Kaposi's sarcoma, oncogenic viruses, and iron.

INTRODUCTION: Iron is required for many cellular processes, but it is also toxic in excess quantities. Therefore, iron homeostasis and utilization must be strictly maintained, and defects in iron absorption or transport result in iron depletion or accumulation. Most research has been directed to enteral and placental transfer of iron, but little is known about iron entry through the skin. We present evidence that exposure to wet clay soils in Africa is an important risk factor for Kaposi's sarcoma (KS) and speculate that iron may be responsible for soil toxicity contributing to the pathogenesis of KS. STUDY DESIGN: Evidence gathered from case control studies and related investigations in Uganda between 1995 and 1998 are summarized. RESULTS: A large case control study of KS in HIV-infected adults disclosed affluence and mobility that suggest enhanced sexual exposure to human herpesvirus-8, the putative aetiologic agent of KS. Another study in endemic KS (HIV-negative) also showed affluence and mobility as risk factors. In addition, barefoot exposure to wet soil was an important risk factor for men with endemic KS. Other studies point to diminish delayed hypersensitivity in the lower limbs of KS patients. Geographic similarities of KS to podoconiosis (non-filarial elephantiasis) in Africa implicate soil absorbtion through the skin in the pathogenesis of KS and podoconiosis. CONCLUSION: The hypothesis of soil exposure as a risk for endemic KS has been strengthened by recent investigation. Particulate soil exposure may cause localized microtrauma and inflammation, predisposing to KS on the extremities in HHV-8 infected men. A role for iron toxicity is yet to be determined.

Poverty and eosinophilia are risk factors for endomyocardial fibrosis (EMF) in Uganda.

OBJECTIVE: To determine the relative risks of socio-demographic, dietary, and environmental factors for endomyocardial fibrosis (EMF) in Uganda. METHOD: Unmatched case control study in Mulago Hospital, Kampala. Cases (n = 61) were sequential patients hospitalized with an echocardiographic diagnosis of EMF from June 1995 to March 1996. Controls (n = 120) were concurrent patients with other forms of heart disease (heart controls, n = 59) and subjects admitted for trauma or elective surgery (hospital controls, n = 61). All consenting subjects answered a structured questionnaire administered by trained interviewers. Complete blood counts, malaria films and stool examination for ova and parasites were performed. Questionnaires elicited information on home address, economic circumstances, variables concerned with environmental exposures and usual diet before becoming ill. RESULTS: After adjustment for age and sex, cases were significantly more likely than controls to have Rwanda/Burundi ethnic origins (P = 0.008). Compared with controls, cases had a lower level of education (P < 0.001 for heart controls and P = 0.07 for hospital controls), were more likely to be peasants (P < 0.001), and to come from Luwero or Mukono Districts (P = 0.003). After further adjustment for peasant occupation, cases were more likely than controls to walk barefoot (P = 0.015), consume cassava as their staple food (P < 0.001) and to lack fish or meat in dietary sauces (P = 0.02). Cases were more likely to exhibit absolute eosinophilia (P = 0.006). The effect of cassava diet was more marked in the younger age group, while the effect of eosinophilia was greater in adults. Socio-economic disadvantage is a risk for EMF. Absolute eosinophilia is a putative cause of EMF, a finding not explained by parasitism. CONCLUSION: Data indicate that relative poverty and environmental factors triggering eosinophilia appear to act in a geographically restricted region of Uganda in the aetiology of EMF.

Risk factors for Kaposi's sarcoma in HIV-positive subjects in Uganda.

