1

Infection in

immunocompromised host

MUDr. Vanda ChrenkováMUDr. Eliška Bébrová

ÚLM 2. LF UK a FN Motol

ImmunodeficiencyImmunodeficiency

•• generalgeneral protectiveprotective mechanismsmechanisms–– skin skin surfacesurface, , mucosamucosa ((sweatsweat, , mucusmucus, , ciliacilia, , stomacstomac, , intestinalintestinal flora)flora)

•• immunologicalimmunological mechanismmechanism–– innateinnate

•• humoralhumoral –– complementcomplement

•• celularcelular –– phagocytesphagocytes (PMN, (PMN, MoMo--MaMa) a NK) a NK--cellscells

–– adaptiveadaptive

•• humoralhumoral –– antibodiesantibodies

•• celularcelular –– T a B T a B lymphocyteslymphocytes

Šedivá, Klinická pediatrie 2012

Primary immunodeficiencyPrimary immunodeficiency

•• very rarevery rare

•• genomic disorders genomic disorders –– mutationsmutations•• antibody antibody -- relatedrelated•• cellular and combinedcellular and combined•• phagocytes deficiencyphagocytes deficiency•• complement deficiencycomplement deficiency

Šedivá, Klinická pediatrie 2012

Secondary immunodeficiencySecondary immunodeficiency

•• very frequent, multiple, diversevery frequent, multiple, diverse•• worldwide worldwide –– malnutrition and HIVmalnutrition and HIV•• in in ČČRR

–– metabolic disorders (DM)metabolic disorders (DM)–– IS therapyIS therapy–– malnutrition, GIT disorders, longmalnutrition, GIT disorders, long--term reduction dietsterm reduction diets–– alcoholismsalcoholisms–– ageage–– severe injurysevere injury–– post post ––viral infection, chronic infectionviral infection, chronic infection–– chronic exposition to chemical pollutantschronic exposition to chemical pollutants–– chronic stress situationchronic stress situation–– severe hepatic disorderssevere hepatic disorders–– lympho/myeloprolipherative disorderslympho/myeloprolipherative disorders–– immunocompleximmunocomplex diseasesdiseases–– sepsissepsis

Šedivá, Klinická pediatrie 2012

AntiAnti--bacterialbacterial immunityimmunity

1.1. extracellular bacteria (extracellular bacteria (S. pyogenes, S. pneumoniae, S. pyogenes, S. pneumoniae, Staphylococcus, Neisseria, Haemophilus, Staphylococcus, Neisseria, Haemophilus, Salmonella, Shigella, PseudomonasSalmonella, Shigella, Pseudomonas...)...)

1.1. opsonisation opsonisation →→ neutrophils/macrophages neutrophils/macrophages →→NADPHNADPH--oxidase oxidase →→ ILIL--1, IL1, IL--6, TNF6, TNF

2.2. later Blater B--ly ly →→ IgM with help of TIgM with help of T--ly IgGly IgG3.3. g+g+ bacteria bacteria –– phagocytosisphagocytosis4.4. gg--bacteria (LPS) bacteria (LPS) –– susceptible to membrane lysis by susceptible to membrane lysis by

complement, cytotoxic cellscomplement, cytotoxic cells–– toxin production toxin production –– neutralising antibodiesneutralising antibodies–– mucosal IgAmucosal IgA–– complement activation by specific antibodiescomplement activation by specific antibodies

Hořejší, Imunologie 2013

2. 2. intracellularintracellular bacteriabacteria andand fungifungi ((Yersinia, Yersinia, mycobacteriamycobacteria,,Listeria, BrucellaListeria, Brucella))

1.1. macrophagesmacrophages oror dendriticdendritic cellscells →→ ILIL--12 12 →→ Th1Th1--ly ly →→IFNIFN--γγ →→ NONO

