CHAPTER 119: APPROACH TO THE PATIENT WITH AN • Goal: differentiate infectious vs. non-infectious conditions.
INFECTIOUS DISEASE
5. Clinical Approach
A. History
• Exposure history
1. Historical Perspective o Past infections, antimicrobial resistance profiles.
• Early belief: communicable diseases due to miasma (“bad o Healthcare exposures: hospital, nursing home,
air”). long-term care.
• Germ theory (Pasteur, Koch, late 19th century) established o Social/behavioral: IV drug use, unsafe sex,
microorganisms as causal agents. occupational risks, hobbies.
o Dietary: raw meat (E. coli, Toxoplasma),
• 20th century:
unpasteurized milk (Listeria, M. bovis), raw seafood
o Discovery of antibiotics and vaccines.
(Vibrio, norovirus), untreated water (Leptospira,
o Elimination of smallpox.
parasites).
• Chronic diseases linked to infections:
o Animal contact: dogs (tick-borne), cats (Bartonella),
o Helicobacter pylori → peptic ulcer disease, gastric
reptiles (Salmonella), rodents (leptospirosis),
carcinoma.
rabbits (tularemia).
o HPV → cervical cancer.
o Travel: international and domestic (e.g., TB,
o HBV/HCV → hepatocellular carcinoma.
malaria, coccidioidomycosis).
• Infectious diseases remain significant due to:
• Host-specific factors
o Emerging/re-emerging pathogens (HIV, SARS-
o Immunocompromise: HIV, cancer, malnutrition,
CoV-2, Ebola, Zika).
chemo, biologics, splenectomy.
o Antimicrobial resistance (CRE, MDR-TB, MRSA,
o Immunization history.
VRE, Candida auris).
B. Physical Examination
o Bioterrorism threat.
• Vital signs
o Fever ≥38.3°C = common indicator.
2. Global Considerations
o Relative bradycardia (Faget’s sign) in typhoid,
• Infectious diseases = second leading cause of death
brucellosis, rickettsioses, Q fever, legionellosis,
worldwide.
malaria, yellow fever.
• 2017: 10.3 million deaths (≈18% of all deaths; up to 58% in
• Skin
sub-Saharan Africa).
o Rash, eschars, ulcers, Janeway lesions, Osler’s
• Disproportionately affect: nodes, petechiae, pressure ulcers.
o Children <1 yr,
• Lymphatics
o Adults >70 yrs,
o Localized vs. generalized lymphadenopathy.
o Populations in low/middle-income countries.
o Epitrochlear nodes always pathologic.
• Geographic epidemiology guides diagnosis (e.g., HIV/AIDS in
• Other
Africa, MDR-TB in former Soviet bloc, India, China).
o Endocarditis stigmata, meningismus,
• Travel and migration: organomegaly.
o Spread historic pandemics (plague, smallpox, 1918 o Note presence of lines, catheters, drains as
influenza). possible portals.
o Modern impact: SARS-CoV-2 pandemic.
C. Diagnostic Testing
o Travelers may spread person-to-person infections
• CBC with differential: leukocytosis (bacteria), lymphocytosis
(HIV, influenza), vector-borne diseases (Zika,
(viruses), eosinophilia (parasites).
chikungunya), and resistant organisms.
• Inflammatory markers: ESR, CRP, procalcitonin (distinguish
bacterial vs viral).
3. The Human Microbiota
• CSF analysis:
• Humans colonized with ~50 trillion bacteria, plus viruses,
o Opening pressure, cell count, protein, glucose,
fungi, archaea.
Gram stain.
• Major reservoirs: GI tract, female genital tract, oral cavity,
o Profiles differ in bacterial, viral, fungal, TB, parasitic
nasopharynx; skin/lungs also important.
meningitis.
• Benefits: metabolism, immune shaping, pathogen
• Cultures: blood, urine, sputum, tissue.
competition.
• Pathogen-specific tests: PCR, antigen detection, serology.
• Most infections arise from commensals (e.g., S. aureus, S.
