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The Special Cases Of Syphilis And Human Immunodeficiency Virus


The Special Cases Of Syphilis And Human Immunodeficiency Virus
Syphilis
Natural history of untreated syphilis
Syphilis is caused by the spirochete bacterium, Treponema pallidum, which enters the body through miniscule breaks in the skin of the external genitalia that occur during sexual intercourse. Once the spirochete has entered, the untreated disease progresses through four consecutive stages: primary, secondary, latent and tertiary syphilis. Antibiotic treatment at any stage short of tertiary can prevent the late, life-threatening sequelae of the disease. Syphilis may also be transmitted from a woman to her fetus at any point during pregnancy, with serious consequences.

The primary lesion of syphilis, the chancre, develops in venereal locations close to where T. pallidum typically enters the body: the penis, labia, perineum, anus or rectum. Chancres are painless, small papules that persist for 1–2 months and heal spontaneously.
The secondary stage of syphilis is a disseminated form. Blood- borne spirochetes populate the dermis throughout the body causing a widespread papular rash over the trunk and extremities. Because the disease is systemic, fever, myalgias, lymphadenopathy, sore throat and headache are common. Secondary syphilis can also be associated with immune complex deposition in the joints, kidneys and eyes, leading to arthritis, glomerulonephritis, nephrotic syndrome and uveitis. Untreated secondary syphilis resolves over 4–12 weeks, leaving the patient symptom free. The subsequent months to years until the onset of symptoms of tertiary syphilis is known as the latent period.
Tertiary syphilis usually appears many years after the disseminated stage. Tertiary syphilis can involve multiple organs, including the cardiovascular and nervous systems. Overall, about one-quarter of untreated patients develop recognizable late (tertiary) complications of syphilis, one-quarter have asymptomatic lesions demonstrable at autopsy and half have no anatomic lesions attributable to syphilis present at autopsy.About half of the patients with symptomatic tertiary syphilis will die as a direct result of the disease, typically of cardiovascular complications.
Infection of the placenta and fetus will occur in virtually 100% of pregnant women who suffer the spirochetemia accompanying primary or secondary syphilis. Complications of syphilis in pregnancy include miscarriage, stillbirth, premature delivery and congenital syphilis. The manifestations of congenital syphilis are protean. Its neonatal mortal- ity rate is 50%. Syphilis is treated with penicillin in all but highly allergic patients.

The Special Cases Of Syphilis And Human Immunodeficiency Virus, Syphilis, Natural history of untreated syphilis, Treponema pallidum, our consecutive stages: primary, secondary, latent and tertiary syphilis, chancre, Epidemiology of syphilis, Biology of T. pallidum, Human immunodeficiency virus, Natural history of untreated HIV infections, Epidemiology of HIV infections,  Biology of HIV,

Epidemiology of syphilis
Syphilis was very common in many parts of the world until antibiotic therapy became available in the 1940s. The prevalence of the disease fell dramatically after World War II but began to increase again in the 1960s. Up to 75% of cases go unreported. Women and men at high risk for contracting syphilis are young, from lower socioeconomic groups, and have multiple sexual partners. Some 10–50 syphilitic organisms are sufficient to cause infection and about one-third of the sexual contacts of an infected person will become infected. The incidence of congenital syphilis parallels that in women and is increasing. Mandatory prenatal screening has reduced the incidence of late congenital syphilis; late or absent prenatal care is the biggest risk factor for congenital syphilis.

Biology of T. pallidum
Treponema pallidum is a member of the bacterial order Spirochaetaceae, and closely related to two other treponemas responsible for human disease: Treponema pertenue, which causes yaws, and T. cara- teum, which causes pinta. Neither electron microscopic examination nor DNA analyses can distinguish between these three organisms. It is believed that the different diseases that develop reflect adaptations of the organism and the host to different points of entry into the body. Treponema pallidum is a relatively fragile organism that cannot survive for more than a few hours outside moist areas of the body. Its microbiology is very poorly understood because the organism cannot be maintained in cell culture.
Most of the manifestations of syphilis are secondary to the inflammatory reaction caused by the organism. Polymorphonuclear cells arriving at the site of the inoculum ingest the spirochetes but do not kill them. Lymphocytes and macrophages are recruited to the site. They also surround, but do not kill the treponemes. Antitreponemal antibodies are produced, sometimes in quantities that cause immune complex glomerulonephritis. It remains both amazing and unknown how T. pallidum is able to evade host defenses and establish an infection. The site of primary infection is surrounded by a mucoid material composed of hyaluronic acid and chondroitin sulfate that may alter the host defenses. The best clue available to explain the persistence of disease is the finding that delayed type sensitivity to treponemal antigens is absent in secondary syphilis. New spirochetes inoculated into the system are not infectious while the original infection persists. This is a common mechanism in chronic parasitic diseases, called “premunition”; the host resists reinfection but cannot clear the initial infection.
Once the systemic phase of the infection is established, spirochetes are present virtually everywhere in the infected tissues. However, inflammation occurs preferentially around small vessels and causes intimal hyperplasia and obliterative endarteritis. The subsequent focal ischemic necrosis and fibrosis are responsible for the many late manifestations of the disease.
The inflammatory changes caused by the spirochetes are most striking in congenital syphilis.  The placenta is diffusely fibrotic with inflammation and necrosis of the fetal blood vessels in the placental villi. The resulting vascular insufficiency leads to poor fetal growth (intrauterine growth restriction) and stillbirth. Fibrosis of the liver and spleen cause fetal anemia. Compensatory extramedullary hematopoeisis promotes hepatosplenomegaly and the development of pleural effusions and ascites (fetal hydrops). Some infants will have a skin rash that closely resembles that of secondary syphilis. A runny nasal discharge loaded with spirochetes (snuffles) may be the only hint of congenital syphilis at birth.
The late manifestations of syphilis, both congenital and tertiary, involve vasculitis and parenchymal damage in the central nervous system.

