CT Halo sign: A systematic review

Journal Pre-proof CT Halo Sign: A Systematic Review Animesh Ray, Ankit Mittal, Surabhi Vyas

PII:

S0720-048X(20)30032-2

DOI:

https://doi.org/10.1016/j.ejrad.2020.108843

Reference:

EURR 108843

To appear in:

European Journal of Radiology

Received Date:

20 November 2019

Revised Date:

12 January 2020

Accepted Date:

14 January 2020

Please cite this article as: Ray A, Mittal A, Vyas S, CT Halo Sign: A Systematic Review, European Journal of Radiology (2020), doi: https://doi.org/10.1016/j.ejrad.2020.108843

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier.

The title of the manuscript: CT Halo Sign: A Systematic Review

Author list:

Corresponding Author: Dr Animesh Ray, Assistant Professor, Department of Medicine, AIIMS, Delhi, India

Co-authors:

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Dr Ankit Mittal, Senior Resident, Infectious Diseases, AIIMS, Delhi, India

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Dr Surabhi Vyas, Assistant Professor, Department of Radiodiagnosis, AIIMS, Delhi, India

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Institution: All India Institute of Medical Sciences (AIIMS), Delhi, 110029

Corresponding author details:

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Dr Animesh Ray, Assistant Professor, Department of Medicine, 3rd Floor Teaching Block, AIIMS, Delhi-110029, India Email: [email protected]

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Ph no. 9560093190

Highlights: 

Interpretation of CT Halo sign varies with the immune status of patients



Highly specific for invasive fungal infections in neutropenic patients



Cannot differentiate pulmonary aspergillosis from pulmonary mucormycosis

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Abstract: Purpose:

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The CT Halo sign or Halo sign (HS) refers to ground-glass opacity surrounding a nodule or mass in the lung parenchyma. We conducted a systematic review to find the etiological associations of HS. We also evaluated the diagnostic performances of HS for invasive fungal infections (IFI) in

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immunosuppressed patients.

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Method:

The systematic review was conducted as per PRISMA guidelines. We searched the PubMed and

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EMBASE database till June 2018 without any restrictions. Only case reports, case series and original articles published in English language were included. A database created from the electronic searches

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was compiled and subsequent analysis was done. [PROSPERO registration: CRD42018094739] Results:

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168 studies were eligible, which included 51 case reports, 15 prospective studies, 102 retrospective

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studies. A total of 1977 patients (out of 6371) with HS were identified with age range between <1year94years. The most common diagnosis in the immunosuppressed, mixed, immunocompetent and not specified groups were IFI (86.9%, n=1194), Cryptococcosis (51.6%, n=124), Cryptococcosis (40%, n=20) and lung neoplasms (81.8%, n=36) respectively. 14 studies (11 retrospective, 3 prospective) were included in quantitative analysis. The pooled sensitivity(sn), specificity(sp) and odd’s ratio (OR) of HS

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for diagnosing IFI were 50.4%, 91% and 6.61 respectively. Also, HS could not reliably differentiate IPA from mucormycosis in the pooled analysis. Conclusions: HS can be seen in a large number of diverse conditions both in immunosuppressed and immunocompetent population. In immunosuppressed patients HS is specific for IFI but cannot rule it out. Additionally, it cannot reliably distinguish between IPA and mucormycosis.

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Key words: invasive fungal infections, invasive pulmonary aspergillosis, systematic review, metaanalysis

CT = computed tomography, IFI = Invasive fungal infections, IPA = Invasive pulmonary aspergillosis,

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IMD = Invasive mould diseases, NLR = Negative likelihood ratio, PLR = Positive likelihood ratio, OR =

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Odd’s ratio,

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Introduction The CT halo sign or halo sign(HS) refers to the presence of ground glass opacity surrounding a nodule or mass in the lung parenchyma. (1) It is the radiological correlate of infiltration (usually hemorrhage but can be neoplastic or inflammatory) surrounding a nodule or mass. (2) It was first reported with reference to IPA in a patient with acute leukaemia but has since been reported in a vast number of conditions - both infectious and non-infectious. (3) Though seen in a wide range of

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aetiologies, HS in the background of immunosuppression is often linked to IFI, notably aspergillus. (4) In this article a systematic review (SR) was done to enumerate the causes of HS and to explore its association with different host conditions. We also conducted a meta-analysis to quantitatively

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determine the diagnostic accuracy of this sign in the background of immunosuppression with

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Materials and methods:

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neutropenia.

We conducted a SR and meta-analysis on the etiological associations of the HS. It was

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registered in PROSPERO (CRD42018094739) and reported in accordance with Preferred Reporting

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Items for Systematic Reviews and Meta-analyses (PRISMA) check list. Search strategy: We first searched the PubMed and Embase databases for any existing SR on HS.

