# US 12,110,564 B2 · Test to distinguish viral-only from bacterial infection or viral/bacterial coinfection using a respiratory swab

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- Number: US 12,110,564 B2
- Document ID: US12110564B2
- Status: Granted
- Kind: B2
- Application number: 17/052,882
- Filed: 2019-05-06
- Published: 2021-11-25
- Granted: 2024-10-08
- Earliest claimed: 2018-05-07
- Assignees: Yale University
- Applicants: Yale University
- Inventors: Ellen Foxman
- Web page: https://patentgrep.com/patent/US12110564B2

## CPC

- C12Q 1/70: involving virus or bacteriophage {(immunoassay for viruses G01N33/56983)}
- C12Q 1/689: for bacteria
- C12Q 1/701: {Specific hybridization probes}
- G01N 33/56911: {Bacteria}
- G01N 33/56983: {Viruses}
- C12Q 2600/158: Expression markers
- G01N 2800/12: Pulmonary diseases
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

In one aspect the invention provides a method for distinguishing between a viral-only infection of the upper respiratory tract or a bacterial or viral/bacterial coinfection in a patient by analyzing a respiratory sample.

## Claims

### Claim 1

A method for detecting a viral-only or a bacterial-associated respiratory infection in a patient, the method comprising:
a. analyzing a respiratory sample from the patient to determine a level of at least one respiratory virus infection-associated molecule and a level of at least one bacterial respiratory infection-associated molecule and a level of a housekeeping gene by measuring mRNA, wherein the at least one respiratory virus infection-associated molecule comprises FAM160A1 and the at least one bacterial respiratory infection-associated molecule comprises SEP15;
b. normalizing the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule to the level of the housekeeping gene to determine a normalized level of the at least one respiratory virus infection-associated molecule and a normalized level of the at least one bacterial respiratory infection-associated molecule; and
c. comparing the normalized level of the at least one respiratory virus infection-associated molecule and the normalized level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one respiratory virus infection-associated molecule and a predetermined reference level of the at least one bacterial respiratory infection-associated molecule, respectively;
wherein if the normalized level of the at least one respiratory virus infection-associated molecule is above the respective reference level, the patient is determined to have a respiratory viral infection; and
if the normalized level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the patient is determined to have a bacterial-associated respiratory infection.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mRNA is measured by reverse transcription-qPCR.

### Claim 3 (depends on 1)

The method of claim 1, wherein the at least one respiratory virus infection-associated molecule further comprises one or more respiratory virus infection-associated molecules selected from the group consisting of CXCL9, CXCL11, IDO1, IRG1, TFEC, EPHA4, DGCR2, DGCR11, SAA2; SAA2-SAA4; SAA4, OR8B4, STAT2, ATP13A3, CXCL10, PLA2G7, DRAM1, ZNF407, MS4A7, ADGRD1, OR6C2, PTTG1IP, NFAT5, GSN, EDA, ROBO2, PRNP, THRAP3, CCDC184, SEMA6D, SOCS6, ITPKC, DGKD, SRPRB, RNF148, TRIM67, CTH, ZMYND11, PNLIPRP3, MAP4, GAD2, KIDINS220, ST5, MCM3AP, LIPG, WBP5, ITPKA, WDR78, PNPT1, FAM184B, P2RX7, VAMP4, ARVCF, TEX9, OR52N4, TAAR2, CP, NIPSNAP3A, NIPSNAP3B, OSTM1, TRIM69, MDM1, SLC32A1, ERN2, LINC01521, AK4, EXOSC6, CHFR, FBXO43, HUS1B, PLCB1, CECR6 and DSG2.

### Claim 4 (depends on 3)

The method of claim 3, wherein the at least one respiratory virus infection-associated molecule further comprises CXCL10.

### Claim 5 (depends on 1)

The method of claim 1, wherein the at least one bacterial respiratory infection-associated molecule further comprises one or more bacterial respiratory infection-associated molecules selected from the group consisting of SLC25A40, ANKRD13A, H2AFZ, TLK1, ARPC2, BSG, MSRB1, PI3, SCAF8, TIAM2, ZMAT2, CAP1, ARPC3, LAMTOR5, ACAA1, RAP1A, SSR2, ZDHHC3, ZNF680, RHOG, PRKACB, SHOC2, CCDC126, FAM102A, TAF10, LSM1, NECAP1, PHB, SNX3, FAM122B, SEC63, U2AF1, ZC3H14, ARHGDIB, ATE1, PSMB7, FLI1, CRTC2, GHITM, UBE2D2, NFU1, IDH3A, ZNF791, PROK2, MLF2, MXI1, EIF4B, NUMA1, PCBD1, BAG6, STX7, CREB1, COPS3, C1orf43, FDFT1, VKORC1, ACTR10, CCND3, GOLGA7, TMEM167A, RPS8, SNORD55, SNORD46, SNORD38A, SNORD38B, ABTB1, HSD17B11, CAMK2G, ATG4C, PHF3, QRICH1, MTHFS, CDK5RAP2, UBE2W, DPY19L1, HIPK1, TXNIP, IRAK4, APOPT1, PROK2 and TRMT112.

