INFECTIONS IN IMMUNE INFECTIONS IN IMMUNE COMPROMISED

John A. Molinari, Ph.D.John A. Molinari, Ph.D.

Director of Infection ControlDirector of Infection ControlTHE DENTAL ADVISORTHE DENTAL ADVISOR

Ann Arbor, MichiganAnn Arbor, Michigan

INFECTIONS IN IMMUNEINFECTIONS IN IMMUNECOMPROMISED PATIENTSCOMPROMISED PATIENTS

Major Immune SystemsMajor Immune SystemsRequired for Host DefensesRequired for Host Defenses

Innate: non-specific, inborn1. Phagocytosis2. Complement

Acquired: specific, adaptive1. Humoral immunity -- antibodies2. Cellular immunity -- sensitized T cells

Immune Compromised PersonImmune Compromised Person

person with impairments in the body’s normal mechanisms of defense against infection.

individual with 1 or more defects in body’s normal defense mechanisms that predispose them to infections, often opportunistic and life-threatening, that would otherwise not occur.

increasing % of population.degree of immune deficiency can vary with time &

therapy.

Categories of Host Defects Associated with Categories of Host Defects Associated with Impaired ResistanceImpaired Resistance

1. defects in cutaneous barriers: (severe dermatological conditions)2. mucous membrane barrier defects: (mucositis; trauma, smoking)3. conditions that cause obstruction of a natural body passage:

(neoplasia; foreign bodies; cystic fibrosis) 4. abnormal number of functional granulocytes: (leukemia, anti-

neoplastic chemo; aplastic anemia; diabetes; congenital disorders)5. cell-mediated immunity abnormalities: (HIV; chemotherapy; aging;

BM transplantation; corticosteroids; severe malnutrition)6. humoral immunity abnormalities: (BM transplantation; aging; HIV;

chronic lymphocytic leukemia; congenital deficiencies; acquired hypogammaglobulinemia)

7. pts with multiple immune defects: aging; severe trauma; alcoholism; obesity; splenectomy; corticosteroids; chemotherapy)

APIC Text IC Epid (2009)

Clinical Disease ManifestationsClinical Disease ManifestationsMay be different in immune compromised

host vs. immune competent person:1. accelerated pace of disease progression.2. initial minor infections may become life-

threatening.3. granulocytopenic patients develop little

purulence at localized infection sites.4. elderly patients may only show confusion as

infection sign.5. patients on corticosteroids may have

diminished fever response to infection.APIC Epid Text (2009)

Early Immunoglobulin Development Early Immunoglobulin Development In Fetus & InfantIn Fetus & Infant

Congenital Immunodeficiency Congenital Immunodeficiency Syndromes: Antibody SynthesisSyndromes: Antibody Synthesis

Selective IgA Deficiency:- most common inherited specific Ab deficiency.- noted in 1 of 700 - 800 persons. - no obvious disease susceptibility.- occurs more commonly in people with chronic

lung disease.- diminished secretory immune protection.- more common than diagnosed ? - increased susceptibility to acute GI, respiratory,

oral infections.

Immunodeficiency ClassificationImmunodeficiency ClassificationCongenital:

- genetically inherited defects.- recessive / autosomal; X chromosome mutations.- recessive defects cause disease when both X

chromosomes have defect -- thus, males with genetic defect in single X chromosome will manifest disease.

- females can be healthy carriers of a specific genetic abnormality.

- before advent of antibiotics & fetal genetic testing, most individuals died in infancy or early childhood.

Immunodeficiency ClassificationImmunodeficiency Classification

Secondary (Acquired): - many extrinsic causes.- defects in T – cells, B – cells, or both.- can also develop as sequelae to initial

microbial infection. - multiple immune defects can occur in

same person (i.e. elderly cancer patient on cancer chemotherapy).

