Pneumococcal Polysaccharide Vaccine, Influenza Vaccines, Preoperative, Lung Resection Surgery, Thoracic Surgery
Conditions
Brief summary
Postoperative pneumonia (POP) affects 4%-24% of lung cancer surgery patients, increasing mortality, stay, costs and worsening prognosis, especially in older patients. Perioperative immunosuppression and synergistic influenza/pneumococcal infection support perioperative vaccination, which may also induce trained immunity; thoracic surgery data are lacking. This multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) trial will enroll \ 1278 patients aged ≥50 undergoing anatomical lung resection for pulmonary nodules or lung cancer, randomized 1:1 to vaccination or no vaccination, with 180-day follow-up. Randomization uses a computer-generated, site-stratified block sequence, concealed via central IWRS or sealed envelopes. An unblinded team handles screening, randomization and vaccination data; surgeons and assessors are blinded. No site may exceed 50% of enrollment. Vaccination group receives 23-valent pneumococcal polysaccharide and quadrivalent influenza vaccines intramuscularly in separate arms 14-28 days preoperatively. Controls receive no vaccine/placebo, with surgery scheduled 14-28 days after randomization. Concomitant indicated treatments are permitted and recorded. Primary endpoint is POP per modified CDC/NHSN criteria: new/progressive imaging infiltrate (excluding atelectasis, edema, embolism, tumor), plus ≥1 clinical sign (fever \>38 °C, WBC ≤4000 or ≥12,000/mm³, or altered mental status if ≥70 years) and ≥2 respiratory signs. Findings on days 3-5 are excluded unless persistent/worsening. Microbiology is confirmatory, not required.
Detailed description
Background: Postoperative pneumonia (POP) is a common complication of lung cancer surgery, with reported incidences of 4% to 24%. It increases mortality, prolongs hospital stay, raises medical costs and worsens long-term prognosis; older patients are at particular risk of severe pneumonia and acute respiratory failure. Surgical stress causes transient perioperative immunosuppression, and influenza virus and Streptococcus pneumoniae act synergistically in causing disease. Observational data suggest that perioperative vaccination reduces postoperative pneumonia after major surgery, but thoracic surgery has rarely been studied. Beyond pathogen-specific antibodies, vaccination may also induce "trained immunity", reprogramming innate immune cells to respond more effectively to non-specific pathogens. Design: Multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) trial. Approximately 1278 patients aged 50 years or older scheduled for anatomical lung resection (segmentectomy, lobectomy, sleeve resection, etc.) for pulmonary nodules or lung cancer will be randomized 1:1 to the vaccination group or the no-vaccination group and followed until 180 days after surgery. Randomization: Computer-generated block randomization sequence produced by an independent statistical team (SAS or R), stratified by site with equal allocation at each site. Allocation is concealed through a central interactive web response system (IWRS) or sealed numbered envelopes. An unblinded team, trained and bound by a confidentiality agreement, performs screening, randomization and collection of vaccination information only. The surgical team and the outcome assessors are blinded to group assignment. No single site may enroll more than 50% of the total sample. Interventions: Vaccination group: 23-valent pneumococcal polysaccharide vaccine (0.5 mL) plus quadrivalent split-virion influenza vaccine (0.5 mL), administered intramuscularly in separate upper arms at a community health service center or designated vaccination site, completed 14 to 28 days before surgery. Control group: no vaccination and no placebo; surgery is likewise scheduled 14 to 28 days after randomization to balance timing, during which routine preoperative respiratory exercises are permitted. Clinically indicated concomitant treatment (e.g., prophylactic antibiotics, analgesics, nutritional support) is permitted; anti-infective drugs, immunomodulators and potent antitussives/sedatives are recorded. Primary endpoint definition: Postoperative pulmonary infection is defined using modified US CDC/NHSN criteria and requires all three of: (1) imaging (required): new or progressive infiltrate, consolidation or ground-glass opacity on chest X-ray/CT, after excluding normal postoperative atelectasis, pulmonary edema, pulmonary embolism and tumor progression; (2) at least 1 clinical sign: fever greater than 38 degrees C without other identified cause, WBC 4000/mm3 or less or 12,000/mm3 or more, or altered mental status without other cause in patients aged 70 or older; (3) at least 2 respiratory signs: new purulent sputum/change in sputum character/increased secretions or suctioning; dyspnea, tachypnea (greater than 24/min) or new/worsening cough; rales or bronchial breath sounds; worsening gas exchange (PaO2/FiO2 240 mmHg or less, SpO2 decrease of 5% or more, increased oxygen or ventilator requirement). Findings within postoperative days 3 to 5 are not counted as infection unless persistent or worsening; CRP and procalcitonin trends support the diagnosis. Microbiological evidence confirms but is not required.
Interventions
Single 0.5 mL intramuscular dose in one upper arm, completed 14 to 28 days before surgery, at a community health service center or designated vaccination site.
BIOLOGICALQuadrivalent split-virion influenza vaccine
Single 0.5 mL intramuscular dose in the opposite upper arm from the pneumococcal vaccine, completed 14 to 28 days before surgery, at a community health service center or designated vaccination site.
Sponsors
The First Affiliated Hospital of Guangzhou Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Caregiver, Outcomes Assessor)
Masking description
PROBE design: participants and the unblinded study team (screening, randomization and vaccination records) know the group assignment. The surgical team and outcome assessors are blinded, and the primary endpoint is adjudicated by an independent Endpoint Adjudication Committee that reviews de-identified materials with all vaccination-related information removed.