### Claim 6 (depends on 1)

The method of claim 1, wherein the housekeeping gene comprises β-actin, HPRT, or GAPDH.

### Claim 7

A method for detecting a viral-only or a bacterial-associated respiratory infection in a patient, the method comprising:
a. analyzing a respiratory sample from the patient to determine a level of at least one respiratory virus infection-associated molecule and a level of at least one bacterial respiratory infection-associated molecule by measuring protein, wherein the at least one respiratory virus infection-associated molecule comprises FAM160A1 and the at least one bacterial respiratory infection-associated molecule comprises SEP15; and
b. comparing the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one respiratory virus infection-associated molecule and a predetermined reference level of the at least one bacterial respiratory infection-associated molecule, respectively;
wherein if the level of the at least one respiratory virus infection-associated molecule is above the respective reference level, the patient is determined to have a respiratory viral infection; and
if the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the patient is determined to have a bacterial-associated respiratory infection.

### Claim 8 (depends on 7)

The method of claim 7, wherein the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule is measured by immunoassay.

### Claim 9 (depends on 8)

The method of claim 8, wherein the at least one respiratory virus infection-associated molecule comprises one or more respiratory virus infection-associated molecules selected from the group consisting of CXCL9, IDO1, IRG1, TFEC, EPHA4, DGCR2, DGCR11, SAA2; SAA2-SAA4; SAA4, OR8B4, STAT2, ATP13A3, CXCL10, PLA2G7, DRAM1, ZNF407, MS4A7, ADGRD1, OR6C2, PTTG1IP, NFAT5, GSN, EDA, ROBO2, PRNP, THRAP3, CCDC184, SEMA6D, SOCS6, ITPKC, DGKD, SRPRB, RNF148, TRIM67, CTH, ZMYND11, PNLIPRP3, MAP4, GAD2, KIDINS220, ST5, MCM3AP, LIPG, WBP5, ITPKA, WDR78, PNPT1, FAM184B, P2RX7, VAMP4, ARVCF, TEX9, OR52N4, TAAR2, CP, NIPSNAP3A, NIPSNAP3B, OSTM1, TRIM69, MDM1, SLC32A1, ERN2, LINC01521, AK4, EXOSC6, CHFR, FBXO43, HUS1B, PLCB1, CECR6 and DSG2.

### Claim 10 (depends on 9)

The method of claim 9, wherein the at least one respiratory virus infection-associated molecule further comprises CXCL10.

### Claim 11 (depends on 7)

The method of claim 7, wherein the at least one bacterial respiratory infection-associated molecule further comprises one or more bacterial respiratory infection-associated molecules selected from the group consisting of SLC25A40, ANKRD13A, H2AFZ, TLK1, ARPC2, BSG, MSRB1, PI3, SCAF8, TIAM2, ZMAT2, CAP1, ARPC3, LAMTOR5, ACAA1, RAP1A, SSR2, ZDHHC3, ZNF680, RHOG, PRKACB, SHOC2, CCDC126, FAM102A, TAF10, LSM1, NECAP1, PHB, SNX3, FAM122B, SEC63, U2AF1, ZC3H14, ARHGDIB, ATE1, PSMB7, FLI1, CRTC2, GHITM, UBE2D2, NFU1, IDH3A, ZNF791, PROK2, MLF2, MXI1, EIF4B, NUMA1, PCBD1, BAG6, STX7, CREB1, COPS3, C1orf43, FDFT1, VKORC1, ACTR10, CCND3, GOLGA7, TMEM167A, RPS8, SNORD55, SNORD46, SNORD38A, SNORD38B, ABTB1, HSD17B11, CAMK2G, ATG4C, PHF3, QRICH1, MTHFS, CDK5RAP2, UBE2W, DPY19L1, HIPK1, TXNIP, IRAK4, APOPT1, PROK2 and TRMT112.

### Claim 12 (depends on 1)

The method of claim 1, wherein the levels of at least two respiratory virus infection-associated molecules and/or at least two bacterial respiratory infection-associated molecules are determined and compared to the respective reference.

### Claim 13 (depends on 1)

The method of claim 1, wherein the levels of at least three respiratory virus infection-associated molecules and/or at least three bacterial respiratory infection-associated molecules are determined and compared to the respective reference levels.

### Claim 14

A method of treating a patient exhibiting symptoms of a respiratory infection, the method comprising:
a. analyzing a respiratory sample from the patient to determine a level of at least one respiratory virus infection-associated molecule and a level of at least one bacterial respiratory infection-associated molecule and a level of a housekeeping gene by measuring mRNA, wherein the at least one respiratory virus infection-associated molecule comprises FAM160A1 and the at least one bacterial respiratory infection-associated molecule comprises SEP15;
b. normalizing the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule to the level of the housekeeping gene to determine a normalized level of the at least one respiratory virus infection-associated molecule and a normalized level of the at least one bacterial respiratory infection-associated molecule; and
c. comparing the normalized level of the at least one respiratory virus infection-associated molecule and the normalized level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one respiratory virus infection-associated molecule and a predetermined reference level of the at least one bacterial respiratory infection-associated molecule, respectively;
wherein if the normalized level of the at least one respiratory virus infection-associated molecule is above the respective reference level, the patient is treated for a respiratory viral infection; and
if the normalized level of the at least one bacterial-associated molecule is above the respective reference level, the patient is treated for a bacterial respiratory infection.

