OVERVIEW OF NEUTROPENIC FEVER SYNDROMES All topics are updated as new evidence becomes available and our peer our peer review process is complete. Literature review current through Dec through Dec 2016. | Thi! to"ic #a!t u"$ate$ Dec u"$ate$ Dec 02, 2015. INTRODUCTION — Cancer Cancer patien patients ts receivi receiving ng ctoto ctoto!ic !ic antineo antineopla plasti stic c t"erap t"erap su##ic su##icien ientt to advers adversel el a##ec a##ectt melopoiesis and t"e developmental integrit o# t"e gastrointestinal mucosa are at ris$ #or invasive in#ection due to coloni%ing bacteria and&or #ungi t"at translocate across intestinal mucosal sur#aces. 'ince t"e magnitude o# t"e neutrop"il(mediated component o# t"e in#lammator response ma be muted in neutropenic patients )1 )1*, a #ever ma be t"e earliest and onl sign o# in#ection. +t is critical to recogni%e neutropenic #ever earl and to initiate empiric sstemic antibacterial t"erap promptl in order to avoid progression to a sepsis sndrome and possibl deat". "is topic will provide provide an overview o# t"e concepts related to neutropenic neutropenic #ever, #ever, including de#initions de#initions o# #ever and neutropenia and categories o# ris$. "e ris$ assessment and diagnostic approac" to patients presenting wit" neutropenic #ever are discussed in detail separatel. "e management o# neutropenic #ever sndromes in cancer patients at "ig" and low ris$ #or complications and t"e prop"la!is o# in#ections in suc" patients are also discussed in detail separatel. -ranulocte trans#usions are also reviewed elsew"ere. %UIDELINES %UIDELINES — -uidelines "ave been developed #or t"e evaluation and management o# #ever in neutropenic patients wit" cancer )2, 2,*. *. "e recommendations below are generall in $eeping wit" t"e 2010 +n#ectious Diseases 'ociet o# America /+D'A guidelines )2 )2* and t"e 201 American 'ociet o# Clinical ncolog /A'C guidelines ) )*. "ese and ot"er +D'A guidelines can be accessed t"roug" t"e +D'A3s website )5 )5*. DEFINITIONS Fever — — "e de#inition o# #ever as an indicator o# in#ection in neutropenic patients "as varied. +n 1464, Carl underlic" proposed t"at t"e mean normal bod temperature was 7C /84.679 wit" an upper limit o# normal o# 47C /100.79, above w"ic" #ever was de#ined )6(4 )6(4**. Despite t"e observation t"at t"ere is a range o# normal bod temperatures, temperatures, in one surve, surve, a ma:orit ma:orit /5 percent percent o# 20 medical pro#essionals pro#essionals reported t"e belie# t"at normal bod temperature is 7C /84.679 )4,8 )4,8*. *. A surve o# members o# t"e ;ritis" 'ociet #or
0.7C /84.2>0.79 wit" a range o# 5.67C /86.079 to 4.27C /100.479, t"e latter de#ining t"e upper limit o# normal ) )*. "e +n#ectious Diseases 'ociet o# America de#ines #ever in neutropenic patients as a single oral temperature o# =4.7C /10179 or a temperature o# =4.07C /100.79 sustained #or =1 "our ) 2*. e agree wit" using t"is de#inition o# #ever in neutropenic patients. 'imilar de#initions "ave been provided #rom 'out" America, ?urope, and Asia ) 11( 1**. 1 +t is $nown #rom animal models t"at glucocorticoids ma "ave a mitigating e##ect on t"e development o# #ever due to bacterial or endogenous progens )1 )1*. *. "e antipretic e##ect o# concomitant use o# glucocorticoids in neutropenic patient patients s ma con#ou con#ound nd t"e recogn recogniti ition on o# an in#ect in#ection ion )15 15*. *. "e presen presence ce o# signs signs o# sstem sstemic ic in#lam in#lammat mator or response sndrome /'+@', including tac"cardia, tac"pnea, or "potension in an a#ebrile neutropenic patient w"o is receiving concomitant glucocorticoids, s"ould raise t"e suspicion o# in#ection. Neutro"enia — Neutro"enia — "e de#inition o# neutropenia varies #rom institution to institution, but neutropenia is usuall de#ined as an absolute absolute neutrop"il count /AC B1500 cells&mic cellsµ, ro, and and severe severe neutropenia neutropenia is usuall usuall de#ined de#ined as an AC B500 cells&m cellsµ icro or an AC t"at is e!pected to decrease decrease to B500 cellsµ cellsµ over t"e ne!t 4 "ours )2,16 )2,16**. "e ris$ o# clinicall important in#ection rises as t"e neutrop"il count #alls below 500 cellsµ and is "ig"er in t"ose wit" wit" a prolon prolonged ged duration duration o# neutro neutropen penia ia /= das. 9or t"e purposes purposes o# t"is t"is discus discussio sion, n, we are $e&ini $e&ining ng neutro"enia a! an 'NC ()** ce##!+,icroL"e "e AC AC can can be calcu calcula late ted d b mult multip ipl lin ing g t"e t"e tota totall w"it w"ite e bloo blood d cell cell /;C /;C coun countt b t"e t"e perce percent ntag age e o# polmorp"onuclear cells /Es and bands /calculator /calculator 1. 1. Assessment o# t"e ris$ o# neutropenia be#ore t"e ;C and di##erential results are available is discussed separatel. Neutro"enic &ever !.n$ro,e! — !.n$ro,e! — A number o# neutropenic #ever sndromes "ave been described )1,14 )1,14*. *. "e +nternational +mmunocompromised
