1887

Sequelae and Long-Term Consequences of Infectious Diseases

Editors: Pina M. Fratamico1, James L. Smith2, Kim A. Brogden3
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Affiliations: 1: Eastern Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Wyndmoor, Pennsylvania; 2: Eastern Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Wyndmoor, Pennsylvania; 3: Department of Periodontics and Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, Iowa, Washington, D.C.
Content Type: Monograph
Format: Electronic, Hardcover
Publication Year: 2009

Category: Clinical Microbiology

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Discover the links between infection with pathogenic microorganisms and such chronic illnesses as cancer, paralysis, arthritis, peptic ulcer, cirrhosis, and neurological disorders. Written and edited by leading experts, reviews the mechanisms used by pathogens to infect mucous surfaces, enter and multiply in the host environment, interfere with host defenses, damage host tissues, and produce long-term consequences. The book also explores the genetic and immunological status of afflicted individuals in terms of infection, disease progression, symptoms, and treatment options.

The first chapter examines the difficulties in establishing critical links between an infectious etiology and a chronic illness. The next group of chapters explores diseases in which the evidence points to a specific bacterium, parasite, virus, fungus, or prion as the cause. There is also a chapter dedicated to diseases suspected of having an underlying infectious etiology, but for which no specific pathogen has been identified. Another chapter discusses epidemiological methods for confirming, refuting, or modifying the links between specific microorganisms and the complications and long-term consequences they cause. The final chapter examines the economic burden associated with the sequelae of infectious agents and suggests future directions for research.

fills a critical void in the scientific literature, offering evidence of the causal links between infectious agents and chronic disorders and, most importantly, stimulating new research in this area. The book offers new insights for anyone involved in the diagnosis, treatment, prevention, and study of infectious disease. It is a recommended graduate-level text, providing students with a deep understanding of the mechanisms of host-pathogen interactions.

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Applied Biosafety

11 August 2014

This is an excellent book for those who want to look beyond the actual infection and explore the aftermath. It provides a unique perspective on the consequences of the infectious process. The reader discovers the links between infection with pathogenic microorganisms and such chronic illnesses as cancer, paralysis, arthritis, peptic ulcer, cirrhosis, and neurological disorders. The antibiotics era and vaccines that are now available make today an exceptional time when the vast majority of infectious diseases are preventable or treatable. As a result, in society today, all too often the notion is that infectious diseases are not that significant. While public health authorities warn against popular practices such as giving infants and children raw milk, sentiment exists that the benefits of the practice outweigh the risks. This ignores the long-term consequences of sequelae of an infection. For example, Guillian Barré syndrome is a rare consequence of an infection with Campylobacter jejuni which can be acquired from ingestion of raw milk. This book provides insight into the risks beyond those immediate concerns of the acute infection. These are important issues for clinicians, public health officials, researchers, and the general public. While some is known, the long-term consequence is fertile ground for future research.

The book is divided into 28 chapters and contains a wealth of knowledge from 62 contributors. It makes excellent use of tables, charts, photomicrographs, and other graphic displays. Immediately following chapter 12 is a selection of color photographs spanning 12 pages. The pathogens covered include a wide range of microorganisms including bacteria, viruses, parasites, and fungi. Chapters are structured to describe the many characteristics of the organisms, the history of disease, what is known about transmission, pathogenesis, host response, and immunity, the potential for complications and sequelae, treatment, prevention, and research opportunities.

This work explores diseases in which the evidence points to a specific bacterium, parasite, virus, fungus, or prion as the cause. The first chapter sets the stage by examining the creative approaches, novel thinking, and collaborative work necessary to establish critical links between an infectious etiology and a chronic illness. The chapters that follow deal mostly with specific diseases or pathogens such as Lyme Borreliosis, Chlamydia pneumonia, Chlamydia trachomatis, enteric pathogens, E. coli, Staphylococci, Streptococci, Helicobacter pylori, Cryptosporidium, malaria, Trypanosatidae, parasitic helminthes, acute viral infections, latent viral infections, chronic viral hepatitis, slow viral infections, superficial mycoses, systemic mycoses, subcutaneous mycoses, prion disease, and Porphyromonas gingivali. One chapter is also dedicated to diseases suspected of having an underlying infectious etiology, but for which no specific pathogen has been identified. The final chapter discusses epidemiological methods for confirming, refuting, or modifying the links between specific microorganisms and the complications and long-term consequences they cause. The final chapter examines the economic burden associated with the sequelae of infectious agents and suggests future directions for research. The text delves into the genetic and immunological status of infected patients with regards to disease progression, symptoms, and treatment options.

