MICROBIOLOGY
Microbiology
Dermatologic manifestations of bacterial and viral infections:
Primary Syphilis -- painless chancre. Secondary syphilis -- maculopapular rash, condylomata lata (flat topped papules -- located at the anus and in skin folds where heat and moisture exist). Rocky Mountain Spotted Fever -- stage 1: erythema chronicum migrans (a red rash that spreads, leaving a clear center -- bulls-eye rash).Menningococcemia --intravascular multiplication of N. meningitidis in the blood can result in a petechial rash (minute hemorrhagic spots the size of a pin that do not blanch when pressed). The rash can enlarge if the organisms multiply in the blood to the leading to fulminant meningoccemia (Waterhouse-Friderichsen syndrome--bilateral hemorrhage into the adrenals). Herpes Zoster (varicella zoster) Virus -- vesicular rash (chicken-pox) that appear on the back of the head and ears then spread to the face, neck, trunk, and extremities. The distinguishing feature from other rashes (small pox) is that lesions will be at different stages (whereas small pox lesions are concentrated on the extremities and are all in the same stage). The lesion are very pruritic (itchy). Coxsackievirus --Coxsackie A: herpangina -- fever, sore throat, and small red-based vesicles over the back of the throat. Hand-foot-mouth disease -- (coxsackie A-16) eruptions of small pearly, gray vesicles on the fingers, toes, palms, and soles often accompanied by painful vesicles and ulceration of the buccal mucous membranes and the tongue with slight fever; disease lasts 4 to 7 days.
Common sexually transmitted diseases:
Viral Gastroenteritis in the pediatric and adult population:
Rotavirus -- Group A: cause most infantile disease (most between 6 - 24 months) -- 30-60% of infantile diarrhea. Occurrence is during the winter months (SW to NE spread). Diarrhea, vomiting, and fever for 5-7 days. Group B: associated with large epidemic of severe diarrhea (3-5 days) in Adults in China. Enteric Adenovirus (serotypes 40 & 41) -- 2nd most common cause of diarrhea in children. Symptoms consist of prolonged diarrhea lasting 5-12 days, vomiting and fever. Norwalk virus -- most common cause of outbreaks of gastroenteritis reported to the CDC.
Epidemics of vomiting and diarrhea in older children and adults, associated with shellfish, food or water.
Epidemics of vomiting and diarrhea in older children and adults, associated with shellfish, food or water.
Common causes of community-acquired and nosocomial pneumonia:
Infections that cause congenital/neonatal complications: ToRCHeS -- all of these organisms can cross the blood-placenta barrier. Toxoplasma gondii -- can cause chorioretinitis, blindness, seizures, mental retardation, microcephaly, encephalitis, and stillbirth if infections is acquired early in gestation. Rubella (Rubivirus) -- risk is greatest with infection early in fetal development. Heart: PDA, VSD, and pulmonary artery stenosis. Eye: cataracts, chorioretinitis. CNS: mental retardation, microcephaly, deafness. CMV -- most common viral cause of mental retardation. Also cause microcephaly, deafness, seizures.
Herpes -- neonate is often infected during delivery. Manifestations vary -- vesicular lesions or CNS involvement.HIV Syphilis -- high rate of mortality (still-birth, spontaneous abortion, and neonatal death). Survivors will go on to develop Early of Late congenital syphilis. Early: occurs w/in 2 years and is like severe adult secondary syphilis -- widespread rash and condyloma latum. "Snuffles" -- mucous membrane involvement with runny nose. Late: similar to adult tertiary syphilis except cardiovascular involvement rarely occurs.
Parasites that frequently cause disease in the U.S.
Entamoeba histolytica - flask-shaped ulcer in large intestine - amoebic liver abcesses (liver paste). Trichomonas vaginalis - strawberry cervix, twitching motility STD. Giardia lamblia - non-bloody diarrhea, malabsorption, trophozoite is “old man with moustache”. Cryptosporidium parvum - diarrhea in immunocompromised. Toxoplasma - acutely like mono. In utero - hydrocephalus, chorioretinitis, brain calcifications also in immunocompromised. Pneumocystis carinii – immunocompromised. Enterobius vermicularis (Pinworm). Ascaris lumbricoides - lives in intestine, pathology in lungs; Toxocara canis (dog Ascaris)
Parasites that cause disease more commonly outside U.S.
