Host-Based Treatments for Severe COVID-19.

COVID-19 has been a global health problem since 2020. There are different spectrums of manifestation of this disease, ranging from asymptomatic to extremely severe forms requiring admission to intensive care units and life-support therapies, mainly due to severe pneumonia. The progressive understanding of this disease has allowed researchers and clinicians to implement different therapeutic alternatives, depending on both the severity of clinical involvement and the causative molecular mechanism that has been progressively explored. In this review, we analysed the main therapeutic options available to date based on modulating the host inflammatory response to SARS-CoV-2 infection in patients with severe and critical illness. Although current guidelines are moving toward a personalised treatment approach titrated on the timing of presentation, disease severity, and laboratory parameters, future research is needed to identify additional biomarkers that can anticipate the disease course and guide targeted interventions on an individual basis.

Biomarkers in Systemic Sclerosis: An Overview.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor ß (TGF-ß) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Prolonged higher dose methylprednisolone versus conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS).

BACKGROUND: Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking. METHODS: We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction (P aO2 /F IO2 ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14. RESULTS: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) versus 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) versus 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) versus 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) versus 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) versus 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in P aO2 /F IO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points. CONCLUSION: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia.

Low arousal threshold: a common pathophysiological trait in patients with obstructive sleep apnea syndrome and asthma.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) and asthma are two diseases with a high epidemiological impact that may often coexist. Both diseases have underlying pathogenic mechanisms (chronic inflammation, genetic predisposition, etc.); it is still unclear whether or not their coexistence is due to a specific pathophysiological factor. In the literature, the pathogenesis of OSAS has four pathophysiological traits: one or more anatomical predisposing factors, a low arousal threshold (low AT), high loop gain, and poor muscle responsiveness. In this study, we hypothesized that a low AT is a common pathophysiological factor in OSAS and asthma. METHODS: A retrospective study of patients attending the Pulmonology Unit of the University Hospital of Trieste was carried out. Low AT was predicted on the bases of the following polysomnography features, as previously shown by Edwards et al.: an AHI of < 30 events/h, a nadir SpO2 of > 82.5%, and a hypopnea fraction of total respiratory events of > 58.3%. RESULTS: Thirty-five patients with asthma and OSAS and 36 with OSAS alone were included in the study. Low AT was present in 71% of patients affected by asthma and OSAS (25 patients out of 35) versus 31% (11 patients out of 36) of patients affected by OSAS alone with a statistically significant difference (p = 0.002) between the two groups. Stratifying for BMI and OSAS severity, the difference between groups remained statistically significant. CONCLUSIONS: This is the first study to describe specific polysomnographic characteristics of patients affected by asthma and OSAS. A low AT may well be the pathophysiological factor common to the two diseases. If confirmed by other studies, this finding could lead to the presence of asthma and OSAS in the same individual being considered a syndrome with a common pathophysiological factor.

In moderate-to-severe asthma, as-needed albuterol-budesonide reduced severe exacerbations vs. albuterol alone.

SOURCE CITATION: Papi A, Chipps BE, Beasley R, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022;386:2071-83. 35569035.

Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors.

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.

The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19. MATERIALS AND METHODS: The present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019. RESULTS: Among 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2% versus 1.9%) and related death (0.3% versus 0.5%) compared with 2019 (p<0.001). A high level of attention is needed to avoid the potential risk of disease progression related to less aggressive escalation of treatment and the reduction in new PAH diagnoses compared with 2019. CONCLUSION: A cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19.

OBJECTIVE: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. METHODS: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. RESULTS: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). CONCLUSION: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.

Risk Reduction and Hemodynamics with Initial Combination Therapy in Pulmonary Arterial Hypertension.

Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.

Chronic Thromboembolic Pulmonary Hypertension: An Observational Study.

