Infections in Immunocompromised Host
Content
Infections in Immunocompromised Host Definition Opportunistic Infection Infection by an organism Does not necessarily cause disease But become pathogenic under certain circumstances (eg. Impaired immune responses) Immunocompromised Hosts Congenital (eg. CSID) Infection (eg. HIV) Chronic diseases (eg. DM) Drugs (eg. corticosteroids, chemotherapy) Malignancy (eg. solid tumor, leukemias) Immune Defects & Commonly Associated Pathogen Immune defects Pathogens Barrier breakdown Burn P. aureginosae, S. aureus Trauma S. pyogenes, S. epidimitis Phagocytic function Absolute disease Enteric GNB, PSAE, Aspergillus spp Chemotaxis S. aureus, Candida spp Microbial killing S. aureus, GNB Humoral immunity Hypogammaglobulinaemia Strep pneumoniae, H. influenzae IgA def Pyogenic bacteria, Giardia lamblia Asplenia Strep pneumonia, H. influenzae Complement def Pyogenic bacteria, Nesseria spp Cell Mediated Immunity Intracellular bacteria Viruses (eg. Herpes family) Fungi (eg. Candida spp, Cryptococcus spp) Parasites (eg. Toxoplasma) Opportunistic Infections in AIDS
Fungi Pneumocystis carinii Pneumonia Candidiasis Aspergillosis Cryptococcosis Histoplasmosis Coccidioidomycosis Microsporidiosis Bacteria Mycobacterium Avium Complex Mycobacterium Tuberculosis Viruses Varicella-Zoster Virus Herpes Simplex Virus Cytomegalovirus Protozoa Coccidiosis (Cryptosporidiosis, Cyclosporiasis, Isosporiasis) Toxoplasmosis Leishmaniasis Chagas Malaria
AIDS Defining OI
Yeast Infection (Candida) Candidiasis (Monoliasis) Infects (Yeast-like fungus) y Skin y Mucosa y Internal organs Normal flora y Mouth y GIT y Vagina y Skin Colonization increases with y Age y Pregnancy y Hospitalization Immunity depend on T lymphocytes Genus Candida y Budding yeast, stain Gram +ve y ID based on biochemical tests & morphology (corn meal agar) C. albicans (most important pathogen) y Budding yeast y True hyphae y Forms germ tubes (pseudohyphae) in presence of serum Other Candida spp C. tropicalis, C. parapsilosis, C. lusitaniae, C. krusei, C. glabrata, C. guilliermondii, C. dubliniensis Oral Candida Thrush
Toxoplasmosis Clinical Toxoplasmosis Acquired Congenital Ocular Immunocompromised patient Toxoplasmosis in AIDS patients Toxo lymphadenopathy Toxo encephalitis (TE) & CNS Toxo Toxo pneumonia Toxo urinary tract infections Toxo disseminated Peritonitis, Chorioretinitis Toxoplasmic Encephalitis (TE) Signs & Symptoms y Headache y Confusion y Ataxia Hemiparesis retinochoroiditis Spinal fluid pleocytosis CT Brain Diffuse/ multiple hypodense CNS lesions (ring enhancement with contrast) Diagnosis Morphology Tachyzoites in circulating y WBC y Bone marrow y Lung y Spleen y Brain Histopathologic examination or TEM examination CT (computed tomographic) scans Culture or animal inoculation (rare) Serologic Serologic Diagnosis Unreliable in immunodeficient (AIDS) patients Normally IgG & IgM rise simultaneously IgG IgM Persists for years Undetectable after cure IgM titer is diagnostic of recent infection in persons with normal immunity Disseminated infection may exist in AIDS patients without demonstrable titer Treatment Pyrimethamine + Sulfadiazine Side effects are common in AIDS patients Can be combined with Dapsone or Clindamycin Prophylaxis TMP-SMX (Trimethoprim-Sulfamethoxazole) Pyrimethamine + Folinic acid Dapsone pyrimethaminedapsone or Dapsone + Pyrimethamine
Painless white oral lesion Easily scraped off Laboratory confirmation KOH, culture, gram stain Candida
Candida albicans/ Candida spp
Candida on Sebaraud Dextrose Agar (SDA)
Oval shape budding Gram +ve organism Appearance of yeast cell from gram staining
Candida
Skin scraping mounted in 10% KOH