BACKGROUND: Kaposi's sarcoma (KS) is associated epidemiologically with HIV infection and with human herpesvirus 8 (HHV-8 or KSHV). Both KS and HIV infection are common in Uganda. We conducted a case-control study of 458 HIV-seropositive. Ugandan adults with KS and 568 HIV-seropositive subjects without KS to examine risk factors for HIV-associated KS. METHODS: We recruited newly diagnosed adult KS cases from five hospitals in Kampala, Uganda and controls from a large referral clinic for HIV infection at Mulago Hospital. All cases and controls were counselled and tested for HIV and answered an interviewer-administered questionnaire about their home, socio-economic conditions, lifestyle and sexual behaviour before they became ill. Only HIV-seropositive subjects were included in the analysis. RESULTS: There were 295 males and 163 females with KS and 227 male and 341 female controls. Age distribution was similar but there was a higher proportion of cases (45%) than controls (29%) residing in rural regions of Uganda. KS cases were more likely than controls to have a higher level of education (X2 for trend, 4.8; P = 0.03), to have occupations associated with affluence [chi 2 for heterogeneity, 17.3 on 5 degrees of freedom (df); P = 0.004] and to come from larger settlements [adjusted odds ratio (OR) for settlements of > 1000 versus 10-99 houses, 1.8; 95% confidence interval (CI), 1.1-3.0]. Cases were more likely than controls to have high household income (chi 2 for trend, 32.6; P < 0.001) and other markers of urban or rural wealth such as owning several cows (chi 2 for trend, 9.5; P = 0.002). Cases were more likely to travel away from home (adjusted OR, 1.6; 95% CI, 1.1-2.3) and more likely to have spent increasing time in contact with water (chi 2 for trend, 12.3; P < 0.001). Few indices of sexual behaviour were related to risk of KS, including reported number of sexual partners. Cases were more likely than controls to be married to one rather than several spouses (adjusted OR, 1.6; 95% CI, 1.2-2.2) and to have reported a history of sexually transmitted diseases (STD) (adjusted OR, 1.6; 95% CI, 1.2-2.3). CONCLUSIONS: Among HIV-infected subjects, KS cases are characterized by better education and greater affluence, compared with controls. Urban address, travel away from home, exposure to water, monogamous marriage and self-reported STD were also more frequent among KS cases than controls. The higher socio-economic status of persons with HIV and KS may be a marker for enhanced exposure to a possibly sexually transmitted agent, or for a delayed exposure to a childhood infection. The risk posed by exposure to water among KS cases requires further study.

PIP: The risk factors for Kaposi's sarcoma in HIV-infected persons were investigated in a case-control study conducted in Kampala, Uganda, in 1994-96. Cases included 458 HIV-positive Ugandans with newly diagnosed Kaposi's sarcoma, while the control group was comprised of 568 seropositive subjects without Kaposi's sarcoma. Men and women with Kaposi sarcoma were significantly more likely than controls to have a higher educational level, have prestigious professional or military jobs, to come from large settlements (over 1000 houses), to have a high household income, to travel away from home more than seven nights per year, and to have spent increasing time in contact with water. In addition, cases were more likely than controls to be married to one rather than several spouses and to have a history of a sexually transmitted disease. Indices of sexual behavior, including reported number of sexual partners and condom use, were unrelated to Kaposi's sarcoma risk. The higher socioeconomic status of HIV-infected persons with Kaposi's sarcoma may be a marker for enhanced exposure to a sexually transmitted agent such as human herpes virus-8 or for delayed exposure to a childhood infection. The puzzling association between exposure to water and Kaposi's sarcoma warrants further investigation.

Echocardiographic diagnosis of heart disease in Uganda.

Five hundred consecutive cardiological patients were reviewed and evaluated by echocardiography in Mulago Hospital as a referral service. All diagnostic problems in cardiology in the hospital and to a certain degree from other institutions were reviewed. The commonest diagnosis was endomyocardial fibrosis (EMF) 19.8%, followed by congenital heart disease (CHD) 15% and rheumatic heart disease (RHD) 11%. The anatomical distribution of fibrotic lesions in EMF (left, right or biventricular) correlated with that found in previous autopsy series from Mulago Hospital thus demonstrating the accuracy of echocardiography. We were able to quantify the contribution of echocardiography to a correct diagnosis which varied between 13% in RHD to 90% in mitral valve prolapse (MVP). Echocardiography was able to confirm the clinical diagnosis of subacute bacterial endocarditis (SBE) in 69% of cases. The obtained data suggests that EMF may be the most common heart disease in Uganda contrary to the pattern of heart disease outlined in earlier works. The favourable cost/benefit ratio of echocardiography (i.e. its easy availability and maintenance), as well as the absence of consumable materials in comparison to other cardiac diagnostic tools such as catheterization, chest X-ray and ECG is emphasized, together with the multipurpose use of the machine.