Representative Secondary (Acquired) Representative Secondary (Acquired) Immune Deficiency ConditionsImmune Deficiency Conditions

- Malnutrition - Transplantation- Neoplasia - Parenteral Drug Abuse - Anti-neoplastic therapy - Diabetes- Effects of aging - Alcoholic cirrhosis- Asplenia - Chronic hepatitis B or C- Trauma - Arthritis- Autoimmune conditions - HIV / AIDS - Other chronic infections - End stage renal disease

(uremia & dialysis)

HIV / AIDS HIV / AIDS

Debilitated Cellular Immunity Defenses:- Kaposi’s sarcoma & other neoplasms- opportunistic fungal & viral infections- severe viral recurrences ( i.e. herpesviruses) - intracellular bacterial infections (i.e. TB) - condyloma acuminatum (maxillofacial; genital)- rapidly progressing periodontal diseases- other unusual microbial & parasitic infections

Oral Infections / Manifestations OfOral Infections / Manifestations OfHIV DiseaseHIV Disease

Fungal Lesions:

- CandidiasisBacterial Lesions:

- Linear Gingival Erythema (HIV-gingivitis)- Necrotizing Ulcerative Gingivitis (NUG),

Periodonitis (NUP), & Stomatitis (NUS)Viral Lesions:

- Oral Hairy Leukoplakia - CMV Infection- HSV Infection - Papillomavirus Infection

Changing Patterns of HIV / AIDS Changing Patterns of HIV / AIDS Opportunistic Infections Opportunistic Infections

Widespread use & success of combination antiretroviral therapy (beginning in 1996): - observed PCP decline, disseminated M. avium

complex (MAC), & invasive cytomegalovirus disease decreases.

- HIV – related immune suppression impt. - respiratory illness: TB & endemic fungal

infections (histoplasmosis, coccidiomycocis). - 100x greater risk invasive pneumococcal

disease.



(uremia & dialysis)

AcquiredImmunodeficiencies

Are MoreThan AIDS

Mycotic Infections: Indicators OfMycotic Infections: Indicators OfPrimary or Secondary DeficiencyPrimary or Secondary Deficiency

Candida albicans:common opportunistic pathogen in many immune compromised persons.

Selective Infection Pressures:- immunosuppression (CA, HIV, diabetes)- changes in normal flora- antibiotic chemotherapy- prolonged steroid therapy



(uremia & dialysis)

NeoplasiaNeoplasiaAcute Leukemia:- infection major cause of death.- mostly opportunistic infections.- gram-bacilli, fungi, herpesviruses.- severe decrease in mature functioning

granulocytes purulence in infections can be diminished or absent.

- neutrophils show impaired ability to migrate. - diminished bactericidal chemotaxis.

NeoplasiaNeoplasia

Chronic Lymphocytic Leukemia:- usually involves B - lymphocytes.- affects humoral (Ab) immune responses.- secondary hypogammaglobulinemia, with

secondary bacterial infection.- primarily respiratory bacterial infections. - encapsulated bacteria: pneumococci,

H. influenzae, group A streptococci.



(uremia & dialysis)

AntiAnti--Neoplastic TherapyNeoplastic Therapy

Representative General Adverse Effects:- bone marrow suppression- generalized edema- alopecia - cystitis - pulmonary fibrosis- bleeding tendencies (due to thrombocytopenia)- ulceration of mucosa tissues- allergic reactions to prolonged drug regimens

AntiAnti--Neoplastic TherapyNeoplastic Therapy

Representrative Maxillofacial / Intra-oral Adverse Effects:- allergic reactions to anti-neoplastic agents- intra-oral ulceration- gingival tissue edema - decreased tolerance of stress of dental visits

(due to steroid therapy) - opportunistic fungal infections ( Candida sp.)


- Malnutrition - Transplantation- Neoplasia - Parenteral Drug Abuse - Anti-neoplastic therapy - Diabetes- Effects of aging - Alcoholic cirrhosis- Asplenia - Chronic hepatitis B or C- Trauma - Arthritis- Autoimmune conditions - HIV / AIDS- Other chronic infections - End stage renal disease

(uremia & dialysis)


- Malnutrition - Transplantation- Neoplasia - Parenteral Drug Abuse- Anti-neoplastic therapy - Diabetes- Effects of aging - Alcoholic cirrhosis- Asplenia - Chronic hepatitis B or C- Trauma - Arthritis- Autoimmune conditions - HIV / AIDS - Other chronic infections - End stage renal disease

(uremia & dialysis)

Immunosuppression In DiabetesImmunosuppression In Diabetes

Est. 7% US adults (8 million).Susceptible to many local & systemic infections.Certain infections tend to be more common.Impaired Innate Cellular Defenses:- PMN abnormalities - adherence, chemotaxis,

phagocytosis, intracellular microbial killing.- prolonged, less effective, pathogen response. - susceptible to metastatic acute infections.- abnormalities in maocytes / macrophages .

