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Opportunistic Infections in 2011

September/October 2011

There was a time when living with HIV meant having to dodge one opportunistic infection bullet after another. In the absence of potent and durable HIV therapy, it was not a question of when, but rather, which nasty, weirdo bug would rear up to put you down.

Before AIDS, words like pneumocystis and toxoplasmosis would have been gibberish to a medical student but, with the epidemic, these and the names of other opportunistic infections, or OIs, became part of a lexicon of dread spoken in San Francisco, New York, and other HIV hot zones. If we now live in the era of highly active antiretroviral therapy (HAART), then it was the era of OIs.

To understand OIs and why they happen, one must appreciate the fortress that is our immune system, built over millennia of natural selection. There are gazillions of germs around and, indeed, inside us that need to stay out of areas of our body that must remain sterile. Those with immune defenses that could keep pathogens in their rightful place and protect the body when attacked from without or within lived to see another day (and also make babies). Those who did not, well, they did not have much fun. The upside of evolution's weeding out the weak is that those who went on to be fruitful and multiply were strong and we, their daughters and sons, are the inheritors of their rich immune systems.

However, all bets are off when a novel virus like HIV attacks the very immune cells responsible for keeping the barbarian bugs outside the walls of our bodily sanctuaries. As the CD4 cell count falls, new infections that come along may fester and spread, rather than being dealt a swift blow by a valiant white blood cell; dormant infections, acquired in some sandbox as a toddler, can emerge as if from some spell and multiply, wreaking their own havoc.

With HAART, however, the empire strikes back and OIs have become endangered in places where potent HIV therapy is a reality. CD4 cells rally in response to durable suppression of the virus and the opportunistic infections that preyed on weak immune systems may have fewer opportunities. Today, OIs are probably the least of your concerns, unless you are one of the millions of people for whom HAART is not available. In fact, in some resource-rich nations, people living with HIV and their health care providers are now preoccupied with the possible consequences of long-term survival and not the maladies that first made us take notice of a new disease 30 years ago. Tellingly, once again medical students know little of pneumocystis and other OIs of yore, as they do not see them often.

Yet, more remains of OIs than a dark legacy. They are down but not out. Sometimes, those who are unaware they are HIV-positive, those who are HIV-positive but not on HIV therapy, or those who are not ready to take their HIV medications correctly present with OIs, some of which are life-threatening. Furthermore, it's bad enough that these OIs can directly cause trouble, but they also may complicate HIV therapy. The rebuilding of the immune system that accompanies successful HAART can trigger an inflammatory response to opportunistic pathogens. It is as if a long-sleeping immune system groggily awakes only to find OIs running amok and then overreacts. These immune reconstitution syndromes can be as damaging and dangerous as the infections themselves.

Despite this risk, several studies indicate that starting HIV therapy soon after the diagnosis of an OI can be lifesaving compared to waiting until weeks later when control of the OI is achieved. The main study to look at this in the U.S. was conducted by the federally funded AIDS Clinical Trials Group (ACTG) and enrolled patients with a variety of OIs, but most had pneumocystis pneumonia and bacterial infections (those with tuberculosis were excluded).1 Immune reconstitutions happened but were not common in this study, and the benefits of HIV therapy led to more aggressive use of antiretrovirals in those with pneumocystis and some other OIs.


Mostly Gone but Not Forgotten

Below is a brief rundown of five OIs. For most readers, this is a catalogue of diseases you will never develop. For all, these diseases are a frightening reminder of what life can be like without potent HIV therapy.


Pneumocystis Pneumonia

This is the sine qua non of OIs and was the sentinel infection seen among gay men three decades ago that signaled the emergence of a new syndrome, later called AIDS. Long identified as pneumocystis carinii, it causes a devastating pneumonia, hence its shorthand is PCP, the last P for pneumonia. In 1999, the germ was renamed pneumocystis jiroveci in honor of Otto Jirovec, who in the 1950s was first to describe the organism in humans. (So, officially, we should be calling this PJP but many of us, especially those of us long in the tooth and gray in the hair, can't stop saying PCP.)

