Atlas of Clinical Andrology

Chapter 12. Cardiovascular anomalies, infections and infectious diseases

CARDIOVASCULAR ANOMALIES

Heart disease

Heart disease is an inclusive term for a variety of disorders of the heart itself as well as a network of blood vessels throughout the body that distribute nutrients and oxygen in arteries and collect waste in veins. The arteries branch into smaller arterioles and then into still smaller capillaries, vessels which are less than one-tenth the thickness of a human hair.

One-fifth of the US population already have one or more forms of heart disease; millions more are at risk. The cardiovascular disease death toll exceeds the combined total of deaths attributable to cancer, accidents and infections. Men are three times more at risk for heart disease than women. Heart disease causes suffering and sorrow for the victims and their families; however, it also has an impact on the economic health of a nation. The total cost of heart-related hospitalizations, doctors’ bills, nursing home services, medication and lost productivity are estimated to be $200 billion per annum in the USA. Men over 60 years of age are recommended to have their blood pressure checked regularly as a preventive measure. Blood pressure measurement is expressed as the systolic over the diastolic blood pressure, with 120 over 80 as the normal adult level, 140 over 90 as borderline high blood pressure and 160 over 95 as a cause for concern.

Ischemic heart disease, characterized by reduced blood supply to the heart, is the most common cause of death in most western countries. Ischemia means ‘reduced blood supply’. The coronary arteries supply blood to the heart muscle and no alternative blood supply exists; thus, a blockage in the coronary arteries reduces the supply of blood to the heart muscle. Most ischemic heart disease is caused by atherosclerosis. Initially there is narrowing of coronary arteries causing angina. The narrowing is mainly caused by fatty plaques lining the wall of the artery. A fatty plaque may rupture leading to a heart attack. (Heart attacks caused by simple narrowing are relatively uncommon.) A heart attack causes damage to heart muscle by cutting off its blood supply.

Complications of a heart attack include temporary damage and pain (ischemia), loss of muscle activity (acute heart failure), permanent heart muscle damage (acute myocardial infarction/infarct), long-term loss of heart muscle activity (chronic heart failure), cardiac arrhythmia (irregular heartbeat which can be fatal) and other structural damage to the heart including damaged heart valves, actual perforation of the heart and a thin-walled fibrous floppy heart.

Preventive measures, including not smoking, treatment of hypertension, regular exercise and diet, are easy to achieve. Obesity exerts unnecessary strain on the heart and increases serum cholesterol and triglyceride levels. Excess saturated fat in the diet should be avoided. Some unsaturated fats may be beneficial in reducing the risk of heart disease when consumed in moderation. Dietary cholesterol has a modest effect on serum cholesterol. Cholesterol- reducing drugs are recommended.

Specialized coronary care can include cardiopulmonary resuscitation (heart massage), defibrillation to revert cardiac arrhythmias, fitting of an artificial pacemaker to prevent cardiac arrhythmias, treatment with drugs such as adrenaline to increase the heart rate, administration of thrombolytic agents to clear away the causative blood clot, anticoagulation therapy to prevent additional blood clots, treatment with isotropic drugs to raise blood pressure, and unblocking of arteries with surgery or angioplasty (‘balloon angioplasty’).

Figure 12.1 Major anatomical anomalies of the heart. (a) Rheumatic fever is apparently a sequela of a streptococcal infection, characteristically originating as a respiratory infection with a sore throat. Involved cardiac areas can include the heart muscle (1), the pericardial sac around the heart (2) and, most frequently, the mitral (3) and aortic (4) valves, and, rarely, the tricuspid valve (5).

(b) Interventricular septal defect (abnormal opening between ventricles). Returned venous blood from right ventricle (3) is shunted to left ventricle (2), causing oxygenated and unoxygenated blood to mix.This imposes an increased workload on both ventricles.

(c) Congestive failure of right heart. Normal circulation shown in small drawing. In right heart failure, the right ventricle (3) has difficulty in delivering venous blood to the lungs. Blood backs up in the atrium (4) and the superior (5) and inferior vena cava (6) causing dilatation, with a back-up of blood, increased pressure in the veins

in the upper and lower parts of the blood and in the liver.

(d) Congestive failure of left heart. In contrast to normal circulation (small drawing), ineffective discharge of the left ventricle (2) causes back pressure in the left atrium (1), enlargement of pulmonary veins (7) and increased pressure in lung vessels. Dotted lines show normal size of pulmonary veins

Preventive therapy after a heart attack can include cardiac surgery, regular administration of anticoagulants to prevent further arrhythmias and of drugs to control heart rhythm, and physical exercise within safe limits to train the heart.

Some major anatomical anomalies of the heart are shown in Figure 12.1.

Pulmonary embolism/deep vein thrombosis

The heart pumps oxygen-rich blood through the arteries to the rest of the body. Veins carry the blood back to the lungs for re-oxygenation. Fighting gravity to push blood up from the legs is difficult and can be complicated by illness, injury or prolonged inactivity. Deep vein thrombosis occurs when a dangerous blood clot forms deep in the leg muscles. The clot can float to the lungs, causing sudden death. Almost 2 million Americans suffer from deep vein thrombosis each year.

Such clots have made headlines when seemingly healthy people collapse after long airplane flights overseas. Most clots actually occur when people are hospitalized for surgery, trauma or some other reason.