PAS stain Invasive candida in blood vessel
Pneumocystis jirovecii Infection Pneumocystis jirovecii Pneumocystis jirovecii (Pneumocystis carinii) Fungus (originally thought as protozoa) Very common infection in AIDS Fatal if untreated Transmission airborne Subclinical infection during childhood (usually well contained) Laboratory Diagnosis of Pneumocystis from Lung Washings or Sputum 3 Types of stains Gomori s Toluidine blue Giemsa or Wright s methenamine-silver Stains cyst wall brown Stains cyst wall blue or Stain trophozoites & or black lavender intracystic sporozoites pale blue with a Stains fungal elements punctuate red nucleus Do not stain the cyst wall
Silver stain Typical black cup-shaped appearance Stand out against paler background Pneumocystis Pneumonia P. jirovecii cause clinically apparent pneumonia (virtually exclusively in immunosuppressed patients) 90% of AIDS patients develop Pneumocystosis y organism proliferation y Little/ No inflammatory response CD4 counts < 200 Signs & Symptoms y Fever y Nonproductive cough y Chest tightness y Shortness of breath Diagnosis y X-ray (20% undetected) y Induced sputum y Bronchial lavage Chemoprophylaxis is successful Sulfa drugs for treatment & prophylaxis
Increasing Diagnostic Yield in Children Children do not produce sputum (or swallow it) Low numbers of organisms Techniques (to diagnose pediatric pulmonary TB y Gastric lavage (3 mornings) y Nasopharyngeal washing (3 mornings) y Induce sputum (3 mornings) Treatment Trimethoprim-Sulfamethoxazole (Drug of choice) Alternatives y IV Pentamidine y Oral Dapsone + Trimethroprim y Adjuvant therapy eg. Corticosteroids
yield)
CXR PCP Diffuse bilateral infiltrates
Immunofluorescence using monoclonal antibodies
H&E Acellular eosinophilic exudates (PCP seen filling the alveoli) Morphology 4 forms y Trophozoites Cysts (diagnostic) y y Precysts y Sporozoites (intracysts bodies) P. jirovecii binds to type I alveolar epithelial cells Attachment to host cells is required for survival
Mycobacteriosis (Mycobacterium Tuberculosis, Atypical Mycobacterium) HIV-TB Mortality rate (13.7% vs 0.5%) st Mortality rate during 1 2 months of treatment Rates of relapse & reinfection y Treatment regimen y Duration of treatment Impact of HIV & TB co-infection is bidirectional y TB affects natural history of HIV infection y HIV infection affects presentation & natural history of TB Differences in clinical presentation Timing of commencement of HAART Issues with drug interactions Protective Mechanism in TB 2 Protective Mechanism - Cellular Immune Response Generation of Cytolytic T-cells in Macrophage & CD4 T lymphocyte response to MTB Macrophage phagocyte bacilli (control intracellular growth) CD4 T lymphocyte prime macrophage to control intracellular growth by releasing cytokines y IFy IL-1 y IL-2 y TNFCytolytic T-cells & CD4 T cells kill autologous infected macrophages Differences in Clinical Presentations HIV + TB Pulmonary disease alone 40% Extrapulmonary disease 34% Both 26% Sputum +ve in Pulmonary disease 57% only patients Rates of diagnosis by sputum culture were similar Radiological abnormalities Among persons with advanced immunodeficiency (CD4 <200) y Intra thoracic adenopathy y Focal lower/ middle lobe infiltrates y Diffuse military/ nodular infiltrates y Sometimes even normal CXR y Cavitation is rare Tuberculin Test Depend on integrity of cellular immunity (CD4 cells count) CD4 cells count Tuberculin Test +ve 3 < 100 cells/ mm 0% 100-200 61% 201-300 42% > 300 91% Anti TB Treatment (current recommendation) 6-months regimens 9-months for patients with delayed y Clinical/ radiological y Microbiologic response (continued symptoms