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Although narrative reviews were present, none of them were SR. We then searched these databases without publication date or language restrictions up to June 2018 with the indexed search terms: (halo) AND pulmonary; (halo) AND lung; (Computed tomography) AND Halo; (Halo) and CT. The reference lists of the included studies were manually searched to identify other eligible articles. Study selection: All articles were reviewed by two reviewers independently (A.R and A.M). All studies including case reports, case series, retrospective and prospective studies that reported HS in lung 4|Page

imaging were reviewed. Next, full text articles were obtained. A study was included if all of the following data were available: a) explicit criteria to define the imaging characteristics, b) etiological diagnosis c) immune status and d) type of study. Editorials, reviews and articles in language other than English were excluded. In case of any disagreements in study selection between the two reviewers, a third reviewer (S.V.) was consulted. Data extraction: The reviewers independently extracted the data on a predesigned spreadsheet, and any discrepancy was resolved after discussion. The following study and patient characteristics were

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extracted: title, type of study, country of origin, number of patients, mean age, male to female ratio, final diagnosis, basis for diagnosis, immune status, neutropenic status of the patients, characteristics of the lesion for which the HS was described. The studies were divided on the basis of type (case

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reports/series or retrospective/ prospective) and immune status of patients (immunocompetent/ immunosuppressed/mixed /not specified). The following definitions were used while grouping the

when

specified

by

the

respective

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studies: All patients with haematological malignancies, receiving chemotherapy, post-transplant or authors

as

immunosuppressed

were

grouped

as

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“immunosuppressed” (IS), all other patients where immune status was known not to be suppressed were grouped as “immunocompetent” (IC). Studies with heterogenous population that included both

not be ascertained.

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IS and IC patients were sub-grouped as “mixed” and as “not specified”. where immune status could

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Imaging characteristics: The criteria or definition to report the HS was recorded.

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Diagnostic criteria: The criteria for diagnosis (histopathological and/or microbiological and/or serological) of etiological conditions were recorded as mentioned in individual studies. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies included in the meta-analysis, the QUADAS-2 tool was used. (5) Studies that were classified as ‘low risk of bias’ and ‘low concern’ in all the domains were considered as studies with high methodological quality.

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The analysis was done in two parts, a qualitative descriptive analysis was done on the data from all the study groups taking into account the immune status of the patient. For quantitative analysis and meta-analysis, only studies on immunosuppressed patients in which the true-negative, true-positive, false-negative, and false positive results could be extracted, were taken into account.

Data analysis:

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Individual study estimates were charted and computed to get pooled estimates of negative likelihood ratio (NLR) and positive likelihood ratio (PLR), sensitivity and specificity. Likelihood ratio model was used in the pooled estimate and represented in the forest plot. Heterogeneity was estimated with I2 test statistic, including 95% CIs. A bivariate random-effects model was used to obtain summary

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estimates of NLR and PLR with corresponding 95% CIs. All statistical analyses were performed with an

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electronic spreadsheet program (Microsoft Office 2016®) and statistical software (Meta-analyst®). Estimation of the publication bias was done by Deek’s funnel plot asymmetry test using STATA 14.(6)

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Results:

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Descriptive analysis:

Figure 1 depicts the PRISMA diagram followed for study selection. initial search yielded 4101 hits (1801

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EMBASE and 2300 PubMed). After screening for eligibility and removing duplicates, 168 fulfilled inclusion criteria for descriptive analysis and 14 (7–20) studies were eligible for the quantitative

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analysis. Out of these 14, 11 were analysed for IFI (7,10–15,17–20) and 11 were analysed specifically for IPA (8,9,11–16,18–20) with 8 studies common to both. [Figure 1] Majority of publications were from USA (13.1%) (3,4,21–40), China (11.9%) (10,41–60), Japan (9.5%) (12,18,50,61–72), Korea (8.9%) (9,13,19,73–84), Brazil (8.9%) (7,11,85–97) and Italy (9.5%) (8,15,98– 111) with poor representation from developing and under developed countries.

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Total number of patients included were 6371 with 3595 (56.4%) males and 2235 (35.08%) females. Information on gender was unavailable in 541 cases. The 168 studies were divided into the following groups: retrospective immunosuppressed(67 studies ,3456 patients), retrospective immunocompetent (7 studies,158 patients), (28,45–48,103,112) retrospective not specified (16 studies, 502 patients), (57,58,71–73,82,83,96,97,108–111,113–115) retrospective

mixed

(12

studies,597

patients),

(39,54–56,81,95,116–121)

case

report

immunosuppressed (20 studies,34 patients), (25–27,43,44,61–63,84,88–90,100,122–128) case report

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immunocompetent (17 studies ,17 patients), (21–24,41,42,85–87,99,129–135) case report not specified (14 studies ,40 patients) (64–68,74,91,92,101,102,136–139) and prospective studies (15 studies with 1567 patients; 1443 immunosuppressed and 124 not specified). (18–20,40,59,60,98,140–

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147) [Table 1]

Number of studies (retrospective studies, case reports/series and prospective studies) addressing

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immunosuppressed patients constituted the majority (101 studies,4933 patients). The causes of

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immunosuppression were haematological malignancies in 31.25% (3,4,8,12–14,16,18–20,29,32– 34,60,61,78,84,98,104,107,122,125,140–143,145,148–159), post-transplant patients [Hematogenous cell

transplant

(HSCT)

in

15.63%

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stem

(4,7,11,17,20,25,34,35,51,62,78,89,94,141,144,151,152,154,160,161), solid organ transplant (SOT) patients in 16.4% (4,10,14,34,36,40,49,69,75,76,93,124,127,140,152,154,162–166)] drug-induced in

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7.8% (4,17,26,27,43,63,70,123,128,154), HIV related in 7.8% (4,14,17,20,53,88,100,140,167,168) and

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not specified in 15.63% (9,15,30,31,37,38,44,50,52,77,79,80,90,106,126,146,147,169–171) of the studies.