2.2. TcTc--lyly

Hořejší, Imunologie 2013

AntiAnti--bacterialbacterial immunityimmunity

2

AntiAnti--viralviral immunityimmunity

•• innateinnate immunityimmunity

–– IFNIFN--αα a IFNa IFN--ββ, NK, NK--cellscells

–– infestedinfested macrophagesmacrophages →→ ILIL--12 12 –– protectionprotection fromfrom earlyearly infectioninfection

•• protilprotiláátkytky

–– mucosalmucosal IgAIgA

–– afterafter organismorganism penetrationpenetration –– neutralisingneutralising IgG, IgM IgG, IgM →→ complementcomplement

•• protectionprotection to to viralviral disseminationdissemination –– neutralisationneutralisation, , blocksblocks rere--infectioninfection

–– TTC C –– lymphocyteslymphocytes –– damagedamage to to infestedinfested cellscells beforebefore viralviral replicationreplication

•• escapeescape immuneimmune mechanismsmechanisms

–– latencylatency, , antigenicantigenic variationvariation, , decoydecoy proteinsproteins

–– host genome host genome integrationintegration (varicella, EBV, papillomaviry)(varicella, EBV, papillomaviry)

Hořejší, Imunologie 2013

AntiAnti--parasite parasite immunityimmunity

protozoaprotozoa–– eextracellularxtracellular parasites (parasites (Entamoeba histolytica, Giardia lambliaEntamoeba histolytica, Giardia lamblia) ) ––

antibodiesantibodies

–– iintracellularntracellular ((Leishmania, Toxoplasma gondii, Plasmodium, Leishmania, Toxoplasma gondii, Plasmodium,

TrypanosomaTrypanosoma) ) -- CD4+ i CD8+ Th1CD4+ i CD8+ Th1--ly a macrophagesly a macrophages

helminthelminthshs

–– ILIL--44

–– tissue infection tissue infection -- typically typically ↑↑ EoEo and circulating IgE;and circulating IgE;

–– intestinal infection intestinal infection -- Th2Th2--lyly

Hořejší, Imunologie 2013

AntiAnti--fungal fungal immunityimmunity

•• innate cellular innate cellular –– phagocytes (PRRs = pattern recognition phagocytes (PRRs = pattern recognition receptors receptors –– direct and indirect recognition)direct and indirect recognition)

–– neutrophils, monocytes, macrophages, dendritic cellsneutrophils, monocytes, macrophages, dendritic cells

–– →→ oxidative burns, NO, antimicrobial peptides, hydrolyses, starvaoxidative burns, NO, antimicrobial peptides, hydrolyses, starvationtion

–– TLR, DectinTLR, Dectin--1, Mannose receptor...1, Mannose receptor...

•• stimulation of adaptive Th1, Th2 i Th17 responsestimulation of adaptive Th1, Th2 i Th17 response

Brown, ARI 2011

Opportunistic pathogensOpportunistic pathogens

•• nonnon--invasive or noninvasive or non--pathogenic in immunocompetent hostpathogenic in immunocompetent host

NeutropeniaNeutropenia

•• polymorphonuclearpolymorphonuclear leucocytes (PMN) < 500/mmleucocytes (PMN) < 500/mm33

–– chemotherapy, acute leukaemia, radiotherapy, early allogeneic stchemotherapy, acute leukaemia, radiotherapy, early allogeneic stem cell em cell transplanttransplant

•• Aetiology:Aetiology:

–– GG--rods (rods (Pseudomonas aeruginosa, enterobakterie, Acinetobacter spp.,Pseudomonas aeruginosa, enterobakterie, Acinetobacter spp.,

Stenotrophomonas maltophilia)Stenotrophomonas maltophilia)

–– G+ cocciG+ cocci ((Staphylococcus aureus, Staphylococcus aureus, Staphylococci coagulase negative, Staphylococci coagulase negative, viridans streptococci ,viridans streptococci ,Enterococcus faecalisEnterococcus faecalis a a Enterococcus faecium)Enterococcus faecium)