A clot moving to the lungs causes pulmonary embolism. Some 80 000 patients suffering from pulmonary embolism die as a result. The following are risk factors:

(1) Hospitalization for a serious illness or surgery;

(2) Other immobility, such as paralysis or longdistance travel by plane, train or car;

(3) Chronic diseases such as high blood pressure, heart disease or cancer;

(4) An inherited tendency for sticky clot-prone blood;

(5) Excess estrogen during pregnancy, from birth control pills or hormone therapy;

(6) Aged over 40 years;

(7) Smoking;

(8) Obesity.

The Centers for Disease Control and Prevention and the American Public Health Association are coordinating extensive investigations in an attempt to prevent these clots and to screen all hospital patients.

SEMEN INFECTIONS

Herpes simplex virus infection

Seventy-five per cent of male infertility is idiopathic, whereas < 5% is due to endocrine disorders, spermatic duct obstruction, antisperm antibodies, toxins, drugs, cryptorchidism, infection, sexual dysfunction and ejaculatory failure. Herpes simplex virus (HSV) DNA has been detected by polymerase chain reaction (PCR) in the sperm of men with genital HSV infection and is associated with infertility. HSV DNA is also localized within the sperm. The virus seems to play a significant role in male infertility, and its early detection by the nested PCR enables successful antiviral therapy to be administered, thus increasing the possibility of restoration of fertility and long-term protection of sperm quality (Kapranos et al., 2003). The detection of herpes viruses within semen facilitates better control of the transmission.

Ralstonia picketti infection of semen

Ralstonia picketti, a rare infection of semen, is usually transmitted through topical saline solutions resulting in infection within the respiratory and gastrointestinal tract. Cytolysosomes are autosomes, or secondary lysosomes, which are specialized for the removal of cellular debris and organelles. These structures, found in various cell types, are activated in response to system stress such as bacterial infection, and seem to be derived from neutrophils and are produced in response to reproductive tract infection with R. picketti (Carrell et al., 2003). It is not known whether this infection is related to sperm phagocytes in the epididymis.

Viral infection of semen

Viral infection of semen occurs with HIV, murine retroviruses, cytomegalovirus (CMV) C and hepatitis B. In HIV infection, and to a lesser extent in CMV and hepatitis B, infected semen appears to be important in disease transmission. Infected semen has also been implicated in the horizontal transmission of murine retroviruses. The transmission of viral, as well as non-viral, agents via this route in man can be almost completely eliminated through the use of condoms.

Sperm washing

Elegant techniques have been developed to eliminate seminal plasma, viral particles, non-spermatic cells and non-motile sperm from semen and to select sperm with the best motility.

In hepatitis C virus (HCV) and HIV seropositive males sperm washing involves the following steps:

(1) Removal of seminal plasma:

(a) dilution of sperm in fresh media;

(b) centrifugation at 400 g for 10 min;

(c) resuspension in sperm media.

(2) First purification of non-spermatic cells and abnormal non-motile sperm:

(a) centrifugation at 300 g for 20 min;

(b) first wash with PureSperm 45%;

(c) resuspension in 2 ml of media.

(3) Selection of sperm with best motility:

(a) centrifugation at 200 g for 10 min;

(b) collection of 0.35 ml of deposit;

(c) incubation at 37°C in 5% CO2;

(d) resuspension in 0.5 ml.

After washing sperm are stored in cryotubes at -80°C (Garrido, 2004).

If washed samples are to be used for ART, viral presence should be tested after washing. The introduction of diagnostic PCR improved detection techniques and the safety of ART. Samples that are HIV negative after washing could still be HCV positive. Garrido et al. (2004) found five out of 41 samples (fraction of motile sperm after washing) were positive for HIV (12%) and five out of 21 were positive for HCV (24%) after washing. The presence of HIV and HCV was lower than 200 IU/ml and 600 IU/ml for HIV and HCV, respectively. Molecular tests are necessary to confirm sperm washing success. Motile sperm can be selected from hemophilic HIV-1 positive patients by discontinuous Percoll gradient centrifugation followed by ‘swim-up’. Semen washing before use may reduce the risk of HIV transmission from an infected man to an uninfected woman. However, an evaluation of the viral presence after washing is required (Garrido, 2004).

VIRAL INFECTIONS

There are several viral infections of the urogenital tract including papilloma viruses (genital types), herpes viruses (herpes simplex 2) and retroviruses (HTLV-III). Sexual intercourse may induce tears or abrasions in the vaginal epithelium or trauma to the urethra allowing viral entry via the genitourinary route. Sexually transmitted viruses in man include HIV, herpes simplex and human papilloma viruses 11, 16 and 18 (responsible for genital warts or condyloma acuminata). Acute hemorrhagic cystitis in young boys is associated with adenovirus 11 and 21. Other viruses, including polyoma viruses, can produce viruria; however, this is generally not associated with symptomatic disease. The biophysical characteristics of cervical mucus, the pH of vaginal secretions and the chemical composition of urine play a role in host defense against infection.

Human T cell leukemia virus

Adult T cell leukemia (ATL) is caused by a retrovirus, human T cell leukemia virus (HTLV), associated with various diseases including neurological disorders ‘tropical spastic paraparesis’ (TSP) or HTLV-1-associated myelopathy (HAM).

The transmission of HTLV occurs through one of three different modes:

(1) Male to female transmission during sexual intercourse via HTLV-1-infected cells in semen;

(2) Transplacental passage of infected maternal lymphocytes or through infected lymphocytes in breast milk;

(3) Blood products; however, unlike HIV, only blood products that involve passage of whole cells from donor to recipient can transmit the virus. The virus is transmitted among intravenous drug abusers, presumably through passage of infected blood lymphocytes in shared needles.