Others

(chronic

granulomatous

disease,

metastatic

melanoma,

etc)

5.4%

(14,17,34,105,140,141,172)

In immunosuppressed group, 54 studies reported patients with neutropenia.(3,8,9,12,13,15,16,18– 20,25,29–33,35,37,44,49,52,61,63,75,77–80,84,89,90,93,94,98,104,106,125,140,142–145,147,149– 7|Page

152,154,155,157,158,160,170) When a study reported more than 50% of the population as neutropenic, it was classified as a study on neutropenic patients, whereas when the population was <50% it was classified as a mixed study with both neutropenic and non-neutropenic patients. Of the remaining

47

studies,

18

were

on

non-neutropenic

patients,

(10,11,27,51,53,62,69,70,100,105,123,124,153,162–165,172) 7 were on mixed group (neutropenic plus non neutropenic)(4,14,34,40,60,93,161) and in 22 studies the status of neutropenia was not specified.(7,17,26,36,38,43,50,76,88,107,122,126–128,141,146,159,166–169,171)

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There were 24 studies in immunocompetent individuals (175 patients) and 12 studies in mixed population (both IS +IC) with 597 patients. 31 studies (666 patients) did not specify the immune status of the patients.

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We also grouped studies with patients >14yrs of age as an adult. The age range was from <1yr to 94yrs. There were 130 studies on adults, and only 5 studies in the paediatric population. while

24

studies

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(66,94,99,105,114)

included whereas

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(4,7,11,13,14,29,31,37,70,75,77,82,107,108,120,140,145,148–150,153,156,160,162)

both

studies did not specify the age group. (35,43,71,80,83,106,147,170,171)

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Lesion characteristics: HS was described most commonly around a nodule (57.8%), followed by mass (4.7%) (3,44,59,63,74,118,135,155) or consolidation (2.3%). (61,88,96,134) In 17.3% studies there was picture

(8,11–15,25,28–

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mixed

30,33,39,47,48,52,53,76,77,79,87,104,106,107,119,120,124,132,137,158) ; in 17.9 % it wasn”t (9,18,31,34,43,54–56,58,69,71,78,80,82,100,103,108,111,113,116,117,128,144–

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specified.

146,150,157,163,166,172)

Etiology: The most common etiology of HS in immunosuppressed population was IMD (IPA being most common). Whereas, cryptococcosis comprised the majority in the immunocompetent and mixed

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population studies. In the “not-specified” group, IPA was the most common cause followed by neoplasms.

[Table

1]

Immunosuppressed: Total number of immunosuppressed patients were 4933; etiological diagnosis made in 1582 (32%) patients. Of these 1374, (86.9%) cases were due to IFI. Among IFI, IPA accounted for 75.4% (1036/1374) and mucormycosis for 3.2% (44/1374) of all cases. Non-mold fungal infections accounted for 1.96% (27/1374) of cases, most common was

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Candida (59.3%) followed by Cryptococcus (29.6%) and PCP (11.1%). In 19.1% (262/1374) cases, the IFI was uncharacterised. Viral pneumonia accounted for 3.4% (54/1582) of cases with RSV (51.85%) being most common followed by CMV pneumonia (20.37%). Bacterial

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pneumonia comprised 2 % of all cases (32/1582). HS was described in other infectious and non-infectious pathologies. [Table 2]

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In studies on neutropenic patients 39 studies reported IPA, 4 reported IMD (not specified),

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Mucor in 7 studies and 2 studies reported mixed infections to be associated with HS. 6 studies found HS with PCP, Phaeohyphomycosis, Organising pneumonia, Lymphoma, Legionella

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jordanis and Marasmiusaliaceus infection.

Immunocompetent: Total number of immunocompetent patients were 175 with 50 having

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an etiological diagnosis for HS. Most common etiology was cryptococcosis (20/50=40%) followed by IPA (10/50=20%). Other uncommon diagnoses were lymphomatoid

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granulomatosis (3/50=6%), schistosomiasis, sarcoidosis, IgG4 related-diseases (each 2/50=4%).

Mixed: Total number of patients in 12 studies on mixed population were 597 and etiological association of HS was made in 242 cases. Cryptococcosis was the most common diagnosis in this subgroup (124 out 242 cases or 51.6%). IPA was seen in 13.2% (32/242) cases and Legionellosis in 3.7% (9/242) cases.

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Not specified: Studies that did not specify the immune status included 666 patients (etiological diagnosis made in 103 cases). In this, the most common diagnosis was that of a neoplastic disease (44/103 = 42.7%). It comprised of primary lung neoplasm (36/44 = 81.8%) and metastases from different primary cancers (8/44=18.2%). Amongst primary neoplasms, 16 cases were of benign origin (13 cases of pulmonary sclerosing pneumocytoma and 3 cases of pulmonary sclerosing hemangioma) and 20 were due to a malignant cause (non-squamous cell carcinoma of lung 11/20, bronchoalveolar carcinoma 5/20). Individually Visceral Larva

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Migrans due to Ascaris suum accounted for the majority of cases (18.4%, 19/103).