Immunosuppression In DiabetesImmunosuppression In Diabetes

Humoral Immunity:- normal Ab levels & vaccination responses.

Cellular Immunity:- decreased T- lymphocyte responses.- abnormal Type IV (delayed) hypersensitivity.

Infections In Diabetics Infections In Diabetics

Head & Neck Infections:Occurring Predominantly (>50%) in Diabetics:

- rhinocerebral mucormycosis - severe otitis externa (multiple causes)

Increased Incidence in Diabetics:- oral candidiasis- esophageal candidiasis- surgical / wound infection

Mucormycosis (Phycomycocis)Mucormycosis (Phycomycocis)

Rare, often fatal, opportunistic fungal infection.Etiologic agents: Rhyzopus; Absidia, Mucor sp.

“common bread molds”Infections most often associated with immune compromised persons (uncontrolled diabetes, liver cirrhosis, cancer, transplant patients).Increased # reported cases in recent years !Clinical Forms:- Rhinocerebral - Pulmonary- Gastrointestinal - Disseminated



(uremia & dialysis)

ID Contributary Factors In Transplant Pts ID Contributary Factors In Transplant Pts

Infection 2nd most impt problem post-transplantationPre-transplant Host Factors:

- ongoing medical conditions (HBV, HCV, diabetes)- lack of specific immunity ( susceptible to primary

EBV, VZV, CMV, etc)- prior MO colonization ( Candida, staph, VRE)- prior latent infection (TB, CMV, HSV, VZV)- prior medications (i.e. immunosuppressives,

antibiotics)

ID Contributary Factors In Transplant Pts ID Contributary Factors In Transplant Pts

Transplant factors:- type of transplant (common infection site)- surgery trauma Immunosuppression:

- immunosuppressive drugs Allograft Reactions:

- graft-vs-host reaction (cofactor in CMV &fungal infection)

- host-vs-graft reaction ?

Common Microbial Etiologies PostCommon Microbial Etiologies Post--TransplantationTransplantation

Bacteria: common gm+ & gm- flora- local contaminant infections & can spread

Fungi: Candida sp.; Aspergillus sp.; Pneumocystis- superficial mycoses which can metastizize- Candida common in liver transplant pts- Aspergillosis airborne from environment

Viruses: Herpesviruses; Papillomaviruses- many donors latently infected

Most Common Infection Source:Other people !



(uremia & dialysis)

Autoimmune Diseases:Autoimmune Diseases:Systemic Lupus Erythematosus (SLE)Systemic Lupus Erythematosus (SLE)

Multiple infection risk factors: 1. functional defect in phagocytic cells.2. CMI defects: lymphopenia, CD4 - cell

lymphopenia, & decreased cytokines.3. reduced Ab levels & low complement levels. 4. low capacity to eliminate microbes -- due to

functional asplenia.5. also, corticosteroids & immunosuppressives

increase infection risks.

SLE InfectionsSLE Infections

Main cause of hospital admission & principal cause of death.

Susceptible to local & systemic infections.Related to immune defects & disease therapy.Viral: VZV, Cytomegalovirus, EBV,

Parvovirus B19.Bacterial: Salmonella, S. pneumoniae, Mtb,

Nocardia, various gram- bacteria.Mycotic: Candida, Pneumocystis carinii.



