Acute Rheumatic Fever

Background

Acute rheumatic fever (ARF) is an autoimmune inflammatory process that develops as a sequela of streptococcal infection. ARF has extremely variable manifestations and remains a clinical syndrome for which no specific diagnostic test exists. Persons who have experienced an episode of ARF are predisposed to recurrence following subsequent (rheumatogenic) group A streptococcal infections. The most significant complication of ARF is rheumatic heart disease, which usually occurs after repeated bouts of acute illness.

Pathophysiology

ARF is characterized by nonsuppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system. An extensive literature search has shown that, at least in developed countries, rheumatic fever follows pharyngeal infection with rheumatogenic group A streptococci.1,2,3,4 The risk of developing rheumatic fever after an episode of streptococcal pharyngitis has been estimated at 0.3-3%.1 More recent investigations of rheumatic fever occurring in the aboriginal populations of Australia suggest that streptococcal skin infections might also be associated with the development of rheumatic fever.5,6 In Oceania and Hawaii, streptococcal strains that are not typically associated with rheumatic fever have been found to cause the disease.

Molecular mimicry accounts for the tissue injury that occurs in rheumatic fever. Both the humoral and cellular host defenses of a genetically vulnerable host are involved. In this process, the patient's immune responses (both B- and T-cell mediated) are unable to distinguish between the invading microbe and certain host tissues.8 The resultant inflammation may persist well beyond the acute infection and produces the protean manifestations of rheumatic fever.

Frequency

United States

The incidence of ARF has declined markedly in the past 50 years in both the United States and Western Europe. Most Western physicians see only the late sequelae of rheumatic heart disease; the diagnosis of an acute case is usually reason enough for a ground rounds presentation. This remarkable decline of rheumatic fever likely reflects improved socioeconomic conditions, as well the decline in prevalence of the classically described rheumatogenic strains of group A streptococci.

Following two decades of almost total absence, a resurgence of ARF occurred in the 1980s among middle-class white children in Salt Lake City, Utah.9 Clusters were also reported in US Army and Navy training camps during the same period.10 These limited outbreaks were associated with mucoid rheumatogenic strains that were rarely seen in the preceding 20 years. Today, ARF remains a rarity in most of the United States, although Hawaii and American Samoa continue to see a significant number of cases, many of which are caused by streptococcal strains not usually associated with rheumatic fever in persons of Polynesian descent.

International

In developing countries, the magnitude of ARF is enormous. Recent estimates suggest that 15.6 million people worldwide have rheumatic heart disease and that 470,000 new cases of rheumatic fever (approximately 60% of whom will develop rheumatic heart disease) occur annually, with 230,000 deaths resulting from its complications. Almost all of this toll occurs in the developing world.12,13 The incidence rate of rheumatic fever is as high as 50 cases per 100,000 children in many areas. Areas of hyperendemicity (eg, indigenous populations of Australia and New Zealand) see an incidence of 300-500 cases per 100,000 children, while the rates are approximately 50-fold lower in their nonindigenous compatriots.6 Rheumatic fever in the 21st century appears to be largely a disease of crowding and poverty.

Mortality/Morbidity

Cardiac involvement is the most serious complication of rheumatic fever and causes significant morbidity and mortality. As stated above, about 60% of the approximately 470,000 patients diagnosed with ARF annually eventually develop carditis, joining the approximately 15 million worldwide with rheumatic heart disease. Those with rheumatic heart disease are at a high risk for additional cardiac damage with subsequent bouts of ARF and require secondary prophylaxis. Morbidity due to congestive heart failure (CHF), strokes, and endocarditis is common among individuals with rheumatic heart disease, and about 1.5% of persons with rheumatic carditis die of the disease annually.

Race

ARF is predominantly a disease of developing countries and is concentrated in areas of deprivation and crowding. It is rampant in the Middle East, in sub-Saharan Africa, in the Indian subcontinent, in certain areas of South America, in Polynesia, and among the indigenous populations of Australia and New Zealand. Although a genetic predisposition to ARF clearly exists,1 the disease does not seem to have a major racial predisposition, as it was once common in the United States and Europe and seems to decline in any locale where living conditions improve.

Sex

Rheumatic fever does not have a clear-cut sexual predilection, although certain clinical manifestations, such as mitral stenosis and Sydenham chorea, are more common in females who have gone through puberty.

Age

ARF is most common among children aged 5-15 years. It is relatively rare in infants and uncommon in preschool-aged children. ARF occurs in young adults, but the incidence of first episodes of ARF falls steadily after adolescence and is rare after age 35 years.6 The lower rate of ARF in adults may represent a decreased risk of streptococcal pharyngitis in this cohort. Recurrent episodes, with their predisposition to cause or exacerbate valvular damage, occur until middle age.

Clinical

History

Rheumatic fever manifests as various signs and symptoms that may occur alone or in various combinations.

Sore throat: Although estimates vary, only 35%-60% of patients with rheumatic fever recall having any upper respiratory symptoms in the preceding several weeks. Many symptomatic individuals do not seek medical attention, go undiagnosed, or do not take the prescribed antibiotic for acute rheumatic fever (ARF) prevention.

Polyarthritis: Overall, arthritis occurs in approximately 75% of first attacks of ARF. The likelihood increases with the age of the patient, and arthritis is a major manifestation of ARF in 92% of adults.

The arthritis of ARF is usually symmetrical and involves large joints, such as the knees, ankles, elbows, and wrists. Tenosynovitis is common in adults and may be severe enough to suggest a diagnosis of disseminated gonococcal disease.
The evolution of arthritis in individual joints tends to overlap; therefore, multiple joints may be inflamed simultaneously, causing more of an additive than a migratory pattern.10
In most instances, the entire bout of polyarthritis subsides within 4 weeks without any permanent damage. If not, a different diagnosis should be entertained.
Carditis: Of first attacks of ARF, carditis occurs in 30%-60% of cases. It is more common in younger children but does occur in adults.
Severe inflammation can cause congestive heart failure (CHF).
Patients with carditis may present with shortness of breath, dyspnea upon exertion, cough, paroxysmal nocturnal dyspnea, chest pain, and/or orthopnea. Carditis may also be asymptomatic and may be diagnosed solely by auscultation or, perhaps, echocardiography (controversial; see Physical).

Sydenham chorea: This occurs in up to 25% of ARF cases in children but is very rare in adults. It is more common in girls. Sydenham chorea in ARF is likely due to molecular mimicry, with autoantibodies reacting with brain ganglioside.14
Sydenham chorea may occur with other symptoms or as an isolated finding. It typically presents 1-6 months after the precipitating streptococcal infection and usually has both neurologic and psychological features.

In the isolated form, laboratory evidence of a preceding streptococcal infection may be lacking.
Like the polyarthritis, Sydenham chorea usually resolves without permanent damage but occasionally lasts 2-3 years and be a major problem for the patient and her family.6
Erythema marginatum: In first attacks of ARF in children, erythema marginatum occurs in approximately 10%. Like chorea, it is very rare in adults.

Patients or parents may report a nonpruritic, painless, serpiginous, erythematous eruption on the trunk. It is usually noted only in fair–skinned patients.
The lesions may persist intermittently for weeks to months.
Subcutaneous nodules are rarely noticed by the patient (see Physical).

Other symptoms may include fever, abdominal pain, arthralgia, malaise, and epistaxis.

Physical

Polyarthritis
Joint involvement in ARF may range from arthralgia to frank polyarthritis characterized by swelling, redness, warmth, and joint tenderness.
The joints frequently involved include the knees, ankles, elbows, and wrists. The small joints of the hands and the spine are rarely involved. Hand involvement tends to occur in poststreptococcal arthritis, a related syndrome without a risk of carditis.
Inflammation begins to subside within a few days to a week and disappears within 2-4 weeks.
The arthritis is classically described as migratory, but, in many cases, new joints are affected before the previously involved joints improve, leaving the appearance of an additive arthritis.10
In most cases, the process does not leave any residual damage. On very rare occasions, periarticular fibrosis occurs after rheumatic arthritis, the so-called Jaccoud joint.

Carditis

Carditis is the only manifestation of ARF with significant potential to cause long-term disability and/or death. It is usually a pancarditis involving the pericardium, myocardium, and endocardium.

The signs of carditis include the development of new murmurs, cardiac enlargement, CHF, pericardial friction rub, and/or pericardial effusion.
Characteristic murmurs of acute carditis include the high-pitched, blowing, holosystolic, apical murmur of mitral regurgitation; the low-pitched, apical, mid-diastolic, flow murmur (Carey-Coombs murmur); and a high-pitched, decrescendo, diastolic murmur of aortic regurgitation heard at the aortic area. Murmurs of mitral and aortic stenosis are observed in chronic valvular heart disease. Isolated aortic disease is distinctly unusual.

The features of CHF include tachycardia, a third heart sound, rales, and edema.
Pericarditis presents as a pericardial rub or effusion.
The use of echocardiography to detect subclinical carditis reveals subclinical rheumatic cardiac disease (both acute and chronic) not appreciated by the standard examination.15,16,17 Whether these subclinical carditis findings carry the same clinical importance as those detected by standard auscultation is unclear; echocardiography findings alone do not currently count toward fulfillment of the Jones criteria, and it is unclear whether they necessitate secondary antibiotic prophylaxis (see Diagnosis). This issue is the most contentious in the rheumatic fever literature18,19 and has major implications for diagnosis and screening. For now, clinicians must rely on their best judgment when evaluating possible carditis detected only with echocardiography.