For some of the topics covered, the association between infectious agent and the complication or sequelae is well established. For example, the association of Campylobacter infection with Guillian-Barré syndrome; Chlamydia trachomatis and pelvic inflammatory disease; Helicobacter pylori infection with peptic ulcers; Epstein Barr virus with malignant disease, including Burkitt’s lymphoma and Hodgkin’s disease; Hepatitis B virus and liver cancer; human herpesvirus 8 and Kaposi’s sarcoma; and human papillomavirus with cervical cancer. For other pathogenic agents, the association is still being researched; these include for example, enteric pathogens as the trigger for Inflammatory Bowel Disease, Streptococci associated with pediatric autoimmune neuropsychiatric disorders, Chlamydia pneumoniae connection to Alzheimer’s Disease, adenovirus E1A linkage to chronic obstructive pulmonary disease, and Porphyromonas gingivalis and the exacerbation of preexisting chronic conditions. The beauty of this work is the breadth of information from what is known to what questions still need to be answered. For future editions of this book, I suggest including the complications associated with Neisseria meningitidis.

The intended audience for this book is wide since it imparts knowledge to anyone involved in the diagnosis, treatment, prevention, and study of infectious disease pathogens. It is of interest to a wide range of medical professionals and to anyone who wants more information about infectious disease pathogens beyond the basic textbook approach. For the experienced professional, this book makes interesting reading, is an excellent review, provides insight into new concepts, and serves as an excellent resource for future considerations. It could be used as a graduate-level text, providing students with a deep understanding of the mechanisms of host-pathogen interactions.

Applied Biosafety - ABSA

www.absa.org Vol. 19, No. 1, Page 49

Reviewer: Michael A. Pentella

Review Date: August 2014

Microbiology Today

10 January 2014

This timely and well written book adopts a novel approach to the host-parasite relationship by concentrating on the chronic sequelae of infections. Not all organisms are covered of course as not all lead to a chronic outcome; however, all the organisms that do lead to chronic disease are covered in considerable and accurate detail. Each chapter is well illustrated and supported by appropriate and up-to-date references, and covers epidemiology, clinical presentation, management and, where known, the pathophysiology leading to the chronic outcome. The authors are recognized experts in their field, again testifying to the accuracy and state-of-the art of the chapter contents. The book is a must for anyone interested in the infectious aetiology of chronic disease and will appeal to both clinicians as well as medical scientisists and students. The book is both reasonably priced as a personal copy and would be a valuable addition to any library.

Society for General Microbiology: Microbiology Today

Reviewer: John Holton, University College London

Review Date: February 2012

The Quarterly Review of Biology

09 January 2014

Broadening Recognition of Infection in Chronic Disease

This volume is a compilation from 62 authors who provide a detailed overview of a frontier in human health: long-term consequences of infection. This book is not a light read. It is densely packed with detail on a broad array of infectious agents from prions and viruses to bacteria, protozoa, fungi, and parasitic worms. The thoroughness of the individual chapters will serve as a resource for readers who are seeking compact yet detailed summaries of illnesses that are associated with particular pathogens after acute phases of infection. There are probably a small number of generalists who will take on the challenge of reading the entire volume. As one such reader, I found it intense but rewarding.Every chapter filled in gaps in my knowledge.The publication could also serve as an excellent textbook for advanced undergraduate and graduate courses on infection and chronic disease.

Whatever one’s background, some structural details contribute to the need for stamina and commitment. The book is infused with specialized terms, many of which are recent inventions. But there is no glossary. Readers who are attempting to extend their knowledge beyond their areas of expertise will therefore need handy internet access. Similarly, abbreviations are used profusely. Most are defined upon first usage in each chapter, but lists of abbreviations and their definitions do not accompany the chapters. Readers with porous short-term memory should therefore be prepared to search for the first use of abbreviations, an activity that becomes increasingly distracting as abbreviations pile up.