GIne!plained #ever H eutropenic #ever wit" neit"er a clinical #ocus o# in#ection nor an identi#ied pat"ogen "e #irst neutropenic #ever is t"e #irst #ebrile episode occurring during a given period o# c"emot"erap(induced neutropenia. A persistent neutropenic #ever sndrome is a #ebrile episode wit"out de#ervescence a#ter at least #ive das o# initial empiric broad(spectrum antibacterial t"erap in "ig"(ris$ neutropenic patients or a#ter at least two das in low(ris$ neutropenic patients. A recrudescent neutropenic #ever sndrome is a #ebrile episode t"at recurs #ollowing initial de#ervescence during a course o# broad(spectrum antibacterial t"erap. "e ,.e#oi$ recon!titution !.n$ro,e is de#ined b #ever and a new in#lammator #ocus or progression o# a pree!isting in#lammator #ocus in temporal relations"ip to neutrop"il recover #rom aplasia. "is sndrome is similar to t"e immune reconstitution in#lammator sndrome t"at can #ollow t"e initiation o# antiretroviral t"erap in patients wit" <+J in#ection. RIS/ OF SERIOUS COMPLIC'TIONS — "e initial clinical evaluation #ocuses on assessing t"e ris$ o# serious complications. "is ris$ assessment dictates t"e approac" to t"erap, including t"e need #or inpatient admission, intravenous /+J antibiotics, and prolonged "ospitali%ation /table 1. Gow(ris$ patients are de#ined as t"ose w"o are e!pected to be neutropenic /absolute neutrop"il count )AC* B500 cellsµ #or K das and t"ose wit" no comorbidities or evidence o# signi#icant "epatic or renal ds#unction. "is group o# patients "as been well studied in randomi%ed trials and "as been s"own to be at low ris$ #or serious complications )2*. Eost patients receiving c"emot"erap #or solid tumors are considered to be low ris$ #or complications reLuiring "ospitali%ation or prolonging "ospitali%ation. Ge de#ine "ig"(ris$ patients as t"ose w"o are e!pected to be neutropenic /AC B500 cellsµ #or = das. atients wit" neutropenic #ever w"o "ave ongoing comorbidities or evidence o# signi#icant "epatic or renal ds#unction are also considered to be "ig" ris$, regardless o# t"e duration o# neutropenia. t"er criteria t"at con#er a "ig"(ris$ status can be #ound in t"e able /table 1. 'ome e!perts "ave de#ined "ig"(ris$ patients as t"ose e!pected to "ave pro#ound neutropenia /AC K100 cellsµ #or = das based on e!perience t"at suc" patients are t"e most li$el to "ave li#e( t"reatening complications )2(*.
on resistance, and t"e costs o# "ospitali%ation and antimicrobial t"erap are signi#icant #actors. +t is t"ere#ore critical to accuratel assess bod temperature in order to aggressivel treat patients wit" neutropenic #ever and to avoid t"e overtreatment o# stable neutropenic patients w"o do not "ave a #ever. "ere is no universall pre#erred met"od #or measuring bod temperature )21*, and t"e met"od used varies b institution. Eost medical #acilities use oral, in#rared tmpanic membrane, a!illar, or rectal t"ermometr as a surrogate o# core bod temperature. e #avor oral t"ermometr in patients wit"out oral mucositis, and tmpanic membrane t"ermometr or a!illar t"ermometr in patients wit" oral mucositis. ?ac" o# t"ese met"ods "as s"ortcomings, and t"e use o# eac" met"od reLuires t"at proper tec"niLue be used to obtain accurate results )4*. erip"eral met"ods o# monitoring temperature /tmpanic membrane, temporal arter, a!illar, and oral t"ermometr do not accuratel re#lect core bod temperature as measured b central met"ods /pulmonar arter cat"eter, urinar bladder, esop"ageal, and rectal t"ermometr and are less sensitive )22*M "owever, central met"ods are not practical or sa#e in neutropenic p atients. "e #ollowing issues appl to t"e use o# t"e various t"ermometr tec"niLues in neutropenic patientsF Gral t"ermometr is t"e most common met"od #or measuring temperature.