Kaposi's sarcoma in childhood: an analysis of 100 cases from Uganda and relationship to HIV infection.

We report 100 cases of Kaposi's sarcoma (KS) in children under 15 years of age treated at the Uganda Cancer Institute in the 6-year period 1989-1994. The incidence of childhood KS has risen more than 40-fold in the era of AIDS, and 78% of 63 cases tested were seropositive for HIV-1. There were 63 boys and 37 girls. The median age was 4 years and the median age of onset was 33 months. Tumour distribution was lymphadenopathic and muco-cutaneous, with 2 major patterns: pattern I, oro-facial dominant (79%); and pattern II, inguinal-genital dominant (13%). A newly described herpes-like virus is implicated as the cause of KS (KSHV), and DNA sequences of this virus were present in all of 8 childhood cases tested. If KSHV is a direct cause of KS, this tumour distribution in children suggests mucosal routes of virus entry, possibly during birth or breast feeding. The dramatic increase of childhood KS implies that the prevalence of causative factors is rising in Uganda.

PIP: During 1989-94 clinicians had treated 100 cases of histologically or clinically confirmed Kaposi's sarcoma (KS) in children under 15 years of age (median age, 4 years) at the Uganda Cancer Institute in Kampala. The male/female ratio was 1.7/1. 78% of the children tested positive for HIV, while 69% of all mothers were HIV positive. 81% of the mothers with an HIV-infected child also tested HIV positive. There were seven discordant child-mother pairs among the 34 pairs tested for HIV. Five children were HIV positive; yet their mothers were HIV negative. There were no child-mother pairs with KS, even though the prevalence of KS in HIV-seropositive adults (7-10%) would predict two mothers with KS. 39% of patients had an infection in a site later involved with KS. The most prominent KS-related findings were lymphadenopathy and mucocutaneous lesions. Scientists have implicated a newly described herpes-like virus as the cause of KS (KSHV). All eight children tested for DNA sequences of this virus had these DNA sequences in archival tissues. The areas of the body most affected by KS were orofacial (79%) and inguinal/genital (13%) areas, sites that favor the entry of a causative agent, e.g., KSHV. The median age of onset of KS symptoms was 33 months for HIV-positive, child-mother pairs and 34 months for HIV-negative, child-mother pairs, suggesting that exposure to a potentially infectious agent occurred at birth or early infancy. It was 36 months for those of unknown HIV status. The high concordancy of child-mother HIV seropositivity suggests that the KS agent could be spread perinatally or during breast feeding. The dramatic increase in the incidence of KS in children (40-fold increase) since the emergence of AIDS suggests that the prevalence of causative factors is also increasing.

Endemic Kaposi's sarcoma in Africa and local volcanic soils.

Endemic Kaposi's sarcoma (KS) in Africa has been attributed to a geographically-determined environmental factor. Endemic KS, a chronic nodular condition predominantly affecting the feet and legs, is believed to arise in the lymphatic endothelium and is associated with chronic lymphoedema. As such, KS bears a resemblance to podoconiosis (non-filarial elephantiasis). The prevalence of both conditions in highland areas close to volcanoes suggests a shared pathogenetic relationship to exposure to volcanic soils. The lymphatics and lymph nodes of patients with podoconiosis contain particulate alumino-silicates in macrophages consistent with the theory that ultrafine clay minerals are absorbed through the feet. The resulting chronic lymphatic irritation, inflammation, and collagenosis causes obstruction and lymphoedema. The geographical proximity of endemic KS to areas containing volcanic clay minerals, its lympho-endothelial origin, predilection for the feet and legs, and its prevalence among rural peasants and cultivators, suggest a common aetiology. Other features point to the participation of a low-grade, possibly sexually-transmitted, infective agent that becomes more pathogenic in the presence of immunosuppression. Damage to the dermal lymphatics of the feet and legs by absorbed clays could impair local immunity to such an agent. Endemic KS would then occur in exposed individuals who harbour the KS infective agent and are susceptible to the KS phenotype (males).