Sensitivity, specificity and likelihood ratio analysis:

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1) IFI: In 11 studies with 1056 cases, the pooled sensitivity of HS for IFI was 0.504 (95% CI: 0.393,

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0.615); pooled specificity was 0.91 (95% CI: 0.755, 0.970). [Table 3] Negative likelihood ratio (NLR) was 0.707 (95% CI: 0.443, 1.128) which was not significant. Positive likelihood ratio (PLR)

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of HS for IFI was 3.779 (95% CI: 1.778, 8.032), odds ratio was 6.613 (95% CI: 2.615,16.724).

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[Figure 2]

2) IPA: On evaluation of studies reporting HS exclusively for IPA (11 studies, 685 cases) both

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sensitivity and specificity of HS increased. The pooled sensitivity of CT Halo for IPA was 0.541 (95% CI:0.397, 0.679); pooled specificity was 0.922 (95% CI: 0.731, 0.981). [Table 4] There was

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also an improvement in the NLR (0.575, 95% CI: 0.288, 1.151), and OR (7.469, 95% CI: 2.218, 25.158) however with a decrease in PLR (3.341, 95% CI:1.591, 7.019). [Figure 3]

3) Studies on neutropenic patients: The specificity increased to 0.939 (95% CI: 0.701, 0.990) when a subgroup analysis was done on studies of neutropenic patients with IPA (8 studies, 407 cases) without any change in sensitivity (0.561; 95% CI: 0.386, 0.722).

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(8,12,13,15,16,18,19,20) There was an increase in PLR to 4.856 (95% CI: 1.574, 14.981) with minor changes in NLR (0.510, 95% CI: 0.171, 1.521). The OR improved to 10.257 (95% CI: 2.381, 44.182) [Figure 4]

4) Studies with Neutropenia and antibiotic resistant fever: In another subgroup analyses, 6 studies (347 cases) that clearly reported HS in fever not responding to broad spectrum antimicrobials in neutropenic patients, were evaluated. (8,13,15,16,18,20) There was a

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marginal increase in sensitivity (0.5918, 95% CI: 0.3541, 0.7932) without much change in the specificity (0.9374, 95% CI: 0.6595, 0.9914). NLR was 0.445 (95% CI: 0.110, 1.803), PLR was

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5.585 (95% CI: 1.423, 21.924) ; OR increased to 12.356 (95% CI: 2.249, 67.889) [Figure 5]

Performance of CT Halo sign for differentiation of IPA from Mucormycosis: 6 studies were analysed

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to assess the ability of HS to differentiate IPA and Mucor.(7–11,16) A 2x2 table was constructed and

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Chi-square test was applied. The HS could not reliably differentiate IPA from Mucormycosis. (p = 0.449) QUADAS-2: It was calculated for all studies that were included in the quantitative analysis. [Figure 6] Although the applicability concern was overall low, the risk of bias was high with respect to patient

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selection and clarity on the definition of index and reference standards. This was probably because most of the studies were conducted before 2008 when the revised EORTC/MSG definitions for invasive

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aspergillosis were formulated. (173)

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Publication Bias: Estimation of the publication bias was done by Deek’s funnel plot asymmetry test which did not reveal any publication bias amongst the 14 studies that were included for final analysis. (6)

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Discussion Halo sign was initially described in a patient with acute leukaemia and IPA.(3) In IPA patients, histopathologically it indicates the presence of alveolar haemorrhage surrounding an area of pulmonary infarction. The pulmonary infarction, caused by the invasion of fungi into the small and medium-sized vessels, causes necrosis which corresponds to the nodule; and the halo of ground glass is formed due to encircling hemorrhage.(2) It has subsequently been described in immunocompetent, critically ill, as well as mixed population due to a wide number of causes. . This review is the first SR

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on diagnostic performances of the commonly reported HS. It comprised of a qualitative analysis, which recorded the etiology of HS in different immune conditions; and a quantitative analysis in immunosuppressed patients for computing diagnostic accuracy. Its role in specific groups like

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immunosuppressed population has never been objectively measured before in terms of odd’s ratio and likelihood ratio.

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Our review revealed that HS was attributed to 71 causes totally. (Table 2) In the immunosuppressed

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(including neutropenic), which comprised of 77.4% of patients, the most common cause was IMD (IPA being most common). The most common cause in immunocompetent and mixed groups was

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cryptococcosis; lung malignancy (primary or metastatic) being most common in non-specified group. Since there was a relatively smaller proportion of studies on non-immunosuppressed group it was

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under-represented in the final analyses.

In the quantitative analysis, the best diagnostic performances were recorded for IPA in neutropenic

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patients. The specificity was highest in this group (92.2%) but with low sensitivity (54.1%), indicating that it cannot be used to rule out IPA. For both IPA and IFI, the CI for pooled NLR crossed 1, suggesting that the absence of HS cannot reliably negate these infections. The performance was almost similar in studies with IFI or IPA. PLR was not reasonably high ( < 10 in all subgroup analyses), indicating that HS by itself cannot confirm the presence of IFI or IPA in immunosuppressed individuals. (174) Also, pooled analyses showed that this sign was not significantly associated with IPA as compared with

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Mucormycosis (32.4% vs 40%, p=.449). It implies based on the presence HS only, differentiation between IPA and Mucor infection cannot be made. It may thus be reasonable to take a therapeutic decision based on the local microbial data or of treating with appropriate broad spectrum anti-fungals covering all such pathogens (Aspergillus, Mucor, Fusarium etc). Interestingly in a few studies, CT scan was done and HS was reported after infection failed to resolve with administration of broad-spectrum antibiotics. We expected the specificity of HS for IFI to increase in this subgroup of studies. However, in 6 studies pertaining to this group, the specificity was almost

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same (≈93%) as to other subgroups, like neutropenic patients or IPA or IFI. In all of the remaining (5 of 11) studies, the relationship of this sign to administration of antibiotics was not categorically stated. It is imperative that future studies focus on this aspect to clarify this issue.

