- A failure of a previously fully constituted and functioning immune system is known as a secondary immunodeficiency state. There are a variety of mechanisms by which secondary failure can occur:
- Drug therapy. Chemotherapy is the best example. The cells of the immune system are often actively proliferating cells, and chemotherapy agents are typically directed at the cell cycle. Corticosteroid therapy that depletes lymphocytes is another example.
- Disease processes that involve organs of the immune system can reduce immune responses. Leukemias and lymphomas that involve lymphoid generation or function can lead to immunodeficiency.
- Disease processes can target specific cells of the immune system. The best example of this is HIV infection.
- Human immunodeficiency virus (HIV)
- Human immunodeficiency virus (HIV) is a lentivirus that contains only RNA. In order for HIV to proliferate, it must infect a cell, use its reverse transcriptase enzyme to create a DNA proviral template from its RNA, and put the newly formed DNA into the host cell genome using its integrase enzyme. Cytokine activation "turns on" HIV genes. This allows HIV to take over the biosynthetic function of the cell so that HIV components are manufactured to create new virions. The new virions are packaged and released with the aid of a protease enzyme.
- HIV is a relatively small virus, with about 9200 kilobases. There are a small number of genes that control production of the structural components and the enzymes of the HIV.
- The major cell type infected by HIV, and the one that eventually leads to a immunodeficient state, is the CD4 lymphocyte. HIV has on its surface proteins that allow it to bind to the CD4 cell surface. These proteins bind with CD4 receptor in conjunction with chemokine receptor. The major CD4 binding protein is gp120. The chemokines on infected cells include CXCR4 an CCR5. In addition to CD4 cells, macrophages and dendritic cells are also infected. However, unlike the CD4 cells, which are typically destroyed by infection, the antigen presenting cells survive and become reservoirs of infection that can transport HIV and infect more CD4 cells. Different chemokines expressed on host cells bind different strains of HIV. Thus, there are M-tropic strains (infecting primarily macrophages) and T-tropic strains (infecting primarily CD4 cells).
- Infection with HIV typically occurs across mucous membranes of the genital tract from one infected person to another. Male-male or male-female transmission is slightly more efficient than female-male transmission because there are more virions in seminal fluid than vaginal fluid. Overall, the process is fairly inefficient, since there are relatively few vrions, so that the risk is about 0.3% per sexual encounter. The rate is increased with inflammation from other sexually transmitted diseases (more lymphocytes and macrophages around), from trauma (anal intercourse), or when there is a higher viral load.
- HIV can be initially captured by dendritic cells (Langerhans cells) in the epithelia which present them to CD4 cells. Both dendritic cells and CD4 cells are transported to lymphoid organs, principally lymph nodes, where proliferation of HIV and infection of additional CD4 cells and antigen presenting cells occurs.
- The body's immune response to HIV can include both specific antibody and cytotoxic CD8 cells. Both of these mechanisms are not able to eliminate the HIV and control infection. What happens is continued proliferation of HIV. Over years, the body is able to compensate by increasing production of CD4 cells. However, eventually the depletion of CD4 cells exceeds the capacity for immune reconstitution, and then signs and symptoms of immunodeficiency occur. The progression of HIV infection can be variable. The average time from initial infection to manifestation of immunodeficiency is 8 to 10 years.
- Persons who are "long survivors" of HIV infection may have chemokine receptor variants that reduce the rate at which HIV infects immune cells. Drug therapy for HIV is targeted either at the reverse transcriptase enzyme or at the protease enzyme. Combination therapy with at least three antiretroviral agents (so-called highly active antiretroviral therapy-HAART) can typically slow the course of the disease.
- Since CD4 cells are the major immune cell type that is depleted, the manifestation of the immunodeficiency is primarily as reduced cell-mediated immunity, with increased viral, protozoal, and fungal infections. However, CD4 cells play a role in humoral responses, too, so that eventually there is at least partial failure of humoral immunity.
- Cytokines released by infected macrophages and CD4 cells can produce immune responses that induce local tissue damage, particularly in the central nervous system.
- The loss of immune surveillance leads to the development of neoplastic processes.
- Case Presentation: HIV infection - Acute
- History: A 24 year old previously healthy man has had a low grade fever along with fatigue and myalgias for the past few days. He has had a mild, low volume watery diarrhea for the past two days along with nausea. He has had headache for the past day. On physical examination, you determine that he has a diffuse erythematous maculopapular rash involving the trunk. He has generalized tender lymphadenopathy. He has a mild diffuse pharyngitis.
