Introduction to Microbial Disease: Pathophysiology and Diagnostics

Infectious diseases have profoundly influenced the human genome and the course of human history. As of early 2023, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Chapters 335 to 337 ) infection has caused nearly 7 million deaths worldwide. Beginning in the 1980s, acquired immunodeficiency syndrome (AIDS; Chapters 353 to 359 ) disrupted the social fabric of many countries, especially in Africa, and distressed health care systems in the United States and other parts of the world. Approximately 38 million people worldwide are currently infected with human immunodeficiency virus (HIV), and since 1981, approximately 37 million people have died (about 700,000 in the United States alone). Deaths due to HIV/AIDS peaked at 1.9 million a year in 2005 and fell to 650,000 by 2021. Even before the SARS-CoV-2 pandemic, about 2.5 million people died annually worldwide from lower respiratory tract infections. Globally, an estimated 241 million new malaria infections occur annually, with 627,000 associated deaths. Each year, over 1.5 million people die worldwide from diarrheal diseases.

Serious infectious diseases may be associated with more morbidity over time due to rising global temperatures ( Chapter 17 ). The World Health Organization (WHO) predicts that climate change will result in 250,000 additional deaths per year between 2030 and 2050. Of this increase, about 110,000 deaths will be related to malaria ( Chapter 316 ) and diarrheal disease owing to expansion of insect vector populations and increased coastal flooding, respectively.

Infection can be defined as the multiplication of microbes (from viruses to multicellular parasites) in blood and/or host tissues. The host may or may not experience symptoms. For example, HIV infection may not cause any overt signs or symptoms of illness for years. The definition of infection also includes multiplication of microbes on the surface or in the lumen of the host, thereby causing signs and symptoms of illness or disease. For example, toxin-producing strains of Escherichia coli ( Chapter 280 ) may multiply in the gut and cause a diarrheal illness without invading tissues. Microbes can cause diseases without actually coming in contact with the host by virtue of toxin production. Clostridium botulinum ( Chapter 271 ) may grow in certain improperly processed foods, producing a toxin that can be lethal on ingestion. A relatively trivial infection, caused by Clostridium tetani ( Chapter 271 ) in a small puncture wound, can cause devastating illness because of a toxin released from the organism growing in tissues. It has now become apparent that multiple virulence factors of microorganisms can be carried in tandem on so-called pathogenicity islands of the genome (the “virulome”).

Humans live in a virtual sea of microorganisms, with all body surfaces having indigenous bacterial microbiota ( Chapter 257 ). An individual’s native microbiota constitute as many cells as their human cells. Our normal microbiota protects us from infection. Alterations of gut microbiota increase susceptibility to infection by pathogens such as Salmonella enterica ( Chapter 284 ) and Clostridioides difficile ( Chapter 271 ). Bacteria that constitute normal microbiota microorganisms are thought to exert a protective effect by several mechanisms: using nutrients and occupying an ecologic niche, thus competing with pathogens; producing antibacterial substances that inhibit growth of pathogens; and inducing host immunity that is cross-reactive against pathogens. These mechanisms appear to be oversimplistic, however. For example, gut colonization with Bacteroides fragilis expressing an immunodominant bacterial polysaccharide causes dendritic cell activation and induction of a T _H 1-mediated response, thereby leading to a splenic response characterized by normal numbers of CD4 ⁺ T cells, lymphoid architecture, and systemic lymphocytic expansion. Thus, a single bacterial molecule in our gut can improve immunologic fitness, and a healthy, diverse microbiome is vital to proper immune system function.

Only a small proportion of microbial species can be considered primary pathogens, and even among these species, a relatively small number of clones cause disease. For example, epidemic meningococcal meningitis and meningococcemia ( Chapter 274 ) are due to a small number of clones of Neisseria meningitidis , and the worldwide explosion of penicillin-resistant Streptococcus pneumoniae ( Chapter 268 ) can be traced to a few clones originating in South Africa and Spain. This observation supports the concept that pathogenic organisms are highly adapted to the pathogenic state and have developed characteristics that enable them to be transmitted, to attach to surfaces, to invade tissue, to avoid host defenses, and thus to cause disease. In contrast, opportunistic pathogens, which may be harmless members of normal microbiota of healthy persons, can act as virulent invaders in patients who have severe defects in host defense mechanisms. However, opportunistic infection is not simply an exploitation of a weakened host by relatively avirulent pathogens. Pseudomonas aeruginosa ( Chapter 282 ), for example, recognizes immunologic perturbations in the host and reacts by expressing virulence factors.

