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Lorber, B. Ann Intern Med 1996;125:844-851

The pathogens and infectious diseases on the left side of the balance were not part of common medical parlance a decade ago. Lorber, B. Ann Intern Med 1996;125:844-851. Are All Diseases Infectious?. Peptic Ulcer Dementia and Paralysis Acute Renal Failure Arthritis Vasculitis

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Lorber, B. Ann Intern Med 1996;125:844-851

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  1. The pathogens and infectious diseases on the left side of the balance were not part of common medical parlance a decade ago Lorber, B. Ann Intern Med 1996;125:844-851

  2. Are All Diseases Infectious? Peptic Ulcer Dementia and Paralysis Acute Renal Failure Arthritis Vasculitis Inflammatory Bowel Disease Diabetes Coronary Artery Disease Cancer Are All Diseases Infectious? Another Look Bennett Lorber, MD 21 December 1999 | Volume 131 Issue 12 | Pages 989-990 Coronaries, Carotids, andChlamydia Obsessive-Compulsive Behavior,Movement Disorders, and Streptococci Major Psychiatric Illness and Borna Disease Virus Kidney Stones and Nanobacteria Lorber, B. Ann Intern Med 1996;125:844-851

  3. Are All Diseases Infectious? Are all diseases infectious? Of course not. But who would have guessed 20 years ago that ulcers could be eradicated with antibiotics, that spongiform encephalopathies were caused by transmissible agents composed only of tiny bits of protein, or that an unknown herpesvirus was the cause of Kaposi sarcoma? We have every reason to believe that science will show still more infectious causes for degenerative, inflammatory, and even hereditary diseases. Although this prospect is sobering, the opportunity for disease prevention through immunization is exciting to contemplate. Lorber, B. Ann Intern Med 1996;125:844-851

  4. Are All Diseases Infectious? Are all diseases infectious? Of course not. But who would have guessed 20 years ago that ulcers could be eradicated with antibiotics, that spongiform encephalopathies were caused by transmissible agents composed only of tiny bits of protein, or that an unknown herpesvirus was the cause of Kaposi sarcoma? We have every reason to believe that science will show still more infectious causes for degenerative, inflammatory, and even hereditary diseases. Although this prospect is sobering, the opportunity for disease prevention through immunization is exciting to contemplate. Lorber, B. Ann Intern Med 1996;125:844-851

  5. Are All Diseases Infectious? Are all diseases infectious? Of course not. But who would have guessed 20 years ago that ulcers could be eradicated with antibiotics, that spongiform encephalopathies were caused by transmissible agents composed only of tiny bits of protein, or that an unknown herpesvirus was the cause of Kaposi sarcoma? We have every reason to believe that science will show still more infectious causes for degenerative, inflammatory, and even hereditary diseases. Although this prospect is sobering, the opportunity for disease prevention through immunization is exciting to contemplate. Lorber, B. Ann Intern Med 1996;125:844-851

  6. "Noninfectious" Diseases and Associated Transmissible Agents*

  7. The global health burden of infection-associated cancers in the year 2002. • Several infectious agents are considered to be causes of cancer in humans. The fraction of the different types of cancer, and of all cancers worldwide and in different regions, has been estimated using several methods; primarily by reviewing the evidence for the strength of the association (relative risk) and the prevalence of infection in different world areas. Parkin DM Int J Cancer 2006 Jun 15;118(12):3030-44

  8. The global health burden of infection-associated cancers in the year 2002. • The estimated total of infection-attributable cancer in the year 2002 is 1.9 million cases, or 17.8% of the global cancer burden. The principal agents are the bacterium Helicobacter pylori (5.5% of all cancer), the human papilloma viruses (5.2%), the hepatitis B and C viruses (4.9%), Epstein-Barr virus (1%), human immunodeficiency virus (HIV) together with the human herpes virus 8 (0.9%). Relatively less important causes of cancer are the schistosomes (0.1%), human T-cell lymphotropic virus type I (0.03%) and the liver flukes (0.02%). Parkin DM Int J Cancer 2006 Jun 15;118(12):3030-44