The volume is organized mainly according to pathogens. Readers seeking information about long-term illnesses associated with particular pathogens will therefore be able to use the book efficiently. This organization will not work well for those who wish to learn about the range of infectious agents that could be causing particular chronic conditions. Such information can be found by working though the index, but the integration of this information is left to the reader. A long table in the last chapter helps, but even this listing is illustrative rather than comprehensive; enteric infections and Neisseria species, for example, are listed in association with Reiter’s syndrome and reactive arthritis, but Chlamydia trachomatis and Gardnerella vaginalis are not.

Some of the content is grouped in ways that confound easy access, even for readers who wish to focus on particular pathogens. For example, three of the four chapters on viruses are entitled: Slow Viral Infections; Latent Viral Infections; and Acute Viral Infections with Rare Late Complications.The distinction between these terms has grown ambiguous as recognition of mild acute phases has improved and as molecular mechanisms of persistence have become better understood. The fourth chapter on viral causation, Sequelae of Chronic Viral Hepatitis, returns to a sharp focus on a narrow category of disease. The information on viral diseases could have been more coherent and the overlap among chapters reduced if the content was organized using a more consistent principle.

The space devoted to chronic illnesses is sometimes out of sync with their medical importance. Some minor illnesses, such as Whipple’s disease, are given a full chapter, whereas a few major illnesses, such as diabetes and Alzheimer’s disease, receive little if any analysis. Resolution of the role of infection for such major diseases will be very important for the future of medicine. The lack of attention to them is therefore a lost opportunity for advancing the health sciences.

Only four of the 28 chapters address general issues that serve to integrate the specialized content of most chapters. This allocation is not sufficient to draw together the massive amount of detail into a unified understanding of infectious processes in chronic disease and the reasons why this area of research is so important.

In the preface, the editors refer to their “hope that this book will fill a critical void in the scientific literature, contributing to providing evidence of the causal links between infectious agents and chronic disorders” (p. xii). Their volume is a noble attempt. The main difficulty is that the critical void is so vast and expertise is so narrow. Even so, their effort could have been more effective if they had targeted the fundamental barriers of expertise that demarcates the void, and then provided a clear conceptual framework on which to assimilate, integrate, and evaluate the teeming information.

Two perspectives could have facilitated this goal: the historical and the evolutionary. The historical perspective can provide valuable insight into why infectious causation of chronic disease is now one of the hottest topics in medicine. An evolutionary perspective can serve as a barometer for the biological validity of arguments and the most promising directions for future study. Together these perspectives help unite what seems to be a collection of ever-diversifying information that defies overarching explanations.

The historical perspective would have been the easiest to incorporate. Over the past century and a half, the recognized scope of infectious disease has gradually expanded from diseases that are conspicuously caused by infection to diseases that are increasingly difficult to link to infectious causes. The first part of this transition is characterized by a shift from conspicuous acute infectious diseases, such as chickenpox and early stages of syphilis, to chronic diseases that follow them, such as shingles and syphilitic insanity. Over the past century, this progression has been dominated by diseases with ever more cryptic early stages of infection, such as peptic ulcers and cervical cancer. This progression is still gradual because the ability to detect pathogens is highly variable among chronic infectious diseases and causal roles are now more difficult to demonstrate even when their presence is not disputed. In Chapter 1, Carbone raises some of these problems, but does not cast them in historical perspective as the most recent phase of the same problem that has been addressed and solved continually throughout the history of the germ theory of disease. 

Other chapters jump into the subject at a recent historical phase without mentioning the longer history that draws attention to the controversy and dismissiveness that always has accompanied the expansion of the germ theory to new categories of infectious disease. Robinson and Atherton’s chapter on Helicobacter pylori, for example, starts with the work of Warren and Marshall, which was eventually accepted after a 15-year struggle, but does not discuss the studies and debates that began over a century before Warren and Marshall received their Nobel Prize. These older studies strongly implicated the bacterium as a cause of peptic ulcers, but were dismissed because critics did not rigorously assess alternative hypotheses and their presumptions about the nature of infectious diseases. Such historical perspectives provide great insight into the current controversies in which arguments against infectious causation incorporate similar logical flaws. History is repeating itself but with different diseases and pathogens. Placing the current situation into historical context might open the eyes of skeptics who think that this most recent episode of the germ theory revolution is overzealous advocacy rather than progressive development of medical science. 

