ReviewPathology of post primary tuberculosis of the lung: An illustrated critical review
Introduction
Mycobacterium tuberculosis (MTB) is an obligate human parasite.1, 2 While it can infect most warm blooded animals, and is highly virulent for some, no animals can reproducibly transmit infection to others.3 Consequently, the continued existence of MTB depends on transmission among humans. Over many millennia, MTB has evolved a complex life cycle that allows it to persist indefinitely in human communities as small as a few hundred people.4 This life cycle includes two distinct types of infection: primary and post primary tuberculosis in addition to prolonged periods of dormancy. The infection typically begins with a first or primary infection that heals spontaneously with the development of an immune response. After 10–30 years, the organisms emerge from dormancy (or the person is reinfected) to develop post primary tuberculosis that produces cavities in the lung that support proliferation of massive numbers of organisms that are coughed into the environment to facilitate transmission to new hosts.
Primary tuberculosis is the infection that occurs in immunocompetent people when they are first infected with MTB.5 Although it may progress causing meningitis or disseminated tuberculosis, especially in very young or immunosuppressed individuals, primary tuberculosis typically develops and spreads as caseating granulomas to regional lymph nodes and systemically for only a few weeks before regressing as immunity develops. While the lesions may heal, they are seldom sterilized and organisms persist. We have many animal models of primary tuberculosis and reasonable access to human tissues and so have made much progress in understanding the development and functions of its characteristic lesion, the caseating granuloma.6, 7, 8, 9
Post primary, also known as adult type or secondary, tuberculosis, in contrast, occurs in people who have developed immunity to primary tuberculosis.10, 11, 12 It differs from primary tuberculosis in the genes that modulate susceptibility, clinical presentation, complications and age distribution of hosts.13 Post primary tuberculosis is typically restricted to the upper lobes of the lungs and does not involve lymph nodes or other organs. About 90% of cases recover spontaneously without therapy. However those that become ill account for 80% of all clinical cases and nearly 100% of transmission of infection. The inability to resolve post primary tuberculosis is not due to inadequate systemic immunity because the victims are solidly immune to infection in their entire bodies except for localized portions of the lung. In fact, the persons most likely to die from acute post primary tuberculosis are immunocompetent young adults ages 15–40 with strong tuberculin specific cell mediated immune reactions.10, 14, 15, 16 Those who survive the acute process are likely to be left with a cavity in a lung that spews massive numbers of organism into bronchi that are coughed into the environment over a period of decades, but fail to produce disease in any other part of the body. Post primary tuberculosis does not confer immunity. It does the opposite. People who have recovered from post primary tuberculosis naturally or through treatment have much higher risk than others in their communities of developing the disease again.1, 17, 18 The recurrent disease frequently results from new infection from the environment, not from reactivation of the first infection. We know very little about the mechanisms of post-primary tuberculosis.
The pathology tuberculosis was described in the 19th and early 20th centuries with two major components termed ‘productive’ and ‘exudative’.19, 20, 21 In 1821, Laennec, using clinical and gross pathologic observations, reported that primary and post primary TB were distinct manifestations of the same disease.22 A half century later with the introduction of microscopes, Virchow disputed this and claimed that they were totally different diseases.23 He reported that primary tuberculosis was a tumor while post primary was an infection. This argument was resolved by Koch’s discovery of the causative organism. However, Koch observed that second exposure to MTB produces a fundamentally different disease than the first.1, 2 From the 1880’s until the 1950’s many authors described the two different histologic patterns of tuberculosis using diverse nomenclatures.19, 20, 24, 25 Productive lesions or tubercles are granulomas, especially caseating granulomas. Exudative lesions are tuberculous pneumonia. Each occurred in multiple variations and progressed through a series of stages. It is unlikely that many important features of the pathology of tuberculosis were not described. However, studies of the pathology of post primary tuberculosis effectively ended when interest in the disease and availability of human lung tissues plummeted with the introduction of antibiotics in the 1950’s. Interest in tuberculosis revived decades later with the realization that the disease had not been eradicated and the rise of modern immunology and molecular biology provided powerful new methods to study it.
Using animal models, these new sciences have greatly expanded understanding of tuberculosis. However, the lack of appropriate human tissues for study made it impossible to validate the animal models. Many species develop caseating granulomas when infected with MTB and some, like rabbits infected with Mycobacterium bovis, develop caseating granulomas that erode into bronchi to produce cavities.26, 27, 28 However, MTB is an obligate human pathogen because it can complete its life cycle only in humans. No other species, under natural conditions, develops the lesions necessary for transmission of infection. The far more complex pathologic descriptions of human pulmonary tuberculosis in the older literature were forgotten amidst the excitement of rapid scientific advances centered on granulomas. In addition, the insistence by many reviewers that animals be infected with small numbers of bacilli by aerosol to produce physiologic infections further restricted the spectrum of models available for study.11, 27 As a result, virtually the entire contemporary literature describes caseating granulomas as the characteristic lesion of all tuberculosis. Models are judged to be “human like” based on their ability to produce caseating granulomas.11, 19, 29 It is a paradigm of contemporary research that cavities form when caseating granulomas erode into bronchi and discharge their softened and liquefied contents into the airways.9, 25, 30 This simplified mechanism that ignores the existence of exudative reactions has guided the research on post primary tuberculosis for generations of investigators.