  9. The global health burden of infection-associated cancers in the year 2002. • The estimated total of infection-attributable cancer in the year 2002 is 1.9 million cases, or 17.8% of the global cancer burden. The principal agents are the bacterium Helicobacter pylori(5.5% of all cancer), the human papilloma viruses(5.2%), the hepatitis B and C viruses(4.9%),Epstein-Barr virus(1%), human immunodeficiency virus (HIV) together with the human herpes virus 8(0.9%). Relatively less important causes of cancer are the schistosomes (0.1%), human T-cell lymphotropic virus type I (0.03%) and the liver flukes (0.02%). Parkin DM Int J Cancer 2006 Jun 15;118(12):3030-44

  10. The global health burden of infection-associated cancers in the year 2002. • There would be 26.3% fewer cancers in developing countries (1.5 million cases per year) and 7.7% in developed countries (390,000 cases) if these infectious diseases were prevented. The attributable fraction at the specific sites varies from 100% of cervix cancers attributable to the papilloma viruses to a tiny proportion (0.4%) of liver cancers (worldwide) caused by liver flukes. Parkin DM Int J Cancer 2006 Jun 15;118(12):3030-44

  11. The global health burden of infection-associated cancers in the year 2002. • There would be 26.3% fewer cancers in developing countries (1.5 million cases per year) and 7.7% in developed countries (390,000 cases) if these infectious diseases were prevented. The attributable fraction at the specific sites varies from 100% of cervix cancers attributable to the papilloma viruses to a tiny proportion (0.4%) of liver cancers (worldwide) caused by liver flukes. Parkin DM Int J Cancer 2006 Jun 15;118(12):3030-44

  12. The Koch Postulates

  13. The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic,but infection leads to transformation of cells by indirect means.

  14. The criteria most often used in determining causality are consistency of the association, either epidemiologic or on the molecular level, and oncogenicity of the agent in animal models or cell cultures. However use of these generally applied criteria in deciding on causality is selective, and the criteria may be weighted differently. Whereas for most of the tumor viruses the viral genome persists in an integrated or episomal form with a subset of viral genes expressed in the tumor cells, some agents (HBV, HCV, helicobacter) are not inherently oncogenic,but infection leads to transformation of cells by indirect means.

  15. Chronic active Epstein-Barr virus infection (CAEBV) is characterised by chronic or recurrent infectious mononucleosis like symptoms, such as fever, hepatosplenomegaly, persistent hepatitis and extensive lymphadenopathy. Patients with CAEBV have high viral loads in their peripheral blood and/or an unusual pattern of EBV-related antibodies. This disease is rare but severe with high morbidity and mortality. Nearly three decades have passed since this disease was first identified, and recent advances in technology have increased our understanding of CAEBV pathophysiology. There is accumulating evidence that the clonal expansion of EBV-infected T or natural killer (NK) cells plays a central role inthe pathogenesis of CAEBV.

  16. However, it remains unclear whether CAEBV is truly a monoclonal lymphoproliferative disorder. EBV-infected T or NK cells are able to evade the host cellular immune system due to the limited expression of viral proteins of reduced antigenicity. Recent studies suggest that infection of T or NK cells is a common event during primary EBV infection. A defect or single nucleotide polymorphism in host immune-modulating genes may allow for the expansion of virus infected cells giving rise to CAEBV.

  17. Summary The hypothesis described here is a logical extension of two areas of observation: First, it has been discovered that viruses (and perhaps other intracellular parasites) catalyze cell fusion as a means of cell-to-cell transmission. Effective cell-to-cell transmission appears to require: (i) induced expression of adhesion molecules on the cell surface; (ii) suppression of p53-dependent apoptosis; (iii) arrest of the cell cycle that would otherwise lead to cell death by ‘‘mitotic catastrophe’’. Suppression of apoptosis and cell death through ‘‘mitotic catastrophe’’ are important for formation of stable syncytia. Expression of Bcl-2 or a viral analogue of Bcl-2 (vBcl-2) is particularly useful to viruses because Bcl-2 both suppresses (p53-dependent) apoptosis and arrests the cell cycle through p27. Bcl-2 may also block any p53-independent cell death (e.g., mitotic catastrophe) that is initiated at the mitochondria.