An evolutionary perspective explains why pathogens have evolved their characteristics. The most relevant evolutionary issue is why some pathogens evolve characteristics that allow them to cause chronic disease whereas others do not. If chronic diseases are attributable to persistent infections, the relevant question becomes: “Why do some pathogens evolve persistence?” A big part of the answer appears to be related to the routes of transmission. When transmission routes offer infrequent opportunities for transmission to new hosts, natural selection favors pathogens that can maintain themselves within the host for time spans that encompass many of these opportunities. Accordingly, pathogens transmitted by sexual or intimate salivary contact and sporadic vector-borne contact tend to be more persistent than those that are transmitted by routes that are continually present.Without such integration of evolutionary thinking, the variation in persistence among pathogens, which ranges from several days to many decades, is just another detail. In contrast, the application of evolutionary principles brings cohesion by suggesting that efforts to identify persistent infectious causes of chronic diseases will be especially productive if they focus on pathogens with particular routes of transmission. The relevance of transmission to the evolution of persistence is not addressed in any of the chapters in this book. 

More generally, evolutionary explanations are virtually absent in this volume. Conversely, an appreciation for the broad potential role of infectious causation of chronic disease is virtually absent from evolutionary perspectives on chronic disease, which tend to focus on aspects of human evolution that may lead to long-term problems with organ systems. To get a sense of how disconnected these two areas are one need only to read this book alongside another work that was published in the preceding year: Evolution in Health and Disease (Stearns and Koella 2008). That volume applied an evolutionary perspective to a wide spectrum of human diseases, but failed to incorporate the advances that have been made in understanding infectious causation of chronic diseases (Ewald 2009). The discussion of particular conditions—such as cancers, low birth weight, miscarriages, preeclampsia, and cardiovascular disease—in these two books are so different that a reader might think that the authors were discussing entirely different phenomena. The volumes provide complementary perspectives. For example, Sequelae and Long-Term Consequences of Infectious Diseases discusses pathogen antigens that are candidates for vaccines (see Chapters 5 and 6), whereas Evolution in Health and Disease discusses how the choice of antigens could cause evolutionary changes in pathogens that ameliorate or exacerbate virulence. But the two books by themselves do not fill the void because the insights and information of each need to be integrated rather than just added together. Neither volume, for example, addresses why pathogens evolve characteristics that lead to persistent infections.

Evolutionary considerations emphasize that a disease manifestation could benefit the pathogen, the host, both, or neither. This important point is not addressed in Sequelae and Long-Term Consequences of Infectious Diseases even though it is broadly relevant. For example, in Chapter 7, Robinson and Atherton consider anemia associated with Helicobacter pylori; they suggest that the bleeding from peptic ulcers could result in a loss of iron and that the bacterium could be sequestering iron, but did not mention the possibility that the anemia results from human sequestration of iron as a defense against Helicobacter. Iron supplementation could be beneficial for the patient if either of the first two explanations is correct, but detrimental if the third explanation is valid.

Some shortcomings are revealed by terminology. The volume separates sequelae from longterm consequences of infection. An attempt to clarify this distinction is made only in the last chapter of the book, where sequelae are defined as “the pathological conditions resulting from a prior disease” (p. 487). The commonalities of sequelae are then given: “[they] often occur at a substantially later date . . . the underlying reasons for the sequelae are difficult to diagnose and very hard to link to the initial infection . . . sequelae from a number of different infections are similar. . . some sequelae result from chronic inflammation and are very difficult to treat” (p. 487). It is unclear how these definitions distinguish “sequelae” from “long-term consequences.” 

The term “trigger” is used casually throughout the volume, and implies a level of validity for hypotheses that have not been adequately tested. A trigger is an initiator of a process rather than a persistent cause. The trigger of a gun initiates a controlled explosion that propels a bullet. The term has crept into the lingo on persistent diseases and has been perpetuated in part by scientists who are biased in favor of the idea that infections cause chronic disease by a hit-and-run mechanism—the infection disrupts the system in such a way that the system is permanently knocked out of whack.