• Imaging: CT, MRI, ultrasound for abscesses,
pneumoniae, P. aeruginosa).
lymphadenopathy.
• Clinical importance:
o Interpreting cultures,
6. Management
o Choosing empiric therapy,
Empirical Therapy (Table 119-5 highlights)
o Minimizing antibiotic damage to beneficial flora.
• Septic shock: vancomycin + antipseudomonal β-lactam (±
second anti-pseudomonal).
4. When to Consider an Infectious Etiology
• Meningitis: vancomycin + ceftriaxone + dexamethasone.
• Presentations: fulminant sepsis → chronic disease →
asymptomatic latency. • CNS abscess: vancomycin + ceftriaxone + metronidazole.
• Clues from history, physical exam, and labs. • Endocarditis: vancomycin + cefepime.
• Pneumonia:
, o Outpatient: macrolide or doxycycline (respiratory
fluoroquinolone if comorbidities).
o Inpatient: β-lactam + macrolide or fluoroquinolone.
o ICU: broader coverage, MRSA/Legionella
consideration.
• Hospital-acquired pneumonia: antipseudomonal β-lactam +
fluoroquinolone/aminoglycoside (add MRSA coverage if risk).
• Skin/soft tissue infections: anti-staphylococcal agents; add
MRSA coverage if indicated.
• Intra-abdominal infection: cefoxitin, or metronidazole +
cephalosporin/fluoroquinolone.
Adjunctive therapy
• IVIG or hyperimmune globulin (e.g., rabies, tetanus, botulism,
HBV, CMV).
• Consider use in toxic shock syndromes.
7. Infection Control
• CDC 2007 isolation precautions.
• Post-exposure prophylaxis for:
o Neisseria meningitidis,
o HIV,
o Anthrax,
o Rabies,
o VZV, tetanus.
8. When to Seek Infectious Disease Consultation
• Indications:
o Difficult-to-diagnose infections.
o Poor response to treatment.
o Complex comorbidities (transplant, autoimmune,
immunosuppression).
o Exotic/unfamiliar diseases.
• Benefits: ↓ mortality (56% reduction in S. aureus bacteremia),
↓ hospital stay, ↓ costs.
9. Perspective
• Infectious diseases = host–microbe evolutionary arms
race.
• Rapid microbial adaptability ensures infections will never be
eliminated.
• Ongoing challenges:
o HIV cure absent,
o TB detection/treatment stagnant,
o New outbreaks (Zika, SARS-CoV-2, Ebola),
o Antimicrobial resistance,
o Bioterrorism threats.
,120: MOLECULAR MECHANISMS OF MICROBIAL • Type III (T3SS) – needle-syringe apparatus; delivers
PATHOGENESIS effectors for uptake, survival.
• Type IV (T4SS) – protein/DNA transfer; Legionella, Coxiella.
• Type V (T5SS) – autotransporters (adhesins, invasins).
• Type VI (T6SS) – bacterial competition and host cell
I. Definition and General Principles manipulation.
• Microbial pathogenesis = interaction of pathogen, host • Type VII (T7SS) – M. tuberculosis ESX-1, phagosome lysis.
tissue, and microbiota leading to disease. Clinical implication: Secretion systems are drug/vaccine targets.
• Stages of infection:
1. Colonization – entry into body V. Intracellular Survival Strategies
2. Infection – attachment, survival, immune evasion A. In Vacuoles
3. Disease – tissue damage (microbe + host immune • Prevent phagolysosome fusion (Legionella, Coxiella).
response) • Remodel vacuole into replication niches (LCV, CCV).
4. Transmission – exit and spread B. In Cytosol
• Key concept: Symptoms often result more from host • Escape vacuole (Listeria, Shigella, Rickettsia).
inflammatory response than direct microbial injury. • Actin-based motility (ActA, IcsA) → spread cell-to-cell.
• Microbiota: influences every stage, protects against • Burkholderia → multinucleated giant cells via T6SS.
pathogens but may also facilitate infection if disrupted. Clinical implication: Intracellular lifestyle = protection from many
antibiotics + immune clearance.