patients receiving "ig"(dose glucocorticoids are at increased ris$ #or Pneumocystis jirovecii /#ormerl P carinii pneumonia.
EPIDEMIOLO%Y — An in#ectious source is identi#ied in appro!imatel 20 to 0 percent o# #ebrile neutropenic episodes )2,2*. #ten t"e onl evidence o# in#ection is bacteremia, w"ic" is documented in 10 to 25 percent o# patients )2*. Appro!imatel 40 percent o# identi#ied in#ections are believed to arise #rom t"e patient3s endogenous #lora )*. "e able lists t"e range o# pat"ogens #ound in patients wit" c"emot"erap(induced neutropenia /table 2. 2acteria# "athogen! — -ram(negative bacilli, particularl Pseudomonas aeruginosa, were t"e most commonl identi#ied pat"ogens in neutropenic patients until t"e 1840s )*. 'ubseLuentl, gram(positive bacteria "ave become t"e most common pat"ogens )5,6*. +n a surve o# 8 "ospitals in t"e Inited 'tates in 1885 and 2000, gram( positive organisms accounted #or 62 and 6 percent o# all bloodstream in#ections, respectivel, w"ereas gram( negative organisms accounted #or onl 22 and 1 percent o# all bloodstream in#ections, respectivel )5*. Common gram(positive cocci include Staphylococcus epidermidis /b #ar t"e most common, Staphylococcus aureus, and streptococciM less common gram(positive organisms include Corynebacterium jei!eium, Bacillus spp, Leuconostoc spp, Lactobacillus spp, Propionibacterium acnes, and "hodococcus spp )*. A number o# c"anges in practice li$el account #or t"e trend toward gram(positive in#ections, including t"e introduction o# long(term indwelling central venous cat"eters )4*, t"e use o# empiric antibiotic regimens #or neutropenic #ever designed to cover P aeruginosa, t"e use o# prop"lactic antimicrobials t"at are primaril active against gram(negative pat"ogens /eg, cipro#lo!acin, and newer c"emot"erapeutic regimens. "e #ollowing observations "ave been made about bacterial in#ections in neutropenic patientsF G;acteria are t"e most #reLuent in#ectious causes o # neutropenic #ever )8*. G-ram(negative bacteria /eg, P aeruginosa are generall associated wit" t"e most serious in#ections. G"e s"i#t #rom gram(negative bacteria to gram(positive bacteria in documented in#ections observed during t"e pre(2000 period "as been replaced b a trend bac$ toward gram(negative bacteria, in general, wit" t"e emergence o# antibiotic(resistant gram(negative strains #rom bloodstream isolates in neutropenic cancer patients )0(*.