Subcutaneous nodules

Subcutaneous nodules are uncommon and are usually associated with severe carditis. They tend to occur several weeks after illness onset, are usually painless, and usually go unnoticed by the patient.
They are found primarily over the bony surfaces or prominences and in tendon sheaths. The common sites include the elbows, knees, wrists, ankles, over the Achilles tendon, the back of the scalp, and spinous process of the vertebrae.2
They usually persist for 1-2 weeks. The main differential diagnosis includes primarily the nodules of rheumatoid arthritis.

Erythema marginatum

The individual lesions of erythema marginatum are evanescent, moving over the skin in serpiginous patterns. Likened to smoke rings, they have a tendency to advance at the margins while clearing in the center.
The lesions may be macular and can develop and disappear in minutes, appearing to change shape while being examined.
They are found on the trunk and proximal aspects of the extremities and often go unnoticed by patients and parents, as they are usually covered by clothing.

Sydenham chorea

This is a neurological disorder characterized by emotional lability, personality change, muscular weakness, and uncoordinated, involuntary, purposeless movements.
The classic weakness is characterized by the inability to sustain a tetanic contraction. Patients are unable to maintain a clenched fist when attempting to grip the examiner's hand. Other findings include dysarthric speech, gait problems, and poor fine-motor skills.14
The motor symptoms usually disappear during sleep and may be partially suppressed by sedation.
They can involve the face, hands, and feet.
The average duration of an untreated ARF attack is 3 months. Chronic rheumatic fever, generally defined as disease persisting for longer than 6 months, occurs in less than 5% of cases.

Causes

Group A beta-hemolytic streptococcal infection may lead to rheumatic fever. The overall attack rate after streptococcal pharyngitis 0.3-3%, but certain genetically predisposed individuals, comprising perhaps 3%-6% of the population, account for those who develop rheumatic fever.6
Studies in developed countries have established that rheumatic fever followed only pharyngeal infections and that not all serotypes of group A streptococci cause rheumatic fever. For example, some strains (eg, M types 4, 2, 12) in a population susceptible to rheumatic disease do not result in recurrences of rheumatic fever. The classic rheumatogenic serotypes are thought to include 3, 5, 6, 14, 18, 19, and 24.2 More recent data, largely from studies of the indigenous peoples of Australia, suggest that skin infections (pyoderma) can predispose to ARF and that various other serotypes may be involved.

Two basic theories have been postulated to explain the development of ARF and its sequelae following group A streptococcal infection: (1) a toxic effect produced by an extracellular toxin of group A streptococci on target organs such as the myocardium, valves, synovium, and brain and (2) an abnormal immune response to streptococcal components. Increasing and compelling evidence now strongly favors the autoimmune explanation. It seems clear that an exaggerated immune response in a susceptible individual leads to rheumatic fever. This probably occurs through molecular mimicry, in which the immune response fails to differentiate between epitopes of the streptococcal pathogen and certain host tissues.

Chronic Kidney Disease

What is chronic kidney disease (CKD)?

Healthy kidneys remove waste from your blood. The waste then leaves your body in your urine. The kidneys also help control blood pressure and make red blood cells.

When the kidneys are damaged, they cannot remove waste from the blood as well as they should. This is called chronic kidney disease. Almost 20 million people in the United States have this disease.

The most common causes of CKD are high blood pressure, diabetes and heart disease. CKD can lead to kidney failure, but early treatment can slow or prevent this. Chronic kidney disease can also be caused by infections or urinary blockages.

Am I at risk for CKD?

You may be at risk if someone in your family has CKD or if you have diabetes or if you have high blood pressure. Talk to your doctor about your risk factors. It is important to diagnose CKD early.

What are the symptoms of CKD?

Most people don't have any symptoms early in the disease. Once the disease progresses, the symptoms can include the following:
Feeling tired
Feeling weak
Loss of appetite
Not sleeping
Not thinking clearly
Swelling of the feet and ankles

How can my doctor tell if I have CKD?

Your doctor will ask you about risk factors for kidney disease, such as diabetes and high blood pressure. Your doctor also will test your blood and urine for signs of CKD.

I have CKD, what can I do to prevent or slow down problems?

Your doctor will talk to you about treating the problems that damaged the kidneys.

If you have high blood pressure, it is important to lower your blood pressure to 130/80 mm Hg or lower. Medicines called ACE inhibitors and angiotensin-II receptor blockers can be helpful. These medicines lower blood pressure and may help keep your kidney disease from getting worse. Exercise and a healthy diet can also help to lower your blood pressure.

If you have diabetes, your doctor will tell you what to do to keep your blood sugar level normal. You may need to change your diet or take medicine.

If you smoke, you must quit. Smoking worsens kidney disease and interferes with medicines used to treat high blood pressure.

Your doctor may also talk to you about your diet. You may need to watch how much protein you eat. Too much protein can make the kidneys work too hard.

You will need to have regular checkups so your doctor can check how your kidneys are working and treat problems caused by CKD.

How else is CKD treated?

You may need to lower your triglyceride (say: try-gliss-er-eyed) and cholesterol levels. Triglycerides are a type of fat. Triglyceride levels often are higher in people who have kidney disease. Your doctor may have you take medicine to lower your triglyceride and cholesterol levels.

CKD sometimes causes anemia. Anemia occurs when your blood doesn't have enough hemoglobin ( a protein that carries oxygen from the lungs to the rest of the body). Symptoms of anemia include feeling tired and weak. If you have anemia, your doctor may have you take medicine.

CKD can also change the way your body uses minerals like calcium and phosphorus. As a result, your bones can become weak. Your doctor may have you avoid certain foods or take medicine.

If you have chronic kidney disease, you may lose your appetite. A nutritionist can help you plan a diet that will keep you strong.

What happens if CKD gets worse?

Even with the right treatments, CKD can get worse over time. Your kidneys could stop working. This is called kidney failure. If this happens, waste builds up in your body. This can cause vomiting, weakness, confusion and coma.

If you have kidney failure, your doctor will send you for dialysis (say: die-al-uh-sis). In dialysis, a machine is used to take waste out of the blood. One kind of dialysis has to be done in a clinic. For another kind of dialysis, the machine is so small it can be strapped to your body while you go about your daily activities.

HIV

Human immunodeficiency virus (HIV) disease was first described in 1981 among 2 groups—one in San Francisco and the other in New York City. Numerous young homosexual men presented with opportunistic infections that, at the time, were typically associated with severe immune deficiency due to Pneumocystis pneumonia (PCP) or aggressive Kaposi sarcoma.1 The HIV virus itself was not identified for another 2 years2 ; during that time, various other causes were considered, including lifestyle factors, chronic drug abuse, and other infectious agents.3

The HIV epidemic spread rapidly and silently in the absence of testing. However, clear clinical implications arose before society became aware of the disease; for example, prior to the recognition of HIV, only one case of Pneumocystis pneumonia not clearly associated with immune suppression was diagnosed in the Unites States between January 1976 and June 1980. In 1981 alone, 42 similar diagnoses were made, and, by December 1994, 127,626 cases of Pneumocystis pneumonia with HIV infection as the only identified cause of immune suppression had been reported to the Centers for Disease Control and Prevention (CDC). Also, Kaposi sarcoma is up to 30,000 times more likely to develop in persons with HIV infection than in immunocompetent persons.

HIV is a blood-borne, sexually transmissible virus. The virus is typically transmitted via sexual intercourse, shared intravenous drug paraphernalia, and mother-to-child transmission (MTCT), which can occur during the birth process or during breastfeeding. The most common route of infection varies from country to country and even among cities, reflecting the population in whom HIV was introduced initially and local practices. Co-infection with other viruses that share similar routes of transmission, such as hepatitis B, hepatitis C, and human herpes virus 8 (HHV8; also known as Kaposi sarcoma herpes virus [KSHV]), is common.

Two distinct species of HIV (HIV-1 and HIV-2) have been identified, and each is composed of multiple subtypes, or clades. All clades of HIV-1 tend to cause similar disease, but the global distribution of the clades differs. This may have implications on any future vaccine, as the B clade, which is predominant in the developed world (where the large pharmaceutical companies are located), is rarely found in the developing countries that are more severely affected by the disease.

HIV-1 probably originated from one or more cross-species transfers from chimpanzees in central Africa.4 HIV-2 is closely related to viruses that infect sooty mangabeys in western Africa.5 Genetically, HIV-1 and HIV-2 are superficially similar, but each contains unique genes and its own distinct replication process.

HIV-2 carries a slightly lower risk of transmission, and HIV-2 infection tends to progress more slowly to acquired immune deficiency syndrome (AIDS). This may be due to a less-aggressive infection rather than a specific property of the virus itself. Persons infected with HIV-2 tend to have a lower viral load than people with HIV-16,7 , and a greater viral load is associated with more rapid progression to AIDS in HIV-1 infections.8,9 Because HIV-2 is rare in the developed world, most of the research and vaccine and drug development has been (perhaps unfairly) focused on HIV-1.

Electron microscopy of human immunodeficiency virus (HIV)–1 virions. Courtesy of CDC/Dr. Edwin P. Ewing, Jr.

A considerable amount of stigma has been attached to HIV infection, mostly because of the virus's association with sexual acquisition and the inference of sexual promiscuity. Consequences of this stigma have included discrimination and reluctance to be tested for HIV infection. However, such attitudes are inappropriate because HIV is poorly transmissible without sexual contact or blood contact and because the expected survival is long in patients with HIV infection who are receiving treatment. HIV is not transmitted during casual contact and is readily inactivated by simple detergents. Much of the concern regarding HIV infection is due to the incurability of the infection and the relentless immune decline and eventual premature death in the vast majority of infected people.

