Chapter 113. Introduction to Infectious Diseases: Host–Pathogen Interactions (Part 6) The microbiology laboratory must be an ally in the diagnostic endeavor. Astute laboratory personnel will suggest optimal culture and transport conditions or alternative tests to facilitate diagnosis. If informed about specific potential pathogens, an alert laboratory staff will allow sufficient time for these organisms to become evident in culture, even when the organisms are present in small numbers or are slow-growing. The parasitology technician who is attuned to the specific diagnostic considerations relevant to a particular case may be able to detect the rare, otherwise-elusive egg or cyst in a stool specimen. In cases where a diagnosis appears difficult, serum should be stored during the early acute phase of the illness so that a diagnostic rise in titer of antibody to a specific pathogen can be detected later. Bacterial and fungal antigens can sometimes be detected in body fluids, even when cultures are negative or are rendered sterile by antibiotic therapy. Techniques such as the polymerase chain reaction allow the amplification of specific DNA sequences so that minute quantities of foreign nucleic acids can be recognized in host specimens. Infectious Diseases: Treatment Optimal therapy for infectious diseases requires a broad knowledge of medicine and careful clinical judgment. Life-threatening infections such as bacterial meningitis or sepsis, viral encephalitis, or falciparum malaria must be treated immediately, often before a specific causative organism is identified. Antimicrobial agents must be chosen empirically and must be active against the range of potential infectious agents consistent with the clinical scenario. In contrast, good clinical judgment sometimes dictates withholding of antimicrobial drugs in a self-limited process or until a specific diagnosis is made. The dictum primum non nocere should be adhered to, and it should be remembered that all antimicrobial agents carry a risk (and a cost) to the patient. Direct toxicity may be encountered—e.g., ototoxicity due to aminoglycosides, lipodystrophy due to antiretroviral agents, and hepatotoxicity due to antituberculous agents such as isoniazid and rifampin. Allergic reactions are common and can be serious. Since superinfection sometimes follows the eradication of the normal flora and colonization by a resistant organism, one invariant principle is that infectious disease therapy should be directed toward as narrow a spectrum of infectious agents as possible. Treatment specific for the pathogen should result in as little perturbation as possible of the host's microflora. Indeed, future therapeutic agents may act not by killing a microbe, but by interfering with one or more of its virulence factors. With few exceptions, abscesses require surgical or percutaneous drainage for cure. Foreign bodies, including medical devices, must generally be removed in order to eliminate an infection of the device or of the adjacent tissue. Other infections, such as necrotizing fasciitis, peritonitis due to a perforated organ, gas gangrene, and chronic osteomyelitis, require surgery as the primary means of cure; in these conditions, antibiotics play only an adjunctive role. The role of immunomodulators in the management of infectious diseases has received increasing attention. Glucocorticoids have been shown to be of benefit in the adjunctive treatment of bacterial meningitis and in therapy for Pneumocystis pneumonia in patients with AIDS. The use of these agents in other infectious processes remains less clear and in some cases (in cerebral malaria, for example) is detrimental. Activated protein C (drotrecogin alfa, activated) is the first immunomodulatory agent widely available for the treatment of severe sepsis. Its usefulness demonstrates the interrelatedness of the clotting cascade and systemic immunity. Other agents that modulate the immune response include prostaglandin inhibitors, specific lymphokines, and tumor necrosis factor inhibitors. Specific antibody therapy plays a role in the treatment and prevention of many diseases. Specific immunoglobulins have long been known to prevent the development of symptomatic rabies and tetanus. More recently, CMV immune globulin has been recognized as important not only in preventing the transmission of the virus during organ transplantation but also in treating CMV pneumonia in bone marrow transplant recipients. There is a strong need for well-designed clinical trials to evaluate each new interventional modality. Perspective The genetic simplicity of many infectious agents allows them to undergo rapid evolution and to develop selective advantages that result in constant variation in the clinical manifestations of infection. Moreover, changes in the environment and the host can predispose new populations to a particular infection. The dramatic march of West Nile virus from a single focus in New York City in 1999 to locations throughout the North American continent by the summer of 2002 caused widespread alarm, illustrating the fear that new plagues induce in the human psyche. The intentional release of deadly spores of Bacillus anthracis via the U.S. Postal Service awakened many from