Background and Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) has a high mortality. The treatment of CTEPH could be balloon pulmonary angioplasty (BPA), medical (MT) or pulmonary endarterectomy (PEA). This study aims to assess the clinical characteristics of CTEPH patients, surgically or medically treated, in a pulmonology referral center. Materials and Methods: A total of 124 patients with PH with suspected CTEPH (53 male subjects and 71 female subjects; mean age at diagnosis 67 ± 6) were asked to give informed consent and then were evaluated. The presence of CTEPH was ascertained by medical evaluations, radiology and laboratory tests. Results: After the evaluation of all clinical data, 65 patients met the inclusion criteria for CTEPH and they were therefore enrolled (22 males and 43 females; mean age at diagnosis was 69 ± 8). 26 CTEPH patients were treated with PEA, 32 with MT and 7 with BPA. There was a statistically significant age difference between the PEA and MT groups, at the time of diagnosis, the PEA patients were younger than the MT patients, whereas there was no statistically significant difference in other clinical characteristics (e.g., smoking habit, thrombophilia predisposition), as well as functional and hemodynamic parameters (e.g., 6-min walk test, right heart catheterization). During three years of follow-up, no patients in the PEA groups died; conversely, eleven patients in the MT group died during the same period (p < 0.05). Furthermore, a significant decrease in plasma BNP values and an increase in a meter at the six-minute walk test, 1 and 3 years after surgery, were observed in the PEA group (p < 0.05). Conclusions: This study seems to confirm that pulmonary endarterectomy (PEA) can provide an improvement in functional tests in CTEPH.

The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung.

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air-liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.

Low sensitivity of rapid tests detecting anti-CoV-2 IgG and IgM in health care workers' serum for COVID-19 screening.

BACKGROUND: the sensitivity and specificity of a rapid antibody test were investigated for the screening of healthcare workers. METHODS: the serum of 389 health care workers exposed to COVID-19 patients or with symptoms, were analysed. All workers underwent monthly the screening for SARS-CoV-2 with detection of viral RNA in nasopharyngeal swabs by RT-PCR. IgG antibody detection in serum was performed by Chemiluminescence Immunoassay (CLIA) and by the Rapid test (KHB diagnostic kit for SARS CoV-2 IgM/IgG antibody after a median of 7.6 weeks (25°-75° percentiles 6.6-11.5). RESULTS: the rapid test resulted positive in 31/132 (23.5%), 16/135 (11.8%) and 0/122 cases in COVID-19 positive individuals, in those with only SARS-CoV-2 IgG antibodies and in those negative for both tests, respectively. Sensitivity was 17.6% (CI95% 13.2-22.7) and 23.5% (CI95% 16.5-31.6), and specificity was 100% (CI95% 97-100) and 100% (CI95% 97-100) considering Rapid test vs CLIA IgG or Rapid test vs SARS-CoV-2 positive RNA detection, respectively. CONCLUSION: the KHB Rapid test is not suitable for the screening of workers with previous COVID-19 infection.

Use of low field nuclear magnetic resonance to monitor lung inflammation and the amount of pathological components in the sputum of cystic fibrosis patients.

PURPOSE: To develop a novel approach to monitor lung ventilation/inflammation in cystic fibrosis (CF) patients. Lung assessment in CF patients is relevant given that most patients succumb to respiratory failure. Respiratory functional tests (forced expiratory volume in the first second; FEV1 ) and inflammatory markers are used to test pulmonary ventilation/inflammation, respectively. However, FEV1 is effort dependent and might be uncomfortable for CF patients. Furthermore, inflammatory marker detection is costly and not rapid. To overcome these limitations, we propose the measurement, by means of low field nuclear magnetic resonance, of the spin-spin relaxation time (T2m ) of water hydrogens present in CF patient sputum. In CF sputum, different biological components are pathologically increased and inversely related to lung functionality. Moreover, we showed that these components alter in a dose-dependent manner the T2m in synthetic CF sputum. METHODS: Sputum samples were obtained from 42 CF subjects by voluntary expectoration; FEV1 , C-reactive protein (CRP), blood neutrophil counts together with cytokine (tumor necrosis factor alpha [TNFα], interleukin [IL]-1ß, IL-4, and vascular endothelial growth factor) quantifications were then evaluated. RESULTS: In sputum samples, we observe that T2m directly correlates (rFEV1 = 0.44; P < 10-4 ; 169 samples) with FEV1 . Moreover, T2m inversely correlates with the circulating inflammation markers CRP/neutrophil number (rCRP = -0.44, P < 10-4 ; rNC = -0.37, P < 2 * 10-4 ; 103 and 86 samples, respectively) and with the sputum inflammatory cytokines TNFα/IL-ß1 (rTNFα = -0.72, P < 10-4 ; rIL-1ß = -0.685, P < 10-4 ; 27 samples). T2m variations also correspond to FEV1 values over time in defined patients. CONCLUSION: These findings, together with the fast, reliable, and simple determination of T2m , make our approach a novel tool potentially usable in the real world of CF patients.