This organism is found in the environment and is essentially harmless to those with intact immune systems. However, when inhaled by someone with HIV disease and a weakened immune system, it can cause a pneumonia that can spread across the lungs, and trigger inflammation and swelling of the lung tissue. In some cases, cysts in the lungs form and pop, leading to collapse of the lung. As fluid accumulates in the lungs, oxygen levels in the body fall. Infected patients develop progressive shortness of breath, especially when walking or exerting themselves. Over the course of days, this can worsen. While cases of pneumocystis in other parts of the body outside the lungs have been reported, this is unusual.

The diagnosis is often suspected when someone with AIDS presents with shortness of breath. A chest x-ray may show involvement across the lungs or only a part of the lung. In some cases, the chest films can be mysteriously normal in appearance, despite extensive infection. Sampling of deep down sputum can lead to the diagnosis by laboratory tests that can identify the germ quickly. A fiberoptic scope, called a bronchoscope, may be needed to get such material, as many people with PCP have a dry cough or produce only scant, pearl-colored sputum.

Given the severity and high attack rate of PCP, it was an early target for intervention and some of the earliest HIV clinical research studies were directed at prevention and treatment of PCP. Today, doctors can treat PCP effectively. Most importantly, PCP may be almost completely prevented with prophylaxis. PCP prophylaxis made a huge and immediate dent in AIDS mortality, even before HAART.

It is recommended that those with a CD4 cell count below 200/mm3 take some form of PCP prophylaxis. For people who start PCP prophylaxis at low CD4 cell counts who then start HAART, prophylaxis can be safely stopped once the counts rise and stay above 200/mm3.2 You can speak to your doctor about your risk and prophylaxis, as well as treatment options.


Toxoplasma Encephalitis

If pneumocystis is an unwelcome visitor, toxoplasma is a guest that stays, refuses to leave, and then messes with your head. Unlike pneumocystis and other OIs that people catch and get sick from, this parasite is an opportunist that is present in the body long before HIV disease weakens the immune system. Only then, when the remnants of the immune system can no longer contain the dormant infection, does the parasite emerge.

Toxoplasma is ingested in raw or under-cooked meat or, inadvertently, cat feces. It is not uncommon in places where meat is preferred on the rare side. In France, the land of steak tartare and goose liver pate, antibodies to toxoplasma that indicate prior exposure and infection are found in the majority of adults. In the U.S., where we tend to like our food charbroiled, fried, or steamed, fewer people are infected.

Upon initial infection with toxoplasma, illness can develop, but then the immune system contains the parasite, which lays low, trouble free. When the immune system is profoundly weakened, like during AIDS, toxoplasma can reactivate and spread. The brain is a favorite site for toxoplasma to take up shop and there it can mass into large tumor-like lesions. Patients present with changes in their thinking and can have a headache and neurological deficits, depending on where the parasite lesions are located. Seizures are not uncommon. The disease can sometimes strike beyond the brain and involvement of the spinal cord and the lungs has been recognized.

This is a tough disease, almost always occurring in people with very advanced AIDS, typically in those with CD4 cell counts below 50/mm3. The diagnosis can be a difficult one to make, since on brain scans like MRI and CT, the brain lesions can look a lot like other infections or cancers, such as brain lymphoma. In the early days of the HIV epidemic, a practical approach to the diagnosis was established as a sort of gentleman's agreement between HIV clinicians and their brain surgeon colleagues, who were often called on to perform a diagnostic brain biopsy. Aggressive treatment for toxoplasma was started in patients with AIDS and suspicious brain lesions and response would indicate the diagnosis of toxoplasmosis to be correct. However, after two weeks, if the lesions remained unchanged or worsened despite toxoplasma therapy, the surgeon would then attempt a brain biopsy to obtain tissue for a diagnosis. Bets are hedged that brain lesions are toxoplasma if the patient has no evidence of antibodies to the parasite in the blood. However, some people with toxoplasma may even lose the ability to make these antibodies, although this is not common.

Treatment for toxoplasma can be effective, but recovery can take time.

Prevention of toxoplasma is usually covered by the same medications used for PCP prophylaxis. Use of medications to prevent toxoplasma may need to be added for those with profoundly low CD4 cell counts (50 to 75/mm3 or less). Patients with AIDS should not handle cat litter, although most cases of toxoplasma in AIDS are from reactivation of disease and not newly acquired infection. As with most OIs, treatment and prevention of toxoplasma is not required once an individual's CD4 count increases to above 100.


