Diagnosis and treatment of invasive aspergillosis

Abstract

Methods for diagnosing, treating, and monitoring the treatment of invasive aspergillosis (IA) are described. The methods can include detecting the presence of one or more volatile organic compounds (VOCs) in the breath of subjects suspected of having IA.

1 . A method for treating a subject with invasive aspergillosis (IA), the method comprising:
 obtaining a sample from a subject;   detecting the presence in the sample of one, two, three, or more volatile organic compounds (VOCs) produced by the  Aspergillus  species in a sample, wherein the VOCs are selected from the group consisting of farnesene, beta-vatirenene, cis-geranylacetone, camphene, alpha-pinene, beta-pinene, limonene, alpha-bergamotene, farnesene, elixene, alpha-santalene, beta-elemene, acoradien, chamigrene, 1,5,9-trimethyl cyclododecatriene, 9-decene-2-one and beta-sesquiphellandrene; and   administering a treatment to a subject when there are one, two, three or more of the VOCs present in the sample.   
     
     
         2 . The method of  claim 1 , comprising:
 detecting the presence in the sample of one, two or three VOCs selected from the group consisting of farnesene, beta-vatirenene and cis-geranylacetone; and   administering the treatment to a subject when there are one, two or all three of farnesene, beta-vatirenene and cis-geranylacetone in the sample.   
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the treatment comprises administration of one or more doses of one or more antifungal compounds. 
     
     
         5 . The method of  claim 1 , wherein:
 the presence of one, two, three, or more of camphene, alpha-pinene, beta-pinene, limonene, alpha-bergamotene, or farnesene in the sample indicates the presence of an  A. fumigatus  infection in the subject;   the presence of one, two, three, or more of elixene, alpha-santalene, beta-elemene, acoradien, chamigrene, and 1,5,9-trimethyl cyclododecatriene in the sample indicates the presence of an  A. terreus  infection in the subject; and   the presence of one or both of 9-decene-2-one and beta-sesquiphellandrene in the sample indicates the presence of an  A. calidoustus  infection in the subject.   
     
     
         6 . The method of  claim 5 , wherein:
 administering the treatment to the subject having an  A. fumigatus  or  A. terreus  infection comprises administering an azole antifungal compound; or   administering the treatment to the subject having an  A. calidoustus  infection comprises administering an amphotericin B formulation.   
     
     
         7 . A method of monitoring efficacy of a treatment for invasive  aspergillosis  (IA) in a subject, the method comprising:
 determining a first level of one, two, three, or more volatile organic compounds (VOCs) produced by the  Aspergillus  species in a sample comprising breath from the subject or headspace from a culture suspected of comprising  Aspergillus  isolated from the subject, wherein the VOCs are selected from the group consisting of farnesene, beta-vatirenene, cis-geranylacetone, camphene, alpha-pinene, beta-pinene, limonene, alpha-bergamotene, farnesene, elixene, alpha-santalene, beta-elemene, acoradien, chamigrene, 1,5,9-trimethyl cyclododecatriene, 9-decene-2-one and beta-sesquiphellandrene, in the subject;   administering a treatment for IA to the subject;   determining a second level of the VOCs in a sample obtained after administration of the treatment to the subject; and   comparing the first and second levels of VOCs, wherein a decrease in the VOCs indicates that the treatment has been effective in treating the IA in the subject, and an increase or no change indicates that the treatment has not been effective in treating the IA in the subject.   
     
     
         8 . The method of  claim 7 , wherein the treatment comprises administration of one or more doses of one or more antifungal compounds. 
     
     
         9 . A method of identifying a candidate compound for the treatment of IA, the method comprising:
 providing a test culture comprising one or more  Aspergillus  species;   detecting a baseline level of fungal volatile organic compounds (VOCs) in the headspace of the culture in the absence of the test compound, wherein the VOCs are selected from the group consisting of farnesene, beta-vatirenene, cis-geranylacetone, camphene, alpha-pinene, beta-pinene, limonene, alpha-bergamotene, farnesene, elixene, alpha-santalene, beta-elemene, acoradien, chamigrene, 1,5,9-trimethyl cyclododecatriene, 9-decene-2-one and beta-sesquiphellandrene;   contacting the test culture with a test compound;   determining a second level of the VOCs in a the test culture;   comparing the second level of VOCs to the baseline level; and   identifying a test compound that decreases levels of fungal VOCs in the test culture as a candidate compound for the treatment of IA.   
     
     
         10 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein detecting the presence in the sample of one, two, three, or more VOCs comprises using a gas chromatography (GC) or spectrometry method. 
     
     
         13 . The method of  claim 12 , wherein the spectrophotometry method is mobility spectrometry (IMS) or differential mobility spectrometry (DMS). 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the subject is a human. 
     
     
         16 . The method of  claim 4 , wherein the antifungal compound is an amphotericin B formulation; an azole antifungal compound; or an echinocandin antifungal compound. 
     
     
         17 . The method of  claim 16 , wherein the amphotericin B formulation is deoxycholate amphotericin B or a lipid formulation of amphotericin B. 
     
     
         18 . The method of  claim 17 , wherein the lipid formulation of amphotericin B is selected from the group consisting of amphotericin B lipid complex (ABLC), liposomal amphotericin B (LAMB), and amphotericin B cholesteryl sulfate complex (AMB colloidal dispersion, ABCD). 
     
     
         19 . The method of  claim 16 , wherein the azole antifungal compound is selected from the group consisting of itraconazole (ITR), voriconazole (VOR), posaconazole (POS), ravuconazole (RAV), and isavuconazole (ISA). 
     
     
         20 . The method of  claim 16 , wherein the echinocandin antifungal compound is selected from the group consisting of caspofungin, micafungin and anidulafungin. 
     
     
         21 . The method of  claim 1 , wherein the sample is a liquid sample or a gas sample. 
     
     
         22 . The method of  claim 21 , wherein the liquid sample comprises culture media or bronchoalveolar washings. 
     
     
         23 . The method of  claim 21 , wherein the gas sample comprises breath of the subject or headspace from a culture isolated from the subject. 
     
     
         24 . The method of  claim 9 , wherein the test compound is selected from the group consisting of polypeptides, polynucleotides, and small molecules.