### Claim 15

A method of treating a patient exhibiting symptoms of a respiratory infection, the method comprising:
a. analyzing a respiratory sample from the patient to determine a level of at least one respiratory virus infection-associated molecule and a level of at least one bacterial respiratory infection-associated molecule by measuring protein, wherein the at least one respiratory virus infection-associated molecule comprises FAM160A1 and the at least one bacterial respiratory infection-associated molecule comprises SEP15; and
b. comparing the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one respiratory virus infection-associated molecule and a predetermined reference level of the at least one bacterial respiratory infection-associated molecule, respectively;
wherein if the normalized level of the at least one respiratory virus infection-associated molecule is above the respective reference level, the patient is treated for a respiratory viral infection; and
if the normalized level of the at least one bacterial-associated molecule is above the respective reference level, the patient is treated for a bacterial respiratory infection.

### Claim 16

A method of determining whether a subject who tests positive for the presence of a bacterial or viral respiratory pathogen is a carrier or if the pathogen is part of a disease process, the method comprising:
a. analyzing a respiratory sample from the subject to determine a level of at least one respiratory virus infection-associated molecule, a level of at least one bacterial respiratory infection-associated molecule, and a level of a housekeeping gene by measuring mRNA, wherein the at least one respiratory virus infection-associated molecule comprises FAM160A1 and the at least one bacterial respiratory infection-associated molecule comprises SEP15;
b. normalizing the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule to the level of the housekeeping gene to determine a normalized level of the at least one respiratory virus infection-associated molecule and a normalized level of the at least one bacterial respiratory infection-associated molecule; and
c. comparing the normalized level of the at least one respiratory virus infection-associated molecule and the normalized level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one respiratory virus infection-associated molecule and a predetermined reference level of the at least one bacterial respiratory infection-associated molecule, respectively;
wherein if the normalized level of the at least one respiratory virus infection-associated molecule is above the respective reference level, the subject is determined to have a respiratory viral infection;
if the normalized level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to have a bacterial-associated respiratory infection;
if the normalized level of the at least one respiratory virus infection-associated molecule is above the respective reference level and the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to have both a respiratory viral infection and a bacterial respiratory infection; and
if neither the level of the at least one respiratory virus infection-associated molecule nor the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to be a carrier.

### Claim 17

A method of determining whether a subject who tests positive for the presence of a bacterial or viral respiratory pathogen is a carrier or if the pathogen is part of a disease process, the method comprising:
a. analyzing a respiratory sample from the subject to determine a level of at least one respiratory virus infection-associated molecule and a level of at least one bacterial respiratory infection-associated molecule by measuring protein, wherein the at least one respiratory virus infection-associated molecule comprises FAM160A1 and the at least one bacterial respiratory infection-associated molecule comprises SEP15; and
b. comparing the level of the at least one respiratory virus infection-associated molecule and the level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one respiratory virus infection-associated molecule and a predetermined reference level of the at least one bacterial respiratory infection-associated molecule, respectively;
wherein if the level of the at least one respiratory virus infection-associated molecule is above the respective reference level, the subject is determined to have a respiratory viral infection;
if the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to have a bacterial respiratory infection;
if the level of the at least one respiratory virus infection-associated molecule is above the respective reference level and the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to have both a respiratory viral infection and a bacterial respiratory infection; and
if neither the level of the at least one respiratory virus infection-associated molecule nor the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to be a carrier.

### Claim 18

A method of detecting a bacterial-associated respiratory infection in a subject, the method comprising:
a. analyzing a respiratory sample from the subject to determine a level of at least one bacterial respiratory infection-associated molecule and a level of a housekeeping gene by measuring mRNA, wherein the at least one bacterial respiratory infection-associated molecule comprises SEP15;
b. normalizing the level of the at least one bacterial respiratory infection-associated molecule to the level of the housekeeping gene to determine a normalized level of the at least one bacterial respiratory infection-associated molecule; and
c. comparing the normalized level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level of the at least one bacterial respiratory infection-associated molecule;
wherein if the normalized level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to have a bacterial-associated respiratory infection.

### Claim 19

A method of detecting a bacterial-associated respiratory infection in a subject, the method comprising:
a. analyzing a respiratory sample from the subject to determine a level of at least one bacterial respiratory infection-associated molecule by measuring protein, wherein the at least one bacterial respiratory infection-associated molecule comprises SEP15; and
b. comparing the level of the at least one bacterial respiratory infection-associated molecule with a predetermined reference level for the at least one bacterial respiratory infection-associated molecule;
wherein if the level of the at least one bacterial respiratory infection-associated molecule is above the respective reference level, the subject is determined to have a bacterial respiratory infection.

### Claim 20 (depends on 18)

The method of claim 18, wherein the housekeeping gene comprises β-actin, HPRT, or GAPDH.