or sputum culture +ve at 2 months) Treatment of HIV & TB TB only 72% 16% 12% 76% IRIS (Immune Reconstituition Inflammatory Syndrome) Worsening/ progression of tuberculosis Occur at original site of disease/ remote site Exclude IRIS with another diagnosis May occur at any time point after initiation of TB treatment Coincides most closely with viral load decline Resolves without any intervention (most cases) (ART can be safely continued) MAC (Mycobacterium Avium Complex) Multiple related species of nontuberculous mycobacteria nd Cause of 2 most common OI among children with HIV (1st is Pneumocystis) Diagnosis Isolation from blood/ bone marrow/ lymph node Multiple mycobacterial blood cultures over time required (to yield +ve result) Techniques to improve recovery of organisms y Radiometric broth medium y Lysis-centrifugation culture Histology Macrophages containing AFB (acid-fast bacilli) Differentiate from Nontuberculous mycobacteria from M. tuberculosis Culture Antibiotic susceptibility testing
CMV Infection CMV (Cytomegalovirus) Member of herpesvirus group Universally throughout all geogprahic locations & socioeconomic groups Typically remains dormant within body Morphology Prevention of CMV Infections Prophylaxis Therapy Administration of antiviral therapy to all* transplant recipients for 3 months (or 100 days**)
Pre-Emptive Therapy Initiation of antiviral therapy when CMV infection is detected Predetermined level of CMV viral load in blood is reached, prior to appearance of clinical symptoms * Except CMV ve recipients of CMV ve donors ** Prophylaxis in allogeneic stem cell transplant not started until engraftment Diagnosis of CMV Infection Disseminated Infections Whole blood is specimen of choice (CMV load in whole blood 0.67log higher than plasma)
Organ Syndromes Local organ samples are best specimens y Secretions y Tissue biopsies
Diagnosis of CMV Infection Conventional Cell Culture
Shell Vial Culture
Surrounding halo & marginated chromatin
Intranuclear owl s eye inclusions in infected tissues
Cytomegalovirus Transmitted person-to-person (by close contact with virus-bearing material) (mainly via oral/ respiratory spread) Worldwide seroprevalence 30-100% Able to replicate in multiple tissue in-vivo Virus may be shed in y Urine y Saliva y Semen y Breast milk y Cervical secretions y Carried in circulating blood cells Types of CMV Infection Primary infection Latent infection Reactivation Re-infection (with a different strain) Cytomegalovirus Infection in AIDS patients Retinitis (62.5%) y Common in CD4 count < 50 y Begins as unilateral disease y Progress to bilateral involvement y May be accompanied by CMV systemic disease Esophagitis (16.7%) CMV isolated from y Esophageal ulcers y Gastric ulcers y Duodenal ulcers Colitis (4.2%) present with diarrhoea Pneumonitis (2.1%) CMV Retinitis
Very sensitive method Not rapid
Rapid method +ve on Day 2 (<30% +ve on Day 1)
Serological Diagnosis of CMV Infection IgG (good marker of past infection) Important for identification (prior to transplant) (patients at highest risk for severe CMV disease) Used to evaluate donor/ recipient Sero +ve individuals Sero ve individuals Possibility of reactivation Risk of primary infection Treatment Antiviral agents (in conjunction with HAART) y Ganciclovir y Foscarnet y Cidovir Can slow down progression of disease (cannot cure it) Administration y Orally y Intravenously (IV) y Intravitreally Systemic treatment Advantages Disadvantages Treat infections elsewhere in body Systemic side effects as well as other eye
