review article neopterin in diagnosis and monitoring of...

Hindawi Publishing CorporationJournal of BiomarkersVolume 2013 Article ID 196432 10 pageshttpdxdoiorg1011552013196432

Review ArticleNeopterin in Diagnosis and Monitoring of Infectious Diseases

Michael Eisenhut

Paediatric Department Luton and Dunstable University Hospital NHS Foundation Trust Lewsey Road Luton LU40DZ UK

Correspondence should be addressed to Michael Eisenhut michael eisenhutyahoocom

Received 10 August 2013 Accepted 28 October 2013

Academic Editor Yvan Devaux

Copyright copy 2013 Michael Eisenhut This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Neopterin is produced by activated monocytes macrophages and dendritic cells upon stimulation by interferon gammaproduced by T-lymphocytes Quantification of neopterin in body fluids has been achieved by standard high-performance liquidchromatography radioimmunoassays and enzyme-linked immunosorbent assays Neopterin levels predict HIV-related mortalitymore efficiently than clinicalmanifestations Successful highly active antiretroviral therapy is associatedwith a decrease in neopterinlevels Elevated neopterin levels were associated with hepatitis by hepatitis A B and C viruses Serum neopterin levels were foundto be a predictor of response to treatment of chronic HCV infection with pegylated interferon combined with ribavirin Neopterinlevels of patients with pulmonary tuberculosis were found to be higher in patients with more extensive radiological changesElimination of blood donors with elevated neopterin levels to reduce risk of transmission of infections with known and unknownviral pathogens has been undertaken Neopterin measurement is hereby more cost effective but less sensitive than screening usingpolymerase chain reaction based assays In conclusion neopterin is a nonspecific marker of activated T-helper cell 1 dominatedimmune response It may be a useful marker for monitoring of infectious disease activity during treatment and for more accurateestimation of extent of disease and prognosis

1 Introduction

Neopterin was first isolated from larvae of bees in workerbees and in royal jelly in 1963 and subsequently from humanurine by Sakurai and Goto in 1967 [1]

Neopterin or 2-amino-4-hydroxy-6-(D-erythro-110158402101584031015840-trihydroxypropyl)-pteridine is produced from guanosinetriphosphate via guanosine triphosphate cyclohydrolase I(GTPCH I) by activated monocytes macrophages dendriticcells and endothelial cells and to a lesser extent in renalepithelial cells fibroblasts and vascular smooth muscle cellsupon stimulationmainly by interferon gamma and to a lesserextent by interferon alpha and beta with its release beingenhanced by tumor necrosis factor [2 3] GTPCH I mRNAexpression is synergistically and independently induced byinterferon gamma through the Jak2Stat pathway of nucleartranscription regulation and through TNF by the NF-kappaBpathway (see Figure 1) [4] Release in response to cytokinesreleased by T-lymphocytes and natural killer cells makeneopterin an indicator of activation of cell mediated immu-nity including release by infections associated with activationof T-lymphocytes and natural killer cells malignancies

autoimmune diseases rejection of transplanted organs andatherosclerosis

At its first isolation in the 1960s neopterin was detectedin the pupae of bees by anion exchange chromatogra-phy followed by paper chromatography [1] In the sev-enties gas chromatographic-massfragmentographic meth-ods were described allowing measurement in urine Sub-sequently detection and quantification of neopterin suc-ceeded in serum urine and other body fluids using stan-dard high pressure and by reverse-phase high-performanceliquid chromatography with fluorescence detection Latersimpler radioimmunoassays and more recently enzyme-linked immunosorbent assays have been developedwhich aresuitable for large numbers of samples [1] Semiquantitativemeasurement with a dipstick system using polyclonal anti-neopterin antibodies has been validated and may be suitablefor bedside testing and in the setting of developing countries[5]

2 Neopterin Release in Viral Infections

21 Relationship of Neopterin Levels to Time Course of ViralInfections During acute viral infections increased neopterin

2 Journal of Biomarkers

MΘJak2Stat pathway

NF-120581B pathway+

GTP Neopterin Nucleus

IFN

TNF

GTPCH I

NK cells

T-cells

120574

Figure 1 Pathways for induction of neopterin production (MΘmacrophage Jak Janus kinase Stat Signal Transducer andActivatorof Transcription and GTPCH guanosine triphosphate cyclohydro-lase)

levels have been observed which correlate with the activity ofdisease This was first described in 1979 [6] and subsequentlyneopterin elevations were noted in infections with hepatitisviruses Epstein-BarrCytomegalomeaslesmumps varicellazoster rubella and influenza viruses [1 7ndash11] Elevatedneopterin levels in body fluids were found at the end of theincubation period before the onset of clinical symptomsThehighest neopterin levels occur just before specific antibodiesagainst the virus become detectable which is about two tofour weeks after onset of increased neopterin production Inacute varicella zoster virus infection peak neopterin levelswere observed at the end of the appearance of the rash and inmeasles virus infection one to three days after appearance ofthe rash [12 13] Immunisation with live viruses for examplemeasles mumps and rubella and virus vaccine resulted ina significant increase of neopterin independent of presenceof any symptoms In measles vaccination neopterin levelswere observed to rise at a median of 5 days after vaccinationabout 7 days before the appearance of antibodies [13] Theseinvestigations point to a future application of measurementsneopterin as a correlate of a successful vaccination Neopterinshould be investigated as a marker to evaluate protective effi-cacy of vaccines stimulating cell mediated immunity againstmycobacterial parasitic or viral diseases The magnitude ofthe elicited neopterin levels could be put into relationship toincidence of the disease immunised against the population ofimmunised children

Serumneopterin levels were also found to be significantlyelevated in symptomatic dengue virus infections with levelshigher than inmeasles and influenza virus disease [14] Levelscorrelated with duration of fever and severity of disease [1415]

Investigations into the physiological functions ofneopterin in viral infections revealed that it is able to delay

the development of the cytopathic effect of coxsackie B5virus in Hep-2 cells [16] A proposed mechanism is thestimulation of inducible nitric oxide synthase expressionleading to an increase in nitric oxide production Othermechanisms include the induction of the translocation of thenuclear factor-kappa B to the nucleus

22 Neopterin as Diagnostic and Prognostic Marker in HIVInfection Testing of 328 samples of 29 HIV infected individ-uals found that 4468 (647) of samples which were HIV-1RNA and p24 antigen positive had elevated neopterin levels(gt10 nmolL) 6216 (28) samples which were both HIV-1and p24 antigen negative had elevated neopterin levels [17]Neopterin levels were also found to be significantly elevatedin HIV-2 infection compared to controls [18]

Studies investigated markers of immune activation fortheir usefulness as prognostic markers in HIV infection andshowed an increase of neopterin levels in people with HIVinfection compared to patients without HIV infection [19ndash22] Neopterin levels hereby were found to increase earlyin the course of HIV infection preceeding CD4+-T-celldecline and clinical manifestations of AIDS [23 24] Plasmaneopterin levels were found to correlate with plasma HIVviral load [25]

Neopterin levels were found to predict HIV related mor-tality [26 27] A retrospective study compared 120573

2microglob-

ulin immunoglobulin A G and M adenosine deaminaseand neopterin levels above normal range as predictors of clin-ical or immunological deterioration in 256 patients with HIVinfection Changes in 120573

2microglobulin levels showed the

greatest sensitivity to detect worsening (43) with neopterinslightly less sensitive (419) followed by immunoglobulinlevels (268ndash352) and adenosine deaminase levels with218 having the lowest sensitivity [28]

