Table 3.

Studies comparing index test to a composite reference standard

Reference	Study population				Index test	Reference test	Results (95% confidence intervals where available)
	Country	n =	Mean age	M:F ratio
Charles et al. [53]	France	90	61.1	2.3	Serum PCT (day of first suspicion of clinical infection)	All of (1) new lung infiltrate on the chest X-ray; (2) ETA culture > 106 CFU/mL; (3) CPIS ≥ 6 points; (4) at least 2 SIRS criteria	Sens = 65.2% Spec = 83%
Chen et al. [52]	China	49	54	1.45	Serum PCT serum CRP CPIS	(1) Persistent or new invasive shadows in the lung; (2) At least two below items: temperature more than 38 °C or less than 36 °C; leucocyte count > 10 or < 4 × 10/L; purulent sputum; (3) Any of the item below: bronchoscopic aspiration or sputum specimen bacterial culture +++ or pathogenic bacteria cultured from blood	CRP Sens = 68.0% Spec = 58.3% PCT Sens = 60.0% Spec = 87.5% CPIS Sens = 72.0% Spec = 75.0%
Grover et al. [44]	UK	91	59	1.5	7 marker score: BAL/blood ratio mTREM-1 and mCD11b, BALF sTREM-1, IL-8 and IL-1b, and serum CRP and IL-6	VAP was predefined as CPIS > 5 and positive BALF microbiology. Non-VAP was predefined as CPIS score < 6 and negative microbiology	Sens = 88.9% Spec = 100%
Jovanovic et al. [64]	Serbia	39	47.9	5.5	Serum sCD14-ST PCT CRP Leucocyte count	New persistent pulmonary infiltrates (not otherwise explainable) on CXR > 48 h after admission to the ICU, PLUS one systemic and two pulmonary criteria Systemic criteria Fever > 38 °C, white cell count < 4000 WBC/mm3 or > 12,000 WBC/mm3 altered mental status, with no other recognized cause (for adults older than 70 years of age) Pulmonary criteria new onset of purulent sputum (or a change in the character of the sputum, increased respiratory secretions or increased suctioning requirements), worsening gas exchange (desaturations, increased oxygen requirements or increased ventilator demand), new onset or worsening cough, and dyspnoea, tachypnoea, rales or bronchial breath sounds	sCD14-ST AUROCC = 0.908 PCT AUROCC = 0.863 CRP AUROCC = 0.703 Leucocyte count AUROCC = 0.668
Klein Klouwenberg et al. [61]	Netherlands	2080	62	1.6	CDC surveillance definition (2013)	Existing local surveillance criteria divided into possible, probable, and definite VAP Possible (CPIS > 6, dubious abnormalities on radiographic examination, semi-quantitative culture from respiratory secretions—ETA or bronchoscopic aspirate) Probable (CPIS > 6, new or progressive infiltrates, consolidation, cavitation or pleural effusion, BAL culture > 104 CFU/mL or PSB culture > 103 CFU/mL OR positive blood culture with pathogen also isolated from airway culture) Definite (CPIS > 6, new or progressive infiltrates, consolidation, cavitation or pleural effusion OR radiographic evidence of lung abscess or empyema, histopathologic evidence of pneumonia (abscess with PMN concentration and positive tissue culture) OR if empyema, positive culture of aspirate))	Sens = 22% (for probable or definite reference standard VAP) Spec = 98%
Klompas et al. [62]	USA	459	55.3	1.5	Objective algorithm of electronic patient record (precursor of CDC surveillance definition 2013)	CDC definition (2008)	Sens = 95 Spec = 100
Liu et al. [68]	China	162	61.6	1.5	BAL neutrophil intracellular organisms	(1) histopathological diagnosis performed within 7 days of bronchoscopy OR (2) BAL culture ≥ 104 CFU/mL, and responded to antibiotic therapy OR (3) rapid cavitation of the lung infiltrate on chest x-ray film or CT scan associated with responded to antibiotic therapy OR (4) positive culture of the pleural effusion, and the same microorganisms isolated from cultures of pleural effusion and lower respiratory tract secretions, and responded to antibiotic therapy OR (5) complete resolution with appropriate antibiotic therapy with no other disease explaining chest radiograph abnormality	Sens = 94.12% Spec = 88.33%
Mauri et al. [71]	Italy	82	59	2.6	BAL fluid pentraxin 3	1. New and persistent radiographic infiltrates associated with at least two of the following: a. Internal body temperature > 38 °C, b. White blood cells count > 12,000 or < 4000 cells/mm3 and/or c. Purulent tracheobronchial secretions; AND 2. BAL culture > 104 CFU/mL and/or significant noncontaminant viral load	Sens = 92% Spec = 60%
Medford et al. [72]	UK	150	62.3	1.5	ETA culture > 105 or BAL culture > 104	New/progressive CXR infiltrates without other obvious cause in patients mechanically ventilated for more than 4 days in the ICU and at least 2 of the following: temperature ≥ 38 °C or ≤ 35 °C, white cell count ≥ 12 or ≤ 4 × 109/L, purulent tracheobronchial secretions, with increasing oxygen requirements, computed tomography evidence of a rapidly cavitating infiltrate, positive pleural fluid culture and/or histological evidence of neutrophilic alveolitis, bronchiolitis, and consolidation in conjunction with pleural fluid microbiology, CT evidence, and histological evidence	BAL Sens = 64.1% Spec = 83.0% ETA Sens = 42.6% Spec = 33.7%
Textoris et al. [78]	France	77	30.75	NR	blood Transcriptome DNA microarray analysis (HuSG9 k)	purulent bronchial sputum; body temperature more than 38 °C or less than 36 °C; leukocytes more than 10 × 109/L or less than 4 × 109/L; chest radiograph showing new or progressive infiltrates; BAL culture ≥ 104 CFU/mL, or ETA culture ≥ 106 CFU/mL	Sens = NR Spec = NR
Vernikos et al. [80]	Greece	54	72	1.3	1) Johansen criteria, 2) Modified CPIS > 6 REF 3) Johansen criteria combined with relative neutrophil count 4) CPIS > 6 combined relative neutrophil count 5) RPDMIa score	CDC definition (2015)	Johansen criteria Sens = 85.7% Spec = 73.7% Modified CPIS > 6 Sens = 62.9% Spec = 73.7% Johansen criteria combined with relative neutrophil count (20% cut off) Sens = 67.6% Spec = 81.3% CPIS > 6 combined relative neutrophil count (20% cut off) Sens = 47.1% Spec = 81.3% RPDMI score Sens = 94.3% Spec = 84.2%
Waltrick et al. [81]	Brazil	168	NR	NR	CDC definition (2013)	CPIS ≥ 7 and miniBAL culture >  = 104 CFU/mL	Sens = 37% Spec = 100%

^aRPDMI score: radiological progression, purulent secretions, duration of mechanical ventilation, immunosuppression