Fungal disease deaths: just ‘$30 a person’ for global AIDS reduction

Manchester University. UK: Early detection and treatment of fungal meningitis and pneumonia can save hundreds of thousands of lives, for a cost of 'only $30' per HIV patient, a conference convened by a University of Manchester academic has concluded.

Hormonal Contraception and the Risk of HIV Acquisition

Plos medicine: In a recent study (meta-analysis), Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa. AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV.

Awakening Cells’ Killer Instinct: Scientists Train Immune System to Destroy Cure-Defying Mutant HIV

Johns Hopkins. US: Soon after infection, HIV forms hideouts where it lies dormant and out of the immune system’s reach — a major barrier to a cure. Recent efforts to activate this latent virus, lure it out of hiding and permanently finish it off have failed. This new study reveals the reason behind the failure — HIV shape-shifts beyond immune system recognition — and charts a therapeutic strategy to eradicate these mutant HIV-infected cells.

HIV evolving into less deadly form

A new study showed that HIV adapts to a person’s immune system, and that some of these adaptations may reduce the virulence of the virus.

The research team looked specifically at HIV in Botswana and South Africa. It found that over time, human immune system proteins, in addition to the use of HIV drugs, may have forced the virus to change into less virulent forms.
This is consistent with the theory that viruses get less virulent over time. The optimal evolutionary strategy for a virus is to be infectious (so it creates more copies of itself) but non-lethal (so its host population doesn’t die out). The "poster boy" for successful long-living viruses is, arguably, the family of viruses that cause the common cold, which has existed for thousands of years.

The authors warn that HIV, even at the reduced virulence, can still trigger the onset of AIDS.
Similarly, this study does not show that HIV virulence in the UK is decreasing, and that the virus remains life-threatening.
The simplest way to protect yourself against HIV infection in the UK is to use a condom during sex and never share needles if you are an injecting drug user.

The study was led by researchers from Oxford and several institutes in Canada, the US, South Africa, Botswana and Japan. It was funded by grants from the National Institutes of Health (US), the Wellcome Trust (UK), the Medical Research Council UK and the Canadian Institutes of Health.

The study was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), a peer-reviewed science journal. It is an open-access study, meaning that anyone can read it online or download it for free
.
The UK media reported the story accurately. It was important that they included a warning that, despite a small decrease in the virus’ potency in some areas of Africa, HIV still causes AIDS. This can significantly shorten life, due to impairment of the immune system if the correct treatment is not followed and made available soon after infection.

More on NHS Choices (UK)

Author : Laurence Huang, M.D. Professor of Medicine University of California San Francisco Chief, HIV/AIDS Chest Clinic San Francisco General Hospital

2008-07-28

HIV/AIDS-Associated Pneumonias

Bacterial pneumonia, Pneumocystis pneumonia (PCP), and Tuberculosis (TB)

Pneumonia is a frequent complication of human immunodeficiency virus (HIV) infection and may be a sign of acquired immune deficiency syndrome (AIDS) in persons with HIV. This article describes the principal pneumonias that are associated with HIV/AIDS. The article describes risk factors for the main pneumonias, their presenting symptoms and signs, typical laboratory abnormalities, and chest X-ray findings. It provides a description of common laboratory tests and diagnostic procedures that are used to evaluate a person with suspected HIV-associated pneumonia, as well as recommended treatment and prevention regimens.

Introduction

Pneumonia is an inflammatory process in the lungs. Usually, pneumonia is caused by infectious micro-organisms such as bacteria, mycobacteria, fungi, viruses, and protozoa, but it also can result from non-infectious processes such as chemical or physical injury to the lungs (aspiration pneumonia). In this article, “pneumonia” will refer specifically to infectious causes of pneumonia. Persons with HIV infection are at greater risk for developing most infectious pneumonias than persons without HIV. Thus, these pneumonias are considered to be HIV/AIDS-associated.

What are the principal HIV/AIDS-associated pneumonias?