PIP: Endemic Kaposi's sarcoma (KS) in Africa is a chronic, nodular condition predominantly affecting the feet and legs. It is believed to arise in the lymphatic endothelium and is associated with chronic lymphoedema. KS therefore bears a resemblance to podoconiosis, or nonfilarial elephantiasis. Both conditions are prevalent in highland areas close to volcanoes, suggesting a shared pathogenetic relationship to exposure to volcanic soils. The lymphatics and lymph nodes of patients with podoconiosis contain particulate alumino-silicates in macrophages consistent with the theory that ultrafine clay minerals are absorbed through the feet. The resulting chronic lymphatic irritation, inflammation, and collagenosis causes obstruction and lymphoedema. The geographical proximity of endemic KS to areas containing volcanic clay minerals, its lympho-endothelial origin, tendency to affect the feet and legs, and its prevalence among rural peasants and cultivators suggest a common etiology with podoconiosis. Other features of endemic KS suggest the involvement of a low-grade, possibly sexually-transmitted, infective agent which becomes more pathogenic in the presence of immunosuppression. Damage to the dermal lymphatics of the feet and legs by absorbed clays may impair local immunity to such an agent, with endemic KS occurring in exposed individuals who harbor the KS infective agent and are susceptible to the KS phenotype.

The value of a clinical definition for epidemic KS in predicting HIV seropositivity in Africa.

Kaposi's sarcoma (KS) in African adults can present in endemic (non-HIV-related) and epidemic (HIV-related) forms. We evaluated the usefulness of a clinical case definition for epidemic KS in predicting HIV seropositivity. A total of 235 patients with KS presenting to the Uganda Cancer Institute from January 1, 1988 to March 31, 1990 were evaluated with history and physical examination. Symptomatic patients underwent chest radiography and upper gastrointestinal endoscopy. One hundred seventy-four patients (80%) underwent HIV ELISA testing with Western blot confirmation. The clinical case definition had a 91% sensitivity and a 95% specificity in predicting HIV seropositivity. Oral KS was the most sensitive specific site of involvement in predicting HIV seropositivity. The clinical case definition is useful in assessing patients to determine prognosis and likelihood of responding to aggressive therapy.

Kaposi's sarcoma: introduction and overview.

KS can be considered to be a paradigm for cancer development. It is readily observable in the skin and has a preneoplastic counterpart. Its development is related to geographic, environmental, genetic, and acquired conditions. Despite a reliably consistent histologic appearance, the tumor displays varied clinical manifestations and natural history that may be attributed to tumor and/or host determinants. Thus, this intriguing neoplasm lends itself to intensive epidemiologic, clinical, and biologic study in an attempt to pin down the etiologic covariants and to develop hypothetical models for further testing.

Intralesional recombinant tumor necrosis factor-alpha for AIDS-associated Kaposi's sarcoma: a randomized, double-blind trial.

The effect of recombinant tumor necrosis factor-alpha (rTNF), injected directly into the tumor, was evaluated in a Phase I/II study of 27 patients with AIDS-associated Kaposi's sarcoma (KS). The maximally tolerated intralesional dose was less than 100 micrograms/m2 and the recommended intralesional dose was 25 micrograms/m2. In a double-blind, randomized, placebo-controlled study, rTNF reduced the cross-sectional area of 15 of 16 (94%) of the injected KS lesions and caused complete disappearance of 3 of 16 (19%) lesions. Only injected lesions showed a response. Rigors and fever were common dose-dependent side effects and were attenuated by meperidine. There were no changes in human immunodeficiency virus (HIV) activity as determined by serum p24 antigen levels. While biologically active, the systemic toxicity of rTNF as well as the lack of distant antitumor effects in noninjected lesions limits its clinical usefulness under the conditions employed in this trial.