(uremia & dialysis)

Infectious Complications In Asplenic PtsInfectious Complications In Asplenic Pts

Critical role in immune surveillance & response.Asplenic pts: lower C3 levels & defective

responses to encapsulated bacterial pathogens- decreased phagocytosis & destruction of

microbes.- failure to recognize polysaccharide Ag’s.- impaired IgM synthesis early in infection.- failure to remove Ab - coated bacteria.- prone to post-splenectomy sepsis (PSS). - S. pneumoniae (#1), H influenzae (#2),

N. meningitidis (#3)

Streptococcus pneumoniae (#1):- etiology in 50 – 90% PSS cases. - age major factor - % cases increase with age.- high mortality rate in children.Haemophilus influenzae (#2):- 32% of PSS mortality.- decreased incidence with conjugated Hib

vaccine use (important to vaccinate pts!!). Neisseria meningitidis (#3):- greater risk for meningococcemia (?)

Microbiology of PSSMicrobiology of PSS



(uremia & dialysis)

Effect of Aging On Immune CompetenceEffect of Aging On Immune Competence

Declining Innate, Humoral & Cellular Immune Declining Innate, Humoral & Cellular Immune ResponsesResponses

Increased Susceptibility to Pneumonias & Certain Increased Susceptibility to Pneumonias & Certain Chronic InfectionsChronic Infections

DEPRESSING !!!DEPRESSING !!!

How old is old ?How old is old ?

Diminished vaccine Diminished vaccine responsesresponses

Pain of ZosterPain of Zoster

•• Deep aching or burning painDeep aching or burning pain•• Altered sensitivity to touch (paresthesia) Altered sensitivity to touch (paresthesia)

that may be painful (dysesthesia)that may be painful (dysesthesia)•• Exaggerated responses to stimuli Exaggerated responses to stimuli

(hyperesthesia)(hyperesthesia)•• Electric shockElectric shock--like painlike pain

Zoster in Immunocompromised PtsZoster in Immunocompromised Pts•• More severe than in normal personsMore severe than in normal persons•• Lesion formation may continue for up to 2 wks, Lesion formation may continue for up to 2 wks,

scabbing may not occur until 3scabbing may not occur until 3--4 weeks into the 4 weeks into the disease coursedisease course

•• Frequent infection in HIV ptsFrequent infection in HIV pts•• Chronic herpes zoster may occurChronic herpes zoster may occur

3 Types of Varicella – Containing Vaccines:Varicella vaccine (Varivax)– approved for persons 12 months and older

Measles-mumps-rubella-varicella vaccine (ProQuad)– approved for children 12 months through 12 years

Herpes zoster vaccine (Zostavax)– approved for persons 60 years and older

Vaccine Recommendations for Adolescents & Adults:All persons 13 years of age and older without

evidence of varicella immunity2 doses separated by at least 4 weeksDo not repeat 1st dose because of extended interval

between doses

Herpes Zoster Vaccine*Herpes Zoster Vaccine*

•• Approved for a single dose among persons Approved for a single dose among persons 60 years and older whether or not they 60 years and older whether or not they report a prior episode of shingles report a prior episode of shingles

•• Persons with a chronic medical condition Persons with a chronic medical condition may be vaccinated unless a may be vaccinated unless a contraindication or precaution exists contraindication or precaution exists for the conditionfor the condition

Methicillin Methicillin -- ResistantResistantStaphylococcus aureusStaphylococcus aureus (MRSA)(MRSA)

•• Major transmission modes:Major transmission modes:1.1. via infected /colonized patientsvia infected /colonized patients2.2. dissemination by infected/ colonized dissemination by infected/ colonized

HCWsHCWs•• Within a facility: Within a facility:

-- HCW hands after contact with infected pt.HCW hands after contact with infected pt.•• Between hospitals & institutions:Between hospitals & institutions:

-- pt transfers & new carrier HCW pt transfers & new carrier HCW employees.employees.