CMV invades retina Compromise light-sensitive receptors (that enable us to see) Does not necessarily cause pain May see floaters/ small specks Experience reduced visual acquity/ decreased peripheral vision Light flashes & sudden vision loss can occur Disease usually start with 1 eye, but often involves both eyes If untreated can cause detached retina & blindness (in just 2-6 months) Clinical appearances y Cotton wool spots (look like HIV retinopathy) y Confluent areas of full thickness retinal necrosis & vasculitis Can progress in a brushfire pattern (from active edge of an active lesion) Retinal vessels in affected area show attenuation (become ghost vessels eventually)
Fungi Pneumocystis carinii Pneumonia Candidiasis Aspergillosis Cryptococcosis Histoplasmosis Coccidioidomycosis Microsporidiosis Bacteria Mycobacterium Avium Complex Mycobacterium Tuberculosis Viruses Varicella-Zoster Virus Herpes Simplex Virus Cytomegalovirus Protozoa Coccidiosis (Cryptosporidiosis, Cyclosporiasis, Isosporiasis) Toxoplasmosis Leishmaniasis Chagas Malaria
AIDS Defining OI
Yeast Infection (Candida) Candidiasis (Monoliasis) Infects (Yeast-like fungus) y Skin y Mucosa y Internal organs Normal flora y Mouth y GIT y Vagina y Skin Colonization increases with y Age y Pregnancy y Hospitalization Immunity depend on T lymphocytes Genus Candida y Budding yeast, stain Gram +ve y ID based on biochemical tests & morphology (corn meal agar) C. albicans (most important pathogen) y Budding yeast y True hyphae y Forms germ tubes (pseudohyphae) in presence of serum Other Candida spp C. tropicalis, C. parapsilosis, C. lusitaniae, C. krusei, C. glabrata, C. guilliermondii, C. dubliniensis Oral Candida Thrush
Toxoplasmosis Clinical Toxoplasmosis Acquired Congenital Ocular Immunocompromised patient Toxoplasmosis in AIDS patients Toxo lymphadenopathy Toxo encephalitis (TE) & CNS Toxo Toxo pneumonia Toxo urinary tract infections Toxo disseminated Peritonitis, Chorioretinitis Toxoplasmic Encephalitis (TE) Signs & Symptoms y Headache y Confusion y Ataxia Hemiparesis retinochoroiditis Spinal fluid pleocytosis CT Brain Diffuse/ multiple hypodense CNS lesions (ring enhancement with contrast) Diagnosis Morphology Tachyzoites in circulating y WBC y Bone marrow y Lung y Spleen y Brain Histopathologic examination or TEM examination CT (computed tomographic) scans Culture or animal inoculation (rare) Serologic Serologic Diagnosis Unreliable in immunodeficient (AIDS) patients Normally IgG & IgM rise simultaneously IgG IgM Persists for years Undetectable after cure IgM titer is diagnostic of recent infection in persons with normal immunity Disseminated infection may exist in AIDS patients without demonstrable titer Treatment Pyrimethamine + Sulfadiazine Side effects are common in AIDS patients Can be combined with Dapsone or Clindamycin Prophylaxis TMP-SMX (Trimethoprim-Sulfamethoxazole) Pyrimethamine + Folinic acid Dapsone pyrimethaminedapsone or Dapsone + Pyrimethamine
Painless white oral lesion Easily scraped off Laboratory confirmation KOH, culture, gram stain Candida
Candida albicans/ Candida spp
Candida on Sebaraud Dextrose Agar (SDA)
Oval shape budding Gram +ve organism Appearance of yeast cell from gram staining
Candida
Skin scraping mounted in 10% KOH
PAS stain Invasive candida in blood vessel
Pneumocystis jirovecii Infection Pneumocystis jirovecii Pneumocystis jirovecii (Pneumocystis carinii) Fungus (originally thought as protozoa) Very common infection in AIDS Fatal if untreated Transmission airborne Subclinical infection during childhood (usually well contained) Laboratory Diagnosis of Pneumocystis from Lung Washings or Sputum 3 Types of stains Gomori s Toluidine blue Giemsa or Wright s methenamine-silver Stains cyst wall brown Stains cyst wall blue or Stain trophozoites & or black lavender intracystic sporozoites pale blue with a Stains fungal elements punctuate red nucleus Do not stain the cyst wall