The spread of HIV was retrospectively shown to follow the trucking routes across Africa from logging camps, and the bush-meat trade combined with aggressive logging and improved transportation in the mid-20th century may have allowed what was likely occasional cross-species transmission events to propagate across the country and, eventually, the globe.10

Since the discovery of HIV and its link to acquired immune deficiency syndrome (AIDS), great strides have been made in understanding its biology and in developing effective treatments. The difficulty in dealing with HIV on a global scale is largely due to the fact that HIV infection is far more common in resource-poor countries. In the developed world, antiretroviral therapy has greatly improved prognosis and increased survival rates. Public education programs have raised awareness such that testing and prevention of infection are more common. Both of these approaches are difficult in countries with undereducated or underfunded populations.

Political denial and inaction have also likely caused considerable damage. Several governments in countries with high HIV infection rates were slow to admit that they had an HIV epidemic, and at least one (South Africa) initially rejected that AIDS was even a problem, then that the disease was caused by HIV infection, and, most recently, that antiretroviral therapy was effective in treating HIV infection and preventing MTCT. Changes have now occurred but have been slow and have had an unknown cost.

For supplementary information, see the eMedicine articles Early Symptomatic HIV Infection and HIV Infection and AIDS.
Pathophysiology

Virology of HIV

HIV-1 and HIV-2 are retroviruses in the Retroviridae family, Lentivirus genus. They are enveloped, diploid, single-stranded, positive-sense RNA viruses with a DNA intermediate, which is an integrated viral genome (a provirus) that persists within the host-cell DNA. There is no fixed site of integration, but the virus tends to integrate in areas of active transcription, probably because these areas have more open chromatin and more easily accessible DNA.11,12 This greatly complicates eradication of the virus by the host, as latent proviral genomes can persist without being detected by the immune system and cannot be targeted by antivirals.


Genome layout of human immunodeficiency virus (HIV)–1 and HIV-2.

HIV contains the 3 species-defining retroviral genes— gag (group-specific antigen; the inner structural proteins), pol (polymerase; also contains integrase and protease—the viral enzymes—and is produced as a C-terminal extension of the Gag protein), and env (envelope; the outer structural proteins responsible for cell-type specificity).

HIV-1 has 6 additional accessory genes— tat, rev, nef, vif, vpu, and vpr. HIV-2 does not have vpu but instead has the unique gene vpx. The only other virus known to contain the vpu gene is simian immunodeficiency virus in chimpanzees (SIVcpz), which is the simian equivalent of HIV.4 Interestingly, chimpanzees with active HIV-1 infection are resistant to disease.13

The accessory proteins of HIV-1 and HIV-2 are involved in viral replication and may play a role in the disease process.14,15 The outer part of the genome consists of long terminal repeats (LTRs) that contain sequences necessary for gene transcription and splicing, viral packaging of genomic RNA, and dimerization sequences to ensure that 2 RNA genomes are packaged. The dimerization, packaging, and gene-transcription processes are intimately linked; disruption in one process often subsequently affects another. The LTRs exist only in the proviral DNA genome; the viral RNA genome contains only part of each LTR, and the complete LTRs are re-created during the reverse-transcription process prior to integration into the host DNA.

The Biologic Basis for AIDS

The specific details of the disease process that leads to AIDS are not fully understood despite considerable progress in the virology of HIV and the immunology of the human host, much of which has been driven by the urge to better understand AIDS.16,17,18

There is a specific decline in the CD4+ helper T cells, resulting in inversion of the normal CD4/CD8 T-cell ratio and dysregulation of B-cell antibody production.19,20 Immune responses to certain antigens begin to decline, and the host fails to adequately respond to opportunistic infections and normally harmless commensal organisms. Because the defect preferentially affects cellular immunity, the infections tend to be nonbacterial (fungal, viral).

The pattern of opportunistic infections in a geographic region reflects the pathogens that are common in that area. For example, persons with AIDS in the United States tend to present with commensal organisms such as Pneumocystis and Candida species, homosexual men are more likely to develop Kaposi sarcoma because of co-infection with HHV8, and tuberculosis is common in developing countries.

Recent work has shown the importance of gut-associated lymphoid tissue (GALT) in HIV replication.21 Although the portal of entry for HIV infection is typically through direct blood inoculation or exposure of the virus to genital mucosal surfaces, the GI tract contains a large amount of lymphoid tissue, making this an ideal site for HIV replication.

GALT has been shown to be a site of early viral seeding and establishment of the proviral reservoir. This reservoir contributes to the difficulty of controlling the infection, and efforts to reduce the levels of HIV provirus through sustained antiretroviral therapy (alone or in combination with interleukin-2 activation of resting HIV-infected T cells) have consistently failed.22

A feature of HIV replication in GALT is that it is compartmentalized, even among different areas of the gut.23 Measurements of CD4+ T cells in GALT show relatively less reconstitution with antiretroviral therapy than that observed in peripheral blood.24,25 At least one report has suggested that early treatment may result in better GALT CD4 T-cell recovery25 , but clinical data generally argue against early initiation of therapy, which has not been shown to improve long-term survival. In addition, HIV replication can be detected even in patients with supposedly suppressed replication, as judged by plasma viral load measurements. CD8+ killer T-cell responses to HIV occur in GALT and do not decline with antiviral therapy as much as peripheral measurements do.26 These findings underscore the limitations of peripheral measurements in what is really a central viral replication.

One theory for the discrepancy between GALT and blood measurements is that ongoing viral replication in the lymphoid tissue, and the resulting immune activation, may actually hamper efficient CD4+ T-cell replenishment.27

Studies of T-cell–replication kinetics have revealed that untreated HIV infection is characterized by rapid T-cell turnover but a defect in T-cell replication from the thymus.28,29 These changes can be reversed with effective long-term antiviral therapy,30,31 suggesting that they are due to a direct effect of the virus or are a feature of the immune response against HIV. It is known that normal cell cycling is necessary to produce a normal cytokine profile32 and that HIV causes cell-cycle arrest,33 but whether this is the exact mechanism is unresolved.

Several of the HIV proteins directly affect T-cell function, either by disrupting cell cycling or down-regulating the CD4 molecule. The loss of T cells is clearly a primary issue, as the T-cell repertoire narrows in terms of which antigens the immune system will recognize and respond to. Antiviral therapy is able to reverse these changes,34 but the degree of reversal is decreased if therapy is initiated very late in the infection and is further decreased when therapy is initiated when CD4 T-cell counts are 200/μL and below. Direct cytotoxic effects of viral replication are likely not the primary cause of CD4 T-cell loss; a significant bystander effect35 is likely secondary to T-cell apoptosis as part of immune hyperactivation in response to the chronic infection. Infected cells may also be affected by the immune attack.

One interesting issue is that the co-receptor usage of the virus strains tends to change over time. The initial infection nearly always involves a strain that uses the chemokine receptor 5 (CCR5) co-receptor found on macrophages and dendritic cells. People who are homozygous for deletions in the CCR5 gene tend to be resistant to infection and may have some protection against progression.36,37 Over time, the receptor usage shifts to chemokine-related receptor (CXCR4) and other related receptors found on CD4 T cells. These virus strains are more likely to cause cell fusion (syncytia formation). This trend is far from absolute but does correlate in many people with disease progression.38

Regardless of the cause for the disruption, a loss of thymic replacements in the face of an induced state of immune activation and T-cell loss seems to be a key component of the mechanism by which HIV narrows the T-cell repertoire and progresses to AIDS.39,40,41

Visible effects of HIV infection come in the form of disrupted lymph-node architecture. This disruption is temporal, and, at one point, lymph-node biopsy was considered as a form of staging the disease.42,43 The disruption of the follicular dendritic network in the lymph nodes and subsequent failure of normal antigen presentation are likely contributors to the disease process. HIV replicates in activated T cells (its promotor is a nuclear factor kappa B [NF-kappa-B]–binding region, the same protein that promotes other proteins in activated T cells and macrophages), and activated T cells migrate to the lymph nodes. As such, much of the viral replication occurs outside of the peripheral blood, even though serum viral load is still a useful surrogate marker of viral replication.

For additional information, see Medscape's HIV Pathogenesis Resource Center.
Phases of HIV Infection
Clinical HIV infection undergoes 3 distinct phases—acute seroconversion, asymptomatic infection, and AIDS. Each is discussed below.

Acute seroconversion

During this phase, the infection is established, and a proviral reservoir is created.44,45 This reservoir consists of persistently infected cells, typically macrophages, and appears to steadily release virus. Some of the viral release replenishes the reservoir, and some goes on to produce more active infection. The proviral reservoir, as measured by DNA polymerase chain reaction (PCR), seems to be incredibly stable. Although it does decline with aggressive antiviral therapy, the half-life is such that eradication is not a viable expectation.

The size of the proviral reservoir correlates to the steady-state viral load and is inversely correlated to the anti-HIV CD8 T-cell responses. Aggressive early treatment of acute infection may lower the proviral load, but, generally, treatment in newly infected (but postseroconversion) patients yields no long-term benefit.

At this point, the viral load is typically very high, and the CD4 T-cell count drops precipitously. With the appearance of anti-HIV antibodies and CD8 T-cell responses, the viral load drops to a steady state and the CD4 T-cell count returns to levels within the reference range, although slightly lower than before infection.

