Connecting the Dots: Could Microbial Translocation Explain Commonly Reported Symptoms in HIV Disease?

Features

Connecting the Dots Could MicrobialTranslocation Explain Commonly Reported

Symptoms in HIV DiseaseNatalie L Wilson DNP ANP-BC MPH AAHIVSDavid E Vance PhD MGSLinda D Moneyham PhD RN FAANJames L Raper PhD CRNP JDMichael J Mugavero MD MHSCSonya L Heath MDMirjam-Colette Kempf PhD MPH

Microbial translocation within the context of HIV Insights into the pathogenesis of HIV infection have

Natalie L Wilson DNP ANP-BCMPH AAHIVS is a PhDCandidate a Clinical Instructor at the University of Ala-bama at Birmingham School of Nursing and a postdoc-toral fellow with Veterans Administration QualityScholars Program Birmingham Veterans AdministrationMedical Center Birmingham Alabama USA David EVance PhD MGS is a Professor and Associate Directorof the Center for Nursing Research University of Alabamaat Birmingham School of Nursing Birmingham AlabamaUSA Linda D Moneyham PhD RN FAAN is SeniorAssociate Dean for Academic Affairs University of Ala-bama at Birmingham Birmingham Alabama USA JamesL Raper PhD CRNP JD is a Professor University of Ala-bama at Birmingham Schools of Nursing andMedicine andNurse Practitioner of 1917 HIVAIDS Outpatient ClinicBirmingham Alabama USA Michael J Mugavero MDMHSC is a Professor and Director of the Clinical Corewith the Center for AIDS Research at the University of Ala-bama at Birmingham School of Medicine BirminghamAlabama USA Sonya Heath MD is a Professor Divisionof Infectious Diseases Department of Medicine Universityof Alabama at Birmingham School of Medicine Birming-ham Alabama USA Mirjam-Colette Kempf PhD MPHis a Professor and Assistant Director Center for NursingResearch University of Alabama at Birmingham Schoolof Nursing Birmingham Alabama USA

disease has been described as one of the contributingcauses of inflammation and disease progression inHIV infection HIV-associated symptoms have beenrelated to inflammatory markers and sCD14 a surro-gate marker for microbial translocation suggesting aplausible link between microbial translocation andsymptom burden in HIV disease Similar pathophysio-logical responses and symptoms have been reportedin inflammatory bowel disease We provide a compre-hensive review of microbial translocation HIV-associated symptoms and symptoms connected withinflammation We identify studies showing a relation-ship among inflammatory markers sCD14 and symp-toms reported in HIV disease A conceptualframework and rationale to investigate the link betweenmicrobial translocation and symptoms is presentedThe impact of inflammation on symptoms supports rec-ommendations to reduce inflammation as part of HIVsymptommanagement Research in reducing microbialtranslocation-induced inflammation is limited butneeded to further promote positive health outcomesamong HIV-infected patients

(Journal of the Association of Nurses in AIDS Care25 483-495) Published by Elsevier Inc on behalf ofAssociation of Nurses in AIDS Care

Key words HIV inflammation microbial translo-cation sCD14 symptom management symptoms

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE Vol 25

httpdxdoiorg101016jjana201407004

Published by Elsevier Inc on behalf of Association of Nurses in AIDS Care

implicated microbial translocation as one of the keydrivers of HIV disease progression and inflammation

No 6 NovemberDecember 2014 483-495

484 JANAC Vol 25 No 6 NovemberDecember 2014

(Brenchley amp Douek 2008 Brenchley et al 2006Marchetti et al 2011 Sandler et al 2011)Microbial translocation is the movement of bacteriaandor microbial products from the gut to thebloodstream Commonly reported gastrointestinal(GI) and systemic symptoms may have arelationship with chronic inflammation induced bycirculating microbial products from the GI tract inpatients with HIV disease Even with effectivecombination antiretroviral therapy (cART) and viralsuppression inflammation from chronic immuneactivation increases the rates of morbidity andmortality among people living with HIV disease(PLWH Brenchley et al 2006 Deeks 2011Kamat Misra et al 2012 Marchetti et al 2011) Itis critical for nurses to have a working understandingof the concepts of microbial translocationinflammation and symptom management in theclinical management of HIV disease

Background and Significance

Chronic inflammation has been identified as a keypredictor in the development of comorbidities andmortality in HIV disease One source of inflammationndash the inflammation of the GI epithelial barrier ndash ulti-mately leads to dysfunction of the protective lining ofthe gut Consequently microbes naturally residing inthe gut are able to pass through the gut-associatedlymph tissue (GALT) into the blood circulation(Estes et al 2010 see Table 1 for definitions) Theimmune system responds to circulating microbeswith systemic and often chronic inflammation(Brenchley et al 2006)