II. Entry into the Host
A. Routes VI. Avoidance of Host Defenses
• Skin/mucosa: breaks, trauma, burns. A. Complement
• Respiratory tract: droplet nuclei (1–5 µm), fomites → TB, • Capsules (e.g., S. pneumoniae).
influenza, COVID-19. • Proteases degrade complement (Streptococcus).
• GI tract: contaminated food/water, fecal-oral spread. • CD59-like proteins (Borrelia).
o Large inoculum → V. cholerae, Salmonella B. Antimicrobial peptides
o Small inoculum → Shigella • Surface modification → reduced negative charge.
• Genitourinary tract: fecal flora ascent, instrumentation. • Proteases (S. aureus).
• Direct toxin ingestion: preformed toxins (e.g., S. aureus, B. C. Oxidative burst evasion
cereus, C. botulinum). • Detox enzymes (superoxide dismutase, catalase).
Clinical implication: Transmission route influences control measures • Block NADPH oxidase assembly.
(masking, hand hygiene, water sanitation). D. NET evasion
• DNases degrade chromatin traps (Streptococcus, S. aureus).
III. Adhesion and Colonization E. PRR Evasion
A. Adhesins • Modify PAMPs: e.g., tetra-acylated LPS (Yersinia pestis at
• Pili/fimbriae – E. coli (FimH, Pap) → UTIs 37°C).
• Type IV pili – Neisseria, Vibrio → motility + microcolony • Avoid TLR5 recognition (flagellin variants, H. pylori).
formation • Block NF-κB/MAPK signaling (effectors: OspF, YopJ, SpvC).
• Flagella – motility and sometimes adhesion (EPEC, EHEC) F. Inflammasome inhibition
• Autotransporter proteins (T5SS) – Bordetella pertussis • Block caspase activation (Shigella, EHEC effectors).
FHA, Shigella IcsA Clinical implication: Evasion explains persistent or relapsing
• MSCRAMMs – S. aureus binding ECM proteins infections.
• Opa proteins – Neisseria adhesion
B. Host Receptors VII. Bacterial Toxins
• Glycans (mannose, sialic acid, fucose) A. AB Toxins
• ECM proteins (fibronectin, collagen, laminin) • Cholera toxin → ↑cAMP → watery diarrhea.
• Integrins/CEACAMs → internalization pathways • Pertussis toxin → G protein modification.
• CFTR – receptor for S. Typhi • Diphtheria toxin, Exotoxin A (Pseudomonas) → block EF-2,
Clinical implication: Adhesion specificity explains tissue tropism and halt protein synthesis.
disease localization (e.g., UPEC → bladder, H. pylori → stomach). B. Pore-forming toxins
• Listeriolysin O (Listeria).
IV. Mechanisms of Microbial Entry into Cells • α-toxin (S. aureus).
A. Trigger mechanism (T3SS-dependent) • Leukocidins.
• Pathogen: Salmonella, Shigella, Chlamydia C. Superantigens
• Inject effectors → actin rearrangement → ruffling → • S. aureus (TSST-1), S. pyogenes exotoxins → massive
bacterial uptake. cytokine release → shock.
B. Zipper mechanism Clinical implication: Toxins = basis of many vaccines/antitoxin
• Pathogen: Listeria (InlA/InlB), Yersinia (Invasin, YadA) therapies.
• Surface proteins bind host receptors → receptor clustering
→ tight engulfment. VIII. Host-Mediated Damage
C. Secretion Systems • Excessive inflammation → tissue injury.
• Cytokine storms → sepsis, toxic shock.
, • ROS/RNS damage to host tissues.
IX. Role of the Microbiota
• Colonization resistance: competition, bacteriocins, T6SS.
• Disruption (antibiotics) → opportunistic infections (C.
difficile).
• Therapy: fecal microbiota transplantation (FMT).
X. Clinical and Therapeutic Implications
• Understanding pathogenesis guides:
o Antibiotic use (extracellular vs intracellular
pathogens).
o Vaccines (target toxins, adhesins, secretion
systems).
o Immunotherapies (enhance complement, block
evasion pathways).
o Microbiome interventions (FMT, probiotics).