23 Neopterin as Surrogate Marker for Viral Load to Mon-itor Response to Antiretroviral Treatment In a land markstudy the effects of dual reverse transcriptase inhibitor (RT)therapy and highly active antiretroviral therapy (HAART)on neopterin levels in patients with HIV infection werecompared to HIV uninfected controls HIV infected patientsnot on treatment and patients who had stopped treatment[22] RT inhibitor treatment decreased circulating levelsof neopterin (mean of 156 for treated versus a mean of223 ngmL for untreated HIV patients 119875 lt 004) HAARTdecreased neopterin levels significantly further This con-firmed results of a previous study on the effects of HAARTon neopterin levels [29] Neopterin levels in patients whodiscontinued HAART became similar to untreated HIVpatients

Neopterin may be a particularly useful surrogate markerfor monitoring of control of HIV replication in settingsin developing countries where HIV RNA viral load mea-surement is not available and may be a cheaper alternativeparticularly if semiquantitative dip stick tests are used forurine samples [5] Longitudinal serial measurements in thesame individual could overcome difficulties with interpreta-tion in settings where chronic parasitic (malaria) or bacterial

Journal of Biomarkers 3

Table 1 Applications of neopterin measurements for monitoring of treatment response in infectious diseases

Infection Treatment Type of sample Change in neopterin levels observed Reference

Humanimmunodeficiencyvirus

Reverse transcriptaseinhibitors and highlyactive antiretroviral

treatment

Bloodcerebrospinal fluid

Mean of 156 ngmL for treated versus a mean of223 for untreated HIV patients

[12 22 29ndash37]

Hepatitis C virusPegylated interferon

combined withribavirin

Blood

The rate of response was twofold higher amongpatients with pretreatment neopterin levelslt16 nmolL than in patients with levelsge16 nmolL

[38]

Mycobacteriumtuberculosis

Antituberculotictreatment Blood urine

Levels declined on twice weekly measurements inall monitored patients with pulmonarytuberculosis on treatment and fell to belowtolerance limits within 10 weeks of treatment in610 patients

[39ndash41]

Plasmodiumfalciparum Chloroquine Urine When clinical disease resolved within 3ndash7 days of

treatment neopterin levels normalized rapidly [42]

Schistosoma mansoni Praziquantel Blood Serum levels normalized on treatment [43 44]

(tuberculosis) infections may elevate the baseline neopterinlevel and could allowmonitoring of response to antiretroviraltreatment in the absence of resistance testing and providemeans to monitor compliance in the outpatient setting (seeTable 1 for list of diseases in which neopterin levels have beenused to monitor treatment response)

24 Viral Hepatitis The first study investigating the role ofneopterin in specific forms of viral hepatitis tested urinarylevels in patients with hepatitis A hepatitis B and non-A non-B hepatitis virus infection [9] The authors notedthat in 51 patients with acute viral hepatitis 49 patients hadelevated urinary neopterin levelswith the highest levels foundin patients with acute hepatitis A While all patients withactive hepatitis B had elevated neopterin levels 4962 HbsAgcarriers (77) had normal urinary neopterin levels Theauthors noted that neopterin levels were not a reflection ofhepatocellular damage as 3 patients with alcoholic hepatitishad normal urinary neopterin levels

In order to address the question whether neopterin is auseful marker for early detection of viral infection in donatedblood products before seroconversion one study inves-tigated neopterin levels in anti-HCV-negative specimenswhich were HCV RNA and HCV core antigen positive Theinvestigators found that 8217 (37) had elevated neopterinlevels (gt10 nmolL) 4115 (35) specimens positive for HBVDNA had elevated neopterin levels [17] In 106 patientswith thalassemia major receiving multiple blood transfu-sion significantly more patients with histologically provenchronic hepatitis (1921 were anti HCV antibody positive)had elevated blood neopterin levels compared to patientswith siderosis of the liver [45] Alanine aminotransferaselevels in HCV infected persons correlated significantly withneopterin levels Serum neopterin levels were found tobe a useful predictor of response to treatment of chronicHCV infection with pegylated interferon combined withribavirin Neopterin concentrations were evaluated in 260HCV patients treated by pegylated interferon combined with

ribavirin Mean and median pretreatment neopterin con-centrations were lower in patients with sustained virologicalresponse than in nonresponders The rate of response wastwofold higher among patients with pretreatment neopterinlevels lt16 nmolL than in patients with neopterin levelsge16 nmolL even after controlling for HCV genotype status[38]

A recent study investigated specifically whether serumneopterin levels can discriminate between patients withreplicative (119899 = 30) and nonreplicative (119899 = 25) HBVcarriage [46] Replicative HBV carriage was defined as HBVDNA gt5 pgmL by hybrid capture system Neopterin levelshad a mean of 145 nmolL in replicative versus 88 nmolLin nonreplicative HBV carriers (119875 lt 005) This resultwas not reproducible in another study which found thatin patients with replicative HBV infection (119899 = 30) meanserumneopterin level was 2473 nmolL and in nonreplicativeHBV (119899 = 30) 148 nmolL a difference which was notstatistically significant [47] This may have been due tolarge standard deviations and small numbers in groups Amore recent investigation found that in chronic hepatitis themean plusmn SD serum neopterin levels were 142 plusmn 56 nmolL203 plusmn 79 nmolL in patients with liver cirrhosis and 52 plusmn14 nmolL in the control group Serum neopterin levelswere significantly higher in patients with chronic hepatitis(119875 = 0005) and cirrhosis patients (119875 = 0008) than incontrol subjects Cirrhotic patients had significantly higherserum neopterin levels than patients with chronic hepatitis(119875 = 0004) There was a positive correlation betweenserum neopterin levels and alanine aminotransferase levelsin patients with chronic hepatitis (119903 = 041 119875 = 0004)and cirrhotic patients (119903 = 039 119875 = 0005) Positivecorrelations were detected between serum neopterin levelsand inflammatory score in patients with chronic hepatitis(119903 = 051 119875 = 0003) and cirrhotic patients (119903 = 049119875 = 0001) [48]

25 Viral Respiratory Tract Infections Neopterin has beeninvestigated as a marker to distinguish viral from bacterial


lower respiratory tract infections The investigators foundthat serum neopterin levels were elevated (gt10 nmolL) in96 of patients with viral LRTIThemedian serumneopterinconcentration was almost 2-fold higher in the viral LRTIgroup than bacterial LRTI patients (305 versus 187 nmolL)and 5-fold higher than those in healthy controls The speci-ficity for correct identification of viral LRTI was 695 for acut-off of gt15 nmolL [49]