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Fleischner’s society describes HS with respect to both nodules and mass. Though, halo was most commonly described around nodules (58%), followed by mixed (17.58%) and mass (4%), it was

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also described around consolidation. In 18.18% cases the associated lesion was not specified. Whether

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there is a difference in the diagnostic performances of HS around different lesions, could not be ascertained in this review, due to lack of studies comparing their implications.

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The limitations of the present SR were that it also included a collection of case reports and series. In studies on non-immunosuppressed groups, publication and reporting biases could not be ruled out.

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There was also considerable heterogeneity in the studies included in quantitative analyses (I2 > 50%). Notably, the study by Kim et al (13) which carried high weightage in the meta-analysis, had significantly

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different results, without any apparent reason, as compared to the other studies and apparently had a significant influence on pooled diagnostic accuracy. Due to lack of studies reporting on the diagnostic performances in immunosuppressed and mixed group, quantitative analyses could not be done in these groups. The ‘gold standard’ against which HS has been compared, differed considerably in different studies over the years, reflecting the changing paradigm in diagnosis of IFI. This has led to non-uniformity in the diagnostic criteria used in studies across the years. Since in majority of the

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studies the immunosuppressed population was from a mixed background, individual analyses for the different underlying conditions was not possible.

Conclusion Halo sign can be seen due to number of causes which depends on the underlying immune condition

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of the patient. In immunosuppressed conditions, most notably neutropenic patients, the most frequent cause is invasive fungal infections with IPA being the most common individual organism reported. In the immunosuppressed group, though the specificity is around 91%, the sensitivity is low

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(around 50.4%). CT halo sign cannot differentiate between IPA and non-IPA fungal infections in this group. Further prospective studies are required to quantitatively analyse the diagnostic performances

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Conflict of interest: none

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of this sign in immunocompetent and mixed population group.

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3. Kuhlman JE, Fishman EK, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology. 1985 Dec;157(3):611–4. 4. Greene RE, Schlamm HT, Oestmann J-W, Stark P, Durand C, Lortholary O, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis Off Publ Infect Dis Soc Am. 2007 Feb 1;44(3):373–9.

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9. Jung J, Kim MY, Lee HJ, Park YS, Lee S-O, Choi S-H, et al. Comparison of computed tomographic findings in pulmonary mucormycosis and invasive pulmonary aspergillosis. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2015 Jul;21(7):684.e11-18.

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10. Qin J, Xu J, Dong Y, Tang W, Wu B, An Y, et al. High-resolution CT findings of pulmonary infections after orthotopic liver transplantation in 453 patients. Br J Radiol. 2012 Nov;85(1019):e959965. 11. Gasparetto EL, Souza CA, Tazoniero P, Davaus T, Escuissato DL, Marchiori E. Angioinvasive pulmonary aspergillosis after allogeneic bone marrow transplantation: clinical and high-resolution computed tomography findings in 12 cases. Braz J Infect Dis Off Publ Braz Soc Infect Dis. 2007 Feb;11(1):110–3. 12. Kami M, Kishi Y, Hamaki T, Kawabata M, Kashima T, Masumoto T, et al. The value of the chest computed tomography halo sign in the diagnosis of invasive pulmonary aspergillosis. An autopsy-based retrospective study of 48 patients. Mycoses. 2002 Oct;45(8):287–94.

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13. Kim K, Lee MH, Kim J, Lee KS, Kim SM, Jung MP, et al. Importance of open lung biopsy in the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies. Am J Hematol. 2002 Oct;71(2):75–9. 14. Henzler C, Henzler T, Buchheidt D, Nance JW, Weis CA, Vogelmann R, et al. Diagnostic Performance of Contrast Enhanced Pulmonary Computed Tomography Angiography for the Detection of Angioinvasive Pulmonary Aspergillosis in Immunocompromised Patients. Sci Rep. 2017 Jun 30;7(1):4483. 15. Bruno C, Minniti S, Vassanelli A, Pozzi-Mucelli R. Comparison of CT features of Aspergillus and bacterial pneumonia in severely neutropenic patients. J Thorac Imaging. 2007 May;22(2):160–5. 16. von Eiff M, Zühlsdorf M, Roos N, Hesse M, Schulten R, van de Loo J. Pulmonary fungal infections in patients with hematological malignancies--diagnostic approaches. Ann Hematol. 1995 Mar;70(3):135–41.

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141. Ekinci A, Yücel Uçarkuş T, Okur A, Öztürk M, Doğan S. MRI of pneumonia in immunocompromised patients: comparison with CT. Diagn Interv Radiol Ank Turk. 2017 Feb;23(1):22–8.