Cryptococcal Meningitis

Cryptococcus is a type of yeast that is found throughout the world, especially in certain trees, like the eucalyptus, and the air and soil beneath them. The fungus can concentrate in bird feces, although birds themselves are not infected, and therefore antibodies to the germ are more commonly found in pigeon handlers. Until the HIV epidemic, it was a rare infection of humans.

With AIDS, cases of meningitis due to Cryptococcus dramatically increased. It is a particularly brutal infection. The organism is first inhaled, causing a mild to moderate lung infection, then slowly spreads, typically to the meninges, the lining of the brain. The meninges do not like this at all. They swell in response. Yeasts multiply with abandon and start to clog up the parts of the brain that drain spinal fluid. Pressure can build in the head, squeezing nerves and the brain itself. Untreated, this results in death, as the soft brain is pushed down into the small opening at the base of the skull where the brainstem and spinal cord connect.

Like most types of meningitis, that caused by Cryptococcus is heralded by headache. The brain is initially not involved; therefore, unlike in toxoplasma encephalitis, thinking is usually unaffected. Neck pain may or may not be present. Cranial nerves that control eye movement course along the skull and, with a buildup of pressure, may be squeezed against the bone, producing an inability to move an eye in one or more directions.

The diagnosis is often made rapidly and that is essential. Tests of the blood and spinal fluid can identify the yeast within hours. Cryptococus can be effectively treated, though it may include challenging side effects. Repeated spinal taps may also help control the pressure around the brain and in some recalcitrant cases, a shunt that drains the fluid from the head into the belly must be inserted and tethered down in the neck and through the chest.

If caught early, recovery may be expected and with eventual improvement of CD4 cell count, treatment can be discontinued. However, the optimal timing of HAART in those with cryptococcal meningitis is unclear. Immune reconstitution reactions to Cryptococcus triggered by HAART can further increase pressure inside the head with devastating consequences. Some data suggest this is more likely early in infection, while other studies indicate that such reactions can occur even if HAART is delayed for weeks.3,4

At present, cautious introduction of HAART is considered after about two weeks of treatment for Cryptococcus. For those with more severe meningitis, some wait longer, until the infection and intracranial pressure are under better control.


Mycobacterium Avium Complex (MAC)

MAC may be one of the most misunderstood of the AIDS OIs. The whole "mycobacterium" thing confuses people into thinking this is a form of tuberculosis (Mycobacterium tuberculosis) and that it is contagious or is responsible for causing pneumonia. It isn't and generally does not.

MAC refers to a group of related organisms that cause similar disease, although most all of these infections are due to one type, called Mycobacterium avium. This OI is subtle. It eschews the bravado of its OI kin and their showy entrances of air hunger, seizures, and brain squeezing. After being breathed in or ingested, MAC disseminates and slowly starts to wear the body down. Fevers start. Weight drops. The patient tires easily. Much of what we picture in advanced AIDS is a product of MAC. Over time, internal lymph nodes, in a last effort at some response, can swell to contain the germ, only to start pressing on nearby organs, causing pain in the abdomen or obstruction of the intestines.

The symptoms of MAC are tell-tale and a blood culture usually detects the bacteria. Treatment response is the rule, rather than the exception. MAC can be treated and prevented. Prophylaxis is recommended for those with CD4 cell counts below 50/mm3. Immune reconstitution to MAC may occur, but can also be treated.


Cytomegalovirus (CMV)

CMV is in a family of virus we all know and hate, herpes. The herpes viruses include HSV (types 1 and 2), VZV (responsible for chickenpox and shingles), EBV (causes mononucleosis and certain types of cancers), HHV-8 (leads to Kaposi's sarcoma), and CMV. A shared family trait is that these viruses are common in humans and once they enter the body, they never leave. All herpes viruses can cause disease and then hide away in the body only to return another day.

CMV is found in most adults. The virus can be caught as a child from the mother or other children. It is also transmitted sexually. Acute infection in neonates can be serious. In adults, infection may cause a mononucleosis-type illness or be completely unnoticed. CMV can cause a variety of diseases, but in people with profound AIDS, its major role on the OI stage is as an infection of the retina of the eye. CMV retinitis was a major scourge of the 1980s and early 1990s when regular eye examinations were an integral part of routine HIV care. Caught early, vision might be able to be controlled with treatment. Found late, vision loss and blindness were common. The virus also caused trouble elsewhere, including the colon, brain, spinal cord, adrenal glands, pancreas, and other organs. In transplant recipients, with immune systems dialed down by medications to prevent organ rejection, CMV is a major problem but more often causes pneumonia and, much less commonly, retinitis.