INFECTIOUS DISEASE
5. Clinical Approach
A. History
• Exposure history
1. Historical Perspective o Past infections, antimicrobial resistance profiles.
• Early belief: communicable diseases due to miasma (“bad o Healthcare exposures: hospital, nursing home,
air”). long-term care.
• Germ theory (Pasteur, Koch, late 19th century) established o Social/behavioral: IV drug use, unsafe sex,
microorganisms as causal agents. occupational risks, hobbies.
o Dietary: raw meat (E. coli, Toxoplasma),
• 20th century:
unpasteurized milk (Listeria, M. bovis), raw seafood
o Discovery of antibiotics and vaccines.
(Vibrio, norovirus), untreated water (Leptospira,
o Elimination of smallpox.
parasites).
• Chronic diseases linked to infections:
o Animal contact: dogs (tick-borne), cats (Bartonella),
o Helicobacter pylori → peptic ulcer disease, gastric
reptiles (Salmonella), rodents (leptospirosis),
carcinoma.
rabbits (tularemia).
o HPV → cervical cancer.
o Travel: international and domestic (e.g., TB,
o HBV/HCV → hepatocellular carcinoma.
malaria, coccidioidomycosis).
• Infectious diseases remain significant due to:
• Host-specific factors
o Emerging/re-emerging pathogens (HIV, SARS-
o Immunocompromise: HIV, cancer, malnutrition,
CoV-2, Ebola, Zika).
chemo, biologics, splenectomy.
o Antimicrobial resistance (CRE, MDR-TB, MRSA,
o Immunization history.
VRE, Candida auris).
B. Physical Examination
o Bioterrorism threat.
• Vital signs
o Fever ≥38.3°C = common indicator.
2. Global Considerations
o Relative bradycardia (Faget’s sign) in typhoid,
• Infectious diseases = second leading cause of death
brucellosis, rickettsioses, Q fever, legionellosis,
worldwide.
malaria, yellow fever.
• 2017: 10.3 million deaths (≈18% of all deaths; up to 58% in
• Skin
sub-Saharan Africa).
o Rash, eschars, ulcers, Janeway lesions, Osler’s
• Disproportionately affect: nodes, petechiae, pressure ulcers.
o Children <1 yr,
• Lymphatics
o Adults >70 yrs,
o Localized vs. generalized lymphadenopathy.
o Populations in low/middle-income countries.
o Epitrochlear nodes always pathologic.
• Geographic epidemiology guides diagnosis (e.g., HIV/AIDS in
• Other
Africa, MDR-TB in former Soviet bloc, India, China).
o Endocarditis stigmata, meningismus,
• Travel and migration: organomegaly.
o Spread historic pandemics (plague, smallpox, 1918 o Note presence of lines, catheters, drains as
influenza). possible portals.
o Modern impact: SARS-CoV-2 pandemic.
C. Diagnostic Testing
o Travelers may spread person-to-person infections
• CBC with differential: leukocytosis (bacteria), lymphocytosis
(HIV, influenza), vector-borne diseases (Zika,
(viruses), eosinophilia (parasites).
chikungunya), and resistant organisms.
• Inflammatory markers: ESR, CRP, procalcitonin (distinguish
bacterial vs viral).
3. The Human Microbiota
• CSF analysis:
• Humans colonized with ~50 trillion bacteria, plus viruses,
o Opening pressure, cell count, protein, glucose,
fungi, archaea.
Gram stain.
• Major reservoirs: GI tract, female genital tract, oral cavity,
o Profiles differ in bacterial, viral, fungal, TB, parasitic
nasopharynx; skin/lungs also important.
meningitis.
• Benefits: metabolism, immune shaping, pathogen
• Cultures: blood, urine, sputum, tissue.
competition.
• Pathogen-specific tests: PCR, antigen detection, serology.
• Most infections arise from commensals (e.g., S. aureus, S.
• Imaging: CT, MRI, ultrasound for abscesses,
pneumoniae, P. aeruginosa).
lymphadenopathy.