The principal HIV/AIDS-associated pneumonias are bacterial pneumonia, Pneumocystis pneumonia (PCP), tuberculosis (TB) and, in certain geographic regions, pneumonias due to endemic fungi (fungi that are found exclusively in a particular geographic region) (Table 1). Occasionally, viruses and protozoa cause pneumonia. In most studies of pneumonia in persons with HIV/AIDS, bacterial pneumonia, PCP, and TB account for the majority of pneumonias.  

Bacterial pneumonia: While bacterial pneumonia does occur in people with a healthy immune system (immunocompetent), the incidence of bacterial pneumonia is significantly higher among persons with HIV infection. (1) In the United States, bacterial pneumonia is the most frequent HIV-associated pneumonia. In fact, bacterial pneumonia may be the first perceptible sign of underlying HIV infection and can occur at any stage of HIV disease and at any CD4 cell count (a CD4 cell is a type of white blood cell that is important in the immune system). Recurrent bacterial pneumonia (defined as two or more episodes within a 12-month period) is an AIDS-defining condition http://www.cdc.gov/MMWR/preview/MMWRhtml/00018871.htm). (2)

As is the case for immunocompetent persons, Streptococcus pneumoniae and Haemophilus species are the major causes of bacterial pneumonias in persons with HIV infection. Two other pathogens – Pseudomonas aeruginosa and Staphylococcus aureus – appear with an increased frequency in persons with HIV infection than they do in immunocompetent persons. In addition, the increasing prevalence of drug-resistant bacteria, including drug-resistant Streptococcus pneumoniae (DRSP) and methicillin-resistant Staphylococcus aureus (MRSA) are important concerns in persons with HIV infection.

Pneumocystis pneumonia (PCP): Prior to the HIV/AIDS epidemic, PCP was a rare cause of pneumonia, occurring primarily in persons whose immune systems were compromised (immunocompromised) from hematologic malignancy (e.g., leukemia, lymphoma), primary immunodeficiency (children), organ transplantation, and chemotherapy for cancer. In 1981, PCP was one of the diseases that signaled the onset of the HIV/AIDS epidemic in the United States. Throughout much of the epidemic, PCP was the leading AIDS-defining opportunistic infection and the most frequent opportunistic infection among persons with HIV/AIDS. In association with the use of antiretroviral medications to treat underlying HIV infection and of preventative therapy (prophylaxis) against Pneumocystis, the incidence of PCP has decreased. However, PCP remains an important cause of disease and death in persons with HIV infection and our understanding of it is incomplete. In addition, there are unanswered questions regarding potential drug resistance to the first-line recommended PCP treatment and prophylaxis medication, trimethoprim-sulfamethoxazole.

 

PCP in humans is caused by the fungal organism, Pneumocystis jirovecii (formerly P. carinii). In approximately 20-25% of cases in the U.S., PCP is the first perceptible sign of underlying HIV infection. PCP is an AIDS-defining condition and, prior to the 1993 U.S. Centers for Disease Control and Prevention (CDC) Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS among Adolescents and Adults, PCP was the AIDS-defining condition for over 40% of new AIDS cases annually.

 

Tuberculosis (TB): TB is caused predominantly by Mycobacterium tuberculosis and, less frequently, by other members of the M. tuberculosis complex. Worldwide, TB is the dominant HIV/AIDS-associated pneumonia. It is estimated that one-third of the world’s population is infected with M. tuberculosis and that the regions of the world that have the highest numbers of persons living with HIV/AIDS are also the regions with the greatest numbers of persons infected with M. tuberculosis. In the United States, the annual number of TB cases has declined, but the proportion of cases among foreign-born persons has increased.