G9ever is o#ten t"e sole mani#estation o# candidemia. ?rt"ematous macronodular s$in nodules occur in some patients wit" candidemia. "e reported median time o# candidemia #ollowing standard remission(induction t"erap #or acute melogenous leu$emia /AE "as been 16 das /range 1 to 25 das #rom t"e #irst da o# t"e ctoto!ic regimen, coincident wit" t"e time o# ma!imum ctoto!ic t"erap(induced intestinal epit"elial damage )4*. Among patients w"o develop disseminated candidiasis #ollowing c"emot"erap, "epatosplenic involvement is commonM signs and smptoms are o#ten not present until t"e neutropenia resolves. "e reported median time to a diagnosis o# "epatosplenic involvement a#ter AE induction t"erap "as been 26 das /range 18 to 1 das #rom t"e #irst da o# t"e ctoto!ic regimen )4*. GCandida albicans accounts #or t"e ma:orit o# candidemiasM C glabrata, C tropicalis, and ot"er Candida spp account #or t"e remainder. A "ig"er proportion o# candidemias are due to non(albicans Candida species w"en #lucona%ole prop"la!is "as been administered. GCandida spp are common #ungal causes o# central venous cat"eter(associated in#ections and can cause disseminated candidiasis. G #spergillus spp is a common #ungal pat"ogen in immunocompromised "osts, w"ic" ma occur #ollowing t"e in"alation o# in#ective conidia /sporesM mani#estations primaril a##ect t"e lower respirator tract /pneumonia and upper respirator tract /sinusitis but ma also involve t"e central nervous sstem, bones, and s$in. /'ee N?pidemiolog and clinical mani#estations o# invasive aspergillosisN. G"e agents o# mucormcosis pulmonar, and&or disseminated in#ections /%gomcosisN. G$usarium spp "ave been immunocompromised "ost. /
increasingl
can cause li#e(t"reatening in immunocompromised "osts. reported
to
cause
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#ungal
r"ino(orbital(cerebral, /'eeNEucormcosis in#ections
in
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G@eactivation o# endemic #ungi /Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides spp s"ould also be considered in patients w"o "ave lived in or traveled to endemic areas, particularl in t"e setting o# prolonged glucocorticoid use or ot"er immunosuppression. rop"la!is and empiric t"erap o# invasive #ungal in#ections in "ig"(ris$ patients /table 1 are discussed in detail separatel. Vira# "athogen! — Jiral in#ections, especiall "uman "erpesviruses, are common in "ig"(ris$ patients wit" c"emot"erap(induced neutropenia /table 1 and are e##ectivel prevented wit" antiviral prop"la!is. /'ee Nrop"la!is o# in#ection during c"emot"erap(induced neutropenia in "ig"(ris$ adultsN. Eost "erpes simple! virus /<'J(1 and (2 in#ections in adults are due to reactivation o# latent in#ections in seropositive patients. "e li$eli"ood o# reactivation is in#luenced b t"e intensit o# t"e c"emot"erap regimen. @eactivation occurs in two(t"irds o# seropositive patients undergoing induction c"emot"erap #or AE and t"ose undergoing "ematopoietic cell transplantation /
M'N'%EMENT — +t is critical to recogni%e neutropenic #ever earl and to initiate empiric sstemic antibacterial t"erap promptl in order to avoid progression to a sepsis sndrome and possibl deat". +n all cancer patients presenting wit" neutropenic #ever, empiric antibacterial t"erap s"ould be initiated immediatel a#ter blood cultures "ave been obtained and be#ore an ot"er investigations "ave been completed. Initia# a!!e!!,ent — A reliable met"od #or obtaining bod temperature must be used and a mec"anism #or estimating t"e absolute neutrop"il count /AC is mandator /see 3emperature measurement3 above and 3eutropenia3 above. "e ris$ o# neutropenia, t"e ris$ o# complications #rom neutropenic #ever, and t"e ris$ o# sepsis must be assessed Luic$l. "ese issues are discussed in greater detail separatel. atients and t"eir #amilies s"ould be instructed b t"eir oncologist to in#orm "ealt"care providers in t"e triage setting about recent c"emot"erap, and providers in t"e triage setting s"ould as$ cancer patients w"o do not o##er t"is in#ormation about recent c"emot"erap. @eceipt o# sstemic antineoplastic t"erap wit"in t"e preceding si! wee$s "as been advocated #or use in emer genc triage departments to identi# patients w"o are li$el to be neutropenic. Ti,ing o& anti3iotic! — "e guidelines o# t"e +n#ectious Diseases or$ing art o# t"e -erman 'ociet o#