–– Fungi (CFungi (Candida sp., Aspergillus sp., Mucor sp.andida sp., Aspergillus sp., Mucor sp. ))

•• febrile neutropenia, sepsis, less bacterial pneumonia, necrotisifebrile neutropenia, sepsis, less bacterial pneumonia, necrotising ng enterocolitis, hepatolienal candidiasis, skin infections enterocolitis, hepatolienal candidiasis, skin infections

Rozsypal, 2008

Febrile neutropeniaFebrile neutropenia

•• PMN < 500/mm3 (or <1000/mm3 tending to decrease in 48 h) PMN < 500/mm3 (or <1000/mm3 tending to decrease in 48 h) and TT >38,5and TT >38,5°°C (or twice > 38C (or twice > 38°°C)C)

•• other symptomsother symptoms

–– nonnon--specific signs specific signs –– apathy, confusion, hypotension, decompensation apathy, confusion, hypotension, decompensation of DM ...of DM ...

–– ↑↑ CRP and procalcitoninCRP and procalcitonin

Beneš, Infekce, 2009

3

•• dg. focus ???dg. focus ???

–– DCD, GITDCD, GIT

–– blood culture, PCR, culture, microscopy blood culture, PCR, culture, microscopy –– direct detection direct detection

•• th. th. →→ aggressive bactericidal therapyaggressive bactericidal therapy

–– highhigh--risk patientsrisk patients

•• 1.choice 1.choice –– enterobacteriaenterobacteria, staphylococci, streptococci, , staphylococci, streptococci, pseudomonas (broadpseudomonas (broad--spectrum antibiotics)spectrum antibiotics)

•• event. + event. + aminoglykosidesaminoglykosides, , vankomycinevankomycine

•• consideration of immediate antifungal therapy consideration of immediate antifungal therapy initiationinitiation

–– lowlow--risk patients risk patients –– good clinical conditiongood clinical condition

•• amoxiciline/clavulanateamoxiciline/clavulanate + + gentamicine/fluoroquinolonegentamicine/fluoroquinolone

Beneš, Infekce, 2009

FebrileFebrile neutropenianeutropenia Antibody disordersAntibody disorders

•• hypogamaglobulinaemiahypogamaglobulinaemia <2,5g/l <2,5g/l –– opsonisation disabilities of capsulated opsonisation disabilities of capsulated bacteriabacteria

•• myeloma, lymphatic leukaemia, losses/synthesis failure myeloma, lymphatic leukaemia, losses/synthesis failure –– longlong--term term diarrhoea, celiac disease, proteinuria, burns, severe injuriesdiarrhoea, celiac disease, proteinuria, burns, severe injuries

•• AeAetiologtiologyy::

–– Streptococcus pneumoniaeStreptococcus pneumoniae

–– Haemophilus influenzaeHaemophilus influenzae

–– Escherichia coliEscherichia coli..

•• symptoms: respiratory infections (symptoms: respiratory infections (mesotitismesotitis, sinusitis, bacterial , sinusitis, bacterial pneumonia), gastrointestinal infection (gastroenteritis), pneumonia), gastrointestinal infection (gastroenteritis), uroinfectionsuroinfections, , skin infections, skin infections, neuroinfectionneuroinfection (purulent meningitis).(purulent meningitis).

Rozsypal, 2008

ImmuneImmune cell cell disordersdisorders

•• T lymphocytes <1000/mmT lymphocytes <1000/mm33 or CD4+ ly <500or CD4+ ly <500--200/mm200/mm33) )

•• →→ intracellular microorganismsintracellular microorganisms

•• examplesexamples

–– HIV HIV

–– immunosuppressive therapy immunosuppressive therapy

–– transient decrease after viral infectiontransient decrease after viral infection

•• measles, rubella...measles, rubella...