Silver stain Typical black cup-shaped appearance Stand out against paler background Pneumocystis Pneumonia P. jirovecii cause clinically apparent pneumonia (virtually exclusively in immunosuppressed patients) 90% of AIDS patients develop Pneumocystosis y organism proliferation y Little/ No inflammatory response CD4 counts < 200 Signs & Symptoms y Fever y Nonproductive cough y Chest tightness y Shortness of breath Diagnosis y X-ray (20% undetected) y Induced sputum y Bronchial lavage Chemoprophylaxis is successful Sulfa drugs for treatment & prophylaxis
Increasing Diagnostic Yield in Children Children do not produce sputum (or swallow it) Low numbers of organisms Techniques (to diagnose pediatric pulmonary TB y Gastric lavage (3 mornings) y Nasopharyngeal washing (3 mornings) y Induce sputum (3 mornings) Treatment Trimethoprim-Sulfamethoxazole (Drug of choice) Alternatives y IV Pentamidine y Oral Dapsone + Trimethroprim y Adjuvant therapy eg. Corticosteroids
yield)
CXR PCP Diffuse bilateral infiltrates
Immunofluorescence using monoclonal antibodies
H&E Acellular eosinophilic exudates (PCP seen filling the alveoli) Morphology 4 forms y Trophozoites Cysts (diagnostic) y y Precysts y Sporozoites (intracysts bodies) P. jirovecii binds to type I alveolar epithelial cells Attachment to host cells is required for survival
Mycobacteriosis (Mycobacterium Tuberculosis, Atypical Mycobacterium) HIV-TB Mortality rate (13.7% vs 0.5%) st Mortality rate during 1 2 months of treatment Rates of relapse & reinfection y Treatment regimen y Duration of treatment Impact of HIV & TB co-infection is bidirectional y TB affects natural history of HIV infection y HIV infection affects presentation & natural history of TB Differences in clinical presentation Timing of commencement of HAART Issues with drug interactions Protective Mechanism in TB 2 Protective Mechanism - Cellular Immune Response Generation of Cytolytic T-cells in Macrophage & CD4 T lymphocyte response to MTB Macrophage phagocyte bacilli (control intracellular growth) CD4 T lymphocyte prime macrophage to control intracellular growth by releasing cytokines y IFy IL-1 y IL-2 y TNFCytolytic T-cells & CD4 T cells kill autologous infected macrophages Differences in Clinical Presentations HIV + TB Pulmonary disease alone 40% Extrapulmonary disease 34% Both 26% Sputum +ve in Pulmonary disease 57% only patients Rates of diagnosis by sputum culture were similar Radiological abnormalities Among persons with advanced immunodeficiency (CD4 <200) y Intra thoracic adenopathy y Focal lower/ middle lobe infiltrates y Diffuse military/ nodular infiltrates y Sometimes even normal CXR y Cavitation is rare Tuberculin Test Depend on integrity of cellular immunity (CD4 cells count) CD4 cells count Tuberculin Test +ve 3 < 100 cells/ mm 0% 100-200 61% 201-300 42% > 300 91% Anti TB Treatment (current recommendation) 6-months regimens 9-months for patients with delayed y Clinical/ radiological y Microbiologic response (continued symptoms or sputum culture +ve at 2 months) Treatment of HIV & TB TB only 72% 16% 12% 76% IRIS (Immune Reconstituition Inflammatory Syndrome) Worsening/ progression of tuberculosis Occur at original site of disease/ remote site Exclude IRIS with another diagnosis May occur at any time point after initiation of TB treatment Coincides most closely with viral load decline Resolves without any intervention (most cases) (ART can be safely continued) MAC (Mycobacterium Avium Complex) Multiple related species of nontuberculous mycobacteria nd Cause of 2 most common OI among children with HIV (1st is Pneumocystis) Diagnosis Isolation from blood/ bone marrow/ lymph node Multiple mycobacterial blood cultures over time required (to yield +ve result) Techniques to improve recovery of organisms y Radiometric broth medium y Lysis-centrifugation culture Histology Macrophages containing AFB (acid-fast bacilli) Differentiate from Nontuberculous mycobacteria from M. tuberculosis Culture Antibiotic susceptibility testing