Seroconversion may take a few weeks, up to several months. Symptoms during this time may include fever, flulike illness, lymphadenopathy, and rash and develop in approximately half of all people infected with HIV.

Asymptomatic HIV infection

At this stage in the infection, persons infected with HIV exhibit few or no signs or symptoms for a few years to a decade or more. Viral replication is clearly ongoing during this time,46 and the immune response against the virus is effective and vigorous. In some patients, persistent generalized lymphadenopathy is an outward sign of infection. During this time, the viral load, if intreated, tends to persist at a relatively steady state, but the CD4 T-cell count steadily declines. This rate of decline is related to, but not easily predicted by, the steady-state viral load.

No firm evidence has shown that the initiation of therapy early in the asymptomatic period is effective, although very late initiation is known to result in a less effective response to therapy and a lower level of immune reconstitution.

AIDS

When the immune system is damaged enough that significant opportunistic infections begin to develop, the person is considered to have AIDS. For surveillance purposes in the United States, a CD4 T-cell count less than 200/μL is also used as a measure to diagnose AIDS, although some opportunistic infections develop when CD4 T-cell counts are higher than 200/μL, and some people with CD4 counts under 200/μL may remain relatively healthy.

Many opportunistic infections and conditions are used to mark when HIV infection has progressed to AIDS. The general frequency of these infections and conditions vary from rare to common but are uncommon or mild in immunocompetent persons. When one of these is unusually severe or frequent in a person infected with HIV and no other causes for immune suppression can be found, AIDS can be diagnosed.47

The following are such opportunistic infections and conditions:
Candidiasis of bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical cancer, invasive*
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (duration >1 mo)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with vision loss)
Encephalopathy, HIV-related
Herpes simplex - Chronic ulcer or ulcers (duration >1 mo) or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (duration >1 mo)
Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of the brain
Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary
Mycobacterium tuberculosis infection, any site (pulmonary* or extrapulmonary)
Mycobacterium infection with other species or unidentified species, disseminated or extrapulmonary
Pneumocystis pneumonia
Pneumonia, recurrent*
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of the brain
Wasting syndrome due to HIV infection
*Added in the 1993 AIDS surveillance case definition




Timeline of CD4 T-cell and viral-load changes over time in untreated human immunodeficiency virus (HIV) infection. From Wikipedia, based on an original from Pantaleo et al (1993).


Frequency
United States

The most recent frequency data concerning HIV infection in the United States are from 2006. According to data from states that have confidential name-based reporting, the national-average incidence of HIV infection is 18.5 per 100,000 population. The incidence rate of late HIV disease (AIDS) is 12.3 per 100,000 population. With improved estimation methods, the number of new HIV infections in 2006 has been estimated at 56,300. Approximately 1 million persons have been diagnosed with AIDS since 1981, and more than 500,000 people have died with AIDS (although reporting limitations mean that not every "death with AIDS" is directly attributable to AIDS itself). Approximately 1.1 million people currently have HIV infection in the United States.

US rates vary by state. See the latest Centers for Disease Control (CDC) surveillance report for full details (maps 1 and 2).

The overall figures may give a false impression that the HIV epidemic is relatively homogenous. In fact, the HIV epidemic is best viewed as numerous separate epidemics among distinct risk groups, although the various epidemics clearly have some level of overlap. In any given area, the infection may be most prevalent among users of intravenous drugs who share needles. In another, the main risk group may be men who have sex with other men. And in yet another, the main risk group may be female sex workers.

These sub-epidemics each follow their own pattern, although there is some degree of interdependence. Nearly all early cases of HIV infection detected in the Western Hemisphere were in homosexual men, but female partners of bisexual men with HIV infection gave rise to an increased spread among heterosexual persons. Contributing to the increased cross-prevalence were persons with hemophilia who had been infected with HIV from contaminated factor VIII and persons who used intravenous drugs, an activity that transcends all sexual preferences. Currently, less than half of new HIV infections are reported in homosexual men, and infected heterosexual women outnumber infected heterosexual men nearly two to one.48



Incidence of HIV infection by risk group. From the CDC Web site (copyright free) derived from the revised 2006 estimated figures.


Additional risk factors may predispose to HIV infection. Concomitant infection with other STDs (eg, gonorrhea, herpes, syphilis) is the most well-known. These infections may cause mucosal ulcerations or tears or a higher concentration of inflammatory cells in the mucosa, which are targets for HIV infection. In addition, certain sexual acts are more likely to lead to HIV infection than others. For example, fellatio carries the lowest risk of transmission (with very few case reports in the literature), while receptive anal intercourse carries the highest risk (a likelihood of approximately 1.5% per act with an infected individual). Higher viral loads in the source partner are associated with higher transmission rates; thus, because barrier contraception is imperfect (although by far the best method to prevent sexual transmission), good control of viral load is important.

The introduction of highly active antiretroviral therapy (HAART) has significantly improved mortality rates. One study of nearly 7000 men with HIV infection found that annual mortality rates decreased from 7% in 1996 to 1.3% in 2004, although the findings highlighted the fact that non–AIDS-related illnesses were accounting for a greater proportion of deaths.49

International

Worldwide, approximately 39.5 million people (1% of the global adult population aged 15-49 y) are infected with HIV. UNAIDS estimates that 4.3 million people were newly infected with HIV and that 2.9 million people died from AIDS in 2006. The vast majority of infections remain in sub-Saharan Africa, where nearly 6% of the population is thought to be infected.

Between 2004 and 2006, the prevalence of HIV infection in central and eastern Asia and Eastern Europe increased by 21%. During this period, the number of new HIV infections in persons aged 15 to 64 years rose by 70% in Eastern Europe and central Asia.

The infection rates in many developed countries remain stable, and some developing countries have achieved significant gains in controlling and even reversing the effects of the HIV epidemic. However, this is partially due to deaths in HIV-infected people, together with simultaneous prevention of new infections. These figures together show that global HIV infection is in a state of flux.

The mortality rate in some countries has greatly increased. In South Africa (a country that, despite having a relatively late-onset HIV epidemic, has developed one of the highest prevalence rates), the all-cause HIV-associated mortality rate increased by 79% between 1997 and 2004. In women aged 25-34 years, mortality rates increased by 500% during this period.

Swaziland has the highest overall prevalence of HIV infection (>33.4% of all adults).

The Ministry of Health in Zambia predicts that, without therapy and assuming current levels of prevalence, young adults have a 50% lifetime risk of dying from AIDS.

In developing nations, co-infection with HIV and tuberculosis is very common. The immunosuppressed state induced by HIV infection contributes not only to a higher rate of tuberculosis reactivation but also to an increased disease severity, as with many other opportunistic infections.

Further details of the global epidemic can be found in the Joint United Nations Programme on HIV/AIDS 2006 Epidemic Update.
Mortality/Morbidity

Untreated HIV infection carries an overall mortality rate of more than 90%. The CD4 T-cell counts remain stable in a small percentage of people with HIV infection. This is usually associated with strong anti-HIV CD8 T-cell responses, a low viral load, and low proviral reservoir. The average interval between initial HIV infection and progression to AIDS is 8-10 years.

Once infection has progressed to AIDS, the survival period is usually less than 2 years in untreated patients. Persons in whom the infection does not progress long-term may not develop AIDS for 15 years or longer, although many still exhibit laboratory evidence of CD4 T-cell decline or dysfunction.50,51,52,53

The appropriate use of combination antiretroviral therapies and prophylaxis for opportunistic infections dramatically improves survival and greatly decreases the risk of secondary opportunistic infections.54,55,49 The risk of AIDS-associated lymphoma is not altered by antiviral therapy and, as such, has grown in prevalence among overall AIDS-defining conditions. Sackoff et al found that, since 1999, the HIV-related mortality rate in New York City has decreased by approximately 50 deaths per 10,000 people with AIDS per year. The rate of non–HIV-related deaths has also seen a more modest but consistent decline, with about 7.5 fewer deaths per 10,000 people with AIDS per year.55 Importantly, many researchers have consistently shown that the primary risk factor for infection affects mortality. For example, the mortality rate among intravenous drug users tends to be higher, whether related to HIV disease or non-HIV disease.

Overall, with the increasing use of antiretroviral therapy and the introduction of better antiviral regimens, survival with HIV infection has increased over time, although it is not yet equivalent to that in uninfected individuals.


Changes in survival of people infected with HIV. As therapies have become more aggressive, they have been more effective, although survival with HIV infection is not yet equivalent to that in uninfected people. Modified from an original published by Lohse et al (2007), "Survival of persons with and without HIV infection in Denmark, 1995-2005."



In addition to the concern for new opportunistic infections, pre-existing infections can reactivate and cause significant disease in people with AIDS. The most important example on a global scale is that of tuberculosis, as reactivated tuberculosis can cause symptomatic disease with lower levels of reactivation. Other important pathogens include cytomegalovirus, (which causes retinitis, pneumonitis, and colitis) and Pneumocystis jiroveci (formerly known as Pneumocystis carinii; the causative organism in Pneumocystis pneumonia). In immunocompetent hosts, these organisms are generally nonpathogenic, and asymptomatic infection is common (and in the case of cytomegalovirus infection, life-long).

Antiviral medications are associated with adverse effects and thus contribute to patient morbidity and mortality rates, especially because of the growing population of long-term survivors who are receiving combination antiviral therapy. In particular, protease inhibitors may cause lipid-profile abnormalities.
Race

In the United States, the prevalence of HIV infection is highest in blacks (71.3 cases per 100,000 population). The prevalence is also high among Hispanic persons (27.8 per 100,000 population). These increased rates are due to socioeconomic factors rather than genetic predisposition.
Sex

In the developed world, HIV infection is much more common in males. Among heterosexuals, females are more likely to acquire HIV infection from an infected male than a male is from an infected female, but a large proportion of infections in males are due to homosexual contact, with or without injection drug use. Males are also more likely to acquire HIV infection from injection drug use alone.

