Infection in the Cellular Immune

Infection in the Cellular Immune-Deficient Host

Introduction

Immune compromised host include

HIV infected patients. (33 M in world; pandemic, 95% live in developing world)
transplant patients on immuno-suppression (10 K in US)
pts with hematologic malignancies (Lymphomas)
pts on immuno-supressive therapy (mainly corticosteroids)
Idiopathic CD4 lymphopenia (½ have hematologic malignancy, other ½ have this).

Cellular Immune System

CD4⁺ Helper T cells: extracellular Ags are processed by Ag APCs (mainly follicular dendritic cells and macrophages). The peptide is presented to T Helper cell (in the context of HLA Class II) which stimulates cell to activate and proliferate Þ secrete cytokines that assist in B cell differentiation, Ab production and Ý cytotoxic T lymphocyte activity through CD8⁺.

CD8⁺ Helper T cells: function to process peptides, of intracellular pathogens, on the surface of the infected cells in the context of MHC Class I which interact with the T cell receptor of the CD8⁺ cells Þ activation of the CTL (cytotoxic T lymphocytes) Þ secretes soluble chemokines.

Principles helpful in approaching the cellular deficient host:

(1) The risk of disease due opportunistic pathogens correlates with degree of immune impairment. (ß in CD4⁺ or drug dose)

(2) The majority of opportunistic infections result from endogenous reactivation of a previously acquired infection.

(3) The observed frequency of certain infections (fungal, mycobacterial or protozoa) depends on the prevalence of asymptomatic infection in the local population

(4) Infections may be severe, present in disseminated forms, and are often characterized by a high density of organisms

(5) Infections are often multiple, commonly presenting as consecutive or concurrent processes.

(6) Fungal, parasitic, and viral infections rarely are curable and usually require long-term suppression therapy.

(7) Bacterial infections are common, due in part to defects in B-cell function, and result in a high prevalence of sinus and respiratory tract infections in HIV-infected persons.

Syndromes (Associated with Pathogens) in the Cellular-Deficient Host (CDH)

(1) Bacterial Infections in the CDH – Ý prevalence due to lack of B cells (no longer "helped" by CD4⁺ T cells)

Strep Pneumonia: Presents abruptly with rigors, normal features. Ý prevalence of invasive Strep bacteremia in patient with HIV

All patients with Strep Pneumonia bacteremia (and patient with asplenia or multiple myeoloma) should be screened for HIV.

Lysteria and Nocardia tend to occur exclusively in CDH.

Nocardia: branching acid fast Gram + rods. Intracellular. Often in patient on steroids but also in HIV disease.
Presents: chronic focal pneumonia (can be peri-hillar), often spreads to lung with ring enhancing lesions.
Progresses over the course of weeks-months; patients presents clinically with insidious change in mental status.

Bartonella: Cat scratch disease. Presents with skin lesions (disseminated disease in CDH) often with multi liver abscesses.

Unique clinical presentation. Causes region lymphadenitis in the normal host

Syphilis: no Ý incidence in CDH but have Ý incidence of neuro-syphyllis because unable to clear CNS of spirochetes

Mycobacterial Infections: Ý Ý Ý in CDH. TB is major for HIV worldwide; Mycobacterium Avium Complex and Kamposi have been greatly reduced in US due to anti retroviral therapy (ARVT). 2 Billion people are infected with TB worldwide and 12million are believed to be co-infected with HIV. If they live long enough, they will progress to clinical TB.

Presentation is generally same as normal host: pleural effusion

unique presentations to CDH: involvement of interthoracic or extra thoracic lymph nodes due to Ý dissemination.

Tends to present with other opportunistic infections and can present earlier than most. When later, course is accelerated (e.g. a greatly reduced incubation period).

MAC: presents with fever, fatigue, wasting, abdominal pain, GI symptoms, possibly hepatosplenomegally or anemia: Ý alk phos suggests liver involvement some times with focal abscess. Massively infiltrates tissue. T cell count < 100 \ can be prevented by macrolide prophylaxis.

In Transplant patient: Risk of Infection is greatest after the transplant procedure.
In AIDS: most pathogens causing fever are bacteria, remainder (30-40%) are classical opportunistic pathogens
Primary site of infection in CDH is the respiratory tract.

(2) Protozoan Infections in the CDH

Pneumocystis carinii: Aids was 1^st recognized in gay men and IV drug users who presented with P. pneumoniae

suggested that process of AIDS involved impairment of cellular immunity. (PCP only infects immuno-suppressed)
presents initially with perihillar the diffuse interstitial to alveolar infiltrates with profound hypoxia. Often have fever of insidious onset (days to weeks), appearing well, with SOB and often non-productive cough. Diagnosed by sputum or BAL silver stain to identify cysts. Lung biopsy reveals lung full of protienatious material with non-staining organisms.
Unique presentations: Focal, cavitary or necrotizing processes. Pentamidine prophylaxis is often not inhaled into apex of lung, so pneumothorax can occur here secondary to cavitary lesion.
60-80 % of HIV patients with CD4⁺ counts < 200 will develop PCP without prophylaxis. Bactrim is >95% effective. TMP-SMX if Bactrim is not tolerated.

Toxoplasma gondii: assoc. with feces of domesticated animals (Cats).