- What does he have?
- The manifestations are protean, and could represent some sort of acute infectious illness. The findings suggest a viral illness. These findings fit with infectious mononucleosis.
- What other historical findings would be helpful?
- Sexual history. You elicit the history that he is sexually active and has had several partners within the last month. You follow up your questioning and determine that the contacts have been both male and female.
- What laboratory tests could be ordered?
- Monospot and HIV. The former is negative. The HIV test is positive.
- What does he have?
- He has an acute retroviral illness. Primary HIV infection, also known as acute retroviral syndrome, may produce a mild and self-limited disease in 50 to 90% of persons infected with HIV, regardless of the mode of transmission. The time from mucosal infection to viremia is about 4 to 11 days. The time from exposure to development of symptoms averages 2 to 6 weeks. The symptoms may persist for 1 to 2 weeks, after which symptoms subside over 1 to 2 months. Prospective studies of acute HIV infections show that fever, fatigue, arthralgia or myalgia, lymphadenopathy, pharyngitis, skin rash, diarrhea, nausea or vomiting, weight loss, night sweats, mucocutaneous ulcerations, and headache are the most common symptoms seen with acute HIV infection. An acute meningoencephalitis may be seen in some recent infections and appear as an "aseptic meningitis." The symptoms of acute HIV infection resemble a flu-like or an infectious mononucleosis-like syndrome. Primary HIV infection is not life-threatening.
- Is there a drug regimen that you would consider using?
- There is some evidence that antiretroviral therapy in the acute phase may have a benefit in reducing viral load which helps eventually slow progression of HIV disease.
- Case Presentation: HIV infection - Chronic latent phase - time to progression
- History: A 41 year old woman had a positive HIV test 11 years ago. She has had one upper respiratory tract infection and one diarrheal illness in the past year. Her weight is approximately 60 kg and she is 162 cm tall. She has lost approximately 2 kg in the past year. On physical examination, she has no lymphadenopathy or detectable hepatosplenomegaly. Her neurologic function is intact. She appears depressed.
- What do you make of these findings?
- She is probably in the latent phase of HIV infection. Primary HIV infection is followed by a burst of viremia in which virus is easily detected in peripheral blood in mononuclear cells and plasma. In the period of clinical latency of HIV infection, there is little detectable virus in peripheral blood, but viral replication actively continues in lymphoid tissues.
- What can you counsel her regarding her prognosis?
- On average, it takes 8 to 10 years to develop clinical manifestations of AIDS following initial HIV infection. She has beaten the average.
- What determines the course of HIV infection?
- Much has to do with statistical variation. For any one individual, it is difficult to predict. There are variations among strains of HIV that so far have not proven to be better or worse in terms of prognosis. The immune system of an individual will determine what may happen. Some persons (perhaps 10% of persons with HIV infection) will become "long survivors" and live much longer than the average. Some of these persons have been shown to have chemokine receptor variations that make HIV infection of their CD4 cells more difficult.
- Should you inquire about her sexual activity?
- Yes, definitely. Persons with HIV infection who appear well can pass the virus on to others. The patient should be counselled regarding this fact and should let sexual partners know her HIV status.
- Is there a drug regimen that you would consider using?
- No, not at this stage of her HIV disease.
- Case Presentation: HIV infection - antiretroviral therapy
- History: A 35 year old man has been known to be infected with HIV for the past 7 years. He is continuing to work at his regular job. He has developed persistent oral thrush in the past two months. Laboratory testing reveals a CD4 lymphocyte count of 384/microliter and an HIV-1 RNA plasma load of 2850 copies/mL. His weight has remained stable for the past 3 years.
- What do these findings suggest?
- He appears to be entering a late phase of HIV infection with a progression to clinical AIDS.
- What should be done?
- He qualifies for antiretroviral therapy. The use of highly active antiretroviral therapy (HAART) can slow the progression to AIDS and, at least in part, help reconstitute the immune system. There are three disadvantages of HAART: (1) it is expensive, costing thousands of dollars per year per drug, (2) at least three antiretoviral drugs must be taken with strict adherence to complex dosing protocols, and (3) the drugs can have serious side effects.
- How do you follow this patient?