Males were also more likely to acquire HIV infection through contaminated blood products during treatment of hemophilia before universal testing of the blood supply was instituted. (The procedures used in purifying factor VIII and producing cryoprecipitate are effective in preserving biologic activity of HIV. To negate this, heat treatment was added to the purification of factor VIII to inactivate HIV and other viruses). This is a small contribution to the predominance of HIV infection in males.

In the developing world, HIV infection is equally common in males and females. The primary route of HIV transmission in the developing world is heterosexual contact.

Age

Young adults tend to be at higher risk of acquiring HIV, typically through high-risk activities such as unprotected sexual intercourse or intravenous drug use.
Clinical
History

The history should be carefully taken to elicit possible exposures to human immunodeficiency virus (HIV). Risk factors include the following:

Unprotected sexual intercourse, especially receptive anal intercourse (8-fold higher risk of transmission)
A large number of sexual partners
Prior or current STDs: Gonorrhea and chlamydia infections increase the HIV transmission risk 3-fold, syphilis raises the transmission risk 7-fold, and herpes genitalis raises the transmission risk up to 25-fold during an outbreak.
Sharing of intravenous drug paraphernalia
Receipt of blood products (before 1985 in the United States)
Mucosal contact with infected blood or needle-stick injuries
Maternal HIV infection (for newborns, infants, and children): Steps taken to reduce the risk of transmission at birth include cesarean delivery and prenatal antiretroviral therapy in the mother and antiretroviral therapy in the newborn immediately after birth.

The patient may present with signs and symptoms of any of the stages of HIV infection. Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash.

The asymptomatic phase is generally benign. Generalized lymphadenopathy is common and may be a presenting symptom.

AIDS manifests as recurrent, severe, and occasionally life-threatening infections and/or opportunistic malignancies. The signs and symptoms are those of the presenting illness, meaning that HIV infection should be suspected as an underlying illness when unusual infections present in apparently healthy individuals.

HIV infection itself does cause some sequelae, including AIDS-associated dementia/encephalopathy and HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause).
Physical

No physical findings are specific to HIV infection. The physical findings are those of the presenting infection or illness.
Generalized lymphadenopathy is common.
Weight loss may be apparent.
Evidence for risk factors or minor concurrent opportunistic infections (eg, herpetic lesions on the groin, widespread oral candidiasis) may be clues to HIV infection.
Many patients with AIDS develop cytomegalovirus retinitis with severe vision loss.
Causes

HIV disease is caused by infection with HIV-1 or HIV-2, both of which cause very similar conditions. They differ in transmission and progression risks.

There is less evidence that treatment of HIV-2 infection slows progression, and certain antiretroviral medications are not effective against HIV-2. The HIV-1 viral-load assays are much less reliable, if they work at all. HIV-2 viral load assays have been developed, but none has been approved by the FDA except as blood donor–screening tools.

Typhoid Fever

Background

Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella typhi. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within one month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications.

S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War.1 The name S typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries.

Transmission

S typhi has no nonhuman vectors. The following are modes of transmission:

Oral transmission via food or beverages handled by an individual who chronically sheds the bacteria through stool or, less commonly, urine
Hand-to-mouth transmission after using a contaminated toilet and neglecting hand hygiene
Oral transmission via sewage-contaminated water or shellfish (especially in the developing world)

An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy volunteers.

Pathophysiology

All pathogenic Salmonella species are engulfed by phagocytic cells, which then pass them through the mucosa and present them to the macrophages in the lamina propria. Nontyphoidal salmonellae are phagocytized throughout the distal ilium and colon. With toll-like receptor (TLR)–5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8), causing inflammation and suppressing the infection.

In contrast to the nontyphoidal salmonellae, S typhi enters the host's system primarily through the distal ilium. S typhi has specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ilium (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic system. S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation. The bacteria then induce their host macrophages to attract more macrophages.

It co-opts the macrophages' cellular machinery for their own reproduction7 as it is carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, the S typhi bacteria pause and continue to multiply until some critical density is reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body.

The gallbladder is then infected via either bacteremia or direct extension of S typhi –infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts

Risk factors

S typhi are able to survive a stomach pH as low as 1.5. Antacids, histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease stomach acidity and facilitate S typhi infection.

HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection; however, the data and opinions in the literature as to whether this is true for S typhi infection are conflicting. If an association exists, it is probably minor.

Other risk factors for clinical S typhi infection include various genetic polymorphisms. These risk factors often also predispose to other intracellular pathogens. For instance, PARK2 and PACGR code for a protein aggregate that is essential for breaking down the bacterial signaling molecules that dampen the macrophage response. Polymorphisms in their shared regulatory region are found disproportionately in persons infected with Mycobacterium leprae and S typhi.12
On the other hand, protective host mutations also exist. The fimbriae of S typhi bind in vitro to cystic fibrosis transmembrane conductance receptor (CFTR), which is expressed on the gut membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del, which is associated with a decreased susceptibility to typhoid fever, as well as to cholera and tuberculosis. The homozygous F508del mutation in CFTR is associated with cystic fibrosis. Thus, typhoid fever may contribute to evolutionary pressure that maintains a steady occurrence of cystic fibrosis, just as malaria maintains sickle cell disease in Africa.

Environmental and behavioral risk factors that are independently associated with typhoid fever include eating food from street vendors, living in the same household with someone who has new case of typhoid fever, washing the hands inadequately, sharing food from the same plate, drinking unpurified water, and living in a household that does not have a toilet.15,12 As the middle class in south Asia grows, some hospitals there are seeing a large number of typhoid fever cases among relatively well-off university students who live in group households with poor hygeine.16 American clinicians should keep this in mind, as members of this cohort often come to the United States for higher degrees.

Frequency

United States

Since 1900, improved sanitation and successful antibiotic treatment have steadily decreased the incidence of typhoid fever in the United States. In 1920, 35,994 cases of typhoid fever were reported. Currently, 200-400 cases of typhoid fever are reported per year in the United States, 75% of which occur in international travelers (mostly to the Indian subcontinent and Latin America)17 within 30 days of entry. The rare outbreaks of typhoid fever due to S typhi transmission within the United States are generally traceable to imported food or to a food handler from an endemic region.

International

Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania. Typhoid fever infects roughly 21.6 million people and kills an estimated 200,000 people every year.

Mortality/Morbidity

With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile illness with a negligible risk of mortality. Untreated typhoid fever is a life-threatening illness of several weeks' duration with long-term morbidity. The case fatality rate in the United States in the pre-antibiotic era was 9-13%.Race

Typhoid fever has no racial predilection.

Sex

Typhoid fever has no sexual predilection.

Age

Most documented typhoid fever cases involve school-aged children and young adults. However, the true incidence among very young children and infants is thought to be higher. The presentations in these age groups may be atypical, ranging from a mild febrile illness to severe convulsions, and the S typhi infection may go unrecognized. This may account for conflicting reports in the literature that this group has either a very high or a very low rate of morbidity and mortality.

Clinical

History

A severe nonspecific febrile illness in a patient who has been exposed to S typhi should always raise the diagnostic possibility of typhoid fever (enteric fever).

Classic typhoid fever syndrome

Typhoid fever begins 7-14 days after ingestion of S typhi. The fever pattern is stepwise, characterized by a rising temperature over the course of each day that drops by the subsequent morning. The peaks and troughs rise progressively over time.

Over the course of the first week of illness, the notorious gastrointestinal manifestations of the disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and narrows the bowel lumen, causing constipation that lasts the duration of the illness. The individual then develops a dry cough, dull frontal headache, delirium, and an increasingly stuporous malaise.2

At approximately the end of the first week of illness, the fever plateaus at 103-104°F (39-40°C). The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days.2 These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or nontyphoidal salmonellosis.

During the second week of illness, the signs and symptoms listed above progress. The abdomen becomes distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse (double beat, the second beat weaker than the first) may develop.

In the third week, the still febrile individual grows more toxic and anorexic with significant weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse and crackles over the lung bases. Abdominal distension is severe. Some patients experience foul, green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the typhoid state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer patches may cause bowel perforation and peritonitis. This complication is often unheralded and may be masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or intestinal hemorrhage may cause death.

If the individual survives to the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days. Intestinal and neurologic complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months. Some survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria indefinitely.

Various presentations of typhoid fever

The clinical course of a given individual with typhoid fever may deviate from the above description of classic disease. The timing of the symptoms and host response may vary based on geographic region, race factors, and the infecting bacterial strain. The stepladder fever pattern that was once the hallmark of typhoid fever now occurs in as few as 12% of cases. In most contemporary presentations of typhoid fever, the fever has a steady insidious onset.

Young children, individuals with AIDS, and one third of immunocompetent adults who develop typhoid fever develop diarrhea rather than constipation. In addition, in some localities, typhoid fever is generally more apt to cause diarrhea than constipation.

Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or fever alone. Some patients, especially in India and Africa, present primarily with neurologic manifestations such as delirium or, in extremely rare cases, parkinsonian symptoms or Guillain-Barré syndrome. Other unusual complications include pancreatitis,24 meningitis, orchitis, osteomyelitis, and abscesses anywhere on the body

Influenza

What is influenza?