• Clinical importance:
o Interpreting cultures,
6. Management
o Choosing empiric therapy,
Empirical Therapy (Table 119-5 highlights)
o Minimizing antibiotic damage to beneficial flora.
• Septic shock: vancomycin + antipseudomonal β-lactam (±
second anti-pseudomonal).
4. When to Consider an Infectious Etiology
• Meningitis: vancomycin + ceftriaxone + dexamethasone.
• Presentations: fulminant sepsis → chronic disease →
asymptomatic latency. • CNS abscess: vancomycin + ceftriaxone + metronidazole.
• Clues from history, physical exam, and labs. • Endocarditis: vancomycin + cefepime.
• Pneumonia:
, o Outpatient: macrolide or doxycycline (respiratory
fluoroquinolone if comorbidities).
o Inpatient: β-lactam + macrolide or fluoroquinolone.
o ICU: broader coverage, MRSA/Legionella
consideration.
• Hospital-acquired pneumonia: antipseudomonal β-lactam +
fluoroquinolone/aminoglycoside (add MRSA coverage if risk).
• Skin/soft tissue infections: anti-staphylococcal agents; add
MRSA coverage if indicated.
• Intra-abdominal infection: cefoxitin, or metronidazole +
cephalosporin/fluoroquinolone.
Adjunctive therapy
• IVIG or hyperimmune globulin (e.g., rabies, tetanus, botulism,
HBV, CMV).
• Consider use in toxic shock syndromes.
7. Infection Control
• CDC 2007 isolation precautions.
• Post-exposure prophylaxis for:
o Neisseria meningitidis,
o HIV,
o Anthrax,
o Rabies,
o VZV, tetanus.
8. When to Seek Infectious Disease Consultation
• Indications:
o Difficult-to-diagnose infections.
o Poor response to treatment.
o Complex comorbidities (transplant, autoimmune,
immunosuppression).
o Exotic/unfamiliar diseases.
• Benefits: ↓ mortality (56% reduction in S. aureus bacteremia),
↓ hospital stay, ↓ costs.
9. Perspective
• Infectious diseases = host–microbe evolutionary arms
race.
• Rapid microbial adaptability ensures infections will never be
eliminated.
• Ongoing challenges:
o HIV cure absent,
o TB detection/treatment stagnant,
o New outbreaks (Zika, SARS-CoV-2, Ebola),
o Antimicrobial resistance,
o Bioterrorism threats.
,120: MOLECULAR MECHANISMS OF MICROBIAL • Type III (T3SS) – needle-syringe apparatus; delivers
PATHOGENESIS effectors for uptake, survival.
• Type IV (T4SS) – protein/DNA transfer; Legionella, Coxiella.
• Type V (T5SS) – autotransporters (adhesins, invasins).
• Type VI (T6SS) – bacterial competition and host cell
I. Definition and General Principles manipulation.
• Microbial pathogenesis = interaction of pathogen, host • Type VII (T7SS) – M. tuberculosis ESX-1, phagosome lysis.
tissue, and microbiota leading to disease. Clinical implication: Secretion systems are drug/vaccine targets.
• Stages of infection:
1. Colonization – entry into body V. Intracellular Survival Strategies
2. Infection – attachment, survival, immune evasion A. In Vacuoles
3. Disease – tissue damage (microbe + host immune • Prevent phagolysosome fusion (Legionella, Coxiella).
response) • Remodel vacuole into replication niches (LCV, CCV).
4. Transmission – exit and spread B. In Cytosol
• Key concept: Symptoms often result more from host • Escape vacuole (Listeria, Shigella, Rickettsia).
inflammatory response than direct microbial injury. • Actin-based motility (ActA, IcsA) → spread cell-to-cell.
• Microbiota: influences every stage, protects against • Burkholderia → multinucleated giant cells via T6SS.
pathogens but may also facilitate infection if disrupted. Clinical implication: Intracellular lifestyle = protection from many
antibiotics + immune clearance.