Pathogenesis of AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma presents the oncologist with a myriad of unanswered questions. What accounts for the genesis, distribution, and natural history of this tumor? How could a tumor with such a singular histologic appearance occur in such diverse clinical circumstances? What accounts for the unusual geographic, ethnic, and demographic features of Kaposi's sarcoma? Clearly, the answers to these questions will involve a multifactorial etiology, and may only be arrived at by methodical, piecemeal dissection of each question.

Primary central nervous system lymphomas in patients with AIDS.

Primary central nervous system non-Hodgkin's lymphomas are observed in approximately 1.9% of all patients with acquired immunodeficiency syndrome (AIDS). The yearly incidence of AIDS-associated tumors has surpassed the yearly incidence from all other causes and could become as frequent as low-grade astrocytomas by 1991. Patients' signs, symptoms, and radiographic studies are not specific for this lesion; brain biopsy usually is necessary to make a definitive diagnosis. Most tumors are high-grade lymphomas and are pathologically similar to the primary central nervous system lymphomas observed before the AIDS epidemic. AIDS-associated tumors respond readily to radiation therapy. However, patient survival remains limited owing to other manifestations of the syndrome.

Hypothesis: AIDS is an autoimmune disease directed at the immune system and triggered by a lymphotropic retrovirus.

By attaching to the CD4 (T4) molecule of the helper-inducer lymphocyte, the human immunodeficiency virus (HIV) envelope imitates the normal ligand for this receptor, namely, an invariant component of the class II major histocompatibility antigen (MHC). Depending on the degree of antigen mimicry, the normal immune response to retrovirus envelope would be expected to recognize and cross-react to self-MHC. By disguising as "self" the virus then provokes an autoimmune attack of class-II-bearing cells and an anti-idiotypic response to the CD4 antigen. As a consequence of this immune response to virus infection, communication between CD4 lymphocytes and antigen-processing cells becomes blocked, resulting in progressive disruption of antigen recognition, immunodysregulation, and dysfunctional responses of catastrophic proportion. If this hypothesis gains support, then there are profound implications for prevention and treatment.

Flow cytometric analysis of lymphocyte phenotypes in AIDS using monoclonal antibodies and simultaneous dual immunofluorescence.

Simultaneous dual immunofluorescence and flow cytometry was used to study sixteen lymphocyte phenotypes in 209 men including: healthy homosexuals, lymphadenopathy patients (LAN), and AIDS patients. Significant differences between the distribution of lymphocytes in healthy homosexuals and healthy heterosexuals were decreased percentages of helper/inducer T cells (Leu 3), increased cytotoxic/suppressor T cells (Leu 2), and consequently a decreased Leu 3/Leu 2 ratio. The increased Leu 2 cells were identified as functionally cytotoxic subset Leu 2+ 15- phenotype rather than suppressor cells which are Leu 15+. Leu 2 and Leu 3 bearing cells exhibited an excess of membrane-bound immunoglobulins which were easily elutable at 37 degrees C. An increased percentage of an HLA-DR framework determinant bearing T cells were also detected. Within the NK cell family, Leu 7 cells were moderately increased and the functionally unidentified Leu 2+ 7+ population was strikingly elevated. LAN or AIDS patients were compared to healthy homosexual controls. Lower percentages of Leu 3 cells and higher percentages of Leu 2 cells were evident in LAN patients. These subsets were similar in LAN and AIDS patients. The increase in Leu 2+ cells was due to the Leu 2+ 15- cytotoxic subset. Fewer T cells had immunoglobulin in LAN and AIDS. A definite increase in Leu 2+ DR+ cells but not Leu 3+ DR+ cells occurred in AIDS compared to LAN or healthy controls. NK cell changes already present in healthy homosexuals persisted in LAN and AIDS patients. No differences in the distribution of B cells was detected in any intergroup comparisons. Changes in monocytes or pan-T cells were relatively insensitive measures of immunologic alterations among any of the groups. These results indicate many of the changes in lymphocyte subsets seen in AIDS and LAN subjects are already present in a carefully screened population of healthy homosexuals in San Francisco. Many of the changes in Leu 2 and NK family of cells suggest a possible adaptive response to viral or neoplastic challenge. Whether these interesting phenotypic alterations relate to functional changes in response to such challenge of the identified subsets waits further investigation.