Thus, the overall mode of HTLV-1 transmission is similar to that of HIV, with the exception that the virus is apparently not readily transmitted by cell-free body fluids.

Gender differences in viral infection rate

The rates of rhinovirus infection for young adult females are higher than those for males of similar age. A greater exposure to young children is thought to account for this difference. Rhinovirus illness rates are also highest for small children and decrease with increasing age. Estimates of rates for families in Seattle, USA, were almost 0.8 per person year for young children and 0.54 for mothers. The illness rates for mothers are greater than those for young adult males. Compensation for this higher illness rate among young adult females in early adult years appears to ensue in later years when illness rates are higher among males. Respiratory syncytial virus (RSV), responsible for serious lower respiratory tract disease, occurs 30% more often in males than in females. In US urban centers the various forms of lower respiratory disease associated with RSV infection are more frequent in white than in black infants.

Viral infections associated with bird population

In 1999 and 2002, several people in the US died from West Nile virus, which is indigenous to the Middle East. Feathered birds, which make long-distance journeys at specific times each year, spread West Nile virus along their migration routes. Mosquitoes, which may bite infected birds, are the only creature that transmits the virus. Caged birds catch the virus from each other; when one bird is infected, all the cage mates die from the virus. Some species succumb after drinking water containing the virus or feeding on a bird that had West Nile virus.

The disease has been confirmed in more than 110 North American species ranging from bald eagles to ruby-throated hummingbirds, Carolina wrens to Canada geese and mockingbirds to purple martins. The virus may have a very large impact on bird populations since thousands of birds have become seropositive, estimated to be more than 15 000 in October 2002. Currently, virologists are studying whether eagles, hawks and owls can transmit the virus to each other. The strain of virus circulating in the USA is also found in Israel, where West Nile was first reported to be killing birds. The USA is being swept with a bird-virulent strain of West Nile virus, in which birds are killed before the virus is picked up in mosquitoes and people. Birds are very sensitive and several thousands of crows have died in the eastern part of the USA; 30-50% of species such as robins and catbirds have antibodies to the virus, indicating that they have had West Nile but survived. Birds in captivity with the disease die within 6 days.

After the West Nile outbreak in New York, one- third of the healthy birds tested had antibodies, showing that they had contracted the virus and recovered. Birds shed a large amount of virus in feces and from their mouths in the case of crows. In the laboratory, house finches and common grackles contracted West Nile fever after drinking water containing the virus. Great horned owls and house sparrows developed it after feeding on infected animals. Oral transmission from bird to bird is quite common. Most birds that die from the virus will not be found because other wildlife eats the carcasses or they decompose. Some 90% of bird carcasses are scavenged within 24 hours.

Of all wildlife, probably no species travels more or farther than birds. Some nest in the Arctic and winter in the tropics. In the fall many eastern birds take a coastal route along South Carolina. Birds from West Nile hotspots, like South Carolina, will pass through or settle there for the winter. Birds that have died of West Nile in North American zoos tend to be species from Central and South America, where loss of habitat puts pressure on many birds. Birds infected in the USA could carry the virus to the tropics. Mosquitoes could feed on the birds then on people from countries where West Nile has not been reported. West Nile virus was not predicted to spread as quickly as it has done. The virus spread from New York to Montana in 3 years. By October 2002 there were 954 confirmed human cases nationwide, and 43 confirmed deaths.

Table 12.1 HIV/AIDS statistics in India (United Nations, 2001)

Total population

1027 million (2001)

Cumulative AIDS cases

25 497 (males)

8297 (females)

Adults living with HIV/AIDS (15-49 years) (1999)

3 500000 (0.7%)

AIDS deaths

310000 (1999)

AIDS orphans

558 000 (1999)

Life expectancy at birth with HIV

64 years (2000-2005)

Life expectancy at birth without HIV

65 years (2000-2005)

Condom usage

Transmission/risk categories

3%

Sexual

28 630 cases (84.72%)

Injectable drug users

1092 (3.23%)

Blood/blood products

1070 (3.17%)

Perinatal transmission

792 (2.34%)

Unavailable history

2210 (6.54%)

HIV/AIDS INFECTIONS

Around 42 million people are currently living with HIV; this amounts to 0.7% of the world population. Of those infected almost 70% live in sub-Saharan Africa, with more than 50% being women and young people aged 15-24 years. In 2001, 1.07 million adults and children were newly infected with HIV in Asia and the Pacific, bringing the total number of people living with HIV/AIDS (PLWHA) in the region to 7.1 million. At the end of 2001, the national adult HIV prevalence rate in India was under 1%, with an estimated 3.97 million PLWHA (Table 12.1). To aggravate the problem, HIV fuels the TB epidemic, which is a particular threat in Asia and the Pacific, where there is more than 60% of the world’s TB burden.

Sperm surface in HIV patients

In the initial stages of HIV infection, the patient may ejaculate motile (and fertile) sperm. Some patients undergoing highly active antiretroviral therapy (HAART) produce active sperm with normal motility. Antiviral regimens affect lymphocytes, sperm chromosomes and morphology, and semen quality in HIV patients. HIV particles are present on the sperm membrane as determined by labeling with monoclonal/polyclonal anti-HIV antibodies. Atomic force microscopy (AFM) is a powerful technique to evaluate any alterations in the sperm of HIV patients, and the effects of HAART including minute details, e.g. viral particles on sperm membrane. AFM, unlike electron microscopy, permits virions to be imaged in their nearly natural environment and detects any possible penetration into the membrane or any budding (Joshi et al, 2000, 2001a, 2001b). An AFM unit attached to a conventional Olympus microscope (BX 60) is employed for the investigation. The system ‘SIS ultra objective’ is obtained from Surface Imaging Systems GmbH (Germany).