Serial monitoring of serum neopterin levels in patientswith severe acute respiratory syndrome (SARS) associatedvirus revealed that all (119899 = 129) investigated patients hadelevated neopterin levels by day 9 [50] Duration of pyrexiain SARS patients correlated positively with neopterin levelsPatients on steroid therapy had significantly lower neopterinlevels Measurement of neopterin in isolation and in rela-tionship to other inflammatory markers like procalcitoninand C-reactive protein were investigated for discrimina-tory power between viral and bacterial lower respiratorytract infections Investigators used the CRPneopterin ratio(CN ratio) to discriminate viral and bacterial etiology ofrespiratory tract infections In a study conducted in HongKong sera obtained on the day of hospitalization for LRTIfrom 139 patients with confirmed bacterial etiology and 128patients with viral etiology were examined A further 146sera from healthy Chinese subjects with no infection wereincluded as controls The area under the receiver operatingcharacteristic (ROC) curve (area under curve [AUC]) fordistinguishing bacterial from viral infections was 0838 forCRP and 0770 for PCT The AUC for distinguishing viralfrom bacterial infections was 0832 for neopterin When themarkers were used in combination AUC of ROC of theCN ratio was 0857 whereas (CRP times PCT)neopterin was0856 [49] In a subsequently reported study the median ofthe CN ratio was 10 times higher in patients with bacterialaetiology than with viral aetiology (125 versus 12mgnmol119875 lt 00001) and 42 times higher than those in healthysubjects (125 versus 03mgnmol 119875 lt 00001) The areaunder the receiver operator characteristic curve for the CNratio was 0840 A cut-off value of ldquoCN ratio gt3rdquo for rulinginout bacterialviral infection yielded optimal sensitivity andspecificity of 795 and 815 respectively [51]

26 Viral Central Nervous System Infections Early studiesshowed elevated neopterin levels in cerebrospinal fluid (CSF)of patients with aseptic meningitis and herpes simplexand measles virus encephalomyelitis [52ndash54] CSF levels ofneopterin seem to reflect intrathecal production bymicrogliaas pterins have a low permeability across the blood brainbarrier with a serum-to-CSF distribution at a quotient of140 [55] It has recently been established that normal CSFneopterin is brain-derived The interindividual variation ofCSF neopterin in healthy adults was found not to dependon serum neopterin concentration variation (coefficient ofvariation CV-CSF = 97 lt CV-serum = 245) Addi-tionally individual normal CSF neopterin concentrationswere found to be invariant to the variation of the albuminquotient QAlb that is CSF neopterin does not derivefrom leptomeninges [56] Patients with viral meningitis hadelevated CSF neopterin levels compared to healthy controls

but normal serum levels [54] CSF neopterin levels corre-lated hereby with CSF monocytic cell count Patients withvarious forms of encephalitis including those caused byherpes simplex virus varicella zoster virus and tick borneencephalitis virus had significantly elevated CSF neopterinlevels compared to controls and higher levels than in patientswith viral meningitis without overlap of levels in the twoconditions In HIV infection there was a clear relationshipbetween the severity of AIDS-related dementia and CSFneopterin levels [12 30ndash32] Higher CSFHIV viral loads wereassociated with higher CSF neopterin levels [33]

After commencement of combination antiretroviral ther-apy (ART) CSF neopterin decreased markedly but remainedslightly above normal levels in a substantial number ofpatients despite several years of receiving ART [32 34ndash36] Even patients with systemic virological failure exhibita substantial reduction of CSF neopterin concentrationsthough above that of virologically suppressed patients [37]In patients on combination ART the lowest CSF neopterinlevels have been found in patients with the lowest CSF viralloads (lt25 copiesmL) [32] No significant difference in CSFneopterin concentrations was found between those treatedwith protease inhibitor- and nonnucleoside reverse transcrip-tase based regimens in combination with 2 nucleoside ana-logues [57]This would support the idea that viral replicationwithin or close to the CSF at least to some extent is partlydriving the inflammatory response It has also been suggestedthat an inflammatory response once triggered may lead to aself-sustaining state of cellular activation as has been seen inpatients with herpes simplex virus type-1 encephalitis [58]Findings in this study are consistent with these reports HIVRNA levels measured in CSF or plasma were not significantlyassociated with CSF neopterin trajectories In addition allstudy participants had experienced virologic control to thelimit of standard detection as a result of their treatment andCSF neopterin levels were the only factor strongly associatedwith subsequent decay rates and the ultimate set-point levels[32]

3 Neopterin Levels in Bacterial Infections

Patients with bacterial infections with species other thanmycobacteria showed significantly lower urinary neopterinlevels compared to patients with viral infections in one study[59] but no statistically significant difference in a more recentstudy [60] Within the group of bacterial infections it wasshown that patients with symptoms for at least 5 days hadsignificantly higher neopterin concentrations than patientswith acute illness This applied particularly to bacterialpneumonia Patients with urinary tract infections were foundto have similar levels to patients with viral infections withdata on urinary neopterin concentrations but not serumconcentrations Thus it remains unclear whether local pro-duction of neopterin takes place in urinary tract infectionsand serumneopterin would stay lowThere was no significantdifference in neopterin levels between patients with febrileneutropenia and underlying haematological and oncologicalconditions and gram-negative versus gram-positive infec-tions [61] In patients on an intensive care unit with sepsis


and septic shock urinary neopterincreatinine ratios werefound to be significantly higher compared to patients withother forms of systemic inflammatory responses syndromes[62] and serum neopterin levels were higher in nonsurvivorscompared to survivors of sepsis andmultiorgan failure scorescorrelated with neopterin levels [63ndash66] In this context itwas however noted that neopterin levels correlated negativelywith reduced renal function reflecting renal failure causing areduced excretion of neopterin Future studies could correctfor reduced excretion due to reduced renal function bycalculation of the serum neopterincreatinine ratio

Investigations on critically ill patients on intensive careunits evaluated neopterin levels as tool to discriminatepatientswith systemic inflammatory response syndromewithand without infectious etiology Neopterin levels were foundto have a specificity of 78 for discriminating infectious andnoninfectious etiology of critical illness [66]

Bacterial meningitis was associated with both elevatedserum and CSF neopterin levels compared to controls [55]In Lyme neuroborreliosismdasha late complication of infec-tion by the tick-born spirochete Borrelia burgdorferimdashhighneopterin concentrations were found in CSF of patientswhereas serumneopterin levels were notmarkedly increasedconfirming intrathecal neopterin production [67] Infectionwith Treponema pallidum subsp pallidum (syphilis) was notassociated with elevated neopterin levels [18] In melioidosisby Pseudomonas pseudomallei neopterin concentrations werefound to be significantly higher than controls [12]

In brucellosis neopterin levels were with a mean525mmolmL significantly higher than healthy controls andpatientswith tuberculosis [68] In leprosy caused byMycobac-terium leprae 75 of patients with tuberculoid and lepro-matous leprosy presented with elevated urinary neopterinexcretion [69]

31 Neopterin Levels in the Course of Mycobacterium tubercu-losis Infection On the basis of in vitro and in vivo data show-ing that macrophages release neopterin in response to stimu-lation by T-lymphocytes [70 71] Fuchs et al [39] investigatedurinary neopterin levels by HPLC in 55 patients with cultureconfirmed pulmonary tuberculosis and compared them with417 normal controls 83 of patients had levels above theupper tolerance limit (containing with 95 probability 975of healthy controls) Neopterin levels were higher than ageand gender matched controls for every extent of pulmonarydisease and correlated with its extent The correlation withextent of pulmonary tuberculosis was also demonstrated forserum levels and levels found in bronchioalveolar lavage fluid[72] Subsequent studies showed higher levels of neopterinin serum and pleural effusions of patients with pulmonarytuberculosis compared to controls [73 74] Peripheral bloodmononuclear cells (PBMNC) from tuberculosis patientsshowed a significantly higher spontaneous production ofneopterin Stimulationwith phytohaemagglutinin or purifiedprotein derivative did not yield higher neopterin productionin PBMNC of patients with tuberculosis showing that it is notthe production capacity for neopterin which is different [74]