t"e states o# neutropenic #ever must be ascertained. aborator con#irmation o# neutropenia ma not be ac"ievable in t"e recommended time#rame o# one "our. Accordingl, t"e inde! o# suspicion based upon limited patient "istor wit" or wit"out vital signs must be raised ver earl in t"e triage process b ta$ing a medical "istor. "e ris$ o# neutropenia, along wit" in#ormation obtained #rom basic vital signs, can be used to develop a management plan and administer initial empiric antibacterial t"erap even be#ore t"e results o# basic laborator investigations are av ailable Diagno!tic eva#uation — nce empiric antibacterial t"erap "as been started, all patients s"ould "ave a t"oroug" "istor and detailed p"sical e!amination, as well as laborator, microbiolog, and imaging studies /table . "is is discussed in detail separatel. Treat,ent regi,en! — "e aim o# empiric t"erap is to cover t"e most li$el and most virulent pat"ogens t"at ma rapidl cause serious or li#e(t"reatening in#ection in neutropenic patients /table 2 )2*. Alt"oug" antibiotics are usuall administered empiricall, t"e s"ould alwas include appropriate coverage #or suspected or $nown in#ections. ?ven w"en t"e pat"ogen is $nown, t"e antibiotic regimen s"ould provide broad(spectrum empiric coverage #or t"e possibilit o# ot"er pat"ogens, unli$e t"e treatment strateg adopted in man immunocompetent "osts. +nitial antibiotic selection s"ould be guided b t"e patient3s "istor, allergies, smptoms, signs, recent antibiotic use and culture data, and awareness o# t"e susceptibilit patterns o# institutional nosocomial pat"ogens )5*. Consideration o# t"e ris$ o# antibiotic(resistant organisms "as emerged as a #actor t"at impacts t"e c"oice o# empiric t"erap and targeted t"erap once a pat"ogen "as been identi#ied, as well as outcomes. 'peci#ic treatment regimens #or patients presenting wit" neutropenic #ever w"o are "ig" ris$ or low ris$ #or serious complications are discussed separatel.. SOCIETY %UIDELINE LIN/S — in$s to societ and government(sponsored guidelines #rom selected countries and regions around t"e world are provided s eparatel. /'ee N'ociet guideline lin$sF eutropenic #ever in adu lts wit" cancerN. INFORM'TION FOR P'TIENTS — IpoDate o##ers two tpes o# patient education materials, R"e ;asicsS and R;eond t"e ;asics.S "e ;asics patient education pieces are written in plain language, at t"e 5 t" to 6t" grade reading level, and t"e answer t"e #our or #ive $e Luestions a patient mig"t "ave about a given condition. "ese articles are best #or patients w"o want a general overview and w"o pre#er s"ort, eas(to(read materials. ;eond t"e ;asics patient education pieces are longer, more sop"isticated, and more detailed. "ese articles are written at t"e 10t" to 12t" grade reading level and are best #or patients w"o want in(dept" in#ormation and are com#ortable wit" some medical :argon.
GAn in#ectious source is identi#ied in appro!imatel 20 to 0 percent o# #ebrile neutropenic episodes. #ten t"e onl evidence o# in#ection is bacteremia, w"ic" is documented in 10 to 25 percent o# patients. Appro!imatel 40 percent o# identi#ied in#ections are believed to arise #rom t"e patient3s endogenous #lora. -ram(positive bacteria are t"e most common causes o# in#ection in neutropenic patients, but gram(negative bacteria /eg, Pseudomonas aeruginosa are generall associated wit" t"e most serious in#ections. "e able lists t"e range o# pat"ogens #ound in patients wit" c"emot"erap(induced neutropenia /table 2. /'ee 3?pidemiolog3 above. G9ungal pat"ogens are more common in "ig"(ris$ patients wit" prolonged persistent or recrudescent neutropenic #ever sndromes but are uncommon in low(ris$ patients. Candida and #spergillus spp account #or most invasive #ungal in#ections during neutropenia. /'ee 39ungal pat"ogens3 above. GA reliable met"od #or obtaining bod temperature must be used, and a mec"anism #or estimating t"e AC is mandator /see 3emperature measurement3 above and 3eutropenia3 above. "e ris$ o# neutropenia, t"e ris$ o# complications #rom neutropenic #ever, and t"e ris$ o# sepsis must be assessed Luic$l. Gatients and t"eir #amilies s"ould be instructed b t"eir oncologist to in#orm "ealt"care providers in t"e triage setting about recent c"emot"erap, and providers in t"e triage setting s"ould as$ cancer patients w"o do not o##er t"is in#ormation about recent c"emot"erap. @eceipt o# sstemic antineoplastic t"erap wit"in t"e preceding si! wee$s "as been advocated #or use in emergenc triage departments to identi# patients w"o are li$el to be neutropenic. /'ee 3+nitial assessment3 above. G+n all patients presenting wit" neutropenic #ever, empiric initial broad(spectrum antibacterial t"erap s"ould be initiated immediatel a#ter blood cultures "ave been obtained and be#ore an ot"er investigations "ave been completed. ?mpiric antibacterial t"erap s"ould be started wit"in 60 minutes o# presentation in all patients presenting wit" neutropenic #ever /algorit"m 1. 'ome investigators "ave argued t"at initial empiric antimicrobial t"erap s"ould be administered wit"in 0 minutesM we agree t"at antibiotics s"ould be given as earl as possible. /'ee 3iming o# antibiotics3 above. Gnce empiric antibacterial t"erap "as been started, all patients s"ould "ave a care#ul "istor and detailed p"sical e!amination as well as laborator, microbiolog, and imaging studies /table . /'ee NDiagnostic approac" to t"e adult presenting wit" neutropenic #everN. G'peci#ic treatment regimens #or "ig"(ris$ and low(ris$ patients presenting wit" neutropenic #ever are discussed separatel.