In 2003 half of world’s HIV cases were women

For the first time in the 20-year history of the AIDS epidemic, as many women as men are infected with HIV. The virus is spreading most rapidly in eastern Europe, where nearly every country is experiencing a major outbreak. It has also marched swiftly across Central Asia and into China, where it was almost non-existent a few years ago. However, there are a number of countries where there is strong empirical evidence that rates of infection are declining, and in each case they are declining among young people. In South Africa HIV infections among pregnant teenage girls fell 25% between 1998 and 2001. In Uganda, the number of new HIV infections has been dropping every year for the past 10 years. This positive trend is the first sign that prevention and education programs are making an impact.

Overall, there is an increase in the sheer number of people being infected; however, there is also an increase in the number of countries now facing epidemics. For example, 10 years ago HIV was confined to small areas of eastern Europe. Today, every country in the region has an HIV problem. No society is immune; although HIV was quite well established in many Asian countries very early on, a very stable low rate of infection persisted in a number of countries. In Indonesia, after many years of silence, an epidemic is growing. As Schwartlander said, ‘Of course HIV was there, but it did not really lead to major epidemics. It was just over the past two years that massive spread of HIV has begun, initially in injecting drug users’. In China, where HIV was ‘virtually non-existent’ a few years ago, there are now 1 million people with HIV, and the number could well rise to 10 million by the end of the decade; again, drug use is a major factor.

Sub-Saharan Africa is still by far the worst-affected region. The situation there also reflects the spread of HIV among women, with about twice as many young women as men being infected. In 2001, 6-11% of women aged 15-24 years had HIV compared with 3-6% of men in the same age group. It is particularly difficult for women in this region to take precautions against HIV because of their subordinate position in society. Rape is common in some countries. The phenomenon of intergenerational sex is also driving much of the epidemic in southern Africa, where between one-quarter and one-third of older men are HIV positive. For example, in Zimbabwe many adolescent girls have sex with men in return for clothes and money for school fees. This shift towards more women being infected will ultimately exacerbate the spread of HIV, because the virus can be spread not only through sex, but also through nursing and childbirth.

Anti-HIV treatment (to prevent virus invading blood cells)

The role of dendritic cells in the initial stages of infection is illustrated in Figure 12.2. Cytokine networks regulate HIV replication (Figure 12.3).

Some 850 000-950 000 people in the USA are infected with HIV and there are about 40 000 new infections each year. Today’s typical HIV therapy cocktail costs about $15 000 a year.

Fuzeon® (enfuviritide) helps to reverse one of the three steps that HIV takes to penetrate immune cells. Fuzeon is difficult to manufacture. Furthermore, it must be taken by injection twice a day, rotating between the abdomen, thigh and upper arm. Other current anti-HIV drugs come in pill form. Fuzeon works for people who have become resistant to other HIV treatments, and as many as 100 000 patients in the USA could benefit. The drug is expected to cost about $20 000 per year. The FDA approved the drug on an accelerated basis, meaning that long-term data on the drug’s effectiveness are not yet available. Fuzeon, a fusion inhibitor, fights HIV in a completely new way. It works by preventing the HIV from invading the white blood cells, which are its primary targets. In contrast, current AIDS drugs all work after the virus has already invaded the cells, by blocking either of two substances that HIV uses to reproduce and spread. The accelerated approval of this new drug should provide new hope for those suffering from advanced HIV infection.

Figure 12.3 Cytokine networks that regulate HIV replication. Cytokines that enhance viral replication (+), inhibit viral replication (-) and enhance or inhibit viral replication depending upon the conditions (+/-) are shown. IL, interleukin; MIP, macrophage inflammatory protein; DFS, stromal cell-derived factor; MDC, macrophage-derived chemokine;TNF, tumor necrosis factor;TGF, transforming growth factor; IFN, interferon; NK, natural killer. From Cohen and Fauci, 2001, with permission

Superinfection

Since AIDS was first recognized about 20 years ago, 26 million people have died - 95% of them in the developing world. About 45 million people worldwide are infected with HIV. About 30 million live in poor countries; more than 6 million of these are in immediate need of HIV drugs, and economists estimate that it would cost $10 billion a year to bring treatment to half of these people by 2005. Superinfection with more than one strain of HIV may be more common than previously thought, and may complicate efforts to make a vaccine. Most cases of ‘superinfections’ are transient and are not detected. Genetic tests on a superinfected woman showed that the two viruses had mixed and produced a hybrid that replaced the original virus.

Sexual transmission of HIV and hepatitis C virus

HIV is detected in both RNA and DNA in different fractions of semen, although their presence in the motile sperm is controversial. Viral DNA in the testicular tissue of men with HIV-1 infection is localized to the spermatozoid, spermatocytes and, rarely, the spermatids. Low numbers of macrophages are infected mainly in the prostate; however, they are not detected in the prostate, epididymis, seminal vesicles or penis. HIV-1 selective infectivity explains venereal spread of the virus. HIV-1 destroys carrier cells causing dramatic impairment of spermatogenesis and atrophy of the testes in men with AIDS. In semen cell subpopulations isolated by immunomagnetic bead techniques, T cells are most commonly infected with HIV (75% of samples), followed by macrophages (38% of samples); however, HIV is never detected in motile sperm or immature germ cells, supporting that both T cells and macrophages, but not germ cells, are the cellular vectors of HIV transmission in semen.