Pathogenic organisms may be acquired by several routes. For example, direct contact has been implicated in acquisition of staphylococcal disease ( Chapter 267 ). Aerosols and droplets spread SARS-CoV-2 ( Chapters 335 and 336 ). Contaminated water is the usual vehicle in Giardia infection ( Chapter 322 ) and typhoid fever ( Chapter 284 ). Food-borne illnesses may be caused by extracellular toxins produced by Clostridium perfringens ( Chapter 271 ) and Staphylococcus aureus ( Chapter 267 ). Blood and blood products may be vectors for transmitting hepatitis B and C viruses ( Chapter 134 ) as well as HIV ( Chapter 353 ). Sexual transmission is also important for these agents and for a variety of other pathogens, including Treponema pallidum (syphilis; Chapter 295 ), Neisseria gonorrhoeae (gonorrhea; Chapter 275 ), and Chlamydia trachomatis (urethritis; Chapter 294 ). The fetus may be infected in utero; infection may be devastating if the agent is rubella virus ( Chapter 339 ), cytomegalovirus ( Chapter 347 ), or parvovirus B19 ( Chapter 342 ). Arthropod vectors are also important, as illustrated by mosquitoes for malaria ( Chapter 316 ) and dengue ( Chapter 352 ); ticks for Lyme disease ( Chapter 296 ), anaplasmosis, and ehrlichiosis; and lice for typhus ( Chapter 302 ).

Pathogens are able to cause disease because of a finely tuned array of adaptations, including the ability to attach to appropriate cells, often mediated by specialized structures, such as pili. Microbes such as Shigella species ( Chapter 285 ) have the ability to invade cells and cause damage. Toxins may act at a distance or affect only infected cells. Pathogens can thwart host defenses by a variety of ingenious maneuvers. The antiphagocytic coat of the pneumococcus ( Chapter 268 ) is an example. Organisms may change their surface antigen display at a rapid rate to outmaneuver the host immune system. Examples include influenza virus ( Chapter 332 ) and trypanosomes ( Chapters 317 and 318 ). Certain pathogens (e.g., Toxoplasma gondii ; Chapter 320 ) can inhibit the respiratory burst of phagocytes, and others (e.g., Streptococcus pyogenes ; Chapter 269 ) can destroy phagocytic cells that have engulfed them. The environment plays an important role in infection, both in transmission and in the host’s ability to combat the invader. The humidity and temperature of air may affect infectivity of airborne pathogens. The sanitary state of food and water, woefully lacking in many areas of the world, is an important factor in the acquisition of enteric pathogens. It is also likely that micronutrient deficiency contributes to the invasion and multiplication of certain pathogens.

Host reaction to infection may result in illness. For example, previous infection with Campylobacter jejuni ( Chapter 279 ) is responsible for about 40% of cases of Guillain-Barré syndrome ( Chapter 388 ). The mechanism is thought to be production of antibodies against C. jejuni lipopolysaccharides that cross-react with gangliosides in peripheral nerves. Similarly, much of the damage resulting from meningitis is due to the host’s response to invading bacterial pathogens.

With some exceptions, infectious diseases are treatable and curable, so it is important to make an accurate diagnosis and to institute appropriate therapy promptly. In acute infections such as pneumonia ( Chapter 85 ), meningitis ( Chapter 381 ), or sepsis ( Chapter 94 ), rapid institution of therapy can be life-saving. In such cases, treatment (based on history, physical examination, and epidemiology of illness in the community) should be started even if a definitive diagnosis has not been confirmed. Antimicrobial therapy for the presumptive causative agent(s) can later be re-evaluated as more definitive diagnostic information becomes available. Rapid diagnostic techniques, including Gram stains, antigen detection, or nucleic acid amplification testing, often can be helpful.