The trigger hypothesis is often applied to immunological disorders probably because evidence of immunological dysfunction can be readily obtained. The alternative hypothesis is that a persistent infection may be continually pushing the immune system into a state in which it is causing damage. The trigger hypothesis is often presented as fact without acknowledging that the persistent infection hypothesis has not been adequately investigated. The authors of this book apparently use trigger to imply that an infection is involved in instigating a process that then can proceed without the need for persistent infection, but because trigger is not defined in the volume, its use may perpetuate confusion over the degree to which chronic illnesses result from persistent infection as a opposed to transient insult. 

The importance of the distinction is clear in several places, such as the treatment of Lyme borreliosis (Chapter 2), an illness for which the controversy over pathogen persistence has been particularly virtriolic. The book rarely addresses, however, the practical reason why this distinction is so important: if the persistent presence of a pathogen is responsible for a chronic disease, effective treatment of the illness with an antiinfective is a possible option (as discussed for asthma in Chapter 3) and treatment with antiinflammatories could be dangerous (as discussed for inflammatory bowel disease in Chapter 4).

Although the concept of proof is of fundamental importance to the entire book, it is not addressed head-on. One of the central problems in resolving the role of infection in chronic disease is that ironclad proof is extremely difficult, if not impossible. The old standard of Koch’s postulates can rarely be fulfilled because experiments on humans are difficult, especially when the disease takes years or decades to develop and the validity of studies on short-lived animals as a model for long-term human disease can be questioned. Writers are fond of claiming that Barry Marshall satisfied Koch’s postulates for peptic ulcers by drinking a solution of Helicobacter pylori (p. 6), but actually he did not. He gave himself a case of gastritis. In the absence of agreed upon criteria for proof, accumulating evidence serves as a basis for arguments and counterarguments until a critical mass of experts agree that a chronic diseases is or is not caused by a candidate infectious agent. If powerful, entrenched experts argue against infectious causation, then the resolution can be suspended indefinitely, as it was for peptic ulcers in the 1950s through the 1970s. However, if there is no powerful anti-infection contingent for a particular disease (as was the case for Burkitt’s lym-phoma in the 1970s and adult T-cell leukemia and AIDS in the early 1980s), evidence for infectious causation that could be argued down has been accepted based on a preponderance of evidence. This scientific environment leaves us increasingly with diseases for which powerful vested interests demand proof for important diseases such as atherosclerosis, Alzheimer’s disease, and breast cancer, even though the comparable level of proof for causation by conventionally accepted agents (e.g., cholesterol, amyloid plaques, or genetic damage alone) never existed. The critical task is to put in place guidelines for chronic diseases that function as Koch’s postulates did for acute infectious diseases. In Chapter 1, which is subtitled “From Hypothesis to Proof,” Carbone masterfully discusses the difficulty of demonstrating infectious causation of chronic diseases and calls for “sound, high-quality hypotheses, testing techniques, and clinical study design” (p. 6). But she does not present any criteria for the establishment of proof. Similar statements about the need for proof and the difficulty in obtaining it are presented throughout the book (e.g., Chapters 3 and 26), but criteria that must be met for acceptance of infectious causation of chronic diseases are not given anywhere in the volume. 

I imagine that the editors struggled with the title to include terminology that would not ruffle feathers. But by using Sequelae and Long-Term Consequences of Infectious Diseases they lost an opportunity to make a more powerful, unifying statement about the infectious causes of disease. The title sets the tone for the book as a whole, which does not provide a clear distinction between sequelae and long-term consequences. Nor is it accurate to think of the chronic manifestations as the consequences of the acute disease—shingles is a consequence not of chickenpox, but rather of the infection by the varicella zoster virus. This fuzziness in both the title and the contents of the volume ceded an opportunity for integrated insight into the role of infection in chronic illness. Long-Term Consequences of Infection would have been a more challenging and farsighted title that could have fulfilled the twin goals of simplification and unification (in this case, “long-term” can be defined as anything that comes after the acute phase of infection). This focus would be challenging by stripping away ambiguous vocabulary to address more clearly the issues related to long-term consequences of infection. It would be farsighted by providing a basis for the unified understanding of chronic disease that is bound to come eventually from integration of the entire spectrum of pathological mechanisms and time frames after the onset of infection. The irony is that the editors hinted at this integration in the first three paragraphs of the preface. The book as a whole, however, did not follow through on this theme, because it did not address the critical issues that have thwarted this unification. Paramount among these issues are the weak consideration of alternative hypotheses of causation that bear on every chronic disease (e.g., triggers versus persistent infection) and the extreme difficulty and inevitable uncertainty in distinguishing between these hypotheses (as opposed to the “proof” of one hypothesis). Full and efficient resolution of these issues requires that we learn from themistakes of previous generations who stumbled in their efforts to understand the role of infection in disease. It also requires that we incorporate what is widely accepted as the fundamental organizing principle for the study of life, evolutionary adaptation through natural selection. 