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142. Caillot D, Latrabe V, Thiébaut A, Herbrecht R, De Botton S, Pigneux A, et al. Computer tomography in pulmonary invasive aspergillosis in hematological patients with neutropenia: an useful tool for diagnosis and assessment of outcome in clinical trials. Eur J Radiol. 2010 Jun;74(3):e172-175.

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143. Weisser M, Rausch C, Droll A, Simcock M, Sendi P, Steffen I, et al. Galactomannan does not precede major signs on a pulmonary computerized tomographic scan suggestive of invasive aspergillosis in patients with hematological malignancies. Clin Infect Dis Off Publ Infect Dis Soc Am. 2005 Oct 15;41(8):1143–9. 144. Maertens J, Van Eldere J, Verhaegen J, Verbeken E, Verschakelen J, Boogaerts M. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis. 2002 Nov 1;186(9):1297–306.

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145. Klimko N.N., Khostelidi S.N., Borzova Y.V., Popova M.O., Volkova A.G., Chernopyatova R.M., et al. Nosocomial invasive aspergillosis in patients with hemato-logical malignancies in SaintPetersburg, Russia. Mycoses. 2011;54 146. Lortholary O., Gangneux J.P., Sitbon K., Lebeau B., Maubrisson F.De., Dromer F., et al. Prospective surveillance of invasive aspergillosis in 4 French regions: 2005-2007. Clin Microbiol Infect. 2009;15 147. Prem S., Kumar R., Mahapatra M., Sharma S., Saxena R. Invasive pulmonary aspergillosis in neutropenic patients: Early diagnosis by thoracic high-resolution CT scan. J Clin Oncol. 2011;29(15). 148. Hauggaard A, Ellis M, Ekelund L. Early chest radiography and CT in the diagnosis, management and outcome of invasive pulmonary aspergillosis. Acta Radiol Stockh Swed 1987. 2002 May;43(3):292–8.

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149. Saghrouni F, Ben Youssef Y, Gheith S, Bouabid Z, Ben Abdeljelil J, Khammari I, et al. Twentynine cases of invasive aspergillosis in neutropenic patients. Med Mal Infect. 2011 Dec;41(12):657– 62.

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150. Anugulruengkitt S, Trinavarat P, Chantranuwat P, Sritippayawan S, Pancharoen C, Thanyawee P. Clinical Features and Survival Outcomes of Invasive Aspergillosis in Pediatric Patients at a Medical School in Thailand. J Med Assoc Thail Chotmaihet Thangphaet. 2016 Feb;99(2):150–8.

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151. Brook O, Guralnik L, Hardak E, Oren I, Sprecher H, Zuckerman T, et al. Radiological findings of early invasive pulmonary aspergillosis in immune-compromised patients. Hematol Oncol. 2009 Jun;27(2):102–6.

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152. Brodoefel H, Vogel M, Hebart H, Einsele H, Vonthein R, Claussen C, et al. Long-term CT follow-up in 40 non-HIV immunocompromised patients with invasive pulmonary aspergillosis: kinetics of CT morphology and correlation with clinical findings and outcome. AJR Am J Roentgenol. 2006 Aug;187(2):404–13.

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153. Althoff Souza C, Müller NL, Marchiori E, Escuissato DL, Franquet T. Pulmonary invasive aspergillosis and candidiasis in immunocompromised patients: a comparative study of the highresolution CT findings. J Thorac Imaging. 2006 Aug;21(3):184–9.

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154. Horger M, Hebart H, Einsele H, Lengerke C, Claussen CD, Vonthein R, et al. Initial CT manifestations of invasive pulmonary aspergillosis in 45 non-HIV immunocompromised patients: association with patient outcome? Eur J Radiol. 2005 Sep;55(3):437–44.

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155. Caillot D, Mannone L, Cuisenier B, Couaillier JF. Role of early diagnosis and aggressive surgery in the management of invasive pulmonary aspergillosis in neutropenic patients. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2001;7 Suppl 2:54–61. 156. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol Off J Am Soc Clin Oncol. 2001 Jan 1;19(1):253–9. 157. Weinbergerova B., Racil Z., Kocmanova I., Sevcikova E., Toskova M., Winterova J., et al. Retrospective analysis of invasive aspergillosis in haemato-oncological department, 2005-2008. Clin Microbiol Infect. 2010;16

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158. Horger M, Einsele H, Schumacher U, Wehrmann M, Hebart H, Lengerke C, et al. Invasive pulmonary aspergillosis: frequency and meaning of the “hypodense sign” on unenhanced CT. Br J Radiol. 2005 Aug;78(932):697–703. 159. Oikonomou A, Müller NL, Nantel S. Radiographic and high-resolution CT findings of influenza virus pneumonia in patients with hematologic malignancies. AJR Am J Roentgenol. 2003 Aug;181(2):507–11. 160. Ribaud P, Chastang C, Latgé JP, Baffroy-Lafitte L, Parquet N, Devergie A, et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis Off Publ Infect Dis Soc Am. 1999 Feb;28(2):322–30. 161. Franquet T., Müller N.L., Lee K.S., Oikonomou A., Flint J.D. Pulmonary candidiasis after hematopoietic stem cell transplantation: Thin-section CT findings. Radiology. 2005;236(1):332–7.