a sense of complacency regarding biologic weapons. "The terror of the unknown is seldom better displayed than by the response of a population to the appearance of an epidemic, particularly when the epidemic strikes without apparent cause." Edward H. Kass made this statement in 1977 in reference to the newly discovered Legionnaire's disease, but it could apply equally to SARS, H5N1 (avian) influenza, or any other new and mysterious disease. The potential for infectious agents to emerge in novel and unexpected ways requires that physicians and public health officials be knowledgeable, vigilant, and open- minded in their approach to unexplained illness. The emergence of antimicrobial- resistant pathogens (e.g., enterococci that are resistant to all known antimicrobial agents and cause infections that are essentially untreatable) has led some to conclude that we are entering the "postantibiotic era." Others have held to the perception that infectious diseases no longer represent as serious a concern to world health as they once did. The progress that science, medicine, and society as a whole have made in combating these maladies is impressive, and it is ironic that, as we stand on the threshold of an understanding of the most basic biology of the microbe, infectious diseases are posing renewed problems. We are threatened by the appearance of new diseases such as SARS, hepatitis C, and Ebola virus infection and by the reemergence of old foes such as tuberculosis, cholera, plague, and Streptococcus pyogenes infection. True students of infectious diseases were perhaps less surprised than anyone else by these developments. Those who know pathogens are aware of their incredible adaptability and diversity. As ingenious and successful as therapeutic approaches may be, our ability to develop methods to counter infectious agents so far has not matched the myriad strategies employed by the sea of microbes that surrounds us. Their sheer numbers and the rate at which they can evolve are daunting. Moreover, environmental changes, rapid global travel, population movements, and medicine itself—through its use of antibiotics and immunosuppressive agents—all increase the impact of infectious diseases. Although new vaccines, new antibiotics, improved global communication, and new modalities for treating and preventing infection will be developed, pathogenic microbes will continue to develop new strategies of their own, presenting us with an unending and dynamic challenge. Further Readings Armstrong G et al: Trends in infectious disease mortality in the United States during the 20th century. JAMA 281:61, 1999 [PMID: 9892452] Bartlett JG: Update in infectious diseases. Ann Intern Med 144:49, 2006 [PMID: 16389254] Blaser MJ: Introduction to bacteria and bacterial diseases, in Principles and Practice of Infectious Diseases , 6th ed, GL Mandell et al (eds). Philadelphia, Elsevier, 2005, p 2319 He nderson DA: Countering the posteradication threat of smallpox and polio. Clin Infect Dis 34:79, 2002 [PMID: 11731949] Hoffman J et al: Phylogenetic perspectives in innate immunity. Science 284:1313, 1999 Hung DT et al: Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science 310:670, 2005 [PMID: 16223984] ProMED- mail: The Program for Monitoring Emerging Diseases. www.promedmail.org Puck JM: Primary immunodeficiency diseases. JAMA 278:1835, 1997 [PMID: 9396644] Tyler KL, Nathanson N: Pathogenesis of viral infections, in Fields Virology , DM Knipe, PM Howley (eds). Philadelphia, Lippincott Williams & Wilkins, 2001, pp 199–244 Weiss ST: Eat dirt— the hygiene hypothesis and allergic diseases. N Engl J Med 347:930, 2002 [PMID: 12239263] Bibliography Berkelman RL, Hughes JM: The conquest of infectious diseases: Who are we kidding? Ann Intern Med 119:426, 1993 [PMID: 8338299] Buckl ey RH: Immunodeficiency diseases. JAMA 268:2797, 1992 [PMID: 1433695] de Jong R et al: Severe mycobacterial and Salmonella infections in interleukin-12 receptor–deficient patients. Science 280:1435, 1998 Grayston JT, Campbell LA: Editorial response: The role of Chlamydia pneumoniae in atherosclerosis. Clin Infect Dis 28:993, 1999 [PMID: 10452623] Henderson DA: Bioterrorism as a public health threat. Emerg Infect Dis 4:488, 1998 [PMID: 9716981] Newport MJ et al: A mutation in the interferon-γ- receptor gene and susceptibility to mycobacterial infection. N Engl J Med 335:1941, 1996 [PMID: 8960473] Picard C et al: Pyogenic bacterial infections in humans with IRAK- 4 deficiency. Science 299:2076, 2003 [PMID: 12637671] Quagliarello V, Scheld MW: Bacterial meningitis: Pathogenesis, pathophysiology, and progress. N Engl J Med 327:864, 1992 [PMID: 1508247] . Chapter 113. Introduction to Infectious Diseases: Host–Pathogen Interactions (Part 6) The microbiology laboratory must be an ally in the diagnostic endeavor. Astute laboratory personnel. should be adhered to, and it should be remembered that all antimicrobial agents carry a risk (and a cost) to the patient. Direct toxicity may be encountered—e.g., ototoxicity due to aminoglycosides,. The parasitology technician who is attuned to the specific diagnostic considerations relevant to a particular case may be able to detect the rare, otherwise-elusive egg or cyst in a stool specimen.