Inflammation of the GI epithelial barrier in HIVdisease resembles inflammatory bowel disease(IBD) and irritable bowel syndrome (IBS) Inflam-mation of the GI epithelial barrier leads tosymptoms including diarrhea bloating andabdominal pain (Berkes Viswanathan Savkovicamp Hecht 2003 Epple amp Zeitz 2012) In IBDIBS inflammation leads to the translocation ofmicrobes naturally residing in the gut intothe bloodstream as seen in HIV disease wheremicrobial products residing in the gut translocatethrough the GALT into the bloodstream(Brenchley et al 2006 Epple amp Zeitz 2012)

Systemic inflammation experienced chronically hasbeen associated with systemic symptoms and condi-tions Symptoms are often adverse experiencesperceived from underlying changes in the bio-psychosocial function of an individual Signs andsymptoms provide key assessment information to sup-port the formulation of diagnostic pathways for clini-cians Symptoms are usually measured by self-reportas opposed to a sign which is an abnormality that canbe detected by the individual and by others observingthe individual (Dodd et al 2001) PLWH often experi-ence and report symptoms to their providers Howeverthe subjectivity of symptoms can limit objective assess-ment by another individual creating huge challengesfor clinicians and scientific investigators as symptomsmay not be objectivelymeasured by another human be-ing unless people report what they are experiencing

Symptoms are often attributed to side effects oftreatment with cART (Johnson Stallworth ampNeilands 2003) Patients initiating antiretroviraltherapy in the early era of the HIV epidemic wereat risk for serious adverse events and major side ef-fects but current cART regimens are simpler bettertolerated more effective and offer lower side-effectprofiles than earlier regimens used in the treatmentof HIV disease (Katlama et al 2009 Lennox et al2009 Madruga et al 2007) And yet manysymptoms persist in some individuals In additionthe symptom burden experienced by PLWH hasbeen associated with poor medication adherencesuch as when people want to avoid symptomsforget to take scheduled doses andor sleep throughmedications due to fatigue (Gay et al 2011) Symp-tom burden is the summation of disease expressionandor the product of the treatment of that diseaseusually referred to as the side effects of treatment(Cleeland amp Reyes-Gibby 2002)

Our purpose was to review how inflammation fromHIV disease may lead to symptoms experienced byPLWH in the context of microbial translocation aswell as how this event may lead to treatment failureWe describe the process and consequences of micro-bial translocation and inflammation and how this in-flammatory process may be related to symptomsexperienced (Figure 1) Furthermore we addressthe gaps in knowledge and challenges in demon-strating a valid hypothesis linking microbial translo-cation and symptoms

Table 1 Key Definitions on Topic-Specific Abbreviations

Topic-specific definitionsGut-associated lymphtissue (GALT)

The GALT is a large lymphatic area clustered behind the gut epithelial tissue that forms themucosal lining of the gastrointestinal tract It is organized into the lamina propria Peyerrsquospatches and isolated lymphoid follicles It is rich in Th17 cells (Estes et al 2010)

T-helper 17 (Th17) Th17 white blood cells are a type of CD41 T cell rich in the GALT They express a CCR5 receptoron their surface and are a prime target for HIV attack once activated in response to HIV(Klatt amp Brenchley 2010)

Chemokine receptor5 (CCR5)

This gene is a receptor that is present on macrophages and T cells like the CD41 cell HIV can attachto this receptor (Klatt amp Brenchley 2010)

Commensal bacteria Friendly bacteria living in the gut These bacteria help to digest food regulate immune function anddefend the gut barrier from harmful bacteria Some strains can be ingested in the form of probiotics(Wilson Moneyham amp Alexandrov 2013)

Microbial translocation and epithelial barrier dysfunctionLipopolysaccharide (LPS) Cell wall component of gram negative bacteria Plasma LPS is directly associated with microbial

translocation Reduced by long term cART but not to health control levels (KitchensampThompson 2005)LPS binding protein (LBP) LBP binds to LPS to form the LPS-LBP complex and presents to cells that produce sCD14 which is able

to bind to this complex and present to lipoproteins that clear the LPS (Kitchens amp Thompson 2005)Soluble CD14 (sCD14) Released by monocytes and macrophages during immune activation in a pro-inflammatory innate

response to circulating microbes in an LPS-LBP complex sCD14 is a more accurate and relevantmeasure of microbial translocation (Sandler et al 2011) It is recommended as a surrogatebiomarker of microbial translocation and epithelial barrier dysfunction (Stehle et al 2012)

Endotoxin coreantibodies (EndoCab)

Released in response to LBP-LPS complex to clear LPS Lower levels are found in HIV Mechanismnot fully understood but may be partially due to HIV-1 Tat protein downregulation impairment ofimmune responses to LPS (Yim Li Lau amp Lau 2009)