Human immunodeficiency virus
Natural history of untreated HIV infections
The first description of human disease associated with HIV infection surfaced in the early 1980s. Acute infection was reported to cause a “mononucleosis-like syndrome” with fever, malaise, muscle aches, headache, fatigue, generalized rash, sore throat, lymphadenopathy and characteristic mucocutaneous lesions. The rapidity of symptom onset after initial contact may reflect the route of viral entry and the viral load of the exposure. Symptoms of primary infection often persist for 2–3 weeks before resolving spontaneously. The disease then enters an asymptomatic phase. This can last from several months to many years. The length of this symptom-free phase appears to depend on the pathogenicity of the infecting viral strain. Coinfection with other viruses or other sexually transmitted disease (STD) pathogens may speed disease progression. During the asymptomatic phase, viral replication continues within infected lymphoid cells (mainly CD4+ T cells). Infected immune cells are destroyed by the virus and, eventually, the host becomes immunocompromised. In this immunocompromised state, the HIV-infected individual is vulnerable to a variety of opportunistic viral, bacterial, fungal and parasitic infections. Oppor-tunistic pathogens such as Pneumocystis carinii, Cryptosporidium and Cryptococcus seldom affect individuals with normally functioning immune systems but can be deadly in those infected with HIV. Patients who are severely immunocompromised are also at risk for the development of certain neoplasms, including Kaposi sarcoma, human papillomavirus-related cervical cancers and some lymphomas. The development of opportunistic infections or neoplasms in a patient infected with HIV defines the acute immunodeficiency syndrome (AIDS). Patient who die of AIDS typically succumb to complications of an opportunistic infection or neoplasm.

Epidemiology of HIV infections
HIV has infected over 60 million people worldwide, and 35 million are presently living with the disease. The developing world accounts for 95% of infections, with over 25 million of those presently infected living in sub-Saharan Africa. The most important risk factor for acquiring HIV infection and succumbing to its complications is poverty.
Viral transmission occurs through direct contact with bodily fluids, most often semen or blood. Viral spread can occur via sexual contact, via parenteral exposure (intravenous drug abuse and transfusions) or via  perinatal  transmission. The  latter  can  occur  during  pregnancy (transmission across the placenta), at delivery or during breastfeeding. Only 25% of children born to untreated HIV-positive mothers will acquire the infection, although this rate can be decreased to less than 1–2% with aggressive antenatal and perinatal therapy. Over 90% of HIV infections  occur  via  heterosexual  transmission.  HIV is  more readily transmitted from the male to female (1 in 500–1000 acts of receptive vaginal intercourse) than female to male (1 in 2000–2500 acts of insertive vaginal intercourse).

Biology of HIV
HIV is a retrovirus. Its genetic material is carried as RNA wrapped in a viral protein coating. The viral surface expresses a receptor called gp120 that binds specifically to receptors on lymphoid cells (Fig. 48.1). Binding promotes viral entry into host cells. Host receptors and co-receptors for viral entry include CCR5, a chemokine receptor on macrophages, CXCR4, a chemokine receptor expressed on T cells, and CD4, a marker for T helper cells that is also expressed on macrophages and dendritic cells. Once viral entry has occurred, infected cells will fuse with CD4+ T helper cells. Viral propagation will continue largely in CD4+ cells.
After entry into a host cell, the retrovirus uses reverse transcriptase to make a DNA copy of its viral RNA genome. The virus then uses an enzyme called integrase to insert its newly synthesized DNA into the host genome and the host cell machinery makes multiple copies of the HIV genome. The virus finally employs an enzyme called protease to reassemble the viral envelope. Viral particles then exit the host cell via budding to infect surrounding receptor-laden immune cells. Multiple viral progeny will be produced within a single infected host cell before it expires.
Reverse transcriptase (RT), integrase and protease are virus-specific enzymes. They can therefore serve as targets for directed therapeutic interventions. Over 20 FDA-approved medications are now available to treat HIV infections. None are curative and optimal therapies typically use combinations of two to four medications. Available antiretroviral medications inhibit each of the HIV-specific enzymes: the HIV protease (protease inhibitors), the RT enzyme [nucleoside RT inhibitors (NRTI), non-nucleoside RT inhibitors (NNRTI)], and HIV integrase (integrase inhibitors). Inhibitors of HIV viral entry have recently been released.
In developed countries, careful therapeutic interventions, combined with close monitoring of CD4+ T-cell counts and viral loads, have radicallyimprovedtheprognosisforthoseinfectedwith HIV. Furtheradvances are challenged by the fact that the HIV reverse transcriptase enzyme makes many mistakes during replication of the viral genome. The virus has no way to readily correct these mistakes. This allows for rapid viral mutation and, unfortunately, the development of resistance to antiretroviral medications. In underdeveloped countries, where the prevalence of disease is highest, medications are scarce or completely unavailable.