We previously reported studies of tissues from several people with untreated primary and post primary tuberculosis that contradicted this paradigm.31 We rediscovered observations from the preantibiotic era that post primary tuberculosis begins as an exudative reaction with infection of foamy alveolar macrophages. The infection progresses to caseous pneumonia that undergoes fragmentation and softening to produce cavities. There were no active granulomas of any kind in these lungs. Caseating granulomas appeared to be characteristic of primary tuberculosis and to play no part in the development of cavities.
In continuing studies, we have examined tissues of over 100 patients with untreated and a few with inadequately treated pulmonary tuberculosis and have reviewed the literature from the preantibiotic era in an effort to refine and extend previous observations. The conclusion is that developing post primary tuberculosis is not a granulomatous disease. It is an exudative reaction, a type of pneumonia that develops in people with sufficient immunity to heal all granulomas. Granulomas do develop in post primary tuberculosis, but only as a late phenomenon that has virtually no role in the development of cavities. As Canetti reported, granulomas do not precede caseation in post primary tuberculosis, but follow it and are typically located at the periphery of the caseum. Moreover, caseum associated with a granuloma is always old and free of nuclear debris. “These two facts established that the caseum precedes the granuloma in the adult lung”.21
Additional studies looked for exceptions to the typical pathologic patterns of post primary tuberculosis. Studies were made of slides of the lungs of infants who were to young to have developed immunity to primary tuberculosis and immunosuppressed adults with HIV and other conditions. We found no evidence that pulmonary cavities ever arise from expansion of caseating granulomas or liquefaction of their contents. All cavities were observed to arise from necrosis of tuberculous pneumonia, frequently in persons with no caseating granulomas in their entire bodies.
This manuscript reviews pathology of each of the stages of post primary tuberculosis: how it begins, regresses or progresses to cavitation and/or fibrocaseous disease. Most post primary tuberculosis regresses spontaneously leaving only small scars in the apex of the lung.1, 2, 32 Those that do not regress typically undergo rapid necrosis to produce cavities. Once formed, cavities can either stabilize and become nearly asymptomatic indefinitely or they can produce chronic relapsing or progressive fibrocaseous disease that results in extensive necrosis and fibrosis. Finally, we asked how the misconceptions of the contemporary literature arose. A review of the literature revealed two additional points. The first was failure to appreciate the differences between infections produced by M. bovis and MTB and the second was misinterpretation of a hypothesis that caseating granulomas seeded tuberculous pneumonia to infer that they directly caused cavities.
With the realization that post primary tuberculosis begins as an infection of alveolar macrophages in people with sufficient immunity to heal caseating granulomas, the key unresolved question of adult tuberculosis shifts away from caseating granulomas to an understanding of how MTB subvert or evade otherwise highly effective systemic immunity to establish a privileged site within foamy alveolar macrophages in certain areas of the lung while the rest of the body remains highly immune. It is hoped that a more accurate understanding of the pathology of post primary tuberculosis may lead to more focused studies, better understanding and eventually control of the world’s most lethal bacterial infection.
Section snippets
Ethics statement
This study was conducted according to the principles expressed in the Declaration of Helsinki. The study was approved by the Institutional Review Board of UT-Houston Medical School IRB protocol number HSC-MS-10-0109, Immunopathology of Tuberculosis. We studied microscope slides of tissues from patients with tuberculosis. All materials were by products of regular surgical or autopsy practice. We were not involved in any way with collecting the tissues and had no contact with any of the patients,
Primary tuberculosis
Primary tuberculosis occurs in previously uninfected individuals with competent immune responses.2, 6 The characteristic lesion, a caseating granuloma, is a localized lesion in tissue consisting of a central area of caseous necrosis surrounded by epitheloid macrophages and then lymphocytes, Figure 1. Caseation necrosis was termed ‘fatty metamorphosis’ by Virchow because it contains abundant lipid and foamy macrophages.9, 23, 33 Caseation is a process of coagulation necrosis in which lipid rich
Discussion
One would think that the pathology of tuberculosis would have been accurately described long ago and that the science of the 21st century would have moved far beyond morphologic descriptions. Such is not the case. Part of the problem is that, since the development of antibiotics, few pathologists have ever seen untreated pulmonary tuberculosis. They remain familiar with primary tuberculosis from examination of lymph node, bone marrow and liver biopsies. They also see autopsies of disseminated
Acknowledgments
We are indebted to the late Dr. Jerome Smith of Galveston, Texas for much advice and case materials from the Galveston County Medical Examiners Office. We are similarly indebted to Dr. Louis Sanchez, the Harris Count Medical Examiner for access to slides of tissues with tuberculosis. Dr. Vadim Karev of First Infectious Disease Hospital, St. Petersburg, Russian Federation gave us paraffin blocks of autopsy lung tissues. The late Dr Grover Hutchins of Johns Hopkins Department of Pathology
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