Proinflammatory cytokinesInterleukin (IL) A type of cytokine a protein substance released from activated white blood cells that communicates

with other cells to stimulate or regulate responsesInterleukin-1 (IL-1) A family of pro-inflammatory cytokines secreted by epithelial cells and leukocytes to induce an acute

response and neutrophil production Increased in HIV disease (Deeks 2011)Interleukin-6 (IL-6) Classic marker of inflammation in HIV Associated with CVD advanced HIV disease and non-AIDS

events Correlation with higher plasma viral loads especially with lower CD41 T cell countsAssociated with immune senescence and the inflammation associated with aging Positivelycorrelated with sCD14 (El-Sadr et al 2006)

Interleukin-8 (IL-8) Secreted by some epithelial and white blood cells in response to HIV-1 exposure (Nazli et al 2010)Interleukin-10 (IL-10) Anti-inflammatory immune modulation inhibiting IFN-g and IL-2 production Associated with IBD

Produced by programmed death (PD-1) triggered monocytes (Said et al 2010)Interleukin-17 (IL-17) Promotes a pro-inflammatory effect and recruitment of neutrophils Produced by a subset of

Th17 cells (Brenchley et al 2008)Interleukin-21 (IL-21) Cytokine with crucial role of B cell differentiation decreased in HIV infection (Ruffin Thang

Rethi Nilsson amp Chiodi 2012)Interleukin-22 (IL-22) Secreted by Th17 cells to promote epithelial healing and proliferation caused by inflammation Can also

act synergistically amplifying other pro-inflammatory cytokines such as IL-17 and cause hyperplastictissue remodeling as seen in acanthosis (Kitchens amp Thompson 2005 Zheng et al 2007)

Interleukin-23 (IL-23) Stimulates production of IL-22 andor IL-17 by Th17 cells in the GALT Plays a key role in IBD(Weaver Elson Fouser amp Kolls 2013)

TNFa Response of enterocytes in response to HIV gp120 Induces inflammation and contributes to thebreakdown of tight gap junctions disrupting barrier function (Nazli et al 2010)

C-reactive protein (CRP) An inflammatory biomarker elevated in HIV disease Associated with increased risk of CVDall-cause mortality AIDS and non-AIDS events and with detectable HIV viral loads(El-Sadr et al 2006)

CoagulationD-dimer Coagulation biomarker also associated with higher levels of sCD14 (El-Sadr et al 2006)

Note cART 5 combination antiretroviral therapy IBD 5 irritable bowel disease CVD 5 cardiovascular disease

Wilson et al Symptom Response 485

Figure 1 Conceptual framework symptomatic consequences of inflammation Inflammation of the epithelial barrier leads topossible gastrointestinal (GI) symptoms and dysfunction of the epithelial barrier Dysfunction of the epithelial barrier leads tomicrobial translocation While microbial translocation has not been associated with GI symptoms the double arrow signifies apossible association as outlined in this reviewMicrobial translocation and inflammation have been associated with some systemicsymptoms Symptom burden has been associated with adherence to combination antiretroviral therapy (cART)


Inflammation of the Epithelial Barrier

HIV has an affinity for Th17 type CD41 T cellsin the GALT These specific cells once activated areprime targets for HIV because of chemokine recep-tor 5 (CCR5) receptors that HIV can bind to whenentering CD41 T cells Th17 type CD41 T cellsare rapidly depleted during HIV infection resultingin the release of signaling proteins called cytokineswhich initiate the inflammatory process Under nat-ural physiological conditions these cells wouldrelease cytokines that would regulate and controlthe inflammatory process However due to the rapiddepletion of the Th17 type CD41 T cells andongoing replication of HIV inflammation continuesand becomes chronic (Klatt et al 2010 Pandreaet al 2007)

Chronic inflammation eventually leads to damageof the tight gap junctions between the epithelial cellsof the GI monolayer protective barrier Under natu-ral physiological circumstances Th17 cells releasea cytokine that can initiate the repair of these junc-tions However due to the depletion of Th17 cellsin GALT repair of the epithelial barrier is impaired(Estes et al 2010 Klatt et al 2010 VerhoevenSankaran Silvey amp Dandekar 2008)

Dysfunction of the Epithelial Barrier

GI barrier dysfunction has many consequencesAlterations to the cellular cytoskeleton and the func-tion of tight gap junctions lead to disruption in epithe-lial permeability Disruption of epithelialpermeability may lead to malabsorption of nutrientsand possibly even medications In addition alter-ations in fluid and electrolyte secretion which maycause symptoms such as diarrhea bloating and con-stipation may also lead to abdominal pain and func-tional symptoms (Berkes et al 2003) GI symptomsare common in IBDIBS disease as well as in HIVdisease Clinicians and PLWH have often attributedthese symptoms to medication toxicities