Influenza (also called "the flu") is a viral infection in the nose, throat and lungs. About 10% to 20% of Americans get the flu each year. Some people can get very sick from the flu. Each year, about 200,000 people go to a hospital with the flu, and 36,000 people die because of the flu and complications.

The flu may cause fever, cough, sore throat, a runny or stuffy nose, headache, muscle aches and tiredness. Most people feel better after 1 or 2 weeks, but for some people, the flu leads to serious diseases, such as pneumonia. The influenza vaccine (the flu shot) can help protect you from getting the flu.

Who is at higher risk?

Some people have a higher risk of flu complications, like pneumonia. If you are in any of these groups, you should get the flu vaccine every year:
- All children aged 6 months up to 19 years
- All adults aged 50 years and older
- All women who are or will be pregnant during the flu season
- People who are living in nursing homes or long-term care facilities
- Individuals who have long-term health problems
- Health care workers who have direct contact with patients
- Caregivers and household contacts of children less than 6 months of age


How can I avoid getting the flu?

The best way to avoid getting the flu is to get the influenza vaccine. You should get the vaccine when it becomes available each fall (in October or November), but you can also get it any time throughout the flu season (into December, January and beyond). The vaccine is available by shot or by nasal spray. The vaccines work by exposing your immune system to the flu virus. Your body will build up antibodies to the virus to protect you from getting the flu. The flu shot contains dead viruses. The nasal-spray vaccine contains live but weakened viruses. You cannot get the flu from the flu shot or the nasal-spray vaccine.

You can also reduce your risk of catching the flu by washing your hands frequently, which stops the spread of germs. Eating healthy, exercising and getting enough sleep also play a part in preventing the flu because they help boost your immune system. 

If you are sick, make sure that you cover your mouth when you cough and wash your hands often to prevent giving the flu to others.

Some people who get the vaccine will still get the flu, but they will usually get a milder case than people who aren't vaccinated. The vaccine is especially recommended for people who are more likely to get really sick from flu-related complications.

Is there anyone who shouldn't get the flu shot?

Yes. The following people should talk to their doctor before getting the flu shot:
- People who have had an allergic reaction to a flu shot in the past
- People with an allergy to eggs
- People who previously developed Guillain-Barré Syndrome (a reversible reaction that causes partial or complete loss of movement of muscles, weakness or a tingling sensation in the body) within 6 weeks of getting a flu shot
- Children less than 6 months of age
- People who have a moderate or severe illness with a fever should wait until they feel better before receiving the flu shot

Is there anyone who shouldn't get the nasal-spray vaccine?

Yes. The following people should talk to their doctor before getting the nasal-spray vaccine:
- Children less than 2 years of age
- Adults 50 years of age and older
- People with long-term health problems
- People with weakened immune systems
- Children or adolescents who are on long-term aspirin therapy
- People with diabetes, kidney disease, heart disease or lung disease
- People with a history of Guillain-Barré syndrome
- Pregnant women
- People who have had an allergic reaction to a flu vaccine in the past or who are allergic to eggs

If I get the flu vaccine, can I still get the flu?

Yes. Even with a flu vaccine, you aren't 100% protected. Each year, the flu vaccine contains 3 different strains (kinds) of the virus. The strains chosen are those that scientists believe are most likely to show up in the United States that year. If the choice is right, the vaccine is 70% to 90% effective in preventing the flu in healthy adults. If you're older than 65, the vaccine is less likely to prevent the flu. Even if you get the flu after being vaccinated, your flu symptoms should be milder than if you didn't get the vaccine. You'll also be less likely to get complications from the flu.

Is the vaccine safe?

Yes. The flu vaccine is safe. There are very few side effects. If you got the flu shot, your arm may be sore for a few days . You may have a fever, feel tired or have sore muscles for a short time. If you got the nasal-spray vaccine, you may have a runny nose, headache, cough or sore throat.

Can I get the flu vaccine if I am pregnant or nursing?

If you are pregnant during flu season, you cannot get the nasal-spray vaccine. However, it is recommended that women who will be pregnant during flu season get the shot. Pregnancy can increase your risk for complications from the flu.

It is also safe to get the flu shot while breast feeding your baby. The flu shot cannot cause you or your nursing baby to get sick.

What are antiviral flu drugs?

Antiviral flu drugs are prescription medicines that can be used to help prevent and/or treat the flu. There are four antiviral flu drugs: amantadine (one brand name: Symmetrel), oseltamivir (brand name: Tamiflu), rimantadine (brand name: Flumadine) and zanamavir (brand name: Relenza). All 4 of these antiviral drugs have been approved to treat the flu. If you take one of these drugs within 2 days of getting sick, it can lessen your symptoms, decrease the amount of time you are sick and make you less contagious to other people. However, most healthy people who have the flu get better without using an antiviral flu drug. Your doctor will decide whether one of these medicines is right for you.

Three of the antiviral flu drugs have also been approved to prevent the flu. These drugs are not a substitute for the influenza vaccine. They are most often used for flu prevention in institutions where people at high risk for flu complications are in close contact with each other, such as nursing homes or hospitals. For example, during a flu outbreak in a nursing home, residents and staff might be given the flu vaccine and an antiviral drug to prevent the flu until the vaccine takes effect.

Asthma

What is Asthma?

Asthma is a disease affecting the airways that carry air to and from your lungs. People who suffer from this chronic condition (long-lasting or recurrent) are said to be asthmatic.
 

The inside walls of an asthmatic's airways are swollen or inflamed. This swelling or inflammation makes the airways extremely sensitive to irritations and increases your susceptibility to an allergic reaction.

As inflammation causes the airways to become narrower, less air can pass through them, both to and from the lungs. Symptoms of the narrowing include wheezing (a hissing sound while breathing), chest tightness, breathing problems, and coughing. Asthmatics usually experience these symptoms most frequently during the night and the early morning.

For information on the different causes of asthma (allergy, colds, stress, exercise, etc) please see page 4 (causes of asthma). 
Asthma is Incurable

Asthma is an incurable illness. However, with good treatment and management there is no reason why a person with asthma cannot live a normal and active life.
What is an Asthma Episode / Attack?

An asthma episode, or an asthma attack, is when symptoms are worse than usual. They can come on suddenly and can be mild, moderate or severe. 

What happens during an asthma attack? 

The muscles around your airways tighten up, narrowing the airway.
Less air is able to flow through the airway.
Inflammation of the airways increases, further narrowing the airway.

More mucus is produced in the airways, undermining the flow of air even more.

Asthma Attacks Vary

 In some asthma attacks, the airways are blocked such that oxygen fails to enter the lungs. This also prevents oxygen from entering the blood stream and traveling to the body's vital organs. Asthma attacks of this type can be fatal, and the patient may require urgent hospitalization. 

Asthma attacks can be mild, moderate, severe and very severe. At onset, an asthma attack does allow enough air to get into the lungs, but it does not let the carbon dioxide leave the lungs at a fast enough rate. Carbon dioxide - poisonous if not expelled - can build up in the lungs during a prolonged attack, lowering the amount of oxygen getting into your bloodstream.

See Your Doctor

If you suffer from asthma you should see your doctor. He/she will help you find out what triggers your asthma symptoms and how to avoid them. You will also be prescribed medications which will help you manage your asthma.

With experience you will learn to keep away from things that irritate your airways, know when to take your medication, and better control your asthma. Effective asthma control allows you to take part in normal everyday activities.

Consequences of Not Controlling Your Asthma

If you don't control your asthma you will miss school or work more often and you will be less likely to be able to take part in some activities you enjoy. In the USA and Western Europe, asthma is one of the leading causes of school absenteeism.

Types of Asthma

Child-Onset Asthma
 
Asthma that begins during childhood is called child-onset asthma. This type of asthma happens because a child becomes sensitized to common allergens in the environment - most likely due to genetic reasons. The child is atopic - a genetically determined state of hypersensitivity to environmental allergens.

Allergens are any substances that the body will treat as a foreign body, triggering an immune response. These vary widely between individuals and often include animal proteins, fungi, pollen, house-dust mites and some kind of dust. The airway cells are sensitive to particular materials making an asthmatic response more likely if the child is exposed to a certain amount of an allergen.

Adult-Onset Asthma

This term is used when a person develops asthma after reaching 20 years of age. Adult-onset asthma affects women more than men, and it is also much less common than child-onset asthma.

It can also be triggered by some allergic material or an allergy. It is estimated that up to perhaps 50% of adult-onset asthmas are linked to allergies. However, a substantial proportion of adult-onset asthma does not seem to be triggered by exposure to allergen(s); this is called non-allergic adult-onset asthma. This non-allergic type of adult onset asthma is also known as intrinsic asthma. Exposure to a particle or chemical in certain plastics, metals, medications, or wood dust can also be a cause of adult-onset asthma. 

Exercise-Induced Asthma

If you cough, wheeze or feel out of breath during or after exercise, you could be suffering from exercise-induced asthma. Obviously, your level of fitness is also a factor - a person who is unfit and runs fast for ten minutes is going to be out of breath. However, if your coughing, wheezing or panting does not make sense, this could be an indication of exercise-induced asthma.

As with other types of asthma, a person with exercise-induced asthma will experience difficulty in getting air in and out of the lungs because of inflammation of the bronchial tubes (airways) and extra mucus. 

Some people only experience asthma symptoms during physical exertion. The good news is that with proper treatment, a person who suffers from exercise-induced asthma does not have to limit his/her athletic goals. With proper asthma management, one can exercise as much as desired. Mark Spitz won nine swimming gold medals during the 1972 Olympics and he suffered from exercise-induced asthma. 