Semen is a relevant vector of HIV transmission to the female partner and progeny. Hepatitis C virus (HCV) is transmissible but to a several times lesser extent than HIV. Serodiscordant couples where the man is infected can bear children with an insignificant risk of infection transmission if adequate methodologies are employed to both sperm cleaning of the virus and the subsequent confirmation of its absence. Sperm washing with density gradients followed by swim-up is the method of choice, with nested PCR to detect any remaining viral sequence (Garrido et al., 2004).

The prevalence of HCV infection in high-risk groups is much lower than that of other sexually transmitted infections, and the risk of apparently sexually transmitted HCV infection does not always correlate with the intensity and duration of sexual exposure. Persons living in long-standing monogamous relationships are at a lower risk of acquiring HCV compared with those having several partners or those constantly exposed to sexually transmitted diseases (STD), possibly due to sexual risk-taking behaviors, although differences in rates of exposure to non-sexual sources are not ruled out. In heterosexual relationships, hepatitis B is readily transmitted sexually and hepatitis C and D are not as easily transmissible via sexual intercourse. The prevalence of HCV infection increases in groups with a high risk of exposure to sexually transmitted viral infections. In drug addicts, HCV RNA is found in almost all serum samples tested. However, Garrido et al. reported that only in one semen sample was there no correlation between CD4 counts, stage of HIV infection, liver damage and HCV RNA in serum or semen. Anti- HCV positive drug users infected with HIV tested for HCV, hepatitis G virus and GB virus-C RNAs by PCR assay hybridization and sequence analysis were HCV viremic; however, HCV RNA was not identified in the semen, but PCR inhibitors were found.

Some European countries have prohibited assisted reproduction protocols in serodiscordant couples with infected men, but have allowed centers to perform semen washing and artificial reproductive techniques (ART).

Although HCV is present at low concentrations in the semen of a few HCV positive patients, Garrido et al. (2004) found no purified sperm fraction used in ART was HCV positive and no seroconversion was observed in women and newborns, thereby suggesting a very low risk of virus transmission. HCV presence in semen implies a possible risk of nosocomial contamination; therefore, safety regulations must be strictly applied by laboratories.

Detection of HCV after extensive sperm washing with a modified RNA extraction protocol demonstrated that even semen treatment in the laboratory is insufficient to eliminate viral presence, and that molecular confirmation is needed before employing semen samples from HCV seropositive patients in ART; there is no correlation between serological status in terms of viral blood levels and positive results after washing.

Semen and blood can be compartmentalized as having different characteristics. Thus, a good post-wash detection technique, including positive and negative controls of each step (RNA extraction, reverse transcription (RT) and PCR), must be included. Detection is performed with RT-PCR dependent methods, which have good sensitivity; however, the relevant presence of polymerase inhibitors interferes with the results, and yields a high number of false negatives. Given the low transmissibility, linked with the sperm washing treatments for HIV, this is not sufficient to ensure that HCV is not present in the semen of HCV positive males, and even in sperm.

Recurrence of HCV after liver transplantation is associated with high blood levels of HCV RNA. Higher blood levels of HCV may promote bodily fluid expression of the virus. Detection of HCV RNA presence in several bodily fluids including seminal plasma is performed by nested PCR; the amplified product is confirmed by Southern blot hybridization and restriction end nuclease digestion. Potential infectivity of bodily fluids in patients testing negative for serum HCV RNA has been discounted. The presence of HCV RNA in saliva and seminal fluid of patients positive for serum HCV RNA has also been discounted. However, the presence of HCV RNA in saliva and seminal fluid of patients positive for serum HCV RNA suggests sexual and household contact as likely modes of no parental transmission of type C hepatitis.

Motility, concentration and morphology of sperm from HIV and HCV patients are comparable, except for the most severe cases, when AIDS is developed. Semen from seropositive men has fewer motile sperm, more round cells and is more viscous than that of controls; there is correlation between the proportion of motile sperm and the percentage of CD4+ lymphocytes in peripheral blood, and no deleterious effect is caused by AZT (zidovudine) administration.

HIV-1 seropositive men at various stages of the disease, without zidovudine therapy and in early- stage disease maintained normal semen parameters, while untreated men with advanced disease had significant reductions in sperm concentration, total sperm count and normal sperm forms.

Men receiving zidovudine, regardless of disease stage, had normal semen parameters similar to those of untreated patients with early-stage disease. Men with AIDS presented pyospermia and abnormal sperm. Fertile men had a greater volume of sperm, higher sperm concentration, per cent motility, per cent rapid and linear motility, and total strictly normal sperm than HIV seropositive men. HIV affects fertility only at the most advanced stages of the disease, and the fertility of asymptomatic or mild symptomatic males is not initially affected by the disease.

INFECTIOUS DISEASES: FROM DIPHTHERIA AND SCARLET FEVER TO AIDS AND SARS

In 1968 many scientists considered infectious diseases to be yesterday’s problem. With the development of antibiotics from the 1940s onwards, diseases such as diphtheria and scarlet fever went from being life-threatening afflictions to treatable infections. Jonas Salk’s vaccine took the fear out of polio, and the tuberculosis sanatoriums were being emptied. Euphoria governed medical science. Researchers liked to think that they were on the crest of a wave sweeping away the threat from parasites, viruses and bacteria. In the 1980s infectious diseases reappeared; however, drugs were not effective as they had been. With increased and sometimes incorrect use, resistance to antibiotics has grown, breathing new life into some old pests. In the late 1980s, patients presented at New York hospitals with new strains of tuberculosis that did not respond to drugs. In the 1990s these swept through Russia. Furthermore, there have been new and frightening diseases. In Zaire in the mid-1970s, a man walked in from the jungle with a severe fever that made him vomit black blood. He died shortly afterwards. Within days many of the nuns who took him in had also fallen ill with Ebola, one of the most easily transmissible viruses. Viruses continued to reappear and to cross from one species to another, including humans, and often the new host has little immunity. Every year brings a different strain of influenza, many of the strains originating in China.