The microbial environment of the gut mucosalepithelium has an extraordinary ability to maintainprotection against pathogenic invasion of harmfulbacteria (Berkes et al 2003) The microbiome com-petes for space and nutrients while also providing aprotective layer of mucous The microbial environ-ment maintains balance for the gut and interactswell with the immune system the commensal floraoperates synergistically with the human immune sys-tem However once the barrier becomes dysfunc-tional microbes are able to invade and pass through


the barrier evade immune intervention and egressinto circulation (Berkes et al 2003) The pathwayof microbial translocation is complex with themain outcome being that microbial products areable to translocate from the gut to the bloodstream

Microbial Translocation

Table 2 Inflammatory Symptoms and Their Associationwith IL-6 and sCD14 Increase

Symptoms FrequentlyReported by PLWH Early ART sCD14 IL-6

Abdominal painAnxiety XChanges in body weightfat X X XCognitive decline X X XDiarrhea X XFatigue X XFever or night sweats X XHeadaches XInsomnia X XJoint painstiffness XLoss of strength X XMuscle pain XNauseavomiting XPeripheral neuropathy X XReduction in appetiteSadness X XSexual problemsShortness of breathcough X XSkin problems X

Note PLWH5 people livingwith HIVinfection sCD145 solubleCD14 IL-6 5 interleukin-6 ART 5 antiretroviral therapyIL 5 interleukinThe symptoms listed are common symptoms currently reported inHIV disease as referenced in the section of this article lsquolsquoSymptomsin HIV Diseasersquorsquo The column labeled lsquolsquoEarly ARTrsquorsquo indicatessymptoms which were often attributed to side effects of earlyera ART including highly toxic antiretroviral drugs (eg zidovu-dine monotherapy stavudine didanosine indinavir nelfinavir)The column labeled lsquolsquosCD14rsquorsquo indicates symptomswith establishedassociations with sCD14 The column labeled lsquolsquoIL-6rsquorsquo indicatessymptomswith established associationswith IL-6 Blank cells indi-cate frequently reported HIV-associated symptoms without re-ported associations with early ART or IL-6 and sCD14

Microbial translocation is not an exclusive featureof HIV disease It has been well described in IBDIBS (Spiller 2009) graft-versus-host disease(Eriguchi et al 2012) abdominal postoperative con-ditions (Sista et al 2013) and liver disease (Wiest ampGarcia-Tsao 2005) Nonhuman primates are oftenused as models to understand the extent of damagecaused by the immunodeficiency virus in humansbecause of similar pathology between nonhuman pri-mates and humans Simian models have similar struc-tural and immunological responses to that of thehuman model and can be infected with the virus forinvestigation and results can be translated to under-stand the pathogenesis in humans (Klatt et al 2010)

Brenchley et al (2006) described microbial trans-location as part of the pathogenic process in simianimmunodeficiency virus (SIV) and HIV infection bydetecting differences in microbial translocation in an-imal models using African Green Monkeys versusRhesus macaques with higher levels of microbialtranslocation in the pathogenically infected Rhesusmacaques Prior to these findings the inflammatoryprocess and marked dysfunction of the immuneresponse was attributed to HIV infection withinGALT and of the GI epithelial barrier Stein et al(1997) described the chronic passage of bacteria leak-ing across a compromised epithelial wall in HIVdisease

GALT houses a rich supply of Th17 and memoryCD41 T cells which express high levels of CCR5 re-ceptors which facilitate entry into cells and result inrapid depletion of these immune cells during theacute phase of HIVSIV infection (Estes et al2010 Pandrea et al 2007) Immune activation inresponse to HIVSIV begins an inflammatoryprocess secreting proinflammatory cytokines suchas tumor necrosis factor-a interleukin (IL)-1 IL-6IL-17 IL-21 and IL-22 that ultimately impair theepithelial barrier (Estes et al 2010 Klatt et al

2010 see Table 2) The immune system which isessential to survival is subverted by HIV infectionand due to the inflammatory response continues asa result of dysfunctional regulation Although treat-ment with cART is unable to prevent acute loss ofCD41 T cells in GALT it does support CD41T cells by suppressing HIV replication and allowingthe body to restore these immune cells In SIVmodels preservation of memory CD41 T cells aswell as the reduction and suppression of inflamma-tion promotes repair and regeneration of the mucosalepithelial barrier (Verhoeven et al 2008)

Without successful cART HIV infection goes onto deplete CD41 T cells in the peripheral blood


lymph nodes and effector tissues leading to AIDS(Klatt amp Brenchley 2010) and the continuous lossof CD41 T memory cells inhibits reconstitution inspite of treatment (Mehandru et al 2006) Addition-ally cART fails to restore CD41 T memory cellsback to preinfection levels and persistent immuneactivation continues in response to low levels ofviremia in GALT leading to chronic mucosal inflam-mation and microbial translocation (Estes et al2010) Even with undetectable levels of viral RNAviral DNA can persist and contribute to ongoing im-mune activation (Chun et al 2008) resulting incontinued structural and immunologic damage(Brenchley amp Douek 2008)