Eighty percent of people with other types of asthma may have symptoms during exercise, but many people with exercise-induced asthma never have symptoms while they are not physically exerting themselves.

Cough-Induced Asthma

Cough-induced asthma is one of the most difficult asthmas to diagnose. The doctor has to eliminate other possibilities, such as chronic bronchitis, post nasal drip due to hay fever, or sinus disease. In this case the coughing can occur alone, without other asthma-type symptoms being present. The coughing can happen at any time of day or night. If it happens at night it can disrupt sleep. 

Occupational Asthma

This type of asthma is triggered by something in the patient's place of work. Factors such as chemicals, vapors, gases, smoke, dust, fumes, or other particles can trigger asthma. It can also be caused by a virus (flu), molds, animal products, pollen, humidity and temperature. Another trigger may be stress. Occupational asthma tends to occur soon after the patients starts a new job and disappears not long after leaving that job.

Nocturnal Asthma

Nocturnal asthma occurs between midnight and 8 AM. It is triggered by allergens in the home such as dust and pet dander or is caused by sinus conditions. Nocturnal or nighttime asthma may occur without any daytime symptoms recognized by the patient. The patient may have wheezing or short breath when lying down and may not notice these symptoms until awoken by them in the middle of the night - usually between 2 and 4 AM. 

Nocturnal asthma may occur only once in a while or frequently during the week. Nighttime symptoms may also be a common problem in those with daytime asthma as well. However, when there are no daytime symptoms to suggest asthma is an underlying cause of the nighttime cough, this type of asthma will be more difficult to recognize - usually delaying proper therapy. The causes of this phenomenon are unknown, although many possibilities are under investigation.

Steroid-Resistant Asthma (Severe Asthma)

While the majority of patients respond to regular inhaled glucocorticoid (steroid) therapy, some are steroid resistant. Airway inflammation and immune activation play an important role in chronic asthma. Current guidelines of asthma therapy have therefore focused on the use of anti-inflammatory therapy, particularly inhaled glucocorticoids (GCs). By reducing airway inflammation and immune activation, glucocorticoids are used to treat asthma. However, patients with steroid resistant asthma have higher levels of immune activation in their airways than do patients with steroid sensitive (SS) asthma. 

Furthermore, glucocorticoids do not reduce the eosinophilia (high concentration of eosinophil granulocytes in the blood) or T cell activation found in steroid resistant asthmatics. This persistent immune activation is associated with high levels of the immune system molecules IL-2 (interleukin 2), IL-4 and IL-5 in the airways of these patients.

What Causes Asthma?
 
According to recent estimates, asthma affects 300 million people in the world and more than 22 million in the United States. Although people of all ages suffer from the disease, it most often starts in childhood, currently affecting 6 million children in the US. Asthma kills about 255,000 people worldwide every year.
Children at Risk

Asthma is the most common chronic disease among children - especially children who have low birth weight, are exposed to tobacco smoke, are black, and are raised in a low-income environment. Most children first present symptoms around 5 years of age, generally beginning as frequent episodes of wheezing with respiratory infections. Additional risk factors for children include having allergies, the allergic skin condition eczema, or parents with asthma.

Young boys are more likely to develop asthma than young girls, but this trend reverses during adulthood. Researchers hypothesize that this is due to the smaller size of a young male's airway compared to a young female's airway, leading to a higher risk of wheezing after a viral infection.
Allergies

Almost all asthma sufferers have allergies. In fact, over 25% of people who have hay fever (allergic rhinitis) also develop asthma. Allergic reactions triggered by antibodies in the blood often lead to the airway inflammation that is associated with asthma.

Common sources of indoor allergens include animal proteins (mostly cat and dog allergens), dust mites, cockroaches, and fungi. It is possible that the push towards energy-efficient homes has increased exposure to these causes of asthma. 

Tobacco Smoke

Tobacco smoke has been linked to a higher risk of asthma as well as a higher risk of death due to asthma, wheezing, and respiratory infections. In addition, children of mothers who smoke - and other people exposed to second-hand smoke - have a higher risk of asthma prevalence. Adolescent smoking has also been associated with increases in asthma risk.
Environmental Factors

Allergic reactions and asthma symptoms are often the result of indoor air pollution from mold or noxious fumes from household cleaners and paints. Other indoor environmental factors associated with asthma include nitrogen oxide from gas stoves. In fact, people who cook with gas are more likely to have symptoms such as wheezing, breathlessness, asthma attacks, and hay fever. 
 

Pollution, sulfur dioxide, nitrogen oxide, ozone, cold temperatures, and high humidity have all been shown to trigger asthma in some individuals.

During periods of heavy air pollution, there tend to be increases in asthma symptoms and hospital admissions. Smoggy conditions release the destructive ingredient known as ozone, causing coughing, shortness of breath, and even chest pain. These same conditions emit sulfur dioxide, which also results in asthma attacks by constricting airways.

Weather changes have also been known to stimulate asthma attacks. Cold air can lead to airway congestion, bronchoconstriction (airways constriction), secretions, and decreased mucociliary clearance (another type of airway inefficiency). In some populations, humidity causes breathing difficulties as well.

Obesity

Overweight adults - those with a body mass index (BMI) between 25 and 30 - are 38% more likely to have asthma compared to adults who are not overweight. Obese adults - those with a BMI of 30 or greater - have twice the risk of asthma. According to some researchers, the risk may be greater for nonallergic asthma than allergic asthma.

Pregnancy

The way you enter the world seems to impact your susceptibility to asthma. Babies born by Caesarean sections have a 20% increase in asthma prevalence compared to babies born by vaginal birth. It is possible that immune system-modifying infections from bacterial exposure during Cesarean sections are responsible for this difference. 

When mothers smoke during pregnancy, their children have lower pulmonary function. This may pose additional asthma risks. Research has also shown that premature birth is a risk factor for developing asthma.

Stress

People who undergo stress have higher asthma rates. Part of this may be explained by increases in asthma-related behaviors such as smoking that are encouraged by stress. However, recent research has suggested that the immune system is modified by stress as well.
Genes

It is possible that some 100 genes are linked to asthma - 25 of which have been associated with separate populations as of 2005.
 

Genes linked to asthma also play roles in managing the immune system and inflammation. There have not, however, been consistent results from genetic studies across populations - so further investigations are required to figure out the complex interactions that cause asthma. 

Mom and Dad may be partially to blame for asthma, since three-fifths of all asthma cases are hereditary. The Centers for Disease Control (USA) say that having a parent with asthma increases a person's risk by three to six times.

Genetics may also be interacting with environmental factors. For example, exposure to the bacterial product endotoxin and having the genetic trait CD14 (single nucleotide polymorphism (SNP) C-159T) have remained a well-replicated example of a gene-environment interaction that is associated with asthma.

Airway Hyperreactivity

Researchers are not sure why airway hyperreactivity is another risk factor for asthma, but allergens or cold air may trigger hyperreactive airways to become inflamed. Some people do not develop asthma from airway hyperreactivity, but hyperreactivity still appears to increase the risk of asthma.

Atopy

Atopy - such as eczema (atopic dermatitis), allergic rhinitis (hay fever), allergic conjunctivitis (an eye condition) - is a general class of allergic hypersensitivity that affects different parts of the body that do not come in contact with allergens. Atopy is a risk factor for developing asthma.

Some 40% to 50% of children with atopic dermatitis also develop asthma, and it is probable that children with atopic dermatitis have more severe and persistent asthma as adults.

Treatment for Asthma
 
Asthma is not so much "treated" as it is "controlled". As a chronic, long-term disease, there is no cure. However, there are tools and medicines to help you control asthma as well as benchmarks to gauge your progress.

The Peak Flow Meter

A peak flow meter is a simple, small, hand-held tool that can help you maintain control of asthma by providing a measurement of how well air moves out of the lungs.

After blowing into the device, the meter reveals your peak flow number. A physician will indicate how often to test as well as how to interpret the result to determine the amount of medication to take. Some people record scores every morning while others use the peak flow meter intermittently. 

Often, each test with the peak flow meter will be judged against your "personal best" peak flow number (found during 2 to 3 weeks of good asthma control). If peak flow tests begin to decline - even before other symptoms are present - it may indicate a looming asthma attack. After taking asthma medication, the peak flow meter can be used to test the effectiveness of drug therapy.

Good Control

Asthma is considered "well-controlled" if:
Chronic and troublesome symptoms (coughing and shortness of breath) are prevented and occur no more than 2 days per week.
There is little need for quick-relief medicines or they are needed less than 2 days per week.
You maintain good lung function.
Your activity level remains normal.
Your sleep level remains normal and symptoms do not wake you from sleep more than 1 to 2 nights per month.
You do not need emergency medical treatment.
You have no more than one asthma attack each year that requires inhalation of corticosteroids.
Your peak flow stays above 80% of your personal best number.

These benchmarks can be obtained by working with a doctor and avoiding factors that can make your asthma flare up. Also be sure to treat other conditions that may interfere with asthma management.

Good control also means avoiding things that trigger asthma or asthma symptoms such as allergens. This may mean limiting time spent outdoors when pollen levels or air pollution levels are highest and limiting contact with animals. Asthma linked to allergies can also be suppressed by getting the necessary allergy shots.

Preventive Checkups

Part of good asthma control is seeing a doctor every 2 to 6 weeks for regular checkups until it is under control. Then checkups may be reduced to once a month or twice a year. 