Staphylococcal Nasal CarriageStaphylococcal Nasal Carriage

•• Chronic carriageChronic carriage•• Periodic bacterial Periodic bacterial

shedding shedding •• Infectious to othersInfectious to others•• Source of healthSource of health--care care

acquired infectionsacquired infections•• Special risks for Special risks for

compromised persons compromised persons who are who are exposedexposed


- Malnutrition - Transplantation- Neoplasia - Parenteral Drug Abuse- Anti-neoplastic therapy - Diabetes- Effects of aging - Alcoholic cirrhosis- Asplenia - Chronic hepatitis B or C- Trauma - Arthritis- Autoimmune conditions - HIV / AIDS - Other chronic infections - End stage renal disease

(uremia & dialysis)

Infections In ParenteralInfections In ParenteralDrug Abusers Drug Abusers

Skin & Soft Tissue Infections:- Staphylococcus aureus:

- abscesses- staph colonization universal in PDAs - most common etiology

- Group A & G streptococci:- bacteremia- cellulitis- associated with long Hx drug abuse (?)

Infections In Parenteral Drug Abusers Infections In Parenteral Drug Abusers

Other Skin & Soft Tissue Infections:- skin ulcers: staph; strept; gram-negative rods- septic thrombophlebitis: staph & streptococci- necrotizing fasciitis: gram-negative bacilli- candidiasis: mycotic infections- wound botulinum: not commonOcular InfectionsPulmonary InfectionsInfective Endocarditis

Let Us Not Forget OneLet Us Not Forget OneTransient Transient Cause of Secondary Cause of Secondary

Immune DeficiencyImmune Deficiency

EMOTIONAL DISCOMFORTEMOTIONAL DISCOMFORT

STRESSSTRESS


- Malnutrition - Transplantation- Neoplasia - Parenteral Drug Abuse- Anti-neoplastic therapy - Diabetes- Effects of aging - Alcoholic cirrhosis- Asplenia - Chronic hepatitis B or C- Trauma - Arthritis- Autoimmune conditions - HIV / AIDS

- Other chronic infections - End stage renal disease (uremia & dialysis)

Infections Related to Steroid UseInfections Related to Steroid Use

Dramatic increase in corticosteroid use c/in last decade.Anti-inflammatory &/or immunosuppressive.Chronic steroid use predisposes to variety of infections by interfering c host defenses.Affect most aspects of immune system.Infections dependent on route of administration, dose, & duration of therapy.Most common: oropharyngeal candidiasis.Most common: oropharyngeal candidiasis.Prolonged CMI suppression important for Prolonged CMI suppression important for opportunistic infection to occur. opportunistic infection to occur.

Klein, et al. IDCNA (2001)Klein, et al. IDCNA (2001)

Infections Related to Steroid UseInfections Related to Steroid Use

increased susceptibility to all types of infection.

most infections caused by pyogenic bacteria.

pts on chronic steroid use at increased risk of surgical wound infections & delayed wound healing:steroids interfere with fibroblast steroids interfere with fibroblast proliferation & collagen synthesis. proliferation & collagen synthesis.

Klein, et al. IDCNA (2001)Klein, et al. IDCNA (2001)

Misuse of Topical Corticosteroids Misuse of Topical Corticosteroids

can cause transient immune suppression in otherwise healthy persons

mainly act on CMI can interfere with macrophage phagocytosiscan interfere with macrophage phagocytosis

& antigen& antigen--processing during immune processing during immune responsesresponses

when mistakenly applied topically onto when mistakenly applied topically onto superficial infections superficial infections -- can inhibit host can inhibit host

immune responses to microbial pathogensimmune responses to microbial pathogensJAM (2009)JAM (2009)

Hepatitis C, G, etc Hepatitis C, G, etc Hepatitis C, G, etc S A R SS A R S

Emerging Infectious Disease Emerging Infectious Disease ChallengesChallenges

DrugDrug--Resistant HIV / AIDSResistant HIV / AIDS

Prions Prions

MDR MDR -- TuberculosisTuberculosis

Diarrheal Diseases Diarrheal Diseases

MalariaMalaria

West Nile VirusWest Nile Virus

Waterborne DiseasesWaterborne Diseases

Acute Lower Respiratory Tract InfectionAcute Lower Respiratory Tract Infection

Compromised PatientsCompromised PatientsAntimicrobial ResistanceAntimicrobial Resistance

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INFECTIONS IN IMMUNE INFECTIONS IN IMMUNE COMPROMISED