Damage to the integrity of the mucosal epithelialbarrier and loss of phagocytic protection in GALTset the stage for microbial products to translocate tothe lymph nodes and then to the plasma through thechronic phase of HIV disease In addition levels oflymphatic microbial products and circulating micro-bial products are associated with the extent of dam-age to the GI tract (Estes et al 2010) Once incirculation these products contribute to and amplifyimmune activation resulting in chronic inflammation(Klatt Canary et al 2013 Klatt Chomont Douekamp Deeks 2013) Even with long-term suppressionof HIV replication in the blood the epithelial barrieris only partially restored (Epple amp Zeitz 2012) Thelack of restoration may be partially due to ongoing re-sidual replication triggering the inflammatory processin the gut and as a result contributing to microbialtranslocation (Baroncelli et al 2009 Reus et al2013) This inflammatory process can lead tosystemic symptom development (Figure 1)

Microbial Translocation and Immune Activation

Circulating microbial products from the gut resultin immune inflammatory processes Brenchley et al(2006) reported microbial translocation as a hallmarkpredictor of immune activation and disease progres-sion describing the differences in pathogenicprogressive HIVSIV infections long-term nonprog-ressors and nonpathogenic SIV models The studyestablished that the source of circulating microbialproducts which were commensal and pathogenicbacteria had passed through the damaged gut epithe-lial barrier Levels of microbial products measured by

the bacterial lipopolysaccharide (LPS) outer coatincreased after the acuteearly phase of HIV infec-tion Levels of LPS were linked to elevated levelsof soluble CD14 (sCD14) (r 5 03 p 5 001) andlower levels of naturally occurring endotoxin core an-tibodies (EndoCAb) to LPS (r520319 p5 0005)which clear LPS from the system In fact signifi-cantly lower levels of EndoCAb were detected inHIVSIV-infected chronic progressors than in earlyacute progressors (p 0001) and those who wereuninfected (p 5 0002) meaning that over time themechanism to remove circulating microbes de-creases HIVSIV-infected nonprogressors exhibithigher levels of LPS and sCD14 than uninfected par-ticipants meaning that even elite controllers andlong-term nonprogressors with HIV disease have ev-idence of microbial translocation which contributesto immune activation (Brenchley et al 2006)

Microbial translocation has been well documentedin the IBDIBS literature In fact there aremultiple sim-ilarities in the pathogenesis of IBDIBS and HIV infec-tion and its impact on the function of the GI systemincluding depletion of Th17 cells in GALT leading toinflammation and subsequent dysfunctionof the epithe-lial barrier (BrenchleyampDouek 2008McGuckin EriSimms Florin amp Radford-Smith 2009) While theunderlying reasons for low levels of EndoCAb in HIVdisease are not clearly understood the effect of HIVinfection on the dysregulation of monocytes allowscontinuing circulation of microbial products whichresults in chronic monocyte immune activation withsCD14 and a proinflammatory response (Yim LiLau amp Lau 2009) Even in the presence of highCD41Tcell counts and suppressedviral loads chronicinflammation existswith stable levels of sCD14 (Hattabet al 2014)

Overall LPS and the sCD14-LPS complex canstimulate the inflammatory pathway In additionthe LPSndashLPS binding protein-bound complex stimu-lates sCD14 which initiates the inflammatorypathway The LPS-sCD14 complex induces the pro-duction of IL-6 activation of the immune systemby circulating microbes is a signature process in theinflammatory cycle (Brenchley et al 2006 CassolRossouw Seebregts amp Cassol 2011 Kamat Misraet al 2012) Therefore sCD14 is a more reliablesurrogate marker for microbial translocation thandirectly measuring bacterial LPS