  18. Second, it has been found that cell fusion plays a role in cancer clone evolution, invasion of normal cells in tissue adjacent to tumors and metastasis to remote normal tissues. Thus, it can be hypothesized that infection of cancer cells with viruses that spread by cell-to-cell transmission may coincidentally contribute to development of aggressive aneuploid clones and facilitate both invasion and metastasis of tumors. Regardless of the role of viruses, suppression of Bcl-2 may be an approach to preventing successful formation of syncytia and limiting the invasion and metastasis of tumors, thus, making surgical removal and radiation treatment more feasible.

  19. HHV-8

  20. HHV-8 HHV-8 (also known as KSHV) is a herpesvirus, which is distantly related to EBV. It is the causative agent of Kaposi's sarcoma and is also associated with several benign and malignant lymphoproliferative diseases. The identification of HHV-8 has led to the recognition of several somewhat rare lymphoproliferative diseases as discrete entities.

  21. HHV-8 HHV-8 has been detected in two benign lymphoproliferations - a plasmablastic variant of multicentric Castleman's disease (MCD) and germinotropic lymphoproliferative disorder. In MCD, the HHV-8 is localized to a unique population of IgM -positive plasmablasts, which are not found in non-HHV-8-associated forms of this disease. They are present in the mantle zone of follicles, occur singly or in clusters, and are not co-infected with EBV. HHV-8-positive plasmablastic lymphoma develops in some cases. Germinotropic lymphoproliferative disorder is characterized by polyclonal or oligoclonal aggregates of plasmablasts co-infected with HHV-8 and EBV within germinal centres.

  22. HHV-8 PEL is a rare lymphoma that occurs in body cavities, usually without a contiguous tumour mass. It is universally associated with HHV-8 and largely occurs in HIV-positive men with low CD4 cell counts. In the vast majority of cases, the tumour cells are infected by both HHV-8 and EBV. PELs are monoclonal B-cell proliferations which morphologically resemble immunoblastic or anaplastic large cell lymphoma; they frequently show plasmacytic differentiation and express CD138 and CD45, although they generally lack pan-B markers. A rare solid tumour occurring in the absence of an effusion, but with almost indistinguishable features from PEL, has been recognized more recently and designated extra-cavitary PEL.

  23. EBV

  24. EBV EBV is a herpesvirus with a worldwide distribution. The vast majority (>90%) of healthy adults are persistently infected by this virus with a reservoir of infection in memory B-cells. In developing countries, infection usually occurs in early childhood, whereas in industrialized countries primary infection is often delayed until adolescence. Infection in childhood usually goes unnoticed, whereas delayed infection frequently results in infectious mononucleosis (IM). The virus is shed in saliva and this is the major vehicle for spread of the virus.

  25. EBV EBV is associated with both benign and malignant diseases, the latter including lymphomas and carcinomas. The three most important EBV-associated lymphomas are Burkitt's lymphoma (BL), Hodgkin lymphoma (HL), and lymphomas occurring in the context of immunosuppression. In addition, the virus is associated with several rarer entities including primary effusion lymphoma (PEL), pyothorax-associated lymphoma, and T/NK cell lymphomas. Since EBV is a ubiquitous virus, the geographical distribution of EBV-associated diseases is not related to the distribution of the virus, but relates to the distribution of co-factors and the presence of immunosuppression.

  26. EBV Although EBV is an extremely efficient transforming agent and infection is almost universal in adults, few individuals develop EBV-associated lymphomas. This is because EBV elicits strong immune responses, particularly CTL responses; it has been estimated that EBV-specific T-cells might constitute up to 5% of circulating CD8+ T-cells. Demonstration of EBV seropositivity is not useful when investigating EBV involvement in lymphoma. It is essential to demonstrate the presence of the virus within the malignant cells before categorizing a tumour as EBV-associated.

  27. EBV Although EBV is an extremely efficient transforming agent and infection is almost universal in adults, few individuals develop EBV-associated lymphomas. This is because EBV elicits strong immune responses, particularly CTL responses; it has been estimated that EBV-specific T-cells might constitute up to 5% of circulating CD8+ T-cells. Demonstration of EBV seropositivity is not useful when investigating EBV involvement in lymphoma. It is essential to demonstrate the presence of the virus within the malignant cells before categorizing a tumour as EBV-associated.

