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IDologist.com
Immunocompromise IVDr. Andrew M. Morris
Mt. Sinai Hospital/University Health NetworkDepartment of Medicine
IDologist.comBig Picture
Host
Macro Flora
Adap
tive Classical
Immune SystemPu
blic H
ealth
IDologist.com
Adap
tive Classical
Immune System
macro-phages
T cells
Macro Flora
exogenous bacteria and fungi, viruses,
parasites
IDologist.comCell-mediated immunity
T lymphocytes and macrophages protect us against exogenous pathogens which our innate immune system would not have encoded
most virusesmost fungimycobacteriasome uncommon exogenous bacteriamost parasites
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Case79 year-old man with
history of sarcoid, requiring high-dose corticosteroids (currently prednisone 40mg daily) for many monthsalso history of steroid-induced DM, cataracts, and osteoporosis
presents with increased SOB over past 4 weeks refractory to a variety of antibiotics
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Case
Step 1: What is the nature and severity of his immunocompromise?
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CaseHistory:
would also want to know: sexual historytravel/immigration history (e.g. TB)history of IVDU (e.g. hepatitis B/C, HIV)exposure to animals (e.g. leptospirosis)crowded conditions (e.g. First Nations reservations, jails)
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CaseHistory:
in a long-standing monogamous relationshipimmigrated from Poland 50 years ago; was in a concentration camp in WWIIno known history of TBno other high-risk exposures
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Case
Physical exam:patient requires a thorough physical exam, focusing on his cardiorespiratory system and evidence of immunocompromise
IDologist.comCasePt’s physical exam:
febrileCushingoid, with multiple bruises, thin skin, etc.no thrushtachypneic, diffuse crackles, respiratory distresspoorly audible heart soundsabdomen benign
IDologist.comCaseWhat is the nature of this man’s immunocompromise?
history and physical exam strongly suggestive of chronic steroid-induced cell-mediated immunosuppressionprior antibiotic exposure puts him at risk of antibacterial-resistant organisms (e.g. fungi, drug-resistant bacteria)war-torn Poland?
IDologist.comHigh-dose prednisone: The Big Picture
VirusesBacteriaFungiProtozoa
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Virusesreactivation from latent viruses (herpesviruses)severe or complicated community-acquired viruses (e.g. influenza, hepatitis C)
High-dose prednisone: The Big Picture
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VirusesBacteria
Mycobacteria (TB, MAI)other weird bacteriae.g. Listeria, Nocardia
High-dose prednisone: The Big Picture
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VirusesBacteriaFungi
mucosal candidiasisPneumocystic jiroveciidimorphic fungi
High-dose prednisone: The Big Picture
IDologist.com
VirusesBacteriaFungiProtozoa
Strongyloides (esp. pulmonary)
High-dose prednisone: The Big Picture
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Back to Caseelderly man with pulmonary sarcoidosison high-dose predisone and broad-spectrum ABx for past whilegrew up in a concentration campindolent pulmonary infiltratesdifferential diagnosis?