Elevated serum neopterin levels were also found inHIV infected patients with tuberculosis and decreased

significantly on antituberculous treatment [40] A relapseof tuberculosis was in 2 cases characterized by increase inneopterin levels

Further studies compared neopterin levels in urineserum and bronchoalveolar lavage fluid and found that theycorrelate significantly in patients with tuberculosis [72 75]The elevation of neopterin in patients with tuberculosis wasmore pronounced in urine than in serum or bronchoalveolarlavage [75]

32 Differentiating Pulmonary Tuberculosis from Other LungDiseases Patients with pulmonary tuberculosis had signifi-cantly higher urinary neopterin levels compared to patientswith lung cancer or pneumonia with more than twice theconcentration reported in adults [74] Pleural fluid neopterinlevels were investigated for its ability to differentiate betweentuberculous and malignant pleural effusion and were foundto be significantly higher in patients with pleural tuberculosisbut performance characteristics including receiver-operatingcharacteristics curve analysiswas inferior to adenosine deam-inase [76]

33Monitoring Response toAntituberculous Treatment Wait-ing for the results of susceptibility tests to select an effectiveantituberculosis drug regimen often causes a delay in effectivetreatment which can be disastrous especially in childrenBecause the X-ray changes tend to resolve very slowly andmay get even worse after starting therapy because of aparadoxical reaction due to immune-reconstitution even inotherwise immune-competent patients other than clinicalstatus there is no reliable parameter to reflect success orfailure of the drug regimen [77]

Urinary neopterin levels declined on twice weekly mea-surements in all monitored patients with pulmonary tuber-culosis on treatment and fell to below tolerance limits within10 weeks of treatment in 610 patients [39] Measurement ofserum neopterin levels in patients on treatment for microbi-ologically confirmed pulmonary tuberculosis confirmed thisobservation and showed a significant decline of levels to nearnormal levels within 6 months of treatment [41] In the con-text of emerging multiple drug resistance and difficulties inmonitoring compliance and drug absorption neopterin needsto be explored as a tool formonitoring of success in treatmentof Mycobacterium tuberculosis infection It may also help todistinguish active from latent disease People with HIV-mtuberculosis coinfection with active tuberculosis respondedwith a reduction of plasma neopterin to antituberculotictreatment but neopterin levels remained above the baselinelevels of HIV negative tuberculosis patients and levels werehigher in patients with lower CD4 count [78]

4 Significance of Neopterin inParasitic Infections

The first study of neopterin levels in parasitic infectionsincluded measurements of urinary neopterin by HPLC inpatients with Plasmodium falciparum and vivax infectionsincluding patients with low grade parasitemia [7] All patients


had elevated urinary neopterin levels compared to uninfectedcontrols to a level of 664 to 5189micromol neopterinmol cre-atinine Levels in patients treated with quinine sulphate andlevels in untreated patients were not significantly different

A subsequent detailed interventional study provided dataon urinary neopterin levels in volunteers experimentallyinfected with Plasmodium falciparum [79] Serial monitoringrevealed that urinary neopterin levels were not elevated untilperipheral blood parasite densities had increased through 3 to4 cycles of intraerythrocytic schizogony A sharp rise in uri-nary neopterin was detectable at the beginning of day 14 afterinfection There was an increase one day after onset of feverIn one patient a urinary neopterin increasewas notedwithoutthe occurrence of fever Neopterin production in falciparummalaria seems to be a direct effect of plasmodial antigenson monocytesmacrophages In vitro studies showed that themonocytic cell line U937 could be stimulated to produceneopterin with lysates of Plasmodium falciparum parasitizedhuman erythrocytes and recombinant P falciparum proteins[80] At a cut-off point of 100 ngmL neopterin had a positiveand negative predictive value of 038 and 098 for detectionof severe falciparum malaria [81] Chloroquine treatmentwas followed by a reduction of urinary neopterin levelsWhen clinical disease resolved within 3ndash7 days of treatmentneopterin levels normalized rapidly [42] Neopterin levels innonimmune patients and young children were higher thanwere those of semiimmune individuals

CSF (CSF) neopterin levels were investigated for abilityto discriminate between different stages of cerebral Try-panosoma (T) brucei (b) gambiense infection

In an investigation of 512 T b gambiense patients origi-nating from Angola Chad and the Democratic Republic ofthe Congo CSF IgM and neopterin were the best in discrim-inating between the two stages (S1 and S2) of disease with864 and 841 specificity respectively at 100 sensitivityWhen a validation cohort (412 patients) was tested neopterin(143 nmolL) correctly classified 88 of S1 and S2 patientsconfirming its high staging power [82] Serum neopterinwas also assessed as a disease marker in human Schistosomamansoni infection and levels were found to reflect the extentof hepatic involvement with higher levels found in patientswith hepatomegaly Treatment with praziquantel led to anormalisation of serum neopterin levels as a result of areduction of egg induced immunopathology [43 44 83]

5 Application of Measurement of Neopterin inScreening of Blood Products for Infections

The detection of new blood borne viruses including HIV andnon-A non-B hepatitis viruses led to investigations into newways of excluding transmission of blood borne viruses bytransfusion of blood products The government of Tirol inAustria introduced routine measurement of neopterin levelsin all donated blood in 1986

A cut-off of 10 nmolL was used and led to the exclusionof 16 of donors (total number of donors = 76587) Themost common cause of elevated levels was in 123 (67)of cases a viral respiratory tract infection 6 donors with

elevated neopterin had an acute toxoplasmosis and 4 hadHIVinfection or non-A-non B-hepatitis [84] In another study526 of 1767 donations with increased neopterin levels werepositive for CMV IgM indicating acute infection 03 ofpatients with low neopterin levels had CMV IgM Serocon-version was detected in 10 patients with initially elevatedneopterin levels on a second serum sample indicating thatneopterin may precede the appearance of CMV antibodiesby 2ndash4 weeks [85] A further study of Austrian blood donorsshowed that neopterin levels were significantly higher in earlycompared to late infection or carrier state All early infections(seroconversions) had elevated neopterin levels while only17 of late and carrier states [86] A recent study found thatusing a neopterin ELISA 61 of CMVDNA-positive sampleshad elevated neopterin levels [87]

With regard to other viruses 55 of donors with abovenormal neopterin had Epstein-Barr virus IgM generatingan almost threefold greater chance of acute EBV infectionin donors with increased neopterin (odds ratio 285 (95confidence interval 15ndash56) With regard to parvovirus B19infection 731060 (69) donors were found to be seroposi-tive for parvovirus B19 IgM [88] A later study by the samegroup found no HPV DNA positive results amongst 1200patients with normal neopterin levels [89]

An investigation of the association of neopterin levelswith chronic hepatitis C virus infection revealed that signifi-cantly more patients with elevated neopterin levels and HCVantibodies were HCV PCR positive for HCV RNA (oddsratio 376 119875 = 0002) [90]

6 Conclusions

Neopterin is a nonspecific marker of activated cell mediatedimmunity involving release of interferon gamma Neopterinmay be a useful marker for more accurate estimation ofextent of disease and hence prognosis Knowledge of allpotential causes of its elevation can overcome problems withreduced specificity in a patient known to have a specificinfectious disease Longitudinal serial measurements in thesame individual could overcome difficulties with interpreta-tion in settings where chronic parasitic (malaria) or bacterial(tuberculosis) infections may elevate the baseline neopterinlevel and could allowmonitoring of response to antiretroviralantituberculous and antiparasitic treatment in the absence ofresistance testing and provide means to monitor compliancein the outpatient setting (see Table 1) This is particularlyimportant in the current context of emerging multiple drugresistance of HIV and mycobacterium tuberculosis