Infectious disease outbreaks coincide with chaotic economic development. Teeming new cities with poor sanitation that lack strong health systems, rapid migration of populations from country to city, changing sexual habits and the breakdown in traditional family structures all provide fertile ground for the spread of new diseases. Foreign travel exacerbates the problem, quickly transferring a virus from a small African village to a large, western city. The microbes that caused the 1918 Spanish flu were transported around the world by boat; today, they would catch a plane. Then there is HIV/AIDS. Since HIV was first identified, more than 20 million people have died from AIDS. By 2010, the total number of infected people is expected to reach 105 million, most of them in poor countries. It is the biggest public health disaster since the Black Death in the 14th century.

Medical science still has its Utopian streak, these days in the form of genetics. The decoding of the human genome has raised hopes of large advances in the understanding and treatment of diseases. Some researchers talk of an era of ‘personalized medicine’, with each patient walking around with a card that shows his or her genetic make-up so that treatments can be tailored specifically. These advances will generate some useful tools for the study of infectious disease. Researchers were able, for example, to pin down the genetic make-up of the severe acute respiratory syndrome (SARS) virus within weeks of its appearance.

Common diseases and related STD in man are shown in Tables 12.2 and 12.3.

CLINICAL APPLICATIONS

Anthrax may be treated and detected by lysin

A novel agent that could help to detect an anthrax attack and serve as an antidote to the deadly disease has been developed. The agent was isolated from a virus that preys on the anthrax bacterium and replicates inside it. When the virus particles need to escape, they order the synthesis of a special enzyme, ‘lysin’, that chews through the bacterium’s cell wall. Although designed to pierce the wall from the inside, the lysin enzyme can also crumble it from outside. Doses of lysin injected into mice infected with a close relative of anthrax saved most of the animals from a certain death. Lysin can be used like an antibiotic to treat people who may have been exposed to spores in an anthrax attack. If injected quickly enough, the lysin would destroy the anthrax bacteria in the bloodstream before they had multiplied and released overwhelming amounts of toxin. Attack strains of anthrax can be made resistant to antibiotics, but not to lysin. Future research is required before the enzyme could be used as a drug.

Table 12.2 Common diseases and related sexually transmitted disease

Disease

Characteristics

Chancroid

 

Description

A sexually transmitted disease characterized by painful genital ulceration and inflammatory inguinal adenopathy. It is uncommon in the US but found worldwide. Chancroid is endemic and a cofactor for HIV transmission

Symptoms

Tender genital papule that ulcerates after 24 h

Irregular edged, painful ulcer(s)

Ulcers may be 1-5 cm in size

Ulcers may occur on the shaft of the penis, glans and meatus in men

Ulcers in women are most commonly occur in labia majora but are also seen in labia minora, perineum, thigh and cervix

Painful inguinal adenopathy with abscess (bubo) formation in 30% of patients

Atypical presentations include folliculitis and foreskin abcess

Causes

Haemophilus ducreyi (gram negative bacterium)

Risk factors

Multiple sexual partners

Uncircumcised males

Prostitutes often are carriers

Medication

Azithromycin 1 g po single dose (more expensive than other treatments) Ceftriaxone 250 mg IM single dose

Ciprofloxacin 500 mg po bid for 3 days or other quinolone

Erthromycin base 500 mg qid for 7 days

Epididymitis

Description

Inflammation of epididymis resulting in scrotal pain, swelling/induration of posterior-lying epididmis/eventual scrotal wall edema, involvement of adjacent testicle/hydrocele formation

Symptoms

Scrotal pain, sometimes extending to the groin region, may begin relatively acutely over several hours Urethral discharge or symptoms of urinary tract infection, such as frequency of urination, dysuria, cloudy urine or hematuria

Initially only posterior-lying epididymis, usually lowermost tail section, will be very tender/indurate

Elevation of testes/epididymis improves discomfort

Entire hemiscrotum becomes swollen, testis becomes indistinguishable from epididymis/scrotal wall becomes thick/indurate, reactive hydrocele may occur

Fever/chills occur with severe infection/abscess formation

Causes

Younger than age 35

usually chlamydial or Neisseria gonorrhoea

look for serous urethral discharge (clamydia) or purulent discharge (gonorrhea)

Older than age 35

coliform bacteria usually but sometimes Staphylococcus aureus or S. epidermidis often associated with distal urinary tract obstruction tuberculosis, if sterile pyuria/modularity of vas deferens sterile urine reflux after transurethral prostatectomy granulomatous reaction following bacillus

Calmette-Guerin (BCG) intravesical therapy for superficial bladder cancer

Prepubertal boys

usually coliform bacteria

evaluate for underlying congenital abnormalities, such as vesicoureteral reflux or ectopic ureter

Table 12.2 (Continued)

Disease

Characteristics

 

At any age

amiodarone, an antiarrhythmic agent, may cause a non-infectious epididymitis, that resolves with decreasing drug use