II. Entry into the Host
A. Routes VI. Avoidance of Host Defenses
• Skin/mucosa: breaks, trauma, burns. A. Complement
• Respiratory tract: droplet nuclei (1–5 µm), fomites → TB, • Capsules (e.g., S. pneumoniae).
influenza, COVID-19. • Proteases degrade complement (Streptococcus).
• GI tract: contaminated food/water, fecal-oral spread. • CD59-like proteins (Borrelia).
o Large inoculum → V. cholerae, Salmonella B. Antimicrobial peptides
o Small inoculum → Shigella • Surface modification → reduced negative charge.
• Genitourinary tract: fecal flora ascent, instrumentation. • Proteases (S. aureus).
• Direct toxin ingestion: preformed toxins (e.g., S. aureus, B. C. Oxidative burst evasion
cereus, C. botulinum). • Detox enzymes (superoxide dismutase, catalase).
Clinical implication: Transmission route influences control measures • Block NADPH oxidase assembly.
(masking, hand hygiene, water sanitation). D. NET evasion
• DNases degrade chromatin traps (Streptococcus, S. aureus).
III. Adhesion and Colonization E. PRR Evasion
A. Adhesins • Modify PAMPs: e.g., tetra-acylated LPS (Yersinia pestis at
• Pili/fimbriae – E. coli (FimH, Pap) → UTIs 37°C).
• Type IV pili – Neisseria, Vibrio → motility + microcolony • Avoid TLR5 recognition (flagellin variants, H. pylori).
formation • Block NF-κB/MAPK signaling (effectors: OspF, YopJ, SpvC).
• Flagella – motility and sometimes adhesion (EPEC, EHEC) F. Inflammasome inhibition
• Autotransporter proteins (T5SS) – Bordetella pertussis • Block caspase activation (Shigella, EHEC effectors).
FHA, Shigella IcsA Clinical implication: Evasion explains persistent or relapsing
• MSCRAMMs – S. aureus binding ECM proteins infections.
• Opa proteins – Neisseria adhesion
B. Host Receptors VII. Bacterial Toxins
• Glycans (mannose, sialic acid, fucose) A. AB Toxins
• ECM proteins (fibronectin, collagen, laminin) • Cholera toxin → ↑cAMP → watery diarrhea.
• Integrins/CEACAMs → internalization pathways • Pertussis toxin → G protein modification.
• CFTR – receptor for S. Typhi • Diphtheria toxin, Exotoxin A (Pseudomonas) → block EF-2,
Clinical implication: Adhesion specificity explains tissue tropism and halt protein synthesis.
disease localization (e.g., UPEC → bladder, H. pylori → stomach). B. Pore-forming toxins
• Listeriolysin O (Listeria).
IV. Mechanisms of Microbial Entry into Cells • α-toxin (S. aureus).
A. Trigger mechanism (T3SS-dependent) • Leukocidins.
• Pathogen: Salmonella, Shigella, Chlamydia C. Superantigens
• Inject effectors → actin rearrangement → ruffling → • S. aureus (TSST-1), S. pyogenes exotoxins → massive
bacterial uptake. cytokine release → shock.
B. Zipper mechanism Clinical implication: Toxins = basis of many vaccines/antitoxin
• Pathogen: Listeria (InlA/InlB), Yersinia (Invasin, YadA) therapies.
• Surface proteins bind host receptors → receptor clustering
→ tight engulfment. VIII. Host-Mediated Damage
C. Secretion Systems • Excessive inflammation → tissue injury.
• Cytokine storms → sepsis, toxic shock.
, • ROS/RNS damage to host tissues.
IX. Role of the Microbiota
• Colonization resistance: competition, bacteriocins, T6SS.
• Disruption (antibiotics) → opportunistic infections (C.
difficile).
• Therapy: fecal microbiota transplantation (FMT).
X. Clinical and Therapeutic Implications
• Understanding pathogenesis guides:
o Antibiotic use (extracellular vs intracellular
pathogens).
o Vaccines (target toxins, adhesins, secretion
systems).
o Immunotherapies (enhance complement, block
evasion pathways).
o Microbiome interventions (FMT, probiotics).