Symptoms in HIV Disease

Symptoms and symptom management are criticalin HIV care While symptom burden is an importantissue for patients and providers symptoms often gounder-recognized Edelman Gordon and Justice(2011) conducted a secondary data analysis of theVeterans Aging Cohort Study and found that pro-viders demonstrated poor sensitivity to the report ofsymptoms even with a symptom checklist completedby patients Providers failed to recognize symptomsassociated with disease progression Symptoms re-ported were fatigueloss of energy cognitive declineshortness of breath loss of appetite muscle achespain and problems with weight loss (Edelmanet al 2011 Justice Chang Rabeneck amp Zackin2001) Among these symptoms functional decline(Erlandson et al 2013 Stehle et al 2012)cognitive decline (Ancuta et al 2008 KamatLyons et al 2012) obesity (Koethe et al 2013)anxiety and sadness (Liebregts et al 2007) havebeen associated with microbial translocation indi-cated by elevated levels of sCD14 andor Gram-negative bacterial LPS along with other inflammatorycytokines Fatigue (Klimas Broderick amp Fletcher2012) muscle aches joint pain (ErikssonAndersson Ekerfelt Ernerudh amp Skogh 2004)poor sleep (Grandner Sands-Lincoln Pak ampGarland 2013) feverchillssweats (Holtzclaw2013) night sweats (Mold Holtzclaw amp McCarthy2012) peripheral neuropathy (Harezlak et al 2011Zheng et al 2011) diarrhea (Liebregts et al2007) anxiety depression (Camacho 2013) andweight losswasting (Stein et al 1997) have beenassociated with chronic inflammation as indicatedby the elevation of proinflammatory cytokinesTable 2 provides a list of HIV-associated symptomsconsistently reported by PLWH and displays thegaps in knowledge in regard to whether each hasbeen associated with inflammation Abdominalpain reduction in appetite and sexual problems arecommonly reported symptoms in HIV disease how-ever there are no relevant data or publications citingan association or lack of one with inflammationTherefore because of the prevalence of these symp-toms in HIV disease it is worth an investigation togain insight into the possible underlying problemscontributing to their development

While there are similarities in pathology andsymptoms between IBDIBS and HIV disease someof the symptoms have not been widely investigatedin the context of microbial translocation in HIV dis-ease For example bloating and abdominal pain arecommonly reported in both HIV disease and inIBDIBS but have not been investigated in thecontext of inflammation and microbial translocationin HIV disease Given the emphasis on patient-centered care over the past decade it is importantto understand and seek ways to validate patient symp-toms and to work toward a model of care that is tunedin to the symptomatic experience of patients Symp-toms that may be associated with inflammation anddisease progression in HIV disease warrant thoroughinvestigation to support providers as they deliversymptom-focused interventions and care

Inflammation Immune Activation and DiseaseProgression

The inflammatory process helps the host fight offforeign antigens However when unregulated inflam-mation causes damage inflammation can also beharmful In the same way many strains of bacteriaserve to protect and maintain functional abilities in asymbiotic relationship with the host Killing all bacte-ria or even altering the normal flora is harmful Somebacterial strains serve to boost and regulate the im-mune response However when bacteria and inflam-mation become unregulated disease develops in thebody (Antoni Nuding Wehkamp amp Stange 2014)

Immune activation is multifactorial and complexIn numerous clinical trials mortality disease pro-gression and opportunistic infections have beenassociated with elevations in inflammatory bio-markers IL-6 C-reactive protein (CRP) and D-dimer (Nixon amp Landay 2010) One important studywas conducted by the Strategies for Management ofAntiretroviral Therapy (SMART) study group Thislarge multicenter randomized clinical trial examinedinterruption and late initiation of cART based onCD41 T cell count with a primary endpoint of newor recurrent opportunistic infection or all causes ofdeath Secondary endpoints were (a) a potentiallylife-threatening symptomatic event requiring medicalintervention or (b) death (El-Sadr et al 2006) In thisstudy participants with higher versus lower levels of


IL-6 were 24 (95 confidence interval [CI] 21 to88) times more likely to develop opportunistic infec-tions participants with higher versus lower levels ofCRP were 76 (95 CI 20 to 285) times more likelyto develop opportunistic disease Baseline and latestIL-6 levels and latest CRP were predictive of diseasedevelopment (Rodger et al 2009) Elevation of D-dimer was predictive of the development of cardio-vascular disease but not opportunistic infection(Rodger et al 2009) The adjusted risk of mortalitywas shown to be eight times greater among partici-pants with high sCD14 levels (95 CI 12 to 139p 5 02) versus low levels of sCD14 Participantswith higher levels of sCD14 in the SMART studyhad increased enterocyte damage in comparison toparticipants with low levels of sCD14 even aftertreatment and adjusting for age (Sandler et al2011) Likewise sCD14 has been shown to be a sur-rogate biomarker for immune activation in controlledand uncontrolled patients on cART (Brenchley et al2006 Kamat Misra et al 2012)

HIV-associated inflammation processes asdescribed above have been shown to cause the earlyonset of non-AIDS-related complications and earlyaging Conditions normally associated with aging inuninfected populations manifest themselves prema-turely in patients living with HIV disease (Deeks2011 Vance McDougall Wilson Debiasi amp Cody2014) As such aging is associated with cognitivedecline cardiovascular disease cancer bonedisease immunosenescence and frailty (Deeks2011) which may be due to chronic inflammationcaused by microbial translocation Microbial translo-cation measured by sCD14 and LPS is associatedwith progression of the thickening of carotid arteriesor subclinical atherosclerosis in HIV disease(Kelesidis Kendall Yang Hodis amp Currier 2012)Patients may experience symptoms such as shortnessof breath fatigue lack of energy and pain due tohardened and thickened arterial walls Atheroscle-rosis is normally associated with older patients andclinicians may not look for it in younger patientsespecially if symptoms are attributed to medicationsHIV or depression