Herpes simplex Description

Viral disease with many manifestations, painful vesicles in clusters on skin, cornea or mucous membranes; may occur as encephalitis, pneumonia or disseminated infection. Course of primary disease is 2 weeks; duration of recurrence varies; viral shedding in recurrence is briefer than with primary disease. Newborns or individuals with immune compromise are at risk for major morbidity or mortality

Symptoms

Vesicles cluster and open as painful ulcerated lesions, often with erythematous base

Herpetic whitlow: localized primary, a finger with intense itching and pain, followed by vesicles that may coalesce with swelling, erythematic, and may mimic pyogenic paronychia; neuralgia and axillary adenopathy sometimes; heals over 2-3 weeks without incision

Primary herpetic gingivostomatitis/pharyngitis: first infection with HSV-I usually in early childhood; incubation from 2 to I2 days, then fever, sore throat, pharyngeal edema and erythematic; small vesicles develop on pharyngeal/oral mucosa, rapidly ulcerate/increase in number to involve soft palate, buccal mucosa, tongue, floor of mouth, lips/cheeks; tender gums may bleed; fetid breath, cervical adenopathy; fever, general toxicity, poor oral intake/drooling

Primary herpes keratoconjunctivitis: by HSV-I usually; can present as unilateral conjunctivitis with regional adenopathy, as blepharitis with vesicles on lid margin

Medication

Acyclovir

primary genital herpes: 400 mg po tid or 200 mg po x 5 doses daily for 7-I0 days

recurrent genital herpes: 800 mg bid or 200 mg po x 5 doses daily for 5 days

for chronic suppression in persons with frequent recurrences: 400 mg bid

primary herpes gingivostomatitis, recurrent herpes labialis and other HSV skin infections: 200 mg

po q4 h x 5 doses daily for I0 days

Penciclovir (Denavir®)

oroherpes recurrence: I% cream q2 h while awake for 4 days

Valacyclovir (Valtrex®)

better bioavailability orally than cycloid, is converted to cycloid; indicated for use only in immunocompetent primary genital herpes: I g po bid for 7-I0 days

recurrent genital herpes: 500 mg po bid for 3-5 days, chronic suppression I g po q/day (I0 or more

recurrences per year) or 500 mg po q/day (9 or less recurrences per year)

Condyloma acuminata

Description

Condyloma acuminata are soft, skin colored, fleshy warts that are caused by the HPV (human papilloma virus).There are at least 70 known types of HPV and types 6, II, I6, I8, 3I, 33, 35 have been associated with condyloma acuminata.The disease is highly contagious, can appear singly or in groups, small or large. They appear in the vagina, or the cervix, around the external genitalia and rectum, the urethra, anus, also conjunctival, nasal, oral and laryngeal warts and occasionally the throat.The incubation period may be from I to 60 months

Symptoms

Tumors, soft, sessile

Surface smooth to very rough

Multiple finger-like projections

Perianal condylomata acuminata usually rough and cauliflower-like

Penile lesions often smooth and popular

Penile lesions often occur in groups of three or four

Male sites - frenulum, corona, glans, prepuce, meatus, shaft, scrotum

Causes

Human papillomaviruses.These are circular double-stranded DNA molecules.There are over 70 HPV subtypes.The causes of common venereal warts are types 6 and II. Cervical dysplasia and carcinoma in situ are likely caused by types I6, I8, 3I, 33, 35

Disease

Characteristics

Diagnosis

Lichen planus

Normal sebaceous glands

Seborrheic keratosis

Molluscum contagious

Keratomas

Scabies

Crohn’s disease

Skin tags

Melanocytic nevi

Vulva intraepithelial neoplasia

Medication

Imiquimod (Aldara®) 5% cream applied overnight 3 times weekly until warts clear for up to 16 weeks Cryotherapy: liquid nitrogen is applied to warts in 5-10 s bursts. Requires 2-3 weekly sessions Podophyllin in tincture of benzoin.Apply directly to warts, leave on 104h,then wash off. Repeat treatment every 7 days until gone

Podofilox (Condylox®) for external warts. Apply to external warts every 12 h (allowing to dry) for

3 consecutive days, may repeat after 4 days

Topical cidofovir gel undergoing trials; applied once daily for 5 days every other week for maximum of 6 cycles

Scientists have a prototype of a lysin-based anthrax detector. An important feature of lysin is that it attacks only anthrax and a rare strain of a closely related bacterium. This allows the lysin to be a quick and sensitive detector for anthrax spores that might be used in an attack.

A hand-held detection device has been developed that would accept an air filtrate or environmental sample. Initially, any anthrax spores are made to germinate from their protective coat. Lysin is applied to the emerging bacteria, making their contents spill out. An antibody-based anthrax detector is already in use, but antibodies are difficult to manufacture and variable in quality. A faster and more sensitive device should be developed. The lysin-based method can detect a sample of 2500 spores in 10 min or as few as 100 spores after an hour’s reaction time. Lysins for other dangerous microbes could be added to the sensitive devices. Scientists are already experimenting on lysins from viruses that attack cholera and Yersinia pestis, the agent of plaque. This would work for many other species of bacteria, because each has its own set of viruses that produce lysins specific for their target bacteria. Lysins could thus provide a whole new class of antibiotics to which bacteria could not develop resistance. Resistance is a matter of particular concern to biological warfare experts who fear that attack microbes could be made more lethal by first making them resistant to common antibiotics. The anthrax strain used in past attacks was virulent but susceptible to the usual antibiotics. A resistant strain would probably have caused many casualties.