It is a good habit to keep track of asthma symptoms and attacks and diagnostic numbers such as the peak flow measurement. Doctors and nurses will ask about these and about daily activities in order to gauge the status of your asthma control.

Medicine

 
Medication for asthma is broadly categorized as either quick-relief medicine or long-term control medicine. Reducing airway inflammation and preventing asthma symptoms is the goal of long-term control medicines, where as immediate relief of asthma symptoms is the goal of quick-relief or "rescue" medicines.

Medications can be ingested in pill form, but most are powders or mists taken orally using a device known as an inhaler. Inhalers permit medicines to travel efficiently through the airways to the lungs.

Inhaler

Medication may also be administered using a nebulizer, providing a larger, continuous dose. Nebulizers vaporize a dose of medication in a saline solution into a steady stream of foggy vapor that is inhaled by the patient.

Long-Term Control

Long-term control medicines are taken every day and are designed to prevent asthma symptom such as airway inflammation. Inhaled corticosteroids are the most effective long-term control medicine - the best at relieving airway inflammation and swelling. They are usually taken daily to greatly reduce the inflammation that initiates the chain reaction of the asthma attack.

Even if taken every day, inhaled corticosteroids are not habit-forming. However, the medicines do have side effects such as the mouth infection known as "thrush". Thrush occurs when the corticosteroids land in your throat or mouth. Spacers or holding chambers have been developed to help avoid this. Thrush can also be avoided by rinsing the mouth out after inhalation. 

Inhaled corticosteroids also increase the risk of cataracts (clouding of the eye's lens) and osteoporosis (weakening of the bones) if taken for long periods of time. 

There are other long-term control medicines available that doctors may prescribe. Most of them are taken by mouth and are designed to open the airways and prevent airway inflammation. Examples include inhaled long-acting B2-agonists (used with low-dose inhaled corticosteroids), leukotriene modifiers, cromolyn and nedocromil, and theophylline.

Quick-Relief Medicines

Quick-relief medicines relieve asthma symptoms when they occur. The most common of these are inhaled short-acting B2-agonists - bronchodilators that quickly relax tight muscles around the airways, allowing air to flow through them. 

The quick-relief inhaler should be used when asthma symptoms are first noticed, but should not be used more than 2 days a week. Most people carry the quick-relief inhaler with them at all times. Quick-relief medicines usually do not reduce inflammation and therefore should not be used as a replacement for long-term control medicines.

Emergency Care

 
If your medicines do not relieve an asthma attack or your peak flow is less than half of what it normally is, emergency medicine may be necessary. Call 911 or have someone take you to the emergency room if you cannot walk because you are out of breath or if you have blue lips or fingernails. 

Lifesaving treatments at the hospital will consist of direct oxygen (to alleviate hypoxia) and higher doses of medicines. Emergency personnel will likely administer a cocktail of short-acting B-2 agonists, systemic oral or intravenous steroids, other bronchodilators, nonspecific injected or inhaled B-2 agonists, anticholinergics, inhalation anesthetics, the dissociative anesthetic ketamine, and intravenous magnesium sulfate.

Intubation (a breathing tube down one's throat) and mechanical ventilation may also be used in patients undergoing respiratory arrest.
Children 

Although quick-relief medicines can relieve wheezing in young children, long-term control medicines will be used to treat infants and young children if symptoms are likely to persist after 6 years of age. 

Like adults, children are treated with inhaled corticosteroids, montelukast, or cromolyn. Often, treatments will be tried for 4 to 6 weeks and stopped if the desired outcome is not seen. Inhaled corticosteroids carry the side-effect of slowed growth, but the effect is generally small and is only apparent for the first few months of treatment.

Elderly

Elderly asthma care may require adjustments to prevent interactions between medicines. Beta blockers, aspirin, pain relievers, and anti-inflammatory medicines can prevent asthma medicines from working correctly and may worsen symptoms. In addition, it may be difficult for older persons to hold their breath for 10 seconds after inhalation of medicines, but spacers have been developed to help this issue.

The increased osteoporosis risk brought on by inhaled corticosteroids may be magnified in older adults with weak bones. It is common to take calcium and vitamin D pills, among other therapies, to keep bones healthy.

Pregnant Women

Proper asthma control is necessary for pregnant women in order to ensure a good supply of oxygen to the fetus. Babies born of asthmatic mothers have a higher chance of premature birth and lower birth weight. For pregnant women, the risks associated with having an asthma attack outweigh any risks associated with asthma medicines. 

Non-medical Treatments

Some people treat asthma using unconventional alternative therapies, but there is little formal data to support the effectiveness of these methods. There is research, however, that has found acupuncture, air ionizers, and dust mite control measures, to have little or no effect on asthma symptoms or lung function. Evidence is inconclusive to support or reject osteopathic, chiropractic, physiotherapeutic, and respiratory therapeutic techniques. Homeopathy may mildly reduce the intensity of symptoms, but this finding is not robust.

Avian Influenza

Avian influenza viruses are found chiefly in birds, but rare infections can occur in humans. Symptoms are generally mild, and include cough and sore throat, but more serious symptoms are possible. Because of concerns over a possible pandemic, researchers are currently studying ways of not only creating a vaccine against avian influenza, but also creating large quantities quickly.

What Is Avian Influenza?

Avian influenza -- commonly called "bird flu" or "avian flu" -- is an infection caused by influenza viruses that occur naturally in birds.
 

Avian Influenza in Birds

Wild birds can carry the avian influenza virus in their intestines, but usually do not get sick from it. The condition can be highly contagious among birds and can make some domesticated birds, including chickens, ducks, and turkeys, sick and even kill them. Infected birds shed the virus in their saliva, nasal secretions, and feces.
 
Susceptible birds become infected when they have contact with contaminated secretions, excretions, or with surfaces that are contaminated with secretions or excretions from infected birds. Domesticated birds may become infected with avian influenza virus through:
 
Direct contact with infected waterfowl or other infected poultry 
Contact with infected surfaces (such as dirt or cages) 
Materials (such as water or feed) that have been contaminated with the virus. 
 
Infection with the avian influenza virus in domestic poultry causes two main forms of the disease that are distinguished by low and high extremes of virulence. The "low pathogenic" form may go undetected, and usually causes only mild symptoms (such as ruffled feathers and a drop in egg production). However, the highly pathogenic form spreads more rapidly through flocks of poultry. This form may cause disease that affects multiple internal organs, and has a mortality rate that can reach 90 to 100 percent, often within 48 hours.
 
One strain of avian influenza, the H5N1 virus, is endemic in much of Asia and has recently spread into Europe. Avian H5N1 infections have recently killed poultry and other birds in a number of countries.

Avian Influenza in Humans

There are many different subtypes of type A influenza viruses. These subtypes differ because of changes in certain proteins on the surface of the influenza A virus, which includes hemagglutinin (HA) and neuraminidase (NA) proteins.
 
There are 16 known HA subtypes and 9 known NA subtypes of influenza A viruses. Many different combinations of HA and NA proteins are possible. Each combination represents a different subtype, and all known subtypes of influenza A viruses can be found in birds.
 
Usually, the term "avian influenza virus" refers to influenza A viruses found chiefly in birds, but infections with these viruses can occur in humans. The risk from the disease is generally low in most people, because the viruses do not usually infect humans. However, confirmed cases of human infection from several subtypes of avian influenza infection have been reported since 1997.
 
Most cases of infection in humans have resulted from contact with infected poultry (domesticated chicken, ducks, and turkeys) or with surfaces contaminated with secretions/excretions from infected birds. The spread of the avian influenza virus from one ill person to another has been reported only rarely, and transmission has not been observed to continue beyond one person.
 
During an outbreak of avian influenza among poultry, there is a possible risk to people who have contact with infected birds or with surfaces that have been contaminated with secretions or excretions from infected birds. Avian influenza H5N1 in humans is currently limited and not a pandemic flu.
 
Human H5N1 influenza infection was first recognized in 1997, when this virus infected 18 people in Hong Kong, causing six deaths. Since 2003, more than 100 human H5N1 flu cases have been diagnosed in Thailand, Vietnam, Cambodia, Indonesia, and China. Of those cases, more than half have died as a result of avian influenza.

Pandemic Versus Seasonal Outbreak of Avian Influenza

Scientists are worried that avian influenza could become an influenza pandemic. An influenza pandemic is different from a seasonal outbreak, or epidemic, of influenza. Seasonal outbreaks are caused by subtypes of influenza viruses that already circulate among people, whereas pandemic outbreaks are caused by:
 

New subtypes 

Subtypes that have never circulated among people 
Subtypes that have not circulated among people for a long time. 
 
Past influenza pandemics have led to high levels of illness, death, social disruption, and economic loss.
 

Human Symptoms of Avian Influenza

Symptoms of avian influenza in humans have ranged from typical influenza-like symptoms (fever, cough, sore throat, and muscle aches) to eye infections, pneumonia, severe respiratory diseases (such as acute respiratory distress), and other severe and life-threatening complications. The symptoms may depend on which virus caused the infection.
 

Prevention and Treatment of Avian Influenza

Vaccines to protect humans against the H5N1 virus currently are under development. In addition, research is underway on methods to make large quantities of avian influenza vaccine more quickly. Studies done in laboratories suggest that the prescription medicines approved in the United States for human influenza viruses should work in treating avian influenza infection in humans. However, the viruses can become resistant to these drugs, so these medications may not always work. Additional studies are needed to demonstrate the effectiveness of these medicines in the long term.