CMV Infection CMV (Cytomegalovirus) Member of herpesvirus group Universally throughout all geogprahic locations & socioeconomic groups Typically remains dormant within body Morphology Prevention of CMV Infections Prophylaxis Therapy Administration of antiviral therapy to all* transplant recipients for 3 months (or 100 days**)
Pre-Emptive Therapy Initiation of antiviral therapy when CMV infection is detected Predetermined level of CMV viral load in blood is reached, prior to appearance of clinical symptoms * Except CMV ve recipients of CMV ve donors ** Prophylaxis in allogeneic stem cell transplant not started until engraftment Diagnosis of CMV Infection Disseminated Infections Whole blood is specimen of choice (CMV load in whole blood 0.67log higher than plasma)
Organ Syndromes Local organ samples are best specimens y Secretions y Tissue biopsies
Diagnosis of CMV Infection Conventional Cell Culture
Shell Vial Culture
Surrounding halo & marginated chromatin
Intranuclear owl s eye inclusions in infected tissues
Cytomegalovirus Transmitted person-to-person (by close contact with virus-bearing material) (mainly via oral/ respiratory spread) Worldwide seroprevalence 30-100% Able to replicate in multiple tissue in-vivo Virus may be shed in y Urine y Saliva y Semen y Breast milk y Cervical secretions y Carried in circulating blood cells Types of CMV Infection Primary infection Latent infection Reactivation Re-infection (with a different strain) Cytomegalovirus Infection in AIDS patients Retinitis (62.5%) y Common in CD4 count < 50 y Begins as unilateral disease y Progress to bilateral involvement y May be accompanied by CMV systemic disease Esophagitis (16.7%) CMV isolated from y Esophageal ulcers y Gastric ulcers y Duodenal ulcers Colitis (4.2%) present with diarrhoea Pneumonitis (2.1%) CMV Retinitis
Very sensitive method Not rapid
Rapid method +ve on Day 2 (<30% +ve on Day 1)
Serological Diagnosis of CMV Infection IgG (good marker of past infection) Important for identification (prior to transplant) (patients at highest risk for severe CMV disease) Used to evaluate donor/ recipient Sero +ve individuals Sero ve individuals Possibility of reactivation Risk of primary infection Treatment Antiviral agents (in conjunction with HAART) y Ganciclovir y Foscarnet y Cidovir Can slow down progression of disease (cannot cure it) Administration y Orally y Intravenously (IV) y Intravitreally Systemic treatment Advantages Disadvantages Treat infections elsewhere in body Systemic side effects as well as other eye
CMV invades retina Compromise light-sensitive receptors (that enable us to see) Does not necessarily cause pain May see floaters/ small specks Experience reduced visual acquity/ decreased peripheral vision Light flashes & sudden vision loss can occur Disease usually start with 1 eye, but often involves both eyes If untreated can cause detached retina & blindness (in just 2-6 months) Clinical appearances y Cotton wool spots (look like HIV retinopathy) y Confluent areas of full thickness retinal necrosis & vasculitis Can progress in a brushfire pattern (from active edge of an active lesion) Retinal vessels in affected area show attenuation (become ghost vessels eventually)