Table 12.4 Disorders of male reproductive organs

Syndrome

Causes

Lesions

Changes in semen

Testicular degeneration

Thermal, localized or systemic infections; nutrition (vitamin A); vascular lesions; aging; obstructive lesions of the head of epididymis; noxious agents; hormonal factors

Testicular size reduced; fibrosis; disturbances in spermatogenesis; seminiferous tubules destroyed some cases

Increase in immature/abnormal sperm with normal motility; ejaculate is thin/watery due to reduction in sperm concentration; giant cells; azoospermia or necrozoospermia

Orchitis

Brucellosis, tuberculosis

Inflammatory changes in testes leading to degeneration of seminiferous tubules

Asthenozoospermia; oligozoospermia;

teratozoospermia: giant cells; erythrocytes/ leukocytes; normal semen volume

Epididymitis

Brucellosis viral infections

Inflammation of epididymis; infiltration of lymphocytes/ neutrophils; dead sperm/giant cells

Poor semen characteristics, contaminated by inflammatory exudates

Seminal vesticulates

Brucellosis

Unilateral inflammation of seminal vesicles; glands enlarged/fibrosed

Purulent exudates in semen;

normozoospermia; asthenozoospermia



Possible adverse effects on humans of meat from antibiotic-fed livestock

Antibiotics used to feed and treat livestock may contribute to adverse after-effects in consumers eating meats and meat products from such animals. The FDA is attempting to limit the extensive use of such antibiotics. FDA regulations released in September 2002 require the maker of a proposed animal antibiotic to assess whether it could encourage the growth of disease-causing bacteria that are resistant to antibiotics used in human medicine. If the drug were too similar to an important antibiotic for people, for instance, it could be kept off the market. Currently, the drug maker has only to show that it does not leave any dangerous residue in meat. Resistant pathogens do form in treated animals and can be transmitted to humans through food. From a public health perspective, the risk must be minimized.

It has long been known that the overuse of antibiotics by doctors and their patients has reduced the ability of the drugs to cure infections. Giving animals antibiotics in their feed can also cause microbes in the livestock to become resistant to the drugs, and people can become infected with the resistant bacteria. The FDA action is part of a contentious worldwide debate over the long-term use of antibiotics in raising livestock. Public health advocates estimate that 70% of antibiotic use in USA occurs on the farm, some to treat sick animals but also to promote growth of flocks and herds. The European Union has banned some animal antibiotics, and farmers in Denmark have stopped using antibiotics to promote growth. The Animal Health Institute, which represents animal drug makers, indicates that advocates exaggerate the hazards of animal antibiotics to human medicine. Animal antibiotics are a tiny part of the problem, and many animal antibiotics are not closely related to those used for humans. Antibiotics can help farmers produce more healthy animals and cheaper meat.

Nasal-mist flu vaccine

Influenza is the cause of 36 000 deaths annually in the USA. Most of the victims are patients with other health problems, children aged under 2 years and people over 65 years. The FDA has approved a nasal-mist flu vaccine FluMistTM to replace the annual injected vaccine, for healthy people aged 5-59 years. FluMist would not be appropriate for people who most need vaccine protection, such as toddlers, the elderly and people with asthma and other chronic diseases. For children from 5 to 8 years, the approval requires two doses of FluMist 6 weeks apart. Patients aged 9-49 years only require one dose. The safety and effectiveness of FluMist has not been proven for people 50 and over. The FDA encourages people over 50 to have the injected flu vaccine.

FluMist contains each of the three live influenza virus strains expected to be active during the flu season. In the 2003-2004 season, these included two types of influenza A, which cause severe illness, and one type of influenza B, which causes a milder form of the disease. The live virus in the vaccine has been modified and weakened so that it produces immunity without causing illness. In the past there have been vaccine shortages at the beginning of some flu seasons because there are few manufacturers of the drug and the formula must be changed each year to match the changes in the circulating virus. FluMist is manufactured by MedImmune Vaccines Inc. (Gaithersburg, MD). Some 4-6 million doses were to be available by October, the start of the flu season. Each dose of FluMist costs $46, more than twice the typical cost of injected flu vaccine.

FUNGI AND BACTERIA

Aspergillus and its conidia formation

Aspergillus is a genus of fungi including some common molds which grow on foods. A few species are known to contain toxic substances and, when eaten, may cause severe intoxication. Molds of this group growing on stored cereals and producing powerful toxins have caused serious social problems. Furthermore, aspergillus fungi, when they occasionally become rampant within the human body, may cause aspergillosis, which has recently increased in occurrence.

Staphylococci

Staphylococci are a group of microbes widely distributed in nature. In human and animal bodies they are found on the skin, in the nasal and oral cavities, and in the digestive tract. They occur abundantly in suppurative foci. Staphylococcus aureus is particularly pathogenic; it is common in the human upper respiratory tract. The cocci growing in the nasal vestibulum are directly involved in infection. This group of microbes has recently attracted attention with regard to hospital-acquired infection and the occurrence of strains resistant to antibiotics. The term staphylococcus comes from its grape-like appearance under the light microscope (staphyle: a bunch of grapes).

Candida albicans

Candida, formerly called monilia, is a genus of yeast-like fungi forming smooth, white colonies on solid media (candidus: glowing shite; monilia: necklace). Among the large number of species, only Candida albicans causes the human infection moniliasis. C. albicans infests the mouth, bronchi, lungs, intestines and vagina as well as the skin and nails. Occasionally sepsis, severe general infection and meningitis may occur. C. albicans, when cultured on an appropriate solid medium, forms cream-like colonies composed of densely grown threads called hyphae.



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