Neopterin for which high quality ELISA systems tomeasure urine and blood levels are commercially available isan underused marker in clinical practice and is suitable forintroduction into the routine clinical laboratory practice

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper


References

[1] HWachter D Fuchs A Hausen et alNeopterin BiochemistryMethods Clinical Application De Gruyter Berlin Germany1991

[2] A Berdowska and K Zwirska-Korczala ldquoNeopterin measure-ment in clinical diagnosisrdquo Journal of Clinical Pharmacy andTherapeutics vol 26 no 5 pp 319ndash329 2001

[3] G Hoffmann B Wirleitner and D Fuchs ldquoPotential role ofimmune system activation-associated production of neopterinderivatives in humansrdquo Inflammation Research vol 52 no 8pp 313ndash321 2003

[4] A Huang Y Y Zhang K Chen K Hatakeyama and J FKeaney Jr ldquoCytokine-stimulated GTP cyclohydrolase I expres-sion in endothelial cells requires coordinated activation ofnuclear factor-120581b and Stat1Stat3rdquo Circulation Research vol 96no 2 pp 164ndash171 2005

[5] S Buhrer-Sekula F F VHamerlinck TAOut LG Bordewijkand P R Klatser ldquoSimple dipstick assay for semi-quantitativedetection of neopterin in serardquo Journal of Immunological Meth-ods vol 238 no 1-2 pp 55ndash58 2000

[6] H Wachter A Hausen and K Grassmayr ldquoErhoehte Auss-cheidung von Neopterin im Harn von Patienten mit malig-nen Tumoren und mit Viruserkrankungenrdquo Hoppe-SeylerrsquosZeitschrift fur physiologische Chemie vol 360 pp 1957ndash19601979

[7] G Reibnegger V Boonpucknavig D Fuchs A Hausen ESchmutzhard and H Wachter ldquoUrinary neopterin is elevatedin patients with malariardquo Transactions of the Royal Society ofTropical Medicine and Hygiene vol 78 no 4 pp 545ndash546 1984

[8] H Tilg R Margreiter M Scriba et al ldquoClinical presentationof CMV infection in solid organ transplant recipients and itsimpact on graft rejection and neopterin excretionrdquo ClinicalTransplantation vol 1 pp 37ndash43 1987

[9] G Reibnegger I Auhuber D Fuchs et al ldquoUrinary neopterinlevels in acute viral hepatitisrdquoHepatology vol 8 no 4 pp 771ndash774 1988

[10] D E Griffin B J Ward E Juaregui R T Johnson andA Vaisberg ldquoImmune activation during measles beta 2-microglobulin in plasma and cerebrospinal fluid in complicatedand uncomplicated diseaserdquo Journal of Infectious Diseases vol166 no 5 pp 1170ndash1173 1992

[11] D ZaknunGWeiss J GlatzlHWachter andD Fuchs ldquoNeop-terin levels during acute rubella in childrenrdquo Clinical InfectiousDiseases vol 17 no 3 pp 521ndash522 1993

[12] D Fuchs G Weiss G Reibnegger and H Wachter ldquoTherole of neopterin as a monitor of cellular immune activationin transplantation inflammatory infectious and malignantdiseasesrdquo Critical Reviews in Clinical Laboratory Sciences vol29 no 3-4 pp 307ndash341 1992

[13] G Reibnegger D Fuchs G Grubauer A Hausen and HWachter ldquoNeopterin excretion during incubation period Clin-ical manifestation and reconvalescence of viral infectionrdquo inBiochemical and Clinical Aspects of Pteridines W PfleidererH Wachter and H C Curtius Eds pp 433ndash447 Walter deGruyter New York NY USA 1984

[14] C P Y Chan J W Y Choi K Y Cao et al ldquoDetection ofserumneopterin for early assessment of dengue virus infectionrdquoJournal of Infection vol 53 no 3 pp 152ndash158 2006

[15] K Babb C V F Carrington andM A Monteil ldquoA preliminarystudy of neopterin as a potential marker for severe dengue virus

infectionrdquo Transactions of the Royal Society of Tropical Medicineand Hygiene vol 93 no 4 pp 447ndash448 1999

[16] O Bratslavska D Platace E Miklasevics D Fuchs and M AMartinsons ldquoInfluence of neopterin and 78-dihydroneopterinon the replication ofCoxsackie type B5 and influenzaA virusesrdquoMedicalMicrobiology and Immunology vol 196 no 1 pp 23ndash292007

[17] C M Nubling M Chudy P Volkers and J Lower ldquoNeopterinlevels during the early phase of human immunodeficiency virushepatitis C virus or hepatitis B virus infectionrdquoTransfusion vol46 no 11 pp 1886ndash1891 2006

[18] P T NrsquoGom ldquoImmune stimulation by syphilis and malaria inHIV-2-infected and uninfected villagers in West Africardquo TheBritish Journal of Biomedical Science vol 54 no 4 pp 251ndash2551997

[19] C M Tsoukas and N F Bernard ldquoMarkers predicting pro-gression of human immunodeficiency virus-related diseaserdquoClinical Microbiology Reviews vol 7 no 1 pp 14ndash28 1994

[20] J L Fahey J M G Taylor B Manna et al ldquoPrognosticsignificance of plasmamarkers of immune activation HIV viralload and CD4 T-cell measurementsrdquo AIDS vol 12 no 13 pp1581ndash1590 1998

[21] S Plaeger H Z Bass P Nishanian et al ldquoThe prognosticsignificance in HIV infection of immune activation representedby cell surface antigen and plasma activation marker changesrdquoClinical Immunology vol 90 no 2 pp 238ndash246 1999

[22] N Amirayan-Chevillard H Tissot-Dupont Y Obadia HGallais J L Mege and C Capo ldquoHighly active antiretroviraltherapy (HAART) and circulating markers of immune acti-vation specific effect of HAART on neopterinrdquo Clinical andDiagnostic Laboratory Immunology vol 7 no 5 pp 832ndash8342000

[23] R N Melmed J M G Taylor R Detels M Bozorgmehri andJ L Fahey ldquoSerum neopterin changes in HIV-infected subjectsindicator of significant pathology CD4 T cell changes and thedevelopment of AIDSrdquo Journal of Acquired Immune DeficiencySyndromes vol 2 no 1 pp 70ndash76 1989

[24] J F Salazar-Gonzalez O Martinez-Maza P Nishanian et alldquoIncreased immune activation precedes the inflection point ofCD4 T cells and the increased serum virus load in humanimmunodeficiency virus infectionrdquo Journal of Infectious Dis-eases vol 178 no 2 pp 423ndash430 1998

[25] D S Stein R H Lyles N M H Graham et al ldquoPredictingclinical progression or death in subjects with early-stage humanimmunodeficiency virus (HIV) infection a comparative analy-sis of quantification of HIV RNA soluble tumor necrosis factortype II receptors neopterin and 120573

2-microglobulinrdquo Journal of

Infectious Diseases vol 176 no 5 pp 1161ndash1167 1997[26] N Sacktor X Liu M Popescu K Marder Y Stern and R

Mayeux ldquoSerum neopterin level predicts HIV-relatedmortalitybut not progression to AIDS or development of neurologicaldisease in gay men and parenteral drug usersrdquo Archives ofNeurology vol 52 no 7 pp 676ndash679 1995

