Opportunistic infections

ANATOMY OR SYSTEM AFFECTED: All

DEFINITION:Diseases caused by microorganisms; typically do not cause severe illness in otherwise healthy people but are potentially life-threatening in people with weakened immune systems

CAUSES: Viruses, bacteria, fungi, protozoa

SYMPTOMS: Fever, weakness, lack of appetite, rash, cough, difficulty breathing, confusion, headache, blurry vision, chest pain, weight loss, night sweats

DURATION: Acute to chronic

TREATMENTS: Antibiotics, antiviral medications, antifungal medications, antiprotozoan medications

Causes and Symptoms

Opportunistic infections can be caused by various microorganisms, including viruses, bacteria, fungi, and protozoa. While they are capable of infecting healthy persons, the infection is typically either without symptoms or with only very mild symptoms. It is only in those who lack a healthy immune system that these organisms cause disastrous infections. Acquired immunodeficiency syndrome (AIDS), resulting from human immunodeficiency virus (HIV), is a widely known disease that weakens the immune system. Other situations that can cause the immune system to be compromised and become susceptible to opportunistic infections include being on chronic glucocorticoid therapy, taking immunosuppressive medications after organ transplantation, undergoing chemotherapy for cancer, being malnourished, or having a genetic predisposition.

Pneumocystis jirovecii is a fungus capable of causing life-threatening pneumonia in the immunocompromised. In those with HIV, the majority of Pneumocystis pneumonia cases develop in those with a very low CD4 cell count. Common symptoms include fever, cough, progressive difficulty breathing (especially with exertion), fatigue, chills, chest pain, and weight loss.

Toxoplasmosis is a ubiquitous infection caused by the intracellular protozoan parasite Toxoplasma gondii, which makes cats its host. Transmission is via ingestion of contaminated soil or undercooked meats that contain the protozoan oocyte. Infection in the healthy person is usually asymptomatic, but the organism can remain dormant in the host indefinitely. In immunocompromised patients, such as those with very low CD4 cell counts, the organism reactivates and causes active infection. The central nervous system is the principal site of involvement. T. gondii can cause encephalitis and masses within the brain. Symptoms may include confusion, fever, seizures, and headache. T. gondii can also cause pneumonia accompanied by difficulty breathing, fever, and cough. Other organs, such as the intestines, liver, bone marrow, bladder, spinal cord, testes, pancreas, eyes, and heart, can also be infected, although this is less common. Pregnant women who have an active infection can pass it to their offspring, leading to infantile neurological deficits, intellectual disabilities, and eye infections.

Mycobacterium avium complex (MAC) causes widespread disease in the immunocompromised. It consists of two nontuberculous Mycobacterium species, M. avium and M. intracellulare. These organisms are ubiquitous in the environment and are transmitted typically through inhalation or ingestion. Acquisition of infection typically takes place when the CD4 count is extreme low. Symptoms include fever, night sweats, abdominal pain, diarrhea, weight loss, weakness, and wasting.

Cytomegalovirus (CMV) is a herpes virus found worldwide. It is commonly transmitted via feces, saliva, breast milk, urine, or genital secretions. In immunocompetent individuals, the virus remains latent and usually does not cause any severe disease. In the immunocompromised, however, the dormant virus reactivates, and infection occurs. Symptoms generally include fever, night sweats, chills, fatigue, and muscle and joint aches. Other symptoms depend on the organ system affected. Gastrointestinal involvement typically produces symptoms of colitis (inflammation of the colon), such as abdominal pain and bloody diarrhea; lung involvement produces a pneumonitis (inflammation of the lung) along with coughing and difficulty breathing; and eye involvement (retinitis) can lead to blindness. The adrenal gland and the nervous system can also be affected.

Another opportunistic fungus associated with immunocompromised hosts is Cryptococcus neoformans, which causes cryptococcosis. The organism is normally found in soil contaminated with pigeon droppings, and transmission is usually through inhalation. The initial site of infection is in the lungs, from where it subsequently spreads to the brain, causing what is known as meningoencephalitis (inflammation of the brain and its surrounding protective tissues). Meningoencephalitis is the most common clinical syndrome in immunocompromised patients, developing slowly over one to two weeks, with symptoms including fever, malaise, headache, stiff neck, photophobia (aversion to bright lights), and vomiting. Disseminated rash is another symptom that occurs in those with a weakened immune system.

There are many other causes of opportunistic infections, including the viruses Varicella and herpes simplex; the Nocardia, Listeria, and the less common Mycobacterium species; the protozoans Cryptosporidium, Isospora, Microsporidia, and Cyclospora; and the fungi Coccidioides, Candida, Histoplasma, and Aspergillus. While all these organisms are capable of causing disease in the healthy, their impact on the immunocompromised is much more severe.

Treatment and Therapy

Treatment of specific infections is important, but what is more important is to correct the underlying deficit, which is the weakened immune system. In some cases, this may not be possible, such as in those who require immunosuppressive therapy after organ transplantation or those undergoing chemotherapy for cancer. However, advances in HIV therapy, such as the implementation of highly active antiretroviral therapy (HAART) and the institution of prophylaxis against opportunistic infections, have dramatically decreased the mortality rate in these patients.