Presents abruptly with change in mental status and focal neurological findings. (Pace = days). with or without Fever
CT of brain reveals single lesion with edema and mass effect. MRI will typically reveal multiple lesions centered around the basal ganglia with enhancement in mass effect.
Diagnosis: can be done by brain biopsy; however incidence of Toxo in lesions with mass effect is so high that it is diagnosed by treating for Toxo after CT or MRI. If they get better it is Toxo, if not, go for biopsy.
Organism is found in every organ upon autopsy, but clinically presents due to infiltration of brain and chorioretinitis which can also be seen in neonates due to their relative cellular deficiency. Can also present in adolescence without immuno-deficiency due to reactivation of neonatal infection.

Intestinal Pathogens: Crypto sporidium, Micro sporidium, Giardia

(3) Fungal Infections in the CDH

C. albicans and other Candida spp.–usu. local disease (oral thrush; candidial esophogitis with dysphagia and odynophagia)

Not an invasive disseminated fungus (unlike the dimorphic [are yeast outside body but fungi inside body] fungi -Cryptococcus, Histoplasma and Coccidio which normally are self limited but disseminated in the CDH)

Thrush is diagnosed when seen on mucus membranes (more difficult when localized to tongue). Scrape Þ KOHÞ look for yeast and pseudo- hyphea, or culture.

Diabetics, neonates and patients on antibiotics are also at risk for thrush. So without these, HIV screen patients with thrush

Aspergillus – a non-dimorphic fungi particularly found in neutropenic AIDS patients on steroids. Treatment has ß ß ß incidence.

Cryptococcus neoformans (see above): usually presents with a meningitis syndrome.

India ink is used as CDF stain (+75%), has capsule. A huge burden of infection is unique presentation in the CDH.

Pt presents with headache measures in weeks to days, without typical bacterial menigial signs – stiff neck, photophobia

difference in mentation may be noted, but not the obtundation seen in bacterial meningitis, unless focal brain involvement.

Labs: CSF can be normal in small # of patients, usually shows mild leukocytosis (10-100 range), glucose normal or ß , Cryptococal Ag is 95% sensitive in CSF and 99% in serum.

Infects host via lungs, enters blood Þ goes to CSF. Is usually primary infection, not reactivation

Meningoencephalitis Syndromes: HIV Þ acute meningitis early in disease and asymptomatic pleocytosis otherwise.

Cryptoccocus is #1 cause in CDH. Others include, Neurologic Syphilis, TB, Lymphoma,

Leptomeningis shows infiltration of organism which uncommonly can extend into brain. More typically, M RI reveals peripheral mass lesions in 10% of CDH.

Major complication is Ý intracranial pressure Þ optic nerve atrophy Þ blindness (uncommon but feared)

Hystoplasma presents in normal host with pulmonary disease, typically self-limiting but can Þ disseminated disease.

Almost always disseminated in AIDS patient. Endemic in the OH valley.
Lung involvement (50% of Hysto CDH patients) is a diffuse pattern that looks like milliary TB, or PCP. So X-rays are hard to interpret. Diagnosis with biopsy.

(4) Viral Infections in the CDH – Herpes family is the biggest problem.

Genital Herpes: more ulcerative and chronic in CDH than in normal.. Ý acyclovir resistance in CDH

CMV: major problem in CDH, especially transplant patient. Involves multiple cites specific to particular immuno deficiency.

AIDS Þ retinitis (#1) and GI ulcer(#2)

Transplant Þ allograph is #1 infection site

bone marrow transplant Þ diffuse interstitial pneumonitis from GVHD in allograph (not autologous) recipients

Steroid patients Þ seldom affected

Ý predisposition to bacterial infection in CDH.

GI ulcers and other GI symptoms are seen in AIDS and sometimes in transplant patients.

Renal transplant presentation of CMV is somewhat unique: mono with fever, leukopenia, thrombocytopenia, allograph dysfunction, other bacterial infections. A combination of these is considered sufficient to treat for CMV.

Among allograph recipients who receive a CMV infected organ, patient previously unexposed to CMV develop primary disease at a higher rate than those already exposed develop a secondary reactivation of disease (as is seen in AIDS patients)

Diagnosis: biopsy; owl eyes – intra nuclear inclusions due to CMV

Papovaviris (JC, BK) Þ Progressive Multifocal Leukoencephalopathy seen mainly in CDH

Tends to affect white matter of the brain.
Radiograph, white matter lesion without mass effect. Indistinguishable from what is seen in HIV. Clinical presentation is very different -abrupt focal neurologic presentations: paralysis, hemiparesthesia, cranial nerve palsies, optic field deficit. AIDS presents without focal findings in subacute manner

Parvovirus: aplastic anemia seen exclusively in CDH or patients with chronic hemolytic anemias.

Papillomavirus: agent of genital wart and neoplasms which progresses more rapidly in CDH- rectal and cervical CA.

Varicella-zoster: dematoma fulminant shingles characterized by erythematous base with crusting lesion.

immunocompetant people are at risk for shingles when age >50. So if age <50 then suspect immunodeficiency.
Unique presentation in CDH: leuko-encephalitis (necrotizing lesions),
AIDS: retino-necrosis that leads to blindness rapidly

Epstein-Barr Virus: causes oral Hairy leukoplakia (striated white appearance on the lateral border of the tongue).

AIDS: No clinical significance
transplant: associated with lymphoproliferative syndrome characterized by malignancy often involving brain or lung.

Human Herpes Virus-8: possible agent of Kaposi’s sarcoma (strong association, but not yet proven) – pathognomonic of AIDS in US, characterized by palpable indurated discolored lesions

seen in non-AIDS patients: older patients of Mediterranean origin and in equatorial Africa among children without HIV