–– production failure of myeloid cell in bone marrow (pharmacotheraproduction failure of myeloid cell in bone marrow (pharmacotherapy, py, irradiation)irradiation)

–– uptake in spleenuptake in spleen

–– phagocytes dysfunctions (metabolic disorders, phagocytes dysfunctions (metabolic disorders, myeloprolipherativemyeloprolipherative d.)d.)

Rozsypal, 2008

CellularCellular immunityimmunity disordersdisorders

AetiologyAetiology::

1.1. BacteriaBacteria ((Mycobacterium tuberculosisMycobacterium tuberculosis a a atypicalatypical mycobacteriamycobacteria, , Salmonella enterica,Salmonella enterica, Legionella pneumophila, Listeria monocytogenes, Legionella pneumophila, Listeria monocytogenes,

Nocardia sp.Nocardia sp.

2.2. FungiFungi ((Pneumocystis jiroveci, Candida sp., Cryptococcus neoformans, Pneumocystis jiroveci, Candida sp., Cryptococcus neoformans,

Histoplasma capsulatumHistoplasma capsulatum, Aspergillus, Mucorales, Aspergillus, Mucorales

3.3. VirusesViruses ((CytomegalovirusCytomegalovirus, , Herpes simplex virusHerpes simplex virus, Varicella, Varicella--zoster virus, zoster virus, EpsteinEpstein--BarrovBarrovéé virus )virus )

4.4. ParasitesParasites ((Toxoplasma gondiiToxoplasma gondii, , Cryptosporidium parvumCryptosporidium parvum, Mikrosporidie, , Mikrosporidie, Strongyloides stercoralisStrongyloides stercoralis ))

Rozsypal, 2008

Clinical symptoms: Clinical symptoms:

•• pneumonia (fungal, Legionella, Pneumocystis, Cytomegalovirus), pneumonia (fungal, Legionella, Pneumocystis, Cytomegalovirus), tuberculosis pulmonary and tuberculosis pulmonary and extrapulmonaryextrapulmonary, , mycobacteriosismycobacteriosis

•• gastrointestinal infection (gastrointestinal infection (oesophagitisoesophagitis -- candidialcandidial, , cytomegaloviralcytomegaloviral, , herpetic; intestinal cryptosporidiosis, herpetic; intestinal cryptosporidiosis, perianalperianal cellulitiscellulitis or abscess), or abscess), hepatic infection (hepatic infection (cytomegaloviralcytomegaloviral hepatitis), hepatitis),

•• skin infection (herpetic, skin infection (herpetic, ectymaectyma, gangrene), , gangrene),

•• neuroinfectionneuroinfection (purulent meningitis (purulent meningitis -- Listeria, Listeria, CorynebacteriaCorynebacteria, , meningitis meningitis cryptococcalcryptococcal, , tuberculoustuberculous), ),

•• fungemiafungemia [Candida, Aspergillus],[Candida, Aspergillus],

•• progressive multifocal progressive multifocal leukoencephalopathyleukoencephalopathy (PML)(PML)

•• JC virus (JC virus (polyomaviruspolyomavirus))

Rozsypal, 2008

Cellular immunity disordersCellular immunity disorders Infection in transplant recipientsInfection in transplant recipients

•• immunosupressiveimmunosupressive therapy therapy →→ graft tolerance graft tolerance –– combinations combinations -- cyclosporine, cyclosporine, azathioprineazathioprine, , gusperimegusperime and and

corticosteroids; tacrolimus corticosteroids; tacrolimus ččii mykofenolatmykofenolat mofetilmofetil, event. with anti, event. with anti--lymphocyte antibodies and lymphocyte antibodies and actinotherapyactinotherapy

•• mechanisms mechanisms –– susceptibility of the graft (locus susceptibility of the graft (locus minorisminoris resistentiaeresistentiae))–– exposition to specific exposition to specific agensagens (nosocomial)(nosocomial)–– microorganisms in the graft microorganisms in the graft –– latent donor infectionlatent donor infection