Chronic inflammation has been associated with anarray of symptoms which have been commonly re-ported by PLWH (Edelman et al 2011 Gay et al2011 Johnson et al 2003) Because inflammation

leads to epithelial barrier dysfunction and epithelialbarrier dysfunction leads to microbial translocationwhich results in inflammation it is plausible thatsome symptoms can be linked to microbialtranslocation In light of the association betweeninflammation and symptoms we need to examinewhich HIV disease symptoms have an associationwith GI epithelial barrier dysfunction and whichsymptoms have an association with inflammationinduced by microbial products circulating in theblood If we can understand the relationship ofmicrobial translocation and symptoms reported byHIV-infected patients we should be able to developintervention studies to reduce the symptom burdenin PLWH (Wilson Moneyham amp Alexandrov 2013)

Discussion

It is important for nurses to educate patients aboutthe significance of discussing symptoms with theirproviders and not assuming the extent of their symp-toms is related to cART It is also important for nursesto familiarize themselves with microbial transloca-tion to encourage patients to ask their providersabout microbial translocation andor to make recom-mendations on interventions to improve gut healthFor example various nutrition strategies can be dis-cussed to support reduction of inflammation in thegut through dietary choices such as decreasing sugarand alcohol intake or taking over-the-counterprobiotics

Inflammatory-related symptoms may create a sig-nificant barrier to successful implementation of clin-ical care by affecting adherence to cART andengagement in care Chronic inflammation from im-mune activation and elevated levels of solubleCD14 (sCD14) and IL-6 have been linked to early ag-ing decline in cognitive function metabolic diseasecardiovascular disease decline in renal function can-cer bone disease and other end-organ diseases(Deeks 2011 Duprez et al 2012 Erlandson et al2013 Kamat Misra et al 2012 Marks et al2013 Pedersen et al 2013 Vance et al 2014) Asnoted in Table 2 many inflammatory-related symp-toms are reported in HIV disease and there are evena few symptoms without any correlation dataResearch studies should be conducted to determine


if these symptoms are an indication of underlyinginflammation in HIV disease If there is a correlationbetween various symptoms and inflammation micro-bial translocation may be a target for interventions toprevent HIV disease progression and reduce symp-toms experienced in chronic HIV disease

Knowledge based on the association betweenepithelial barrier inflammation and GI symptomsand the association between subsequent microbialtranslocation and systemic symptoms is limited In-terventions targeted toward improving gut healthand microbial translocation still require rigorousresearch in PLWH Research designs that addressboth the quality of life and the association and predic-tive perspectives of microbial translocation are war-ranted Primary steps to improve symptommanagement strategies would be to conduct studiesinvestigating the association between symptoms andmicrobial translocation This would include exam-ining the association between microbial translocationand reported GI and systemic symptoms commonlyexperienced in HIV disease Characterizing the over-all symptom experience in HIV disease in terms ofprevalence and the underlying influence of inflamma-tion caused by immune activation in response to mi-crobial translocation would support clinical trials todevelop new treatment strategies

We have addressed the relationship between symp-toms of inflammation and microbial translocation inPLWH As symptom burden has been associatedwith poor adherence to HIV medications a possibletarget to improving symptoms may be to reducesymptom burden If there is an association betweensymptom burden and microbial translocation thereduction of microbial translocation may supportadherence strategies In addition reducing inflamma-tion of the epithelial barrier may reduce GI symptomsand microbial translocation as seen in the IBDIBSdisease model with probiotic use (Wilson et al2013)

There are many challenges to symptom researchincluding numerous confounders and the subjectivenature of the symptom experience Strategies target-ing microbial translocation may become an objectivesupplement to measure improvement of outcomeswith symptom management Given the complexityof symptoms in HIV disease an interdisciplinaryapproach from the perspectives of nursing medicine

nutrition clinical and scientific communities wouldsupport a more holistic patient-centered model tosymptom management Adjunct treatment strategiesdesigned to heal and reduce inflammation of theepithelial barrier have the potential to reduce thesymptom experience thereby improving adherenceNew treatment strategies may also slow disease pro-gression by reducing microbial translocation one ofthe key predictors of HIV-associated morbidity andmortality

Key Considerations

Nurses need to have a working understandingof the key drivers of disease progression suchas microbial translocation to support patientunderstanding of the HIV disease process

Symptoms should be regarded as important andaddressed by providers in HIV disease

Nurses have the opportunity to educate patientsabout discussing symptoms with their pro-viders and not assuming the symptoms aredirectly related to HIV medications