 

Mycobacterium Tuberculosis electron micrograph. CDC

While TB occurs in immunocompetent persons, the incidence of TB is significantly higher among persons with HIV infection. TB may be the first perceptible sign of underlying HIV infection and can occur at any stage of HIV disease and at any CD4 cell count. The presence of HIV infection increases the probability that a person who is latently infected with M. tuberculosis will progress to active TB and thus TB is an AIDS-defining condition http://www.cdc.gov/MMWR/preview/MMWRhtml/00018871.htm). (2)

TB is transmitted from person to person via airborne droplets that contain M. tuberculosis. In a person with TB, these droplets are typically generated through coughing and a number of factors influence whether an individual who is exposed to a person with TB will become infected with M. tuberculosis. Once infected, a person’s risk of progressing to active TB (e.g., pneumonia) depends in part on their underlying immune status. Among immunocompetent persons, infection with M. tuberculosis is asymptomatic in an estimated 90% of cases, resulting in latent tuberculosis infection (LTBI), a state in which dormant mycobacteria with the potential to cause future disease persist in the body for life. In these people, the lifetime risk of progressing from LTBI to active TB is approximately 10%. In contrast, people with HIV infection are at an increased risk of progressing from LTBI to active TB at an estimated rate of approximately 5%–10% per year.

 

What are the risk factors for pneumonia?

In general, the CD4 cell count is an excellent indicator of the risk of opportunistic infection, including pneumonia, in an individual with HIV infection (Table 2). (3) As described previously, persons with HIV infection can develop bacterial pneumonia and TB at any CD4 cell count. However, the incidence of both pneumonias increases progressively as the CD4 cell count decreases. PCP and pneumonia caused by the fungus Cryptococcus neoformans typically occur in persons with a CD4 cell count below 200 cells/μL (or a CD4% below 14%). When the CD4 cell count is below 200 cells/μL, persons with bacterial pneumonia often have accompanying bacteremia (presence of bacteria in the bloodstream) and those with TB often have disseminated disease (disease that has spread throughout the body). Bacterial pneumonia due to Pseudomonas aeruginosa usually occurs in persons with a CD4 cell count below 100 cells/μL. Lastly, diseases caused by endemic fungi (Histoplasma capsulatum, Coccidioides immitis), non endemic fungi (Aspergillus fumigatus and other Aspergillus species), Cytomegalovirus (CMV), and nontuberculous mycobacteria (Mycobacterium avium complex, MAC) occur at CD4 cell counts below 50 cells/μL. These latter diseases are less common in the current era but when they do occur they are often disseminated throughout the body and are still associated with a high mortality.

Injection drug use and cigarette smoking are both associated with an increased risk for bacterial pneumonia. (1) Exposure to another person with TB is a risk factor for infection with Mycobacterium tuberculosis and persons with HIV infection are at greater risk of progressing from latent tuberculosis infection (LTBI) to active TB. (3) Environmental exposure to H. capsulatum or C. immitis, typically through activities in an endemic area that disturb soil containing the fungus, is a risk factor for these infections. (3)

Prior bacterial pneumonia and prior PCP are risk factors for recurrent disease. (3) Persons with oral candidiasis (a fungal infection in the mouth) are also at an increased risk for PCP. (3) Persons with neutropenia (a low number of neutrophils, cells that help the body defend itself against certain infections) are at increased risk for bacterial infections and fungal infections such as those caused by Aspergillus species.

What are the symptoms of pneumonia?

In general, the cardinal symptoms of pneumonia are fever, cough, and breathlessness or shortness of breath (dyspnea). The duration and characteristics of these symptoms differ among the major pneumonias and can be used to rank the probability of these pneumonias in a given person.
For example, persons with bacterial pneumonia typically present with a short duration of symptoms (three to five days) and a cough that is productive of pus-containing (purulent) sputum (matter coughed up from the lungs). These persons may also present with chills or rigors and pleurisy (chest pain during breathing). In contrast, persons with PCP usually present with a longer duration of symptoms (two to four weeks) and a dry, non-productive cough. Similarly, persons with TB present with a longer duration of symptoms, but also frequently report constitutional complaints such as night sweats, anorexia (loss of appetite), and weight loss. Thus, bacterial pneumonia would be the most likely diagnosis in a person with 3 days of fever, cough productive of purulent sputum, dyspnea, and pleurisy and a compatible chest radiograph. Persons who present with a mixture of these symptoms or persons whose symptoms change characteristics (for example, an initially non-productive cough that subsequently becomes productive of purulent sputum) may have pneumonia from more than one cause. Persons with HIV infection, perhaps more than any other underlying disease, appear to present with more than one concurrent illness. Although precise data on the frequency of dual pneumonias in persons with HIV infection are scarce, these data and clinical experience indicate that this occurs in approximately 10% of cases.  