Treatment for CMV disease was onerous and required indwelling central intravenous catheters and hours of hook ups to medications. Eye surgery was often done to correct the damage or implant devices to leak drugs into the eye to control the wildfire of CMV retinal disease.

However, CMV disease was one of the OIs to retreat the quickest with the first antiretroviral cocktails. One day, people were walking into clinics with white flashes and blind spots and the next day they weren't. It was amazing. There were bad cases of immune reconstitution to CMV, most notably, clouding of the fluid of the eye that led to loss of vision. This is almost unheard of nowadays.

CMV may continue to do some dirty work in people living with HIV. There is some tantalizing evidence that a component of the inflammation associated with HIV may be due to co-infection with CMV.5 The theory is that a relative inability of those with HIV, even at higher CD4 cell counts, to keep the virus in check allows it to replicate and trigger immune activation and subsequent inflammatory chemical release. More work is being done to follow up on this and to determine if treating CMV has a role in reducing risk of inflammation-related diseases in people with HIV.


Other OIs

There are many other important OIs. In the middle of the country, people with HIV are at increased risk of histoplasmosis, a fungus that behaves a lot like TB in its presentation. TB itself is an opportunist that preys on those with HIV, especially when CD4 cell counts starts to dwindle, and is the leading OI of consequence in the developing world. Candida causes thrush, and may be an early sign of HIV; varicella virus (VZV) re-emerges as shingles; a germ called JC virus leads to progressive multifocal leukoencephalopathy (PML), an often fatal brain infection that can leave patients bewildered and debilitated; and bugs that cause diarrhea, like cryptosporidia, can always ruin someone's day. The good news is that these, like the classic OIs described above, are on the run. The bad news, they are not completely gone. OIs are often geographic and other pathogens predominate in different parts of the world, an issue for the traveler with HIV and low CD4 cell counts.

Other infections have become the new OIs. Human Papilloma Virus (HPV) is at the root of cancerous and pre-cancerous lesions on the cervix, anus, and mouth. These cancers can happen in those with intact immune systems and, therefore, in those living with HIV, infection may be seen across the CD4 cell count spectrum. In some ways, syphilis has become an HIV opportunist, not by dint of a waning immunity, but because of behavior and the opportunities to spread among those with HIV and their partners. Mini-epidemics of the disease among men who have sex with men are occurring all over the country.


Conclusion

OIs are no longer the plague on top of the plague that they once were, at least in the U.S. and other places where HAART is widely available. That means that the people most at risk for serious OIs are those unaware of their HIV infection, those without access to or not ready to start antiretroviral therapy, and those who are not able to adhere to HIV treatment. In addition, there are the people who are veterans of the HIV battle and have exhausted all treatment options or whose CD4 cell counts remain stuck below 200/mm3 even though their HIV is controlled.

The concentration of risk of OIs in these groups remains a challenge for the HIV treatment community. For most of those living with HIV, however, OIs should be a back-burner issue. HAART, earlier diagnosis of HIV infection, and increased access to quality HIV care means it is much more likely a person with HIV will live a healthier life. And that is the way it should be.

David Alain Wohl, M.D., is an Associate Professor of Infectious Diseases and Co-Director of the AIDS Clinical Trials Unit at the University of North Carolina. Metabolic complications associated with HIV infection and the nexus between HIV and incarceration are his major areas of research interest. His e-mail address is wohl@med.unc.edu.

This article is supported by funding from Merck.


References

  1. Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4(5):e5575.
  2. Furrer H, Egger M, Opravil M, et al. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. New England Journal of Medicine 1999;340:1301-6.
  3. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC. Clin Infect Dis. 2010 Feb 1;50(3):291-322.
  4. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009 10;58(RR-4).
  5. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. Naeger DM, Martin JN, Sinclair E, Hunt PW, Bangsberg DR, Hecht F, Hsue P, McCune JM, Deeks SG. PLoS One. 2010.

This article was provided by Positively Aware. It is a part of the publication Positively Aware. Visit Positively Aware's website to find out more about the publication.
 
See Also
Strategies for Managing Opportunistic Infections
More on Opportunistic Infections & Complications
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