- The plasma HIV-1 RNA level can be used to determine the effectiveness of HAART. Ideally, the plasma viral load should be suppressed to undetectable levels. An increasing level suggests treatment failure and possible drug resistance. The patient should be monitored for development of AIDS-related illnesses. If the CD4 count drops below 200/microliter, then prophylaxis for opporuntistic infections such as Pneumocystis should be considered.
- Case Presentation: HIV infection - Late - AIDS
- History: A 42 year old man has had HIV infection for the past 10 years. He has been on HAART for the past 2 years. He currently has a plasma HIV-1 RNA of 30,500 copies/mL. His CD4 count is 79/microliter. He recently had a bout of Pneumocystis carinii (jirovecii) pneumonia, despite receiving prophylactic therapy with trimethoprim-sulfamethoxazole (Bactrim).
- What do these findings indicate?
- He has clinical AIDS in a late stage that is progressing despite therapy.
- What options are available at this point (consider quality of life issues)?
- One could continue to battle HIV with additional HAART combinations. Alternative medical therapies are popular with patients with incurable diseases. The therapies do not halt the progression of the disease, but the quality of life may be subjectively better in such patients, and they don't cost a lot. The most commonly reported alternative therapies for AIDS include exercise, lifestyle changes, dietary supplements, counseling, herbal medications, megavitamins, and prayer. Of the persons who used such therapies, 70% reported a quality of life improvement.
- Case Presentation: HIV infection - Congenital AIDS
- History: A 23 year old G2P1 woman gives birth to a term baby. The baby has no evidence for congenital anomalies. The baby does well for several weeks, but then is no longer gaining weight as much as expected. Over the next 5 months, the baby has a watery diarrhea that persists for weeks at a time. At 4 months of age, the baby becomes septic and is treated for Hemophilus influenzae meningitis. On physical examination at 6 months of age, the baby is noted to have generalized lymphadenopathy. Oral thrush is noted as well. Laboratory findings include:
| Hgb |
9.4 g/dL |
| Hct |
28.3% |
| MCV |
99 fL |
| Platelet ct |
97,000/microliter |
| WBC count |
3334/microliter |
| WBC diff |
39 segs, 4 bands, 42 lymphs, 15 monos |
- Quantitative Immunoglobulins
-
| IgA | 52 mg/dl | 8 - 67 |
| IgG | 713 mg/dl | 206 - 676 |
| IgM | 101 mg/dl | 33 - 97 |
- What do these findings suggest?
- The number and nature of the infections suggests an immune deficiency. The CBC shows a pancytopenia. However, there is no deficiency of immunoglobulins. A primary or secondary immunodeficiency is possible. Disorders of humoral immunity are unlikely. One could order tests for analysis of cell mediated immunity.
- Additional laboratory findings include:
-
| Lymphocyte subsets |
|
|
| CD4 cells (absolute) |
402 |
1580 - 4850 |
| CD8 cells (absolute) |
1001 |
680 - 2470 |
NBT test of neutrophils is normal
- What do these findings suggest and what tests can you order?
- There is a marked reduction in CD4 cells. There is no primary immunodeficiency state that does this. The secondary immunodeficiency state associated with a diminished CD4 count is caused by HIV infection. You cannot order the standard HIV test done by enzyme immunoassay that looks for antibody, because you may just detect maternal antibody. Instead, you must look for HIV antigen, DNA, or RNA. Additional findings in this case include:
- HIV-1 RNA 500 copies/mL
- HIV-1 RNA 500 copies/mL
- What additional history would you like to obtain?
- The maternal history is important. The mother obviously has to be infected (her HIV test is positive) and her risk factors and contacts need to be pursued. HIV infection is a reportable infectious disease in all states, and the health department must follow up the contacts of the infected person.
- What is the pathophysiology of the baby's condition?
- HIV can be congenital. About 30% of congenital HIV infections are acquired in utero, 60% around the time of delivery, and 10% via breast milk. Congenital HIV infection has a variable course-some babies may manifest opportunistic infections with a low CD4 count indicative of AIDS soon after birth, while immunologic deterioration takes years in most cases.
- Could this have been prevented?
- It would be most useful for persons at risk for HIV infection to be tested prior to becoming pregnant. Testing in the obstetrical setting is still important, because giving zidovudine to the mother can reduce the risk of transmission from an average 25% to 8%. They can be counselled to avoid breast feeding.
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