Treatment of Pneumocystis pneumonia requires the demonstration of organisms from respiratory specimens. Treatment consists of anti-Pneumocystis regimens typically for twenty-one days, with or without corticosteroids. The latter is used in severe cases when oxygenation becomes problematic. Symptoms typically worsen after two to three days of therapy as a result of increased inflammation in response to dying microorganisms. After initial therapy, prophylactic therapy against future infections is instituted.

Treatment of toxoplasmosis requires antiprotozoan medications for at least six weeks. Prophylaxis against future infection is also required, which is the same medication as that used for Pneumocystis prophylaxis. In high-risk persons, as a means of prevention it is important to avoid undercooked meats and cat litter boxes. Treatment of MAC involves combination antibiotics for at least twelve months, with subsequent prophylaxis.

CMV infection is treated with antiviral agents. Immunoglobulin may be used to reduce the risk of infection in certain transplant recipients. If the eye is involved, then a pellet that releases an antiviral agent may be implanted into the eye with surgery. While not curative, this treatment may hinder the progression of the eye disease.

The treatment of cryptococcosis is with antifungal agents, initially with combination medications for what is known as induction therapy, followed by consolidation therapy, and finally maintenance therapy. Because the disease can also cause an increased pressure surrounding the brain, frequent lumbar punctures are sometimes required to relieve this pressure. If it is severe enough, a drain placed in the spinal cord may be necessary to continuously relieve the pressure.

While prophylactic therapy is needed when the CD4 cell count is low, it may be withdrawn when the CD4 cells improve.

Perspective and Prospects

Pneumocystis was originally identified by the Brazilian physician Carlos Chagas in 1909. Chagas was also the discoverer of the protozoan Trypanosoma cruzi, the organism that causes Chagas disease, a form of trypanosomiasis. Initially, he mistakenly thought that the Pneumocystis cysts found in the lungs of rats were part of the T. cruzi life cycle. It was in 1910 that the Italian physician Antonio Carini discovered that these cysts were also present in lungs without T. cruzi infection, and he thus concluded that these cysts were a different type of infection. In 1912, Pierre and Marie Delanoe at the Pasteur Institute also confirmed that these cysts were present in the absence of T. cruzi infection, and they subsequently named the cystlike organisms Pneumocystis carinii, after Carini. Because these infections appeared to affect only rats, however, the organism did not become a major issue at that time.

It was not until the 1940s that P. carinii was found to cause pneumonia in human infants and adults. However, these patients all had compromised immune systems, whether from malnutrition, genetic immune deficiencies, or immunosuppressive medications. Before the AIDS epidemic, there were fewer than one hundred confirmed cases per year in the United States. It was later determined that there are several species of Pneumocystis, one of which causes disease in rats and another in humans. It was in 1999 when the name P. jirovecii (named after the Czech parasitologist Otto Jiroveci) was officially coined to refer to the organism that infects humans. P. carinii still refers to the disease-causing organism in rats. It was also in 1999 that Pneumocystis was recognized as a fungus rather than a protozoan, as previously thought.

In late 1980 to early 1981, the described a cluster of five cases of Pneumocystis pneumonia in young gay men. Subsequently, the number of cases of Pneumocystis pneumonia increased, as did the number of Kaposi sarcoma cases (rare HIV-related skin cancer). It was soon realized that both of these illnesses also affected heterosexuals, intravenous drug users, and others who were immunocompromised. In 1982, the CDC officially coined the term “acquired immunodeficiency syndrome,” or AIDS, for this syndrome. In 1983, Luc Montagnier and his team from the Pasteur Institute isolated a virus that was thought to be the causative agent of AIDS, which they termed lymphadenopathy-associated virus. In 1984, Robert Gallo and his team from the United States also isolated a virus presumptive to cause AIDS; they named it human T lymphotropic virus type III (HTLV-III). Later, it was recognized that both viruses were the same, and the virus was officially termed human immunodeficiency virus (HIV) in 1986.

In the beginning of the AIDS epidemic, death was certain. Treatment of HIV did not begin until 1986, when the Food and Drug Administration (FDA) approved the first antiviral agent, zidovudine, a nucleoside reverse transcriptase inhibitor (NRTI)—an agent that inhibits viral replication. However, single-agent therapy did not prove to be as effective due to drug resistance. In 1995, newer classes of antiviral medications were approved—non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI)—and began the trend of combination therapy of what is now known as highly active antiretroviral therapy (HAART). The thought behind combination therapy is that if the virus develops a genetic mutation and becomes resistant to one drug, the other two will still be active against it. However, while successful, even this powerful combination of drugs is still not adequate to achieve a complete cure, since the virus is capable of remaining dormant inside cells and becoming resistant to medications after even a brief episode of missed doses.

In 2007, the FDA approved two new classes of antiretroviral therapy, integrase inhibitors and CCR5 co-receptor antagonists, which are used for advanced stages of HIV infection.

As of 2023, there are currently no available vaccines effective against HIV, although there are vaccines in various stages of clinical trial. A report in 2009 of a study of healthy volunteers with an experimental HIV , RV144 in Thailand showed only a modest success rate (about 31 percent) in the prevention of HIV. However, the trial helped researchers better understanding the type of vaccine needed. While there are still obstacles to conquer in the fight against HIV, the battle against opportunistic infections has made great strides with the introduction of HAART and prophylactic medications.

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