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Infection in the Immunocompromised Host

I'm going to talk about the management of complications of infections - both in HIV-infected individuals as well as other people with compromised immune systems. CD4 deficits result in infections with pathogens that require T cell function. The majority of opportunistic complications that occur in HIV infection are pathogens that need T cells that we have usually used T cells to defend against. However, there are defects also in B cell function at early stages of infection and this is why, in early infection, some of the earliest manifestations of disease may be recurrent bacterial pneumonia with pneumococcus.

What are the most opportunistic complications in HIV infection? As I mentioned, these are the common pathogens that require T cells to defend. These include Pneumocystis carinii and Toxoplasma gondii. Pneumocystis most commonly presents as a pneumonia. Toxoplasma most commonly presents as a central nervous system infection. Cytomegalovirus, in HIV infection, most commonly presents as eye involvement or retinitis and this is one of the unique manifestations of CMV in HIV disease, is that it presents with eye involvement, which is very rarely seen in any other immunocompromising state. Mycobacterium avium complex is an atypical mycobacterium that presents in late stage HIV infection, which we will talk about. This is a pathogen that essentially was considered a curiosity until the AIDS epidemic in the mid 1980's. This organism really shows you the profound defect.

Cryptococcus and Candida are the two most common fungal pathogens. Cryptococcus most commonly presents as a meningitis and Candida most commonly presents as mucosal involvement - either in the mouth, esophagus or recurrent vaginitis. Human papilloma virus can present either as genital warts or as a precursor lesion for cervical cancer in women and anal carcinoma.

What causes this immune hit is the decline in CD4 positive T lymphocytes. These are the different kinds of white cells that are circulating and in tissue and the T lymphocytes are made up predominantly of CD4 and CD8 positive cells. As HIV progresses, the numbers of CD4 cells go down, their function decreases as well and various things happen to CD8 cells, some of which we do not understand. Whether or not these are still working or not probably also influences what happens to people over time.

Over the course of infection, a healthy person's T cells are made up of naive cells, memory cells for the most cells, and these naive T cells are capable of responding to newly presented pathogens, whereas the memory cells are already programmed to respond to certain pathogens, so we have memory cells which are PCP cells so that when we get exposed to Pneumocystis, these memory cells get called into action by the infantry in the immune response and defend against that pathogen. We have memory cells for mycobacteria, tuberculosis and other infections. When someone gets infected with HIV and then progresses.

In terms of preventing opportunistic complications, we judge prevention based on where somebody's immune system is. Pneumocystis carinii is the most common opportunistic pathogen in HIV infection. The risk for this disease increases when the CD4 count is less than 200. So these are the people we think about preventing the disease or after an event of oral thrush.

The first choice for prophylaxis is trimethoprim sulfa given usually at a dose of one double strength daily. There are alternative regimen; one double strength three times a week, one single strength daily. TMP sulfa is a big pill and some people can't tolerate it. The single strength pills are smaller and a little better tolerated. All of these are acceptable regimens, but the recommendation from the Public Health Service is one double strength daily. The reason why this is preferred over the alternatives.

Toxoplasma risk occurs at a CD4 count of less than 100 to 150 or so. The nice thing about this is that TMP sulfa is also effective prophylaxis for toxoplasma. Since you are prophylaxing for Pneumocystis at a count of less than 200, those people will also be effectively prophylaxed against the development of toxoplasma.

Pyrimethamine, dapsone and atovaquone are also acceptable alternatives, but TMP sulfa is the first choice here. It is a useful screen to do an IgG antibody to determine who is at risk but it is a screen - it may be negative, particularly in late-stage disease and this may occur in up to twenty to thirty percent of individuals. So again, this is less relevant because you are using TMP sulfa anyway to prevent the PCP, so it's not like you are going to make a decision based on an IgG antibody.

Mycobacterium avium complex risk increases at much lower CD4 counts. A CD4 count of less than 50 is when the vast majority of cases of this disease occur. Prophylaxis can be given with clarithromycin at 500 mg twice a day or azithromycin 1200 mg once a week. This is when you would use azithromycin to treat bacterial sinusitis, pneumonia, bronchitis.

For MAC infection, there is actually better data. If the CD4 count goes above 100 for three to six months and virologic suppression is maintained, disease is unlikely, i.e., there have been no cases and prophylaxis can be stopped. So this is a more selected group - not just do the counts go up, but the virus needs to be suppressed. People are extending this observation now, looking at people who respond and their virus is not completely suppressed and that data is being accumulated. Normally, when we treat people with MAC infection with HIV disease, we treat for life. If someone bounces their CD4 count up, it is not in general listed by the Public Health Service that treatment be stopped. However, many people are using these same criteria to stop therapy after six months to see what happens; that data is ongoing as well. You can pretty safely stop prophylaxis therapy and follow the patient closely. Again, if the count goes below 100, prophylaxis should be restarted.

For CMV infection, findings are similar. If CD4 count goes up for three to six months with a suppressed viral load and if the infection is not life threatening, since we don't use primary prophylaxis for CMV, we are talking about people who have had disease and now have a CD4 response and are doing well. The reason it is important here is because therapy here is more invasive; it often is an IV that someone is getting either daily or every week or every other week, so stopping therapy here would be potentially a big advantage. Because it is the eye, and because you are worried about vision.

Now let's look at some clinical presentations and discuss the most likely diagnoses. One of the common clinical presentations is fever and diffuse pulmonary infiltrate. So someone comes in with fever, cough and has an x-ray that shows not a lobar pneumonia, but diffuse infiltrates. The CD4 count here is incredibly important because again, we talked about what happens at less than 200; that is when you see PCP. You can see tuberculosis regardless of where the CD4 count is, but below 200.