•• herpetic viruses (CMV, EBV, HHVherpetic viruses (CMV, EBV, HHV--6), hepatic viruses (HBV, HCV), 6), hepatic viruses (HBV, HCV), retroviruses (HIV), adenoviruses, retroviruses (HIV), adenoviruses, papillomavirusespapillomaviruses

•• Toxoplasma gondiiToxoplasma gondii

•• exceptionally exceptionally –– arbovirusarbovirus, , malaricmalaric plasmodia, plasmodia, leishmanialeishmania

Rozsypal, 2008

4

Infection after aggressive Infection after aggressive

cytostatic therapycytostatic therapy•• cellular immunitycellular immunity

–– memory lymphocytes a plasmatic cells partially keep the memory lymphocytes a plasmatic cells partially keep the functionality and antibodiesfunctionality and antibodies´́ halfhalf--life is several weeks, but life is several weeks, but there are no reactions to new antigenic stimulus, stops there are no reactions to new antigenic stimulus, stops prolipherationprolipheration and differentiation of lymphocytes and and differentiation of lymphocytes and cellular immunity starts malfunctioningcellular immunity starts malfunctioning

•• reactivation of latent infections reactivation of latent infections –– herpetic viruses, herpetic viruses, adenoviruses, tuberculosis, toxoplasmosisadenoviruses, tuberculosis, toxoplasmosis

•• risk of opportunistic infections risk of opportunistic infections –– Listeria, Aspergillus, Listeria, Aspergillus, Pneumocystis...Pneumocystis...

–– incidence of opportunistic infection 1 incidence of opportunistic infection 1 –– 6 months post 6 months post chemotherapychemotherapy

Beneš, Infekce, 2009

Infection after aggressive Infection after aggressive

cytostatic therapycytostatic therapy

•• highhigh--dose cytostaticdose cytostatic thth.. event. with corticosteroidsevent. with corticosteroids

–– especially haematooncological malignancyespecially haematooncological malignancy

–– severe autoimmune diseasessevere autoimmune diseases

–– transplant medicine transplant medicine –– stem cellsstem cells

•• damage to dividing cellsdamage to dividing cells

–– rapid onset of neutropeniarapid onset of neutropenia

–– mucositismucositis•• painful inflammation and ulceration of oral cavity and gut mucospainful inflammation and ulceration of oral cavity and gut mucosa a

(like herpetic (like herpetic stomatitisstomatitis))

•• 3rd degree 3rd degree –– cannot eat, 4th degree cannot eat, 4th degree –– cannot drinkcannot drink

–– development on 3th to 5th day (max 10th day) and slow development on 3th to 5th day (max 10th day) and slow retreat in several weeksretreat in several weeks Beneš, Infekce, 2009

Infection Infection afterafter „„biologicalbiological““ therapytherapy

•• drugs influencing intercellular communication drugs influencing intercellular communication -- interleukinesinterleukines and other and other signal moleculessignal molecules

–– monoclonal antibodies artificial (rituximab, alemtizumab, monoclonal antibodies artificial (rituximab, alemtizumab, bevacizumab, abciximab...)bevacizumab, abciximab...)

–– antianti-- TNFTNF--αα

–– deterioration of infection process, in longdeterioration of infection process, in long--term administration term administration possible activation of latent infections (TBC) and atypical infepossible activation of latent infections (TBC) and atypical infections ctions pneumocystispneumocystis pneumonipneumoniaa, invasive fungal diseases, , invasive fungal diseases, listeriosislisteriosis, , mycobacteriosismycobacteriosis

Beneš, Infekce, 2009

Infection on Infection on corticosteroidscorticosteroids

Janeway 2007

Infection on Infection on corticosteroidscorticosteroids

•• complexcomplex interventionintervention in in immuneimmune mechanismsmechanisms (B(B-- andand TT--lymphocyteslymphocytes, , neutrophilesneutrophiles, monocytes , monocytes andand productionproduction ofof cytokinescytokines))