[27] S Nyamweya J Townend A Zaman et al ldquoAre plasmabiomarkers of immune activation predictive of HIV progres-sion a longitudinal comparison and analyses inHIV-1 andHIV-2 infectionsrdquo PLoS ONE vol 7 no 9 Article ID e44411 2012

[28] C Martınez-Bru M Cortes T Planella et al ldquo1205732-microglob-

ulin and immunoglobulins are more useful markers of diseaseprogression in HIV than neopterin and adenosine deaminaserdquoAnnals of Clinical Biochemistry vol 36 pp 5601ndash608 1999


[29] V Daniel C Susal A Melk et al ldquoReduction of viral load andimmune complex load on CD4+ lymphocytes as a consequenceof highly active antiretroviral treatment (HAART) in HIV-infected hemophilia patientsrdquo Immunology Letters vol 69 no2 pp 283ndash289 1999

[30] D Fuchs F Chiodi J Albert et al ldquoNeopterin concentrationsin cerebrospinal fluid and serum of individuals infected withHIV-1rdquo AIDS vol 3 no 5 pp 285ndash288 1989

[31] B J Brew L Pemberton P Cunningham and M G LawldquoLevels of human immunodeficiency virus type 1 RNA incerebrospinal fluid correlate withAIDS dementia stagerdquo Journalof Infectious Diseases vol 175 no 4 pp 963ndash966 1997

[32] A Yilmaz C T Yiannoutsos D Fuchs et al ldquoCSF neopterindecay characteristics after initiation of antiretroviral therapyrdquoJournal of Neuroinflammation vol 10 article 62 2013

[33] S Spudich M Gisslen L Hagberg et al ldquoCentral nervous sys-tem immune activation characterizes primary human immun-odeficiency virus 1 infection even in participants with minimalcerebrospinal fluid viral burdenrdquo Journal of Infectious Diseasesvol 204 no 5 pp 753ndash760 2011

[34] S Abdulle L Hagberg B Svennerholm D Fuchs and MGisslen ldquoContinuing intrathecal immunoactivation despite twoyears of effective antiretroviral therapy against HIV-1 infectionrdquoAIDS vol 16 no 16 pp 2145ndash2149 2002

[35] L Hagberg P Cinque M Gisslen et al ldquoCerebrospinal fluidneopterin an informative biomarker of central nervous systemimmune activation in HIV-1 infectionrdquo AIDS Research andTherapy vol 7 article 15 2010

[36] A Eden R W Price S Spudich D Fuchs L Hagberg and MGisslen ldquoImmune activation of the central nervous system isstill present aftergt4 years of effective highly active antiretroviraltherapyrdquo Journal of Infectious Diseases vol 196 no 12 pp 1779ndash1783 2007

[37] S Spudich N Lollo T Liegler S G Deeks and R W PriceldquoTreatment benefit on cerebrospinal fluid HIV-1 levels in thesetting of systemic virological suppression and failurerdquo Journalof Infectious Diseases vol 194 no 12 pp 1686ndash1696 2006

[38] G F Oxenkrug P J Requintina D L Mikolich et alldquoNeopterin as a marker of response to antiviral therapy inhepatitis C virus patientsrdquo Hepatitis Research and Treatmentvol 2012 Article ID 619609 4 pages 2012

[39] D Fuchs A Hausen M Kofler H Kosanowski G Reibneggerand H Wachter ldquoNeopterin as an index of immune responsein patients with tuberculosisrdquo Lung vol 162 no 6 pp 337ndash3461984

[40] M Hosp A M Elliott J G Raynes et al ldquoNeopterin 1205732-

microglobulin and acute phase proteins in HIV-1-seropositiveand -seronegative Zambian patients with tuberculosisrdquo Lungvol 175 no 4 pp 265ndash275 1997

[41] T Turgut H Akbulut F Deveci C Kacar and M H MuzldquoSerum interleukin-2 and neopterin levels as useful markers fortreatment of active pulmonary tuberculosisrdquo Tohoku Journal ofExperimental Medicine vol 209 no 4 pp 321ndash328 2006

[42] H Wachter D Fuchs A Hausen G Reibnegger and E RWerner ldquoNeopterin as marker for activation of cellular immu-nity immunologic basis and clinical applicationrdquo Advances inClinical Chemistry vol 27 pp 81ndash141 1989

[43] K Zwingenberger G Harms H Feldmeier O Muller ASteiner andU Bienzle ldquoLiver involvement in human schistoso-miasis mansoni Regression of immunological and biochemicaldisease markers after specific treatmentrdquo Acta Tropica vol 45no 3 pp 263ndash275 1988

[44] K Zwingenberger J Richter J G S Vergetti and H FeldmeierldquoPraziquantel in the treatment of hepatosplenic schistosomiasisbiochemical disease markers indicate deceleration of fibrogen-esis and diminution of portal flow obstructionrdquo Transactions ofthe Royal Society of Tropical Medicine and Hygiene vol 84 no2 pp 252ndash256 1990

[45] S Leonardi E Avola A Sciacca F Di Gregorio and SMusumeci ldquoNeopterin as a marker of C hepatitis in tha-lassaemia majorrdquo Journal of Pediatric Gastroenterology andNutrition vol 12 no 3 pp 315ndash318 1991

[46] I Kaleli M Demir N Cevahir M Yilmaz and S DemirldquoSerum neopterin levels in patients with replicative and non-replicativeHBV carriersrdquoBMC Infectious Diseases vol 6 article157 2006

[47] N Demirturk T Demirdal O C Aktepe N Aykin S Orhanand F Cevik ldquoSerum neopterin levels in patients with HBVinfection at various stagesrdquo Hepato-Gastroenterology vol 54no 75 pp 903ndash905 2007

[48] E M Gulcan I Tirit A Anil E Adal and G Ozbay ldquoSerumneopterin levels in children with hepatitis-B-related chronicliver disease and its relationship to disease severityrdquo WorldJournal of Gastroenterology vol 14 no 44 pp 6840ndash6843 2008

[49] M Ip T H Rainer N Lee et al ldquoValue of serum procalcitoninneopterin and C-reactive protein in differentiating bacterialfrom viral etiologies in patients presenting with lower respi-ratory tract infectionsrdquo Diagnostic Microbiology and InfectiousDisease vol 59 no 2 pp 131ndash136 2007

[50] B Zheng K Y Cao C P Y Chan et al ldquoSerum neopterinfor early assessment of severity of severe acute respiratorysyndromerdquo Clinical Immunology vol 116 no 1 pp 18ndash26 2005

[51] T H Rainer C P Y Chan M F Leung et al ldquoDiagnostic utilityof CRP to neopterin ratio in patients with acute respiratory tractinfectionsrdquo Journal of Infection vol 58 no 2 pp 123ndash130 2009

[52] S Fredrikson P Eneroth and H Link ldquoIntrathecal productionof neopterin in aseptic meningo-encephalitis and multiplesclerosisrdquo Clinical and Experimental Immunology vol 67 no 1pp 76ndash81 1987

[53] D E Griffin B J Ward E Jauregui R T Johnson and AVaisberg ldquoImmune activation duringmeasles interferon-120574 andneopterin in plasma and cerebrospinal fluid in complicated anduncomplicated diseaserdquo Journal of Infectious Diseases vol 161no 3 pp 449ndash453 1990