ACKNOWLEDGEMENTS

My comments on cancer have been informed by work that I have conducted with support from the Rena Shulsky Foundation. 

REFERENCES

Ewald P. W. 2009. Evolutionary medicine: a synthesis in progress. Review of Evolution in Health and Disease, Second Edition, edited by S. C. Stearns and J. C. Koella. Quarterly Review of Biology 84:75–80.

Stearns S. C., Koella J. C. 2008. Evolution in Health and Disease. Second Edition. Oxford (UK): Oxford University Press.

The Quarterly Review of Biology

Vol. 87, No. 1

Reviewer: Paul W. Ewald, Department of Biology, University of Louisville

Review Date: March 2012

Doody Enterprises

02 February 2013

At A Glance

Discover the links between infection with pathogenic microorganisms and such chronic illnesses as cancer, paralysis, arthritis, peptic ulcer, cirrhosis, and neurological disorders. Written and edited by leading experts, this bookt reviews the mechanisms used by pathogens to infect mucous surfaces, enter and multiply in the host environment, interfere with host defenses, damage host tissues, and produce long-term consequences. The text also explores the genetic and immunological status of afflicted individuals in terms of infection, disease progression, symptoms, and treatment options.The first chapter examines the difficulties in establishing critical links between an infectious etiology and a chronic illness. The next group of chapters explores diseases in which the evidence points to a specific bacterium, parasite, virus, fungus, or prion as the cause. There is also a chapter dedicated to diseases suspected of having an underlying infectious etiology, but for which no specific pathogen has been identified.

Other chapter discusses epidemiological methods for confirming, refuting, or modifying the links between specific microorganisms and the complications and long-term consequences they cause. The final chapter examines the economic burden associated with the sequelae of infectious agents and suggests future directions for research. This text fills a critical void in the scientific literature, offering evidence of the causal links between infectious agents and chronic disorders and, most importantly, stimulating new research in this area. The book offers new insights for anyone involved in the diagnosis, treatment, prevention, and study of infectious disease. It is a recommended graduate-level text, providing students with a deep understanding of the mechanisms of host-pathogen interactions. Key Features * Provides a unique, single source dedicated to the sequelae and long-term consequences of infection by microbial pathogens *Elucidates the many mechanisms that microorganisms use to cause disease *Explores a variety of chronic illnesses known or suspected to be caused by bacteria, viruses, fungi, parasites, and prions *Serves as a springboard for new research into the causes of chronic illnesses as well as cures and preventive measures *Enables both specialists and non-specialists to bring themselves up to date on the latest evidence and open questions.

Description

This book provides detailed descriptions of important conditions caused by microorganisms and their long term sequelae in humans. Many involve multiple organ systems. At times, a summary of current treatment is provided.

Purpose

The purpose is to enhance understanding of the impact of not only the immediate effects of pathogens causing infectious diseases, but also the long-term consequences. These are important issues for both clinicians and public health officials.

Audience

Clinicians, laboratory scientists, medical students, and members of the pharmacological industry and government agencies are the intended audience. Medical students, however, may need to take more time to understand some topics such as parasitology and virology. The authors are authorities in the field.

Features

This book covers the major disease states caused by bacteria, parasites, viruses, and fungi. Epidemiological and infection prevention measures are mentioned as well. The innovative aspect of this book is its coincise summary of how a microorganism can impact long-term outcomes of certain conditions. Placing additional pictures throughout each chapter, not just in the middle of the book, would improve the book.

Assessment

This is a very detailed and resourceful book about the long-term sequelae of microorganisms in humans. Undoubtedly, a broad audience of clinicians, researchers, and public health officials will benefit from reading it.

Doody Enterprises

Reviewer: Rudolf Kotula, MD (South Denver Infectious Diseases Associates)

Review Date: Unknown

©Doody’s Review Service

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