What are the clinical signs of pneumonia?

Persons with pneumonia typically have a fever (oral temperature greater than 37.5°C or 99.5°F). They may have tachycardia (heart rate greater than 100 beats per minute) and tachypnea (respiratory rate greater than 20 breaths per minute). Persons with bacterial pneumonia and accompanying septicemia (infection that has spread into the bloodstream) may have hypotension (abnormally low blood pressure). Pulse oximetry (a non-invasive method for measuring the level of oxygen in the arteries [arterial oxygen saturation] or percentage of hemoglobin molecules bound with oxygen molecules) provides an estimate of the severity of pneumonia. Although persons with mild pneumonia may have a normal arterial oxygen saturation (greater than 94%), most persons with pneumonia will have a low arterial oxygen saturation at rest that frequently decreases further upon exertion. In particular, persons with PCP characteristically have a decrease in their arterial oxygen saturation by 3-5% upon exertion. Persons with severe pneumonia will generally appear ill and in respiratory distress (labored breathing, inability to speak using full sentences). They may have cyanosis (a bluish or purplish discoloration of the skin that is due to insufficient oxygenation of the blood). The lung examination is usually abnormal in persons with pneumonia. One exception to this rule is PCP where up to 50% of persons with PCP may have lung examinations that fail to reveal any abnormalities.  

What laboratory tests might my doctor order?

Depending on a host of factors that include CD4 cell count, symptoms and signs, and an assessment of the probability of pneumonia and its severity, clinicians may order a variety of laboratory tests (tests that may help suggest a particular pneumonia).

Chest radiograph (X-ray)

The X-ray or chest radiograph is the cornerstone of the evaluation of suspected pneumonia. In most cases, clinicians will obtain frontal (PA or posteroanterior) and lateral views of the chest. If abnormalities are seen, ideally the chest radiograph will be compared with any prior radiographs to determine whether the noted abnormalities are new or old and, if old, whether they have changed or are stable (unchanged).

Persons with bacterial pneumonia will present with an abnormal chest radiograph. Usually, the abnormality is on one side; abnormalities on both sides suggest a more severe pneumonia. Most often, the chest radiograph reveals an abnormality that is consolidated on one-side, in a specific area of the lung (Figure 1). Occasionally, the radiograph also reveals a pleural effusion (excessive fluid in the space that surrounds the lung).

Persons with mild PCP occasionally may present with a normal chest radiograph. Characteristically, however, the radiograph reveals abnormalities on both sides. Most often, abnormalities contain symmetric, fine reticular or granular opacities (Figure 2). Occasionally, cysts or pneumatoceles (thin-walled, air-filled spaces that are located within the lung) are seen. Pleural effusions are rarely due to PCP.

Persons with disseminated TB may present with a normal chest radiograph. Pulmonary TB in persons with HIV infection can present with a variety of radiographic abnormalities, depending in part on the person’s CD4 cell count. In persons with a high CD4 cell count (i.e., CD4 greater than 400 cells/μL), the characteristic radiograph reveals upper lung zone abnormalities and frequently, cavitation (the presence of thick-walled, irregularly margined, air-filled spaces that are located within the lung) (Figure 3). In contrast, in persons with a low CD4 cell count (i.e., CD4 less than 200 cells/μL), middle and/or lower lung zone abnormalities (Figure 4) or diffuse abnormalities are as frequent as upper lung zone abnormalities and cavitation is less frequent. In addition, a miliary pattern (innumerable tiny, 1-5 mm sized nodules throughout the chest radiograph) (Figure 5) and intrathoracic lymphadenopathy (enlargement of the lymph nodes within the lung or thorax) are more common in persons with a low CD4 cell count. The chest radiograph may also reveal a pleural effusion.