[54] M Bociąga-Jasik A Ciesla A Kalinowska-Nowak P SkwaraA Garlicki and T Mach ldquoRole of IL-6 and neopterin in thepathogenesis of herpetic encephalitisrdquoPharmacological Reportsvol 63 no 5 pp 1203ndash1209 2011

[55] L Hagberg L Dotevall G Norkrans M Larsson H Wachterand D Fuchs ldquoCerebrospinal fluid neopterin concentrations incentral nervous system infectionrdquo Journal of Infectious Diseasesvol 168 no 5 pp 1285ndash1288 1993

[56] L K Kuehne H Reiber K Bechter L Hagberg and DFuchs ldquoCerebrospinal fluid neopterin is brain-derived andnot associated with blood-CSF barrier dysfunction in non-inflammatory affective and schizophrenic spectrum disordersrdquoJournal of Psychiatric Research vol 47 no 10 pp 1417ndash14222013

[57] A Yilmaz R W Price S Spudich D Fuchs L Hagbergand M Gisslen ldquoPersistent intrathecal immune activation inHIV-1-infected individuals on antiretroviral therapyrdquo Journal ofAcquired Immune Deficiency Syndromes vol 47 no 2 pp 168ndash173 2008


[58] E Aurelius M Forsgren B Skoldenberg and O StrannegardldquoPersistent intrathecal immune activation in patients withherpes simplex encephalitisrdquo Journal of Infectious Diseases vol168 no 5 pp 1248ndash1252 1993

[59] H Denz D Fuchs A Hausen et al ldquoValue of urinary neopterinin the differential diagnosis of bacterial and viral infectionsrdquoKlinische Wochenschrift vol 68 no 4 pp 218ndash222 1990

[60] B Pourakbari S Mamishi J Zafari et al ldquoEvaluation of pro-calcitonin and neopterin level in serum of patients with acutebacterial infectionrdquo Brazilian Journal of Infectious Diseases vol14 no 3 pp 252ndash255 2010

[61] C Prat J M Sancho J Dominguez et al ldquoEvaluation ofprocalcitonin neopterin C-reactive protein IL-6 and IL-8as a diagnostic marker of infection in patients with febrileneutropeniardquo Leukemia and Lymphoma vol 49 no 9 pp 1752ndash1761 2008

[62] T BaydarO Yuksel T T Sahin et al ldquoNeopterin as a prognosticbiomarker in intensive care unit patientsrdquo Journal of CriticalCare vol 24 no 3 pp 318ndash321 2009

[63] N T Fisgin Y Aliyazicioglu E Tanyel et al ldquoThe value ofneopterin and procalcitonin in patients with sepsisrdquo SouthernMedical Journal vol 103 no 3 pp 216ndash219 2010

[64] W Strohmaier H Redl G Schlag and D Inthorn ldquoD-erythro-neopterin plasma levels in intensive care patients with andwithout septic complicationsrdquo Critical Care Medicine vol 15no 8 pp 757ndash760 1987

[65] B Robin D Fuchs W Koller and H Wachter ldquoCourse ofimmune activation markers in patients after severe multipletraumardquo Pteridines vol 2 no 2 pp 95ndash97 1990

[66] E Ruokonen L Ilkka M Niskanen and J Takala ldquoProcalci-tonin and neopterin as indicators of infection in critically illpatientsrdquoActa Anaesthesiologica Scandinavica vol 46 no 4 pp398ndash404 2002

[67] T Gasse C Murr P Meyersbach E Schmutzhard HWachter and D Fuchs ldquoNeopterin production and tryptophandegradation in acute lyme neuroborreliosis versus late lymeencephalopathyrdquo European Journal of Clinical Chemistry andClinical Biochemistry vol 32 no 9 pp 685ndash689 1994

[68] G Cakan F B Bezirci A Kacka et al ldquoAssessment of diag-nostic enzyme-linked immunosorbent assay kit and serologicalmarkers in human brucellosisrdquo Japanese Journal of InfectiousDiseases vol 61 no 5 pp 366ndash370 2008

[69] E Schmutzhard D Fuchs A Hausen G Reibnegger and HWachter ldquoIs neopterinmdasha marker of cell mediated immuneresponse helpful in classifying leprosyrdquo East African MedicalJournal vol 63 no 9 pp 577ndash580 1986

[70] C Huber J R Batchelor D Fuchs et al ldquoImmune response-associated production of neopterin Release from macrophagesprimarily under control of interferon-120574rdquo Journal of Experimen-tal Medicine vol 160 no 1 pp 310ndash316 1984

[71] R Margreiter D Fuchs A Hausen et al ldquoNeopterin as anew biochemical marker for diagnosis of allograft rejectionExperience based upon evaluation of 100 consecutive casesrdquoTransplantation vol 36 no 6 pp 650ndash653 1983

[72] K H Mohamed A A M T Mobasher A R I Yousef et alldquoBAL neopterin A novel marker for cell-mediated immunity inpatients with pulmonary tuberculosis and lung cancerrdquo Chestvol 119 no 3 pp 776ndash780 2001

[73] M F Baganha AMota-PintoM A PegoM A TMarquesMA S Rosa and A J A R Cordeiro ldquoNeopterin in tuberculousand neoplastic pleural fluidsrdquo Lung vol 170 no 3 pp 155ndash1611992

[74] C Immanuel R Swamy M Kannapiran et al ldquoNeopterin as amarker for cell-mediated immunity in patients with pulmonarytuberculosisrdquo International Journal of Tuberculosis and LungDisease vol 1 no 2 pp 175ndash180 1997

[75] I Yuksekol M Ozkan O Akgul et al ldquoUrinary neopterinmea-surement as a non-invasive diagnostic method in pulmonarytuberculosisrdquo International Journal of Tuberculosis and LungDisease vol 7 no 8 pp 771ndash776 2003

[76] G Cok Z Parildar G Basol et al ldquoPleural fluid neopterin levelsin tuberculous pleurisyrdquo Clinical Biochemistry vol 40 no 12pp 876ndash880 2007

[77] E Horak I Gassner B Solder H Wachter and D FuchsldquoNeopterin levels and pulmonary tuberculosis in infantsrdquo Lungvol 176 no 5 pp 337ndash344 1998

[78] L E Hanna K Nayak S Subramanyam P Venkatesan P RNarayanan and S Swaminathan ldquoIncomplete immunologicalrecovery following anti-tuberculosis treatment in HIV-infectedindividuals with active tuberculosisrdquo Indian Journal of MedicalResearch vol 129 no 5 pp 548ndash554 2009

[79] A E Brown D A Herrington H K Webster et al ldquoUrinaryneopterin in volunteers experimentally infected with Plasmod-ium falciparumrdquo Transactions of the Royal Society of TropicalMedicine and Hygiene vol 86 no 2 pp 134ndash136 1992

[80] C A Facer ldquoMalaria antigene stimulate neopterin secretion byPBMC and U937 celtsrdquo Microbiology and Immunology vol 39no 3 pp 207ndash211 1995

[81] R Te Witt M E van Wolfswinkel P L Petit et al ldquoNeopterinand procalcitonin are suitable biomarkers for exclusion ofsevere Plasmodium falciparum disease at the initial clinicalassessment of travellers with imported malariardquo Malaria Jour-nal vol 9 no 1 article 255 2010