  28. HCV

  29. HCV HCV is a major cause of liver disease but has also been implicated in several extrahepatic disorders. There is very good evidence that it is associated with mixed cryoglobulinaemia, a lymphoproliferative disorder that sometimes evolves into B-cell NHL. The association between HCV and NHL is more controversial. Studies documenting a positive association have generally been performed in areas of high HCV prevalence, such as Italy; surveys carried out in low prevalence areas have frequently failed to detect evidence of HCV infection in NHL patients.

  30. HCV HCV is a major cause of liver disease but has also been implicated in several extrahepatic disorders. There is very good evidence that it is associated with mixed cryoglobulinaemia, a lymphoproliferative disorder that sometimes evolves into B-cell NHL. The association between HCV and NHL is more controversial. Studies documenting a positive association have generally been performed in areas of high HCV prevalence, such as Italy; surveys carried out in low prevalence areas have frequently failed to detect evidence of HCV infection in NHL patients.

  31. HCV Recent large case-control studies from both high and low prevalence areas have reported significant differences in HCV infection rates between cases and controls and therefore, on balance, this association appears real. In a case-control study of 796 subjects attending hospitals in Italy, Mele et al detected evidence of viral infection in 17.5% of B-cell NHL cases compared with 5.6% of controls (odds ratio 3.1, confidence intervals 1.8-5.2). Likewise, in a study of 1497 individuals in the US, Engels et al found significant differences between cases and controls, although only 3.9% of their NHL cases and 2.1% of controls had evidence of HCV infection (odds ratio 1.96, confidence intervals 1.07-4.03). HCV is mainly associated with low-grade B-cell NHLs, particularly marginal zone lymphomas; an association with DLBCLs has also been reported.

  32. HCV Recent large case-control studies from both high and low prevalence areas have reported significant differences in HCV infection rates between cases and controls and therefore, on balance, this association appears real. In a case-control study of 796 subjects attending hospitals in Italy, Mele et al detected evidence of viral infection in 17.5% of B-cell NHL cases compared with 5.6% of controls (odds ratio 3.1, confidence intervals 1.8-5.2). Likewise, in a study of 1497 individuals in the US, Engels et al found significant differences between cases and controls, although only 3.9% of their NHL cases and 2.1% of controls had evidence of HCV infection (odds ratio 1.96, confidence intervals 1.07-4.03). HCV is mainly associated with low-grade B-cell NHLs, particularly marginal zone lymphomas; an association with DLBCLs has also been reported.

  33. HCV HCV is an RNA virus, which does not have a DNA intermediate in its life cycle and therefore cannot integrate into host cell DNA. It infects and replicates in hepatocytes but can also infect peripheral blood mononuclear cells. Despite this tropism, the role of the virus in lymphomagenesis is probably indirect and related to chronic antigenic stimulation.

  34. Terapia con PEG-Interferone e Ribavirina di pazienti affetti da epatite cronica da HCV e da linfoma non-Hodgkin (NHL) indolente. Studio sponsorizzato dall’ISTITUTO SUPERIORE DI SANITÀ in collaborazione con: GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto) e ILL (Intergruppo Italiano Linfomi)

  35. Terapia con PEG-Interferone e Ribavirina di pazienti affetti da epatite cronica da HCV e da linfoma non-Hodgkin (NHL) indolente. • OBIETTIVI • Obiettivo Primario • Conseguimento di risposta clinica della malattia linfoproliferativa in pazienti che vanno incontro a risposta virologica. • Obiettivi Secondari • Durata della risposta virologica ed ematologica. • Osservazione di modifiche biologiche in NHL associate ad infezione da HCV. • DISEGNO DELLO STUDIO. • Studio osservazionale, multicentrico.