•• intracellularintracellular pathogenspathogens•• severityseverity ofof immunosupressionimmunosupression correlatedcorrelated withwith the the dailydaily dosagedosage•• AetiologyAetiology::

–– BacteriaBacteria (Staphylococcus sp., Salmonella sp., Mycobacterium tuberculosis(Staphylococcus sp., Salmonella sp., Mycobacterium tuberculosis))–– FungiFungi (Candida sp., Cryptococcus neoformans, Aspergillus sp., (Candida sp., Cryptococcus neoformans, Aspergillus sp.,

Pneumocystis jiroveci)Pneumocystis jiroveci)–– VirusesViruses ((HerpeticHerpetic virusesviruses -- HSV, VZV)HSV, VZV)

•• ClinicalClinical symptomatologysymptomatology:: PneumoniaPneumonia ((bacterialbacterial, fungal), , fungal), pulmonarypulmonarytuberculosis, tuberculosis, pulmonarypulmonary aspergillosis, aspergillosis, gastrointestinalgastrointestinal infection infection ((gastroenteritisgastroenteritis), ), hepatichepatic infection (CMV), infection skin infection (CMV), infection skin andand soft soft tissuetissue((pyodermiapyodermia, herpes zoster), , herpes zoster), neuroinfectionneuroinfection ((purulantpurulant meningitis, meningitis, ListeriaListeria, , CryptococcusCryptococcus))

Rozsypal, 2008

Infection post Infection post splenectomysplenectomy

•• absence absence ofof destructiondestruction ofof nonnon--opsonisatedopsonisated encapsulatedencapsulatedbacteriabacteria

•• AetiologyAetiology:: Streptococcus pneumoniaeStreptococcus pneumoniae, , Haemophilus Haemophilus

influenzae,influenzae, Neisseria Neisseria meningitidismeningitidis), ), rarelyrarely PlasmodiumPlasmodium andandBabesiaBabesia

•• ClinicClinic:: PeracutePeracute pneumococcalpneumococcal sepse (sepsis acutissima, sepse (sepsis acutissima, overwhelming pneumococcal sepsis syndrome, overwhelming overwhelming pneumococcal sepsis syndrome, overwhelming postsplenectomy infection, OPSI), severe postsplenectomy infection, OPSI), severe malariamalaria, , babesiosisbabesiosis

•• ProphylaxisProphylaxis:: VaccinationVaccination, , chemoprophylaxischemoprophylaxis (penicilin, co(penicilin, co--amoxicilin, kotrimoxazol) post amoxicilin, kotrimoxazol) post splenectomysplenectomy (<3 roky) (<3 roky) andand in in asplenicasplenic childrenchildren (<5 (<5 yrsyrs).).

Rozsypal, 2008

5

Infections in diabetesInfections in diabetes

Definition:Definition: malfunction malfunction of of fagocytfagocyteses because of intracellular because of intracellular absence of absence of gglucosalucosa

Clinical presentationClinical presentation::

•• PneumoniPneumoniaa (ba(baccteriteriaal, l, fungalfungal), ), urouroinfecinfectiontion, , neuroinfecneuroinfectiontion(cerebr(cerebraal mul muccormyormycosiscosis), ), skin and mucosa skin and mucosa infeinfectionsctions((vulvovaginitivulvovaginitiss, , balanitibalanitiss, , pyodermipyodermiaa, erysipel, erysipelasas, , CCandidandidaaintertrigo, intertrigo, dermatodermatophphytyteses, herpes zoster), , herpes zoster), soft tissue soft tissue infecinfectiontion, diabetic , diabetic footfoot..

•• infections are prolonged and infections are prolonged and visvis versa the infection can lead versa the infection can lead to diabetes decompensationto diabetes decompensation

TThheraperapyy:: necessity ofnecessity of euglyeuglycecemimiaa..

Rozsypal, 2008

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