Nurses should educate patients on interven-tions to reduce inflammation

Symptom management research should beginto target microbial translocation

Nurses are in a critical position to make symp-tom management recommendations

Disclosures

The authors report no real or perceived vested in-terests that relate to this article that could beconstrued as a conflict of interest

Acknowledgments

Dr Wilson is a fellow in the VA National QualityScholars program The Department of Veterans Af-fairs Quality Scholars Fellowship (VAQS) is fundedby the Department of Veterans Affairs Office of


Academic Affiliations (OAA) The opinions ex-pressed in this article are those of the authors aloneand do not reflect the views of the Department of Vet-erans Affairs Dr Wilson also wishes to thank LauraGraham and Patricia Patrician for their technicalassistance in the development and production ofthis manuscript

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(Brenchley amp Douek 2008 Brenchley et al 2006Marchetti et al 2011 Sandler et al 2011)Microbial translocation is the movement of bacteriaandor microbial products from the gut to thebloodstream Commonly reported gastrointestinal(GI) and systemic symptoms may have arelationship with chronic inflammation induced bycirculating microbial products from the GI tract inpatients with HIV disease Even with effectivecombination antiretroviral therapy (cART) and viralsuppression inflammation from chronic immuneactivation increases the rates of morbidity andmortality among people living with HIV disease(PLWH Brenchley et al 2006 Deeks 2011Kamat Misra et al 2012 Marchetti et al 2011) Itis critical for nurses to have a working understandingof the concepts of microbial translocationinflammation and symptom management in theclinical management of HIV disease

Background and Significance

Chronic inflammation has been identified as a keypredictor in the development of comorbidities andmortality in HIV disease One source of inflammationndash the inflammation of the GI epithelial barrier ndash ulti-mately leads to dysfunction of the protective lining ofthe gut Consequently microbes naturally residing inthe gut are able to pass through the gut-associatedlymph tissue (GALT) into the blood circulation(Estes et al 2010 see Table 1 for definitions) Theimmune system responds to circulating microbeswith systemic and often chronic inflammation(Brenchley et al 2006)

Inflammation of the GI epithelial barrier in HIVdisease resembles inflammatory bowel disease(IBD) and irritable bowel syndrome (IBS) Inflam-mation of the GI epithelial barrier leads tosymptoms including diarrhea bloating andabdominal pain (Berkes Viswanathan Savkovicamp Hecht 2003 Epple amp Zeitz 2012) In IBDIBS inflammation leads to the translocation ofmicrobes naturally residing in the gut intothe bloodstream as seen in HIV disease wheremicrobial products residing in the gut translocatethrough the GALT into the bloodstream(Brenchley et al 2006 Epple amp Zeitz 2012)

Systemic inflammation experienced chronically hasbeen associated with systemic symptoms and condi-tions Symptoms are often adverse experiencesperceived from underlying changes in the bio-psychosocial function of an individual Signs andsymptoms provide key assessment information to sup-port the formulation of diagnostic pathways for clini-cians Symptoms are usually measured by self-reportas opposed to a sign which is an abnormality that canbe detected by the individual and by others observingthe individual (Dodd et al 2001) PLWH often experi-ence and report symptoms to their providers Howeverthe subjectivity of symptoms can limit objective assess-ment by another individual creating huge challengesfor clinicians and scientific investigators as symptomsmay not be objectivelymeasured by another human be-ing unless people report what they are experiencing

Symptoms are often attributed to side effects oftreatment with cART (Johnson Stallworth ampNeilands 2003) Patients initiating antiretroviraltherapy in the early era of the HIV epidemic wereat risk for serious adverse events and major side ef-fects but current cART regimens are simpler bettertolerated more effective and offer lower side-effectprofiles than earlier regimens used in the treatmentof HIV disease (Katlama et al 2009 Lennox et al2009 Madruga et al 2007) And yet manysymptoms persist in some individuals In additionthe symptom burden experienced by PLWH hasbeen associated with poor medication adherencesuch as when people want to avoid symptomsforget to take scheduled doses andor sleep throughmedications due to fatigue (Gay et al 2011) Symp-tom burden is the summation of disease expressionandor the product of the treatment of that diseaseusually referred to as the side effects of treatment(Cleeland amp Reyes-Gibby 2002)

Our purpose was to review how inflammation fromHIV disease may lead to symptoms experienced byPLWH in the context of microbial translocation aswell as how this event may lead to treatment failureWe describe the process and consequences of micro-bial translocation and inflammation and how this in-flammatory process may be related to symptomsexperienced (Figure 1) Furthermore we addressthe gaps in knowledge and challenges in demon-strating a valid hypothesis linking microbial translo-cation and symptoms





































































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Documents

Connecting the Dots: Could Microbial Translocation Explain Commonly Reported Symptoms in HIV Disease?