  36. Terapia con PEG-Interferone e Ribavirina di pazienti affetti da epatite cronica da HCV e da linfoma non-Hodgkin (NHL) indolente. • Criteri di Inclusione. • Età: >18, <70 anni. • HCV-RNA+ (positività a PCR qualitativa). • NHL indolenti: linfoma della zona marginale (MZL) con o senza linfociti villosi, leucemia linfatica cronica / linfoma linfocitico a piccole cellule (CLL/LL), linfoma linfoplasmacitoide / macroglobulinemia di Waldenstrom (LPL/WM), linfoma follicolare (FL) di grado 1-2 (App. 1-2). • Pazienti con indicazione al trattamento con terapia antivirale (PEG-Interferone e Ribavirina) per epatite cronica secondo le note CUF. • Nessun trattamento precedente per epatite. • Assenza di indicazioni immediate per trattamento chemioterapico. • IPI 0-1 (App. 3). • Hemoglobina >10 g/l. • Polimorfonucleati (PMN) > 1500/l. • Piastrine (PLTS) >80000/l. • Malattia ematologia misurabile. • Consenso informato e firmato secondo IGH/EU/GCP e leggi nazionali. • Test di Coombs negativo. • Funzione tiroidea nella norma. • Funzione renale nella norma.

  37. Terapia con PEG-Interferone e Ribavirina di pazienti affetti da epatite cronica da HCV e da linfoma non-Hodgkin (NHL) indolente. CRITERI DI ELEGGIBILITA’. • Età > 18 < 70 anni • HCV-RNA+ (PCR qualitativa positiva) • Linfomi indolenti: linfoma della zona marginale (MZL) con o senza linfociti villosi, leucemia linfatica cronica / linfoma linfocitico a piccole cellule (CLL/LL), linfoma linfoplasmacitoide macroglobulinemia di Waldenstrom (LPL/WM), linfoma follicolare (FL) di grado 1-2 • Pazienti con indicazione al trattamento con terapia antivirale (PEG-Interferone e Ribavirina) per epatite cronica secondo le note CUF. • Nessun trattamento precedente per NHL o epatite • Assenza di indicazione per trattamento chemioterapico immediato • IPI 0-1 • Emoglobina > 10 g/l • Cellule polimorfonucleate (PMN) > 1500/l • Piastrine (PLTS) > 80000/l • Consenso informato firmato • N.B.: L’anemia (emoglobina < 10 g/dl) rappresenta criterio di esclusione per terapia combinata • con ribavirina; questi pazienti verranno trattati con monoterapia PEG-inerferone.

  38. Terapia con PEG-Interferone e Ribavirina di pazienti affetti da epatite cronica da HCV e da linfoma non-Hodgkin (NHL) indolente. Criteri di Esclusione. • Linfomi aggressivi • Cirrosi epatica in fase avanzata. • Crioglobulinemia di tipo II senza diagnosi istologica o immunofenotipica di NHL o CLL.

  39. Terapia con PEG-Interferone e Ribavirina di pazienti affetti da epatite cronica da HCV e da linfoma non-Hodgkin (NHL) indolente. Valutazione a 3 mesi: • Pazienti con evidenza di progressione ematologica fuori dallo studio • Tutti gli altri continueranno il trattamento per almeno altri tre mesi Valutazione a 6 mesi: • Interruzione del trattamento nelle seguenti situazioni: • Progressione ematologica • Pazienti con persistente replicazione virale (HCV-RNA+) • Genotipo virale 2, 3 con HCV-RNA negativo • Pazienti con genotipo virale 1, 4 e 5 con HCV-RNA negativo continueranno il trattamento fino al mese 12. Valutazione a 12 mesi. • Valutazione finale ematologica e virologica per tutti i pazienti arruolati nello studio (AASLD Practice Guideline, Hepatology, April 2004)

  40. Helicobacter pylori

  41. Pathogen-Host Interactions in the Pathogenesis of Helicobacter pylori Infection Suerbaum S and Michetti P. N Engl J Med 2002;347:1175-1186

  42. Natural History of Helicobacter pylori Infection Suerbaum S and Michetti P. N Engl J Med 2002;347:1175-1186

  43. MALT LYMPHOMAS: PRESENTATION • Nonspecyfic dyspepsia • Epigastric pain • B symptoms uncommon • Endoscopic reveal of nonspecific gastritis or peptic ulcer • (mass lesion unusual) • Elevated LDH or 2- microglobulin uncommon

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