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Back to Casemost likely causes (noting indolent course and immune status):
worsening of underlying diseasereactivation tuberculosisnon-tuberculous mycobacteriaPneumocystis jiroveciiother fungi
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Back to CaseBAL:
Mycobacterium aviumfilamentous fungus ... Scopulariopsis cinereus
unfortunately, patient passed away shortly after BAL (and before microbiology results were available)
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Summarysimilar to HIV/AIDS, patients with chronic steroid-mediated immunosuppression are at risk from:
viral reactivationmycobacteriaPCP and other fungiparasites
history-taking helps prioritize these
IDologist.comHæmatopoietic stem cell transplantation
HSCT (or “bone marrow transplantation”) is:increasingly common for a variety of conditions, but primarily for leukaemia and lymphomacan be:
autologous (using pt’s own stem cells)allogeneic (using matched donor’s stem cells)sygneneic (identical twin donor)
IDologist.comHæmatopoietic stem cell transplantation
prior to transplantation, most HSCT recipients must receive a “conditioning” procedure (usually cytotoxic agents chemotherapy with or without radiation) conditioning causes:
transient severe neutropeniaqualitative defects in phagocytosispronounced defects in both humoral and cellular immunityvarying degrees of mucositis
IDologist.comHæmatopoietic stem cell transplantation
donor lymphocytes (esp. if not HLA-matched), can attack the host ... Graft-Versus-Host Disease, GVHDconditioning damages the gut which becomes leaky:
gut microflora attract effector cells, and cytokines ... and subsequently lymphocytes are activated
IDologist.comHæmatopoietic stem cell transplantation
Conditioning regimens damage gut tissues, allowing lipopolysaccharide from bacteria in the bowel to leak into adjacent tissues and the bloodstream. Microbes activate effector cells, leading to release of inflammatory cytokines (e.g. IL-1, Il-6, IL-12 and TNF α. As part of the innate immune response, neutrophils, macrophages, and eosinophils migrate to the damaged tissue and cause further injury. Dendritic cells containing captured antigen migrate to lymphoid organs (particularly Peyer’s patches), where they mature and induce a response involving the proliferation of donor T cells and the secretion of cytokines: IL-2 and IFN-γ activate effector cells which damage tissues. This further increases inflammation and injury. Activated T cells enter the circulation, migrate, and damage other organs, particularly the skin and liver.
NEJM 2006;354:1813-26
IDologist.comHSCT: Pre-engraftment
because of the conditioning regimen, one of the most common and important problems prior to engraftment is mucositis:oral mucositisgut mucositis, with diarrhea, cramping
mucositis predispose patients to prolonged venous catheters so that they receive i.v. medications and intravenous nutrition, or TPN (Total Parenteral Nutrition)because of marrow failure, patients also receive supportive therapy with blood products
IDologist.comHSCT: Pre-engraftment
the first 30 days following HSCT are therefore similar to FNP, with disease primarily being caused by organisms colonizing the skin and GI tract of the hostreactivation of HSV, largely due to loss of memory cells, is also a common problemAspergillus comes later
IDologist.comHSCT: Post-engraftmentd30-100 is dominated by reduced cell-mediated immunityfor allogeneic recipients, the scope of disease is determined by the presence/absence of GVHD, and the intensity of subsequent immunosuppressivesherpesviruses are extremely important:
pulmonary or GI CMVEBV-associated post-transplantation lymphoproliferative disorder (PTLD)
towards the latter half of this period, fungi (Aspergillus and Pneumocystis) are important
IDologist.comHSCT: Late Phase
after d100 patients receiving autologous HSCT are largely “out of the woods”for allogeneic recipients, the scope of disease in the Late Phase continues to be determined by the presence/absence of GVHD, and the intensity of subsequent immunosuppressivesin allo-HSCT recipients, cell-mediated and humoral immunity is particularly impaired:
Cell-mediated deficiency ➙ virus (esp. latent virus reactivation and community-acquired resp. viruses)Humoral deficiency ➙ encapsulated bacteria
IDologist.comLatent Viruses
herpesviruses (HSV, ZVZ, EBV, CMV, HHV-6/-7 and KSHV) are the most important and common latent viruses that reactivateHOWEVER, there are other latent viruses (usually benign) that reactivate with severe cellular immunosuppression:
Polyoma virusesBK VirusJC Virus
Papillomaviruses
IDologist.comPolyoma Viruses
polyoma viruses are DNA viruses with latency that are acquired in childhoodBK virus persists in the urogenital tract (held in check by cell-mediated immunity)
in HSCT recipients, reactivation of BK virus causes hæmorrhagic cystitisin renal Tx recipients, BK virus can cause renal graft failure (BK nephropathy)
JC virus causes latent CNS infectionin transplant recipients, it can cause Progressive Multifocal Leukoencephalopathy