Epithelial-Mesenchymal Transition: A Major Pathogenic Driver in Idiopathic Pulmonary Fibrosis?

Despite the fact that epithelial-mesenchymal transition (EMT) is a common downstream mechanism of all fibrosing diseases, whether it represents a leading process in the development of idiopathic pulmonary fibrosis has been widely discussed and is still a matter of debate. According to the most recent advances, EMT is thought to be mainly driven by the overexpression of several developmental pathways upstream of dysfunctional epithelial regeneration, which indeed normally occurs after damage and during tissue turnover. Future research should likely be directed at investigating the molecular mechanisms underlying epithelial dysfunction, in order to allow for both the removal of the wording "idiopathic" from idiopathic pulmonary fibrosis ("IPF") and for the identification of earlier and more effective therapeutic targets than the late process of fibrosis.

Late Bowel Iischemia and Colovaginal Fistula after Low Anterior Resection in a COVID-19 Patient.

The spread of SARS-CoV-2 in Italy has been rapid, with over 230.000 infections and 33.000 deaths (May 31st, 2020). The full impact of COVID19 on surgery is still unknown, as its effects on healthcare strategy, hospital infrastructure, staff, regional economy and colorectal disease progression, may not be evident before several months. No systematic reports are available about a higher incidence of COVID19 infections in patients with cancer. However, available data indicate that older people are more vulnerable, particularly when there are underlying health conditions such as chemotherapy or active cancer. Herein, we present the case of a patient with rectal cancer treated with pull-through technique low anterior rectal resection and coloanal anastomosis with protective loop ileostomy, complicated with Sars-CoV-2 infection and late (31st post-operative day) colic ischemia with colo-vaginal fistula. Late intestinal ischemia is a rare complication and can be secondary to several traditional factors, but certainly small vessel thrombosis related to Coronavirus disease must be taken into consideration.

A retrospective study of endobronchial ultrasound transbronchial needle aspiration versus conventional transbronchial needle aspiration in diagnosis/staging of hilar/mediastinal lymph node in lung cancer: Which role in clinical practice?