[82] N Tiberti A Hainard V Lejon et al ldquoCSF neopterin asmarker of the meningo-encephalitic stage of Trypanosomabrucei gambiense sleeping sicknessrdquo PLoS ONE vol 7 no 7Article ID e40909 2012

[83] K Zwingenberger H Feldmeier J A N Queiroz et al ldquoLiverinvolvement in human schistosomiasis mansoni Assessmentby immunological and biochemical markersrdquo ParasitologyResearch vol 74 no 5 pp 448ndash455 1988

[84] M Hoenlinger D Fuchs A Hausen et al ldquoSerum-neopterin-bestimmung zur zusaetzlichen Sicherung der BluttransfusionrdquoDeutscheMedizinischeWochenschrift vol 114 no 5 pp 172ndash1761989

[85] M Honlinger D Fuchs G Reibnegger D Schonitzer MP Dierich and H Wachter ldquoNeopterin screening and acutecytomegalovirus infections in blood donorsrdquo Clinical Investiga-tor vol 70 no 1 article 63 1992

[86] H Schennach G Hessenberger P Mayersbach D Schonitzerand D Fuchs ldquoAcute cytomegalovirus infections in blooddonors are indicated by increased serum neopterin concentra-tionsrdquoMedical Microbiology and Immunology vol 191 no 2 pp115ndash118 2002

[87] M Ziemann S Krueger A B Maier A Unmack S Goergand H Hennig ldquoHigh prevalence of cytomegalovirus DNA inplasma samples of blood donors in connection with serocon-versionrdquo Transfusion vol 47 no 11 pp 1972ndash1983 2007

[88] H Schennach P Mayersbach D Schonitzer D Fuchs HWachter and G Reibnegger ldquoIncreased prevalence of IgMantibodies to Epstein-Barr virus and parvovirus B19 in blooddonations with above-normal neopterin concentrationrdquo Clini-cal Chemistry vol 40 no 11 pp 2104ndash2106 1994


[89] H Schennach A J Lanthaler P Mayersbach et al ldquoHumanparvovirus B19 detection in asymptomatic blood donors asso-ciation with increased neopterin concentrationsrdquo Journal ofInfectious Diseases vol 186 no 10 pp 1494ndash1497 2002

[90] H Schennach D Schoenitzer and D Fuchs ldquoAssociationbetween chronic hepatitis C virus infection and increasedneopterin concentrations in blood donationsrdquo Clinical Chem-istry vol 44 no 10 pp 2225ndash2226 1998

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


MΘJak2Stat pathway

NF-120581B pathway+

GTP Neopterin Nucleus

IFN

TNF

GTPCH I

NK cells

T-cells

120574

Figure 1 Pathways for induction of neopterin production (MΘmacrophage Jak Janus kinase Stat Signal Transducer andActivatorof Transcription and GTPCH guanosine triphosphate cyclohydro-lase)

levels have been observed which correlate with the activity ofdisease This was first described in 1979 [6] and subsequentlyneopterin elevations were noted in infections with hepatitisviruses Epstein-BarrCytomegalomeaslesmumps varicellazoster rubella and influenza viruses [1 7ndash11] Elevatedneopterin levels in body fluids were found at the end of theincubation period before the onset of clinical symptomsThehighest neopterin levels occur just before specific antibodiesagainst the virus become detectable which is about two tofour weeks after onset of increased neopterin production Inacute varicella zoster virus infection peak neopterin levelswere observed at the end of the appearance of the rash and inmeasles virus infection one to three days after appearance ofthe rash [12 13] Immunisation with live viruses for examplemeasles mumps and rubella and virus vaccine resulted ina significant increase of neopterin independent of presenceof any symptoms In measles vaccination neopterin levelswere observed to rise at a median of 5 days after vaccinationabout 7 days before the appearance of antibodies [13] Theseinvestigations point to a future application of measurementsneopterin as a correlate of a successful vaccination Neopterinshould be investigated as a marker to evaluate protective effi-cacy of vaccines stimulating cell mediated immunity againstmycobacterial parasitic or viral diseases The magnitude ofthe elicited neopterin levels could be put into relationship toincidence of the disease immunised against the population ofimmunised children

Serumneopterin levels were also found to be significantlyelevated in symptomatic dengue virus infections with levelshigher than inmeasles and influenza virus disease [14] Levelscorrelated with duration of fever and severity of disease [1415]

Investigations into the physiological functions ofneopterin in viral infections revealed that it is able to delay

the development of the cytopathic effect of coxsackie B5virus in Hep-2 cells [16] A proposed mechanism is thestimulation of inducible nitric oxide synthase expressionleading to an increase in nitric oxide production Othermechanisms include the induction of the translocation of thenuclear factor-kappa B to the nucleus

22 Neopterin as Diagnostic and Prognostic Marker in HIVInfection Testing of 328 samples of 29 HIV infected individ-uals found that 4468 (647) of samples which were HIV-1RNA and p24 antigen positive had elevated neopterin levels(gt10 nmolL) 6216 (28) samples which were both HIV-1and p24 antigen negative had elevated neopterin levels [17]Neopterin levels were also found to be significantly elevatedin HIV-2 infection compared to controls [18]

Studies investigated markers of immune activation fortheir usefulness as prognostic markers in HIV infection andshowed an increase of neopterin levels in people with HIVinfection compared to patients without HIV infection [19ndash22] Neopterin levels hereby were found to increase earlyin the course of HIV infection preceeding CD4+-T-celldecline and clinical manifestations of AIDS [23 24] Plasmaneopterin levels were found to correlate with plasma HIVviral load [25]

Neopterin levels were found to predict HIV related mor-tality [26 27] A retrospective study compared 120573

2microglob-

ulin immunoglobulin A G and M adenosine deaminaseand neopterin levels above normal range as predictors of clin-ical or immunological deterioration in 256 patients with HIVinfection Changes in 120573

2microglobulin levels showed the

greatest sensitivity to detect worsening (43) with neopterinslightly less sensitive (419) followed by immunoglobulinlevels (268ndash352) and adenosine deaminase levels with218 having the lowest sensitivity [28]

23 Neopterin as Surrogate Marker for Viral Load to Mon-itor Response to Antiretroviral Treatment In a land markstudy the effects of dual reverse transcriptase inhibitor (RT)therapy and highly active antiretroviral therapy (HAART)on neopterin levels in patients with HIV infection werecompared to HIV uninfected controls HIV infected patientsnot on treatment and patients who had stopped treatment[22] RT inhibitor treatment decreased circulating levelsof neopterin (mean of 156 for treated versus a mean of223 ngmL for untreated HIV patients 119875 lt 004) HAARTdecreased neopterin levels significantly further This con-firmed results of a previous study on the effects of HAARTon neopterin levels [29] Neopterin levels in patients whodiscontinued HAART became similar to untreated HIVpatients

Neopterin may be a particularly useful surrogate markerfor monitoring of control of HIV replication in settingsin developing countries where HIV RNA viral load mea-surement is not available and may be a cheaper alternativeparticularly if semiquantitative dip stick tests are used forurine samples [5] Longitudinal serial measurements in thesame individual could overcome difficulties with interpreta-tion in settings where chronic parasitic (malaria) or bacterial






treatment



[12 22 29ndash37]



Blood


[38]




[39ndash41]











































6 Conclusions






References








































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















treatment



[12 22 29ndash37]



Blood


[38]




[39ndash41]











































6 Conclusions






References








































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































6 Conclusions






References








































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References








































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article neopterin in diagnosis and monitoring of...

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