development [13–15, 18, 28, 39, 50, 114–195]. In this regard, the drug, favipiravir (T-705) has been shown to inhibit a variety of influenza viruses, including highly pathogenic avian influenza H5N1 viruses. Finally, numerous antivirals such as entry inhibitors, nucleoside analogues such as cidofovir, viral enzyme inhibitors (such as terminase and helicase enzyme inhibitors), and translation inhibitors may be utilized in an off-label indication for treatment of viral infections [13, 113].
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.
This case is, to our knowledge, the first report of ARDS due to fulminant pulmonary blastomycosis in the emergency medicine literature. While this entity is uncommon, it has been described in ICU patients. Of note, an experienced EP, faced with a young patient with undifferentiated, near-fatal CAP, recognized the importance of definitive antimicrobial therapy and prescribed broad spectrum antibiotics including doxycycline (for zoonotic bacterial pathogens), as well as empiric antiviral and antifungal therapy. This patient’s blastomycosis was covered empirically (and as it turns out, definitively) with amphotericin from the time of his arrival in the ED. This report addresses one potential approach to fulminant pneumonitis from an unknown pathogen, which represents an important gap in existing guidelines on early antimicrobial therapy.
There is ample evidence that a delay in definitive antibiotic therapy negatively affects outcomes in severe bacterial infection. This delay is most often due to unrecognized infection, failure to initiate antibiotic therapy in the ED, or failure to anticipate antimicrobial resistance. In fact, among hypotensive ICU patients with septic shock (nearly 40% of whom had pneumonia), each hour delay in effective antimicrobial therapy after the first hour was associated with an average decrease in survival of 8%.3 The Surviving Sepsis Campaign, while not addressing fulminant pneumonia specifically, does recommend that empiric antimicrobial therapy include one or more drugs that have activity and adequate tissue penetration against “all likely pathogens,” including viruses and fungi.5 Professional society guidelines on the management of critically ill patients with severe CAP highlight the need to cover empirically for resistant organisms including Pseudomonas aeruginosa and community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA).6 In our experience, patients with septic shock rarely receive antifungal or antiviral therapy. Besides knowledge of non-bacterial pathogens endemic to a certain geographic area (e.g. Coccidioides spp. and hantavirus in the southwestern U.S.), these guidelines are of limited utility to an EP caring for an intubated patient because treatment is initiated before a detailed travel and exposure history can be obtained.
A diverse list of pathogens can cause fulminant pneumonia and ARDS in an immunocompetent host. In fact, there is evidence that multilobar lung involvement is independently associated with a twofold increased likelihood of treatment failure in CAP.7,8 Usual pathogens include standard or atypical bacteria, such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Group A Streptococcus, Legionella spp., or aerobic gram-negative bacteria, including Pseudomonas aeruginosa. Massive aspiration can lead to a polymicrobial pneumonia that often includes anaerobes, or in the case of freshwater aspiration, infection with Aeromonas hydrophila.9 In our case, antibacterial coverage included piperacillin-tazobactam, levofloxacin, and vancomycin. Endemic fungal infections, such as blastomycosis, histoplasmosis, or coccidioidomycosis, have also been associated with fulminant pneumonia; thus, we gave amphotericin. One must also consider viruses such as influenza A and B (for which we gave oseltamivir), but also varicella zoster virus10 or herpes simplex,11 and thus it may be prudent to administer acyclovir in the appropriate setting. Respiratory viruses that are prevalent, detectable on polymerase chain reaction-based assays but without specific treatment include respiratory syncytial virus, parainfluenza virus, rhinovirus, adenovirus, human metapneumovirus, multiple coronaviruses (the etiologic agents of severe acute respiratory syndrome [SARS] and of Middle East respiratory syndrome [MERS]), and hantaviruses (responsible for the hantavirus pulmonary syndrome [HPS]). Fulminant pneumonia can also be caused by rare zoonotic bacteria often recognized in the U.S. for their potential as biological weapons, namely Bacillus anthracis (anthrax), Francisella tularensis (tularemia), and Yersinia pestis (pneumonic plague), for which we gave doxycycline. Lastly, fulminant pneumonitis can be due to non-infectious vasculitic or idiopathic disorders, which are typically corticosteroid-responsive, and methylprednisolone was given in this case.
Blastomycosis can be asymptomatic or mimic bacterial pneumonia following the inhalation of aerosolized spores from the Blastomyces dermatitidis mold living in moist soil. This endemic fungus is found most commonly surrounding the Great Lakes and the St. Lawrence, Ohio, and Mississippi Rivers.12 In states where blastomycosis is a reportable disease (Arkansas, Louisiana, Michigan, Minnesota, and Wisconsin), it is relatively rare; annual incidence rates vary from 1–2 cases per 100,000 population to as high as 10–40 cases per 100,000 population in several northern Wisconsin counties.13,14 Fulminant pneumonia leading to ARDS and respiratory failure occurs in a minority of cases, with mortality of 50–89%. (Contemporary mortality may be lower in the era of extracorporeal membrane oxygenation support).15,16 Extrapulmonary blastomycosis can occur by hematogenous spread of yeast to the skin, bones, and joints. Delay in diagnosis is relatively common; clinicians even in endemic areas often fail to consider blastomycosis in the initial differential for severe CAP. The diagnosis is made by isolating the organism in culture. Rapid evidence of blastomycosis is often obtained by visualizing the broad-based budding yeast forms in a sputum smear or potassium hydroxide prep. In severe infections, Blastomyces can cross-react with the urine Histoplasma antigen assay yielding a positive result before the final culture is available, as occurred in our case. Treatment of severe pulmonary or disseminated blastomycosis is with liposomal amphotericin B for 1–2 weeks until clinical improvement is noted, then daily itraconazole for at least one year.17
Pneumonia was defined as the presence of a new or progressive infiltrate found using either chest radiography or chest CT scan, in addition to two or more of the following: fever, sputum production, rhinorrhea, sore throat, dyspnea, or a diagnosis of pneumonia by the attending physician. The outcome was designated as all-cause mortality up to 30 days after hospital admission.
The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included hospital length-of-stay (LOS), intensive care unit (ICU) admission, and readmission rates at 30, 90, and 180 days after the index hospitalization.