The conventional-trans bronchial needle aspiration (c-TBNA) has been the first procedure for sampling hilar/mediastinal lymph node for the diagnosis/staging of lung cancer. In the last decade the endobronchial ultrasound trans bronchial needle aspiration (EBUS-TBNA) was introduced in clinical practice and became the first-choice exam in diagnosis and staging of lung cancer. The aim of this study was to compare the diagnostic accuracy (DA), sensitivity and adequacy of c-TBNA and EBUS-TBNA. It was a retrospective and observational multicenter study. The first endpoint was diagnostic accuracy of EBUS-TBNA versus c-TBNA. The secondary end-points were sensitivity and adequacy. Two hundred and nine consecutive patients underwent the procedure, 99 EBUS-TBNA and 110 c-TBNA. When lymph nodes with short axis <2 cm the diagnostic accuracy for correct diagnosis was 94.2% in EBUS-TBNA group and 89.7% in c-TBNA group (p=0.01); the sample adequacy was 70.3% and 42%, respectively (p=0.01); the sensitivity was 93% (95% CI, 82-98%) and 86.4% (95% CI, 67.6-95.6%), respectively (p=0.002). In lymph nodes with short axis ≥2 cm the diagnostic accuracy was 95.7% in EBUS-TBNA group and 93% in c-TBNA group (p=0.939); the sample adequacy was 68.7% and 68.3%, respectively (p=0.889); the sensitivity was 95.1% (95% CI, 83-99%) and 92.1%, respectively (95% CI, 78.7-97.7%) (p=0.898). The EBUS-TBNA in patients with lymph nodes size <2 cm presented a statistically significant difference in the DA, adequacy and sensitivity compared to c-TBNA procedure, while there were no significant differences in the DA, adequacy and sensitivity between EBUS-TBNA and c-TBNA in patients with lymph node size ≥2 cm. The results of our study indicated that the EBUS-TBNA should be the first-choice procedure for the diagnosis/staging in lung cancer patients with lymph node size <2 cm. In patients with lymph node size ≥2 cm, instead, both procedures can be used for the diagnosis/staging of lung cancer.

Epithelial⁻Mesenchymal Transition in the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a serious disease of the lung, which leads to extensive parenchymal scarring and death from respiratory failure. The most accepted hypothesis for IPF pathogenesis relies on the inability of the alveolar epithelium to regenerate after injury. Alveolar epithelial cells become apoptotic and rare, fibroblasts/myofibroblasts accumulate and extracellular matrix (ECM) is deposited in response to the aberrant activation of several pathways that are physiologically implicated in alveologenesis and repair but also favor the creation of excessive fibrosis via different mechanisms, including epithelial⁻mesenchymal transition (EMT). EMT is a pathophysiological process in which epithelial cells lose part of their characteristics and markers, while gaining mesenchymal ones. A role for EMT in the pathogenesis of IPF has been widely hypothesized and indirectly demonstrated; however, precise definition of its mechanisms and relevance has been hindered by the lack of a reliable animal model and needs further studies. The overall available evidence conceptualizes EMT as an alternative cell and tissue normal regeneration, which could open the way to novel diagnostic and prognostic biomarkers, as well as to more effective treatment options.

Corticosteroids in Patients Hospitalized With Community-Acquired Pneumonia: Systematic Review and Individual Patient Data Metaanalysis.

Background: Our aim was to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patient data from randomized, placebo-controlled trials and to explore subgroup differences. Methods: We systematically searched Medline, Embase, Cochrane Central, and trial registers (all through July 2017). Data from 1506 individual patients in 6 trials were analyzed using uniform outcome definitions. We investigated prespecified effect modifiers using multivariable hierarchical regression, adjusting for pneumonia severity, age, and clustering effects. Results: Within 30 days of randomization, 37 of 748 patients (5.0%) assigned to corticosteroids and 45 of 758 patients (5.9%) assigned to placebo died (adjusted odds ratio [aOR], 0.75; 95% confidence interval [CI], .46 to 1.21; P = .24). Time to clinical stability and length of hospital stay were reduced by approximately 1 day with corticosteroids (-1.03 days; 95% CI, -1.62 to -.43; P = .001 and -1.15 days; 95% CI, -1.75 to -.55; P < .001, respectively). More patients with corticosteroids had hyperglycemia (160 [22.1%] vs 88 [12.0%]; aOR, 2.15; 95% CI, 1.60 to 2.90; P < .001) and CAP-related rehospitalization (33 [5.0%] vs 18 [2.7%]; aOR, 1.85; 95% CI, 1.03 to 3.32; P = .04). We did not find significant effect modification by CAP severity or degree of inflammation. Conclusions: Adjunct corticosteroids for patients hospitalized with CAP reduce time to clinical stability and length of hospital stay by approximately 1 day without a significant effect on overall mortality but with an increased risk for CAP-related rehospitalization and hyperglycemia.