IDologist.comPolyoma Viruses
decoy cells from a patient with hæmorrhagic cystitis
renal biopsy from a patient with BK nephropathy, showing tubules with epithelial cells
showing viral inclusions
NEJM 2000;342:1309-15
IDologist.comPolyoma Viruses
Am J Transplant 2005; 5: 1151–1158
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HSCT: Prevention Strategiesprevention is usually better than cureprevention has 3 components:
prophylaxis (prior to infection)pre-emption (treating when pt. is infected, but prior to overt disease)minimizing exposure
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ProphylaxisHSCT recipients are kept in single rooms, with minimal contact with others and careful attention to hand-washingTMP-SMX (or an alternative agent) is used prophylactically starting in the post-engraftment period to prevent Pneumocystis jirovecii, along with Toxoplasma infectionit is unclear if “prophylactic” ABx during pre-engraftment are worthwhilevaccination strategies are very aggressive
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CMV~80-90% of adults are infected with CMVin HSCT, CMV is one of the most important diseases, because it causes serious illness AND we have few treatment optionsthe highest risk of acquiring CMV post-HSCT occurs when the recipient has no CMV-specific Ab, and yet the donor is CMV-positive (CMV D+R-, risk ~30%)
the risk is less if the recipient is + (CMV D+R+ or D-R+), and is rather low if CMV D-R-
IDologist.comCMV: Prevention vs Pre-emption
one strategy is to treat all CMV-mismatched patients (CMV D+R- or D-R+) with (val)ganciclovir starting a few days after transplantationanother approach is to follow the patient clinically, and to measure CMV Ag levels quantitatively:
at the first sign of reactivation, the patient is started on antiviral medication
IDologist.comSolid Organ Transplantation
the infectious diseases principles behind solid organ transplantation (SOT) ~ HSCTthe principle differences:
there is no GVHD, but rather allograft rejection (which can take on various forms)although there is not much/major “conditioning” risk, there is considerable surgical riskorgans (unlike stem cells) often come from persons in whom the past medical history is limited: thus there is an important (and unknown) risk of transplantation-acquired infection
IDologist.comSolid Organ Transplantation
NEJM 2007;357:2601-14
IDologist.comSolid Organ Transplantation
the risk of infection for solid organ transplants is partially related to the immunosuppressive regimensome organs have specific infectious problems, related to
surgical morbidityunderlying illnessallograft anatomy
because many patients are cared for in the ICU, intensive care-associated infections (e.g. line infections, ventilator-associated pneumonia, C. difficile) are frequent
IDologist.comSolid Organ Transplantation
lung transplantation is frequently complicated by post-transplantation pneumonia:
from the host’s own oral flora, which is often colonized with MDR bacteria and fungifrom the transplanted organanatomical dysfunction/intubation
liver transplantation is frequently complicated by infections at the anastomotic (surgical) siterenal transplantation is frequently complicated by pyelonephritis
IDologist.comPost-Transplantation Lymphoproliferative Disorder
EBV-associated lymphoproliferation is seen in other conditions (cf. Burkitt’s lymphoma, HIV-associated NHL)unquestionably related to EBV infection, immunosuppression and unregulated B-cell growthrecall that EBV infection “immortalizes” B cells
Transpl Inf Dis 1999;1:204–212
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What I haven’t talked aboutdiabetes - infections are mostly related to problems of vascular supply and skin integrity (with injury esp. due to sensory loss)TNF modulators (for rheumatologic conditions and inflammatory bowel disease) - infections are most importantly due to mycobacteriaalcoholism - its unclear if it really is a state of immunocompromiseother immunomodulators
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Public Health and Macro Floramacro flora are passed to the host primarily from other persons, food, and waterexamples of such Macro Flora are influenza, HIV, SARS coronavirus, viral hepatitis, M. tuberculosis, listeria, syphilis, and malariaalthough it is questionable whether such diseases can be eliminated in the foreseeable future, minimizing these diseases are possible
IDologist.com
Public Health and Macro FloraPublic Health measures should be aimed at reducing the likelihood that a healthy person will encounter and be infected by pathogenic microbes
reduce overcrowdingpromote frequent hand-washingminimize promiscuity and maximize safe sex practicesmaintain safe separation between animals and humansensure a safe (i.e. uncontaminated) food chainpromote vaccinationmonitor and control travel and immigration
IDologist.comLast Thought
Infectious diseases always change/emerge to make life
prematurely short for the unfortunate fewscary or bothersome for the manyinteresting, stimulating, and challenging for the lucky few