White blood cell (WBC) count
The white blood cell (WBC) count measures the number of leukocytes in the blood. Leukocytes are cells that help the body defend itself against many infections. Thus, in persons with pneumonia,                       especially bacterial pneumonia, the WBC count may be elevated. Arterial oxygen saturation and arterial

Blood gas analysis

Persons with mild pneumonia may have a normal arterial oxygen saturation (greater than 94%), but most will have a low arterial oxygen saturation at rest that frequently decreases further upon exertion. People who have a low arterial oxygen saturation may undergo additional testing with an arterial blood gas (ABG).

An ABG is an invasive procedure whereby blood is obtained from an artery, most often the radial   artery, located at the wrist. The resulting arterial blood is sent for analysis of a person’s pH and partial pressures of carbon dioxide (PaCO2) and oxygen (PaO2). Most persons with pneumonia will have a low PaO2 and will be short of breath. These people typically require supplemental oxygen to raise their PaO2 and relieve their symptoms.  

What diagnostic tests might my doctor order?

There are a variety of diagnostic procedures and microbiologic tests that might be obtained in the evaluation of suspected pneumonia in a person with HIV infection. Which procedures might be obtained and which tests might be performed depend on the specific pneumonia being evaluated and the severity of that pneumonia.                     Sputum examination and culture                  Persons with bacterial pneumonia typically have a productive cough. When they spontaneously                         cough up sputum, it may be collected and sent to the laboratory for Gram’s stain (a method for                         staining specimens and then examining the stained specimen under a microscope to identify                                 possible bacterial causes of infection) and bacterial culture. If bacteria are identified, testing will be                  done to determine which antibiotics the bacteria are susceptible to and to which ones they may                         be resistant.  

Similarly, persons with TB often have a productive cough; occasionally the cough produces sputum that is blood-tinged or has highly visible bright, red blood. In the case of suspected TB, sputum specimens will be collected over two or three days, preferably the first morning specimen each day, and sent to the laboratory for acid-fast bacillus (AFB) stain and mycobacterial culture. If M. tuberculosis is identified in culture (often requiring a few weeks), testing will be done to determine which anti-tuberculous medications the mycobacteria are susceptible to and to which ones they may be resistant.

 

M. tuberculosis nucleic acid amplification tests or direct amplification tests can be performed directly on clinical specimens such as sputum. Typically, these tests are performed on persons whose AFB smear was positive. A positive nucleic acid amplification test in a person who is AFB smear-positive indicates TB.

 

In contrast to bacterial pneumonia and TB, persons with PCP typically have a non-productive cough. In these persons, clinicians may induce sputum production by having the person inhale hypertonic saline solution that has been reduced to a fine, aerosol spray.

 

Fungal pneumonias can occasionally be diagnosed by sputum examination and culture, including those due to Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. Pneumonia due to Toxoplasma gondii and Strongyloides stercoralis can also occasionally be diagnosed by sputum examination. However, the diagnosis of invasive pulmonary aspergillosis typically requires demonstration of the fungus in lung tissue specimens obtained from biopsy. Similarly, the diagnosis of CMV pneumonia typically requires demonstration of the viral inclusions in lung tissue specimens obtained from a biopsy.

Blood cultures

Streptococcus pneumoniae is the most frequent cause of bacterial pneumonia and pneumococcal pneumonia is often accompanied by bacteremia. Bacteremia occurs especially when the CD4 cell count is below 200 cells/μL. Thus, blood cultures may be collected in cases of suspected bacterial pneumonia. If bacteria are identified in culture, antibiotic susceptibility testing can be done.

Similarly, TB is often accompanied by mycobacteremia, especially when the CD4 cell count is below 200 cells/μL. The probability of disseminated TB is also increased when the CD4 cell count is below 200 cells/μL. Thus, mycobacterial blood cultures may be collected in these cases. If M. tuberculosis is identified in culture, susceptibility testing can be done.

At present, Pneumocystis jirovecii cannot be cultured. However, other fungi such as Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis can be cultured. Thus, fungal blood cultures may be collected when these pneumonias are suspected.

                 Serology                 The serum cryptococcal antigen (sCrAg) is an extremely sensitive and specific test for                   cryptococcemia (the presence of cryptococcus in the bloodstream) and cryptococcal meningitis.The sCrAg assay (test) should be performed on all persons with pneumonia where cryptococcus is a possibility. Persons with a positive sCrAg assay should have an evaluation to determine the extent of disease (e.g., lumbar puncture or “spinal tap” for possible meningitis). However, the sCrAg assay may be negative in HIV-infected patients who have isolated cryptococcal pneumonia (pneumonia that is limited to the lungs). Persons with a negative sCrAg assay but with respiratory complaints or chest radiograph findings should undergo further pulmonary evaluation for possible isolated cryptococcal pneumonia.

The Histoplasma capsulatum polysaccharide antigen test is a sensitive and specific test for the presence of the fungus that causes histoplasmosis. The antigen can be measured in urine, blood and other fluids, including BAL fluid, which is a procedure where saline is squirted into the lungs through a bronchoscope (see below) and then recollected, so it can be tested. At present, the urine test is the most widely used.

The galactomannan assay has been used for the diagnosis of invasive aspergillosis. Galactomannan is a major constituent of Aspergillus cell walls and can be measured in urine, blood and other fluids, including BAL fluid. The precise use of this assay in persons with HIV infection requires additional study.

Bronchoscopy

Bronchoscopy is an invasive procedure performed by a specialist in pulmonary medicine. After administration of topical anesthetic, a bronchoscope is inserted through the mouth (or occasionally the nose) and passed into the trachea and the bronchi. During bronchoscopy, lung samples may be taken, most often by bronchoalveolar lavage (BAL, a procedure where saline is instilled into the lung, then suctioned back into a specimen container) or biopsy (a procedure where forceps are used to remove a small piece of lung tissue). These specimens can then be sent for microscopic examination and culture as described for sputum specimens.

Bronchoscopy with BAL is the gold standard procedure to diagnose PCP. Less commonly, it is used to diagnose bacterial pneumonia or TB. Bronchoscopy with biopsies is a means of obtaining lung tissue to diagnose invasive pulmonary aspergillosis and CMV pneumonia.

Thoracentesis and pleural biopsy

Persons who have evidence of a pleural effusion on their chest radiograph may undergo additional radiographic testing to determine whether the effusion is free-flowing. In such cases, a thoracentesis may be performed. Thoracentesis is an invasive procedure where a small needle is inserted into the pleural space and pleural fluid is removed. The fluid can then be sent for microscopic examination and culture as described for sputum specimens. Pleural biopsy (an invasive procedure to obtain a small piece of pleural tissue) may also be performed in persons with a free-flowing pleural effusion.

What are the treatments for HIV-AIDS-associated pneumonia?

The treatment of HIV/AIDS-associated pneumonia depends on the specific pneumonia that is either diagnosed by one of the procedures described above or is based on the person’s clinical presentation (empirical treatment). In general, the treatment of pneumonia in persons with HIV infection is similar or identical to that in persons without HIV. Table 3 provides a list of typical empiric treatment regimens for bacterial pneumonia, TB, and PCP. In the case of bacterial pneumonia, the initial antibiotic regimen may be altered if a specific bacteria is identified and its antibiotic susceptibility is determined.
It is important to note that the duration of treatment also differs for these three pneumonias. Persons with bacterial pneumonia are typically treated for 10-14 days and those with PCP are usually treated for 21 days. Persons with TB are treated for a minimum of six months if the M. tuberculosis is sensitive to the first-line anti-tuberculous medications and longer if the organism is resistant to one or more of these medications. For further details, please refer to the current Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and HIV Medicine Association (HIVMA)/Infectious Diseases Society of America (IDSA) guidelines, Treating Opportunistic Infections Among HIV-Infected Adults and Adolescents (http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=14&ClassID=4) and the same organizations’ Treating Opportunistic Infections Among HIV-Exposed and Infected Children. (4) (5)  

What can I do to prevent pneumonia?

There are several steps that a person with HIV infection can take to decrease their risk of pneumonia.
First, persons who smoke cigarettes and those who use injection drugs should strongly consider quitting as these behaviors are associated with an increased risk for bacterial pneumonia.
Second, screening for LTBI should be performed annually and after any exposure to a person with TB. Persons who are found to be latently infected with M. tuberculosis should be evaluated for active TB. If no evidence of TB is found, these persons should receive treatment for LTBI, usually the drug isoniazid for 9 months. Third, persons who have a CD4 cell count less than 200 cells/μL (or a CD4% less than 14%) and those with oral candidiasis regardless of their CD4 cell count should receive primary PCP prophylaxis (preventative therapy to prevent a first occurrence), usually with trimethoprim-sulfamethoxazole. Persons who have had PCP should receive secondary PCP prophylaxis (preventative therapy to prevent a recurrence), usually with trimethoprim-sulfamethoxazole as well. Finally, persons with HIV infection can receive vaccines and/or preventive therapy to prevent certain HIV/AIDS-associated pneumonias. (3) For example, the U.S. Public Health Service and Infectious Diseases Society of America (IDSA) guidelines recommend that persons with HIV infection whose CD4 cell count is greater than 200 cells/μL receive the 23-valent pneumococcal polysaccharide vaccine. This vaccine offers protection against 23 types of pneumococcal bacteria (http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-ppv.pdf). The pneumococcal vaccine may also be given to persons with HIV infection whose CD4 cell count is less than 200 cells/μL, but the effectiveness of the pneumococcal vaccine may be diminished. In addition, the guidelines recommend that persons with HIV infection receive an annual flu vaccine. For further details, please refer to the current U.S. Public Health Service and Infectious Diseases Society of America (IDSA) guidelines, Guidelines for the Prevention of Opportunistic Infections Among HIV-Infected Persons (http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=13&ClassID=4). (3)  

Conclusion

Persons with HIV infection are at greater risk for developing most infectious pneumonias than persons without HIV. If indicated by the person’s immune  (i.e., CD4 cell count) and virologic (i.e., plasma HIV RNA or “viral load”) status, strict adherence to antiretroviral medications and PCP prophylaxis, receipt of the 23-valent pneumococcal vaccine, and regular screening for LTBI offer the best hope for prevention of the most common HIV/AIDS-associated pneumonias. Those persons who develop symptoms that may indicate possible pneumonia should seek prompt medical attention so that the appropriate laboratory tests and diagnostic procedures may be performed and the appropriate treatment may be initiated.  

More Information

Web Resources Department of Health and Human Services AIDS Info: http://aidsinfo.nih.gov/
Department of Health and Human Services Centers for Disease Control and Prevention (HIV/AIDS): http://www.cdc.gov/hiv/
Department of Health and Human Services Centers for Disease Control and Prevention (Global HIV/AIDS): http://www.cdc.gov/nchstp/od/gap/default.html
The National Institutes of Health Office of AIDS Research (OAR): http://www.oar.nih.gov/
University of California San Francisco HIV InSite: http://hivinsite.ucsf.edu/
Books
Raphael Dolin, Henry Masur, and Michael Saag. AIDS Therapy. 3^rd Edition.
Peter Walzer and Melanie T. Cushion. Pneumocystis Pneumonia. 3^rd Edition