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162. Hekimoglu K, Tezcan S, Coskun M, Dogrul MI, Moray G, Haberal M. MDCT evaluation of early pulmonary infection types after liver transplantation. Transplant Proc. 2015 Mar;47(2):473–7. 163. Muñoz P, Vena A, Cerón I, Valerio M, Palomo J, Guinea J, et al. Invasive pulmonary aspergillosis in heart transplant recipients: two radiologic patterns with a different prognosis. J Heart Lung Transplant Off Publ Int Soc Heart Transplant. 2014 Oct;33(10):1034–40.

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164. Diederich S, Scadeng M, Dennis C, Stewart S, Flower CD. Aspergillus infection of the respiratory tract after lung transplantation: chest radiographic and CT findings. Eur Radiol. 1998;8(2):306–12.

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165. Rappaport DC, Chamberlain DW, Shepherd FA, Hutcheon MA. Lymphoproliferative disorders after lung transplantation: imaging features. Radiology. 1998 Feb;206(2):519–24.

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166. Kahkouee S., Mosadegh L., Baghi D.K., Armand S. Invasive pulmonary aspergillosis in solid organ transplant patients: A CT challenge. Chest. 2013;144(4).

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167. Godoy MCB, Rouse H, Brown JA, Phillips P, Forrest DM, Müller NL. Imaging features of pulmonary Kaposi sarcoma-associated immune reconstitution syndrome. AJR Am J Roentgenol. 2007 Oct;189(4):956–65. 168. Carignan S., Staples C.A., Müller N.L. Intrathoracic lymphoproliferative disorders in the immunocompromised patient: CT findings. Radiology. 1995;197(1):53–8.

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169. Mayer JL, Lehners N, Egerer G, Kauczor HU, Heußel CP. CT-morphological characterization of respiratory syncytial virus (RSV) pneumonia in immune-compromised adults. ROFO Fortschr Geb Rontgenstr Nuklearmed. 2014 Jul;186(7):686–92.

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170. Patout M., Fercocq C., Alanio A., Touratier S., Raffoux E., Derouin F., et al. Breakthrough invasive pulmonary aspergillosis (IPA) in patients receiving posaconazole prophylaxis (PPxis). Eur Respir J. 2014;44 171. Lass-Flörl C, Resch G, Nachbaur D, Mayr A, Gastl G, Auberger J, et al. The value of computed tomography-guided percutaneous lung biopsy for diagnosis of invasive fungal infection in immunocompromised patients. Clin Infect Dis Off Publ Infect Dis Soc Am. 2007 Oct 1;45(7):e101-104. 172. Shrot S, Schachter J, Shapira-Frommer R, Besser MJ, Apter S. CT halo sign as an imaging marker for response to adoptive cell therapy in metastatic melanoma with pulmonary metastases. Eur Radiol. 2014 Jun;24(6):1251–6. 26 | P a g e

173. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008 Jun 15;46(12):1813–21.

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174. Deeks JJ. Systematic reviews of evaluations of diagnostic and screening tests. BMJ. 2001 Jul 21;323(7305):157–62.

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Figure Legends:

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Figure 1: Study selection flowchart

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Figure 2: Forest plot summary estimates of PLR, NLR and OR in 11 studies on IFI

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Figure 3: Forest plot summary estimates of PLR, NLR and OR in 11 studies on IPA

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Figure 4: Forest plot summary estimates of PLR, NLR and OR in 8 studies on neutropenic patients

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Figure 5: Forest plot summary estimates of PLR, NLR and OR in 6 studies on antibiotic resistant fever in neutropenic patients

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Figure 6: Quality assessment of included studies based on QUADAS-2

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Table Legends:

Table 1: Distribution of studies based on immune status

1582

50

IPA

Cryptococcosis

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Not specified Case Reports: 14 Retrospective: 16 Prospective: 1 0

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175

597

666

242

103

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4933

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Studies in the paediatric age group Total number of cases Number of Halo sign observed Most common aetiology

re

Type of Study

Immunosuppressed(IS) Immunocompetent(IC) Mixed (IS+IC) Case Reports: 20 Case Reports: 17 Retrospective: Retrospective: 67 Retrospective: 7 12 Prospective: 14 2 1 0

Cryptococcosis

Neoplastic aetiologies

Table 2: List of causes associated with CT Halo sign

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Non-Fungal: Bacterial pneumonia (not specified) (10,15,17,105) Staphylococcal pneumonia (95) Respiratory Syncytial Virus (RSV) (7,169) Cytomegalo Virus (CMV) (7,70,121) Viral pneumonia (not specified) (10,17) Influenza (159) Herpes Simplex virus (HSV) (121) Varicella pneumonia (23) Mycobacterial infection (17,62,95) Legionellosis (39) Schistosomiasis (24,38,133,138) Nocardia (43,135) Actinomycosis (95) Visceral Larva Migrans (VLM) Ascaris suum (67,72) Pulmonary Toxocariasis (64,67,114) Pleuropulmonary paragonimus (73) Psittacosis (86) Q-fever (115) Legionella jordanis pneumonia (25) Septic Embolism (113) Mixed infections (30,141)

Non-infectious causes Neoplastic Etiology: Kaposi sarcoma (88,100,121,167) Non squamous cell cancer lung (59) Squamous cell Carcinoma lung (136) Adenocarcinoma lung (71,91,102) Bronchioloalveolar carcinoma (109,111) Primary angiosarcoma lung (21) Lymphoma (18,168) Post-transplant lymphoproliferative disorder (PTLD) (124,165,168) MALT lymphoma (119) Mycosis fungoides (68) Metastases from angiosarcoma (50,101,121) Metastases from melanoma (172) Metastases from choriocarcinoma (65) Metastases from adeno carcinoma of GIT (110) Metastases from Mucinous cystic neoplasm of pancreas (22,132) Metastases from osteosarcoma (108) Metastases from bone and soft tissue tumours (66) Metastases from Mullerian tumour (41) Metastases (primary not specified) (95) Pulmonary sclerosing pneumocytoma (82) Pulmonary sclerosing hemangioma (58) Plasmacytoma (95) Lymphoproliferative disease (95)

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Infectious causes Fungal: Invasive Pulmonary Aspergillosis Mucormycosis (8,9,19,32,34,61,77,79) Invasive mold disease (not specified) (98,104) Chronic necrotising pulmonary aspergillosis (112) Aspergillus colonisation (116) Scedosporium (105) Pneumocystis pneumonia (30,70,84) Pulmonary Candidiasis (51,121,153,161) Cryptococcosis (45,47,51,53–56,81,95,120) Phaeohyphomycosis (37) Histoplasmosis (85) Paracoccidioidomycosis (92) Coccidioidomycosis (121) Hormographiella aspergillata pneumonia (126) Marasmiusaliaceus pneumonia (125)

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Non-neoplastic Etiology: Post Tracheo-Bronchial Biopsy lung injury (36) Sarcoidosis (103,130) Lymphomatoid granulomatosis (28) Amiodarone induced pneumonitis (129) IgG4 related disease (42,87) Chronic eosinophilllic pneumonia (99) Cocaine induced pulmonary disease (96) Organizing pneumonia (19,97,117) Primary amyloidosis (137) Hypersensitivity pneumonitis (139) Wegener's granulomatosis (121) Idiopathic HES (83)

Table 3: Sensitivity & Specificity of studies with IFI

3

4

2

3

15

15

2

75

11

6

12

3

13

12

0

23

4

18

18

38

10

11

6

72

17

51

2

54

5

4

0

26

38

32

24

56

22

14

Sensitivity (95% CI) 0.717 (0.506, 0.863) 0.429 (0.144, 0.770) 0.500 (0.328, 0.672) 0.647 (0.404, 0.832) 0.519 (0.334, 0.700) 0.182 (0.070, 0.396) 0.476 (0.279, 0.682) 0.250 (0.161, 0.366) 0.550 (0.260, 0.809) 0.543 (0.426, 0.655) 0.718 (0.609, 0.807)

Specificity (95% CI) 0.944 (0.495, 0.997) 0.600 (0.200, 0.900) 0.974 (0.902, 0.993) 0.200 (0.066, 0.470) 0.979 (0.741, 0.999) 0.679 (0.546, 0.787) 0.923 (0.839, 0.965) 0.964 (0.868, 0.991) 0.981 (0.764, 0.999) 0.919 (0.883, 0.945) 0.650 (0.492, 0.781)

274 31

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Blum et al 1994 (20) Won et al 1998 (19) Kami et al 2000 (18) Kim et al 2002 (13) Kami et al 2002 (12) Franquet et 2003 al (17) Escuissato 2005 et al (7) Bruno et al 2007 (15) Gasparetto 2007 et al (11) Qin et al 2012 (10) Henzler et al 2017 (14) C.I. = Confidence Interval

False True + 0 8

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False 6

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True + 16

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Year

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Study

Year

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Study

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Table 4: Sensitivity & Specificity of studies only with IPA:

Blum et al (20)

True False False True + + -

Sensitivity (95% CI)

Specificity (95% CI)

1994

16

6

0

8

0.717 (0.506, 0.863)

0.944 (0.495, 0.997)

Eiff et al (16) 1995

7

11

0

13

1998

2

3

3

4

2000

15

15

2

75

0.395 (0.206, 0.621) 0.400 (0.100, 0.800) 0.500 (0.328, 0.672)

0.964 (0.616, 0.998) 0.571 (0.230, 0.856) 0.974 (0.902, 0.993)

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4

0

31

6

12

3

51

2

54

4

0

26

70

11

13

0

2

10

22

14

31

0.750 (0.508, 0.897) 0.647 (0.404, 0.832) 0.250 (0.161, 0.366) 0.550 (0.260, 0.809) 0.271 (0.191, 0.368) 0.958 (0.575, 0.997) 0.718 (0.609, 0.807)

0.984 (0.794, 0.999) 0.200 (0.066, 0.470) 0.964 (0.868, 0.991) 0.981 (0.764, 0.999) 0.542 (0.346, 0.725) 0.808 (0.514, 0.943) 0.650 (0.492, 0.781)

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Kami et al 2002 13 (12) Kim et al 2002 11 (13) Bruno et al 2007 17 (15) Gasparetto 2007 5 et al (11) Jung et al 2015 26 (9) Sassi et al 2016 11 (8) Henzler et al 2017 56 (14) C.I. = Confidence Interval

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