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Age 50 years or older, any sex * American Society of Anesthesiologists (ASA) physical status I to III * Pulmonary nodule or lung cancer scheduled, based on imaging evaluation, for anatomical lung resection (including segmentectomy, lobectomy, sleeve resection, etc.) * Expected postoperative survival of at least 6 months * Agrees to wait 14 to 28 days after enrollment before surgery * Signed informed consent and willing to comply with the study protocol
Exclusion criteria
* Previous pneumococcal vaccination within 5 years, influenza vaccination within 1 year, or any other vaccination within 4 weeks * Known allergy to any vaccine component * Active autoimmune or inflammatory disease (e.g., Guillain-Barre syndrome, systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease, Hashimoto thyroiditis); type 1 diabetes, hypothyroidism controlled by replacement therapy alone, and skin conditions not requiring systemic treatment (e.g., vitiligo, psoriasis) are allowed * HIV antibody positive; active tuberculosis; active hepatitis B (HBV-DNA above the lower limit of detection); or active hepatitis C (HCV antibody positive and HCV-RNA above the lower limit of detection) * Pulmonary infection, or active infection requiring systemic treatment (e.g., severe pneumonia, bacteremia, sepsis), within 1 month before surgery * Use of antibiotics or antiviral drugs within 1 month before surgery * History of allogeneic organ transplantation (solid organ or allogeneic bone marrow) * Other surgery or invasive treatment within 1 month before surgery (diagnostic needle biopsy excluded) * Emergency surgery, or risk of disease progression (e.g., short tumor doubling time) that does not allow waiting for the 14-day vaccine response window * Pregnant or breastfeeding women * Prior neoadjuvant therapy (chemotherapy, radiotherapy, targeted therapy, immunotherapy, etc.), or planned adjuvant therapy within 30 days after surgery * Any serious illness, uncontrolled concurrent disease, psychiatric disorder, active or uncontrolled infection, other medical history or laboratory abnormality that, in the investigator's opinion, may interfere with participation or interpretation of results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with postoperative pulmonary infection within 30 days after surgery | From surgery to 30 days after surgery | Pulmonary infection defined by modified US CDC/NHSN criteria (new or progressive pulmonary infiltrate on imaging, at least 1 clinical sign and at least 2 respiratory signs), confirmed by an independent Endpoint Adjudication Committee blinded to group assignment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants with postoperative pulmonary infection within 90 days after surgery | From surgery to 90 days after surgery | Same definition and blinded adjudication as the primary outcome. |
| Proportion of participants with postoperative pulmonary infection within 180 days after surgery | From surgery to 180 days after surgery | Same definition and blinded adjudication as the primary outcome. |
| Incidence of severe pneumonia | Within 30, 90 and 180 days after surgery | Severe pneumonia defined as 1 major criterion (invasive mechanical ventilation; septic shock requiring vasopressors) or at least 3 minor criteria (respiratory rate 30/min or more; PaO2/FiO2 250 or less; multilobar infiltrates; confusion/disorientation; BUN 20 mg/dL or more; WBC below 4000/mm3 due to infection; platelets below 100,000/mm3; core temperature below 36 degrees C; hypotension requiring aggressive fluid resuscitation). |
| Incidence of respiratory failure | Within 30, 90 and 180 days after surgery | Type I: PaO2 below 60 mmHg with normal or low PaCO2 (50 mmHg or less). Type II: PaO2 below 60 mmHg with PaCO2 above 50 mmHg. |
| Incidence of Streptococcus pneumoniae infection | Within 30, 90 and 180 days after surgery | Any of: S. pneumoniae isolated from sputum, bronchoalveolar lavage fluid or blood culture; positive urinary pneumococcal antigen; or a 4-fold or greater rise in serum pneumococcal antibody titer between acute and convalescent samples. |
| Incidence of influenza virus infection | Within 30, 90 and 180 days after surgery | Any of: positive influenza RT-PCR on nasopharyngeal swab, sputum or bronchoalveolar lavage fluid; positive rapid antigen test; positive viral culture; or positive influenza-specific IgM or a 4-fold or greater rise in IgG titer. |
| Postoperative length of hospital stay | From end of surgery to hospital discharge, assessed up to 180 days | Number of days from leaving the operating room to hospital discharge. |
| Rate of postoperative ICU admission | From surgery to hospital discharge, assessed up to 180 days | — |
| Length of ICU stay | From surgery to hospital discharge, assessed up to 180 days | Duration of ICU stay in hours. |
| Rate of unplanned postoperative antibiotic use | From surgery to 180 days after surgery | Proportion of participants in whom antibiotics are restarted for suspected infection after discontinuation of postoperative prophylactic antibiotics. |
| Duration of postoperative chest tube drainage | From surgery to chest tube removal, assessed up to 180 days | Number of days the chest tube remains in place after surgery. |
| 30-day unplanned readmission rate | Within 30 days after surgery | Readmission due to fever, dyspnea or thoracic infection. |
| Total hospitalization costs | From admission for surgery to 180 days after surgery | Total costs including drug, examination, surgical and material costs. |
| Antibiotic costs | From admission for surgery to 180 days after surgery | — |
| Incidence of adverse events and serious adverse events | From randomization to 180 days after surgery | Including local and systemic vaccine reactions; graded according to NCI-CTCAE version 5.0. |
Contacts
CONTACTYi Zhao
Outcome results
None listed