Trypanosoma brucei - Africa - sleeping sickness, Winterbottom’s sign. Trypanosoma cruzi - S. America - reduviid bug, Chaga’s disese, arrhythmias,CHF.Leishmania tropica (Asia) and mexicana (C. and S. America) - sandfly, cutaneous ulcers. L. braziliensis (C. and S. America) - also mucocutaneous involvement. L. donovani (Asia and S. America) - visceral involvement
Plasmodium malariae (least common), falciparum (most common, most deadly), vivax and ovale (both have latent liver phase) - Anopheles mosquito. Chlonorchis sinensis - SE Asia – cholangiocarcinoma. Paragonimus westermani - SE Asia - causes hemoptysis, CNS involvement in 1%. Schistosomas - all cause liver granulomata, cirrhosis. S. haemotobium - Africa - adults in bladder-squamous cell carcinoma, no Katayama fever. S. japonicum - SE Asia - adults in superior mesenteric vein, Katayama fever. S. mansoni - all but developed world - adults in inferior mesenteric vein, Katayama fever Onchocerca volvulus - Africa and S. America - black fly, river blindness Wucheria bancrofti/Brujia malayi - Aedes/Culex mosquitos, elephantiasis.
Herpes Simplex (HSV-1) encephalitis is the most common cause of viral encephalitis
Brain tissue swelling, cell death (medial temporal lobe lesion). Fever, focal neurological abnormalities, mental status changes. Treat with Acyclovir (one of the few treatable viral encephalitides)
Tests for diagnosis of viral infections
Culture (gold standard) - examine for cytopathic effect (CPE) - takes a few days to two weeks. Can add red cells to check for hemagglutinins. 100% specificity (for showing a virus is there, not specific ID), poor sensitivity . Without antigen detection (shell vial technique) can only make presumptive ID of virus. Antigen detection - can do on cell specimens from patient or on culture (shell vial technique). Immunofluorescence assay - Ab labeled w/ fluorescing compound - use UV microscope. ELISA, immunoperoxidase - Ab labeled w/ enzyme that changes substrate color. Serology for IgG (four-fold rise of two specimensis diagnostic), IgM - single result is diagnostic. DNA probes/PCR. Electron microscopy for ID of viral particles - expensive, insensitive
Know the microscopic appearance of organisms - too difficult to summarize here, easier to see
Fever patterns -
Roseola (HHV-6) - very high fever for 3-5 days, comes down w/ a rash for 1-3 days. Plasmodia - spiking fevers- P. malariae (q 72 hrs.); vivax, ovale (q 48 hrs.), falciparum (varies). Brucellosis - undulant fever - fever increases to peak in evening, declines to normal by morning
Immunology
Some Immunologic Tests – ELISA – see above . Coombs test – anti-Ig Ab is added to red cells to look for agglutination. Direct - looks for Ab bound to rbc’s. indirect – looks for Ab in serum – serum added to naked rbc’s, then anti-Ig added. Complement-fixation tests – utilize Ig’s ability to fix complement to look for various antigens
Immune complex diseases (Type III hypersensitivity)
Serum sickness – circulating foreign Ag leads to Ab formation and deposition of Ag-Ab complexes (in arteries, glomeruli, synovia) that activate complement to cause tissue damage (arthritis, rash, fever). Arthus reaction – vasculitis from Ag injection into skin – Ag-Ab complexes form at injection site. SLE – DNA-anti-DNA complexes in kidneys, vessels to cause glomerulonephritis, vasculitis. Post-streptococcal GN – Strep Ag deposits in kidney, Ab binds (Arthus-type reaction)
Human antibodies exhibit an enormous range (~108) of specificity’s. The genetic basis
forthis involves several factors:
VDJ recombination
the heavy chain of the immunoglobulin is made up of a variable (V), diversity (D), and junctional/joining (J) segment. The gene possesses greater than 200 V, 20 D, and 6 J coding sequences. During B cell development the sequences between the V, D, and J sequences are removed via recombination to provide for a single open reading frame. Heavy chain recombination precedes light chain rearrangement. The light chains can utilize either the kappa or lambda genes for generation of a functional Ig protein. Light chain possesses V and J segments: No D. During B cell development, the sequence between the V segment (more than 100 coding sequences) and the J segment (1 or more J segments, depending on the light chain) is removed via recombination to provide for a single open reading frame.
Class switching
Only the heavy chain. The isotype is defined by those sequences (known as the constant region, i.e. codes for IgG, IgM etc.) that are invariable and downstream of the VDJ recombination. Isotype switching utilizes recombination to remove such constant region sequences so as to allow the VDJ sequence to be placed upstream of different C regions.
Affinity maturation
After the B cells have been activated and class switched, a portion are found that migrate to the spleen and lymph nodes. Two things happen: rapid proliferation, every 6-12 hours=1 division B cells sustain somatic mutation at Ig chains. Aim of this process is to create Ig with higher affinity for antigen. Those B cells that lose affinity for antigen are eliminated.
Immune system evasion and antigenic variation
Inhibition of complement activation. Capsules with sialic acid residues that prohibit alternative pathway activation. Group B and Group A streptococcal C5a-ase.
Presence of antiphagocytic factors. Capsular polysaccharide. M-proteins
Genetic variation of surface proteins. Pilli of GC
Inhibit phagolysosome fusion- mycobacteria
Scavenge reactive oxygen species- glycolipid of M. leprae
Block killing- hemolysins of L monocytogenes
Immune deficiencies
Transient physiologic hypogammaglobulinemia occurs in infants between the ages of approximately 3 and 6 months. Although infants born with adult levels of placentally transferred IgG, a low level of IgG results from: The disappearance of maternal antibody which has a half life of 22-28 days. The infants low early rate of synthesis of secretable immunoglobulins
Congenital agammaglobulinemia (Bruton’s disease) is a sex-linked (male) disorder that affects infants between the ages of 5 and 6 months. These patients have an apparently normal thymus and CMI. Clinical features include: Recurrent pyogenic infections. digestive tract disorders. Cause—may occur in the transition from pre-B to B cells and involves the loss of a tyrosine kinase gene. The pre-B cells are normal. Diagnosis is made by noting the absence of tonsils (on examination), germinal centers (on lymph node biopsy), and B cells (on peripheral smear) Serum immunoglobulins levels of less that 10% also suggest the disease. Treatment—passive transfer of adult serum immunoglobulin can be administered prophylactically to diminish infections.
Dysgammaglobulinemia. Patients of varying age present with a selective immunoglobulin class deficiency. Diagnosis—Most patients have decreased IgA levels with 1:600-800 of those patients having levels of less than 5mg/dl. Immunologic features include: Loss of mucosal surface protection. Failure of IgA bearing cells to differentiate into secreting plasma cells, although their numbers are normal. increased susceptibility to autoimmune disease
Congenital thymic aplasia (DiGeorge syndrome) is characterized by hypocalcemia, tetany and an absence of T cells. Cause—Not hereditary. It is caused by unknown intrauterine injury to the third and fourth pharyngeal pouches that occurs between the third and sixth weeks of gestation
Clinical Features: Thymus and parotid glands are not developed. Depressed CMI permits opportunistic infections (Candida, Pneumocystis, viruses). Apparently normal germinal centers, plasma cells, and serum immunoglobulin. Treatment—These patients die early. Vaccination with live vaccines (measles) is contraindicated. The transplantation of fetal thymic tissue is experimental and may be complicated by a graft-versus-host reaction.
Chronic mucocutaneous candidiasis is a highly specific T cell disorder that is characterized by an absence of immunity to Candida. Patients have apparently normal T cell absolute numbers and functions. Approximately 50% of patients with this disorder also have endocrine dysfunctions (hypothyroidism)
Wiskott-Aldrich syndrome is a sex-linked (male) disorder occurring mainly in children. The syndrome has three main features 1) thrombocytopenia (bleeding), eczema, and recurrent infections. An increased incidence of lymphoreticular malignancies or lymphomas occur. Immunologic features include: Depressed CMI and a low serum IgM level, but normal IgG and IgA levels. oor response to bacterial capsular polysaccharide antigens. Cause—May be an absence of specific glycoprotein receptors on T cells and platelets. Treatment—Bone marrow transplantation may be effective
Severe combined immunodeficiency disease (SCID) is a rare disorder characterized by a genetic defect in stem cells that results in the absence of the thymus gland and t and b cells. Affected children are extremely susceptible to infections and have a very short life span. Immunologic features—A deficiency in the enzyme adenosine deaminase (ADA) occurs in 50% of patients. This deficiency results in the accumulation of toxic deoxyadenosine triphosphate (DATP), which inhibits ribonucleotide reductase and prevents DNA synthesis. A mutation in the g chain of the IL-2 receptor gene is found in other patients with SCID. Treatment—Gene therapy with ADA is experimental
Chronic granulomatous disease (CGD) results from a genetic defect in the nicotimamide adenine dinucleotide phosphate (NADPH) oxidase system in neutrophils. Patients are susceptible to infections by age 2 years, especially organisms of low virulence. Immunologic features—Neutrophils bactericidal activity (respiratory burst) is defective because of depressed NADPH oxidase, superoxide dismutase activity and decreased hydrogen peroxide levels. Diagnosis is based on failure of neutrophils and macrophages to reduce a nitroblue tetrazolium dye. Treatment with IFN-g has been successful
Absence of spleen can be due to surgical removal after a trauma, treatment of certain hematologic diseases or as a result of infarction in sickle cell disease. Increased susceptibility to encapsulated organisms such as Streptococcus pneumonia. The spleen is required for induction of protective humoral immune responses to the thymus-independent capsular polysaccharide antigens of such organisms.
MHC/HLA serotypes. Class I antigens are found on all nucleated cells (3 gene loci: HLA-A,HLA-B, and HLA-C). Class II antigens are found on immunologic effector cells (e.g.macrophages, B cells, activated epithelial cells; 3 gene loci: HLA-DP, HLA-DQ, and HLA-DR)
Familial inheritance
Many alleles of class I and class II molecules are present at each locus on chromosome. Haplotypes from both parents are inherited and expressed codominantly.
Disease associations
DR4 Rheumatoid arthritis. DR3, DR4 IDDM. DR3 Sjogren’s syndrome. B27 ankylosing spondylitis.
Transplant compatibility
Matching the donor and recipient at the HLA locus improves graft acceptance. Both the donor and recipient are typed for HLA profiles using DNA sequence analysis of the HLA genes or more than 200 specific anti-HLA antisera. HLA antigens on allographs stimulate recipient CD4+ T cells while respond by secreting cytokines and by inducing adhesion molecules. IL-2 activates CD8+ T cells to a state of cytotoxicity, thus releasing effector molecules such as perforins. IFN-g activates monocytes/macrophages to expresses delayed type hypersensitivity, resulting in increased lysosomal activity, phagocytosis, respiratory burst and release of TNF-a. Activated selectins, integrins, intercellular adhesion molecules (ICAM) and vascular cell adhesion molecules (VCAM) promote leukocyte extravasion into the graft bed. Acute rejection. Within weeks. Chronic rejection. Episodic bouts of rejection, occurring months to years after transplantation. Hyperacute rejection. Within minutes—graft never takes because of pre-existing sensitivity
Allergies
Common antigens
Penicillin. Procaine. Insect venom. Pollen. Molds. Foreign serum. Fungal spores. House dust. Animal dander.
Antigen-IgE-mast cell complex
Excess IgE antibody is produced and binds avidly via its FC domain to its receptor on the surface of mast cells and basophils. When antigen is reintroduced into the sensitized host, it binds to and aggregates several cell-bound IgE antibody molecules, forming the complex. The resulting membrane perturbation causes degranulation of the mast cells and release of histamine, leukotrienes, serotonin, bradykinin, etc. These agents rapidly contract smooth muscle, increase vascular permeability and secretions, change coagulability, and induce hypotension
Mechanism of immunotherapy
A hyposensitive state is achieved by repeated injection of the agent into subliminal doses. Parenteral exposure favors the synthesis of IgG which combines avidly with the allergen in the circulation, thus blocking union with cell-associated IgE and mediator release.
Granulomas are a method by which the host can wall off the organisms and sequester the infection.
Role of macrophages
Occur if the antigen persists in the tissues and continues to stimulate host reactivity. Chronic stimulation by intracellular organisms releases chemotactic agents (e.g. IL-1, IL-8) leading to an inflammatory cell influx. IL-4 and IFN-g promote the retention of macrophages and cause the fusion of monocytes at the site, leading to an epithelioid cell granuloma derived from macrophages, histocytes, and epithelioid cells. Foreign body vs. immune. Caseating versus non-caseating. Common causes
Vaccines
Types
Live attenuated vaccines permit replication in the hose, increasing antigenic stimulation. Weakened so as to not cause illness, but still stimulate immune system. Killed vaccines have been inactivated. Multiple doses must be given and adjuvants might be required. Adjuvants are substances added to increase immunogenicity (aluminium hydroxide gel). Recombinant vaccines requires identification of an epitope and synthesis of the antigen
Macrophages and NK cells function
Macrophages
Phagocytosis. Cytokine production. Antigen presenting cell. Principle effector of CMI—Activated by antigen-stimulated T-cells to more efficiently perform microbicidal functions. Participate in humoral immune responses, because they bind opsonized particles much more avidly that non-opsonized particles.
Natural Killer cells
Lack the specific TCR for antigen recognition. Kill target cells that display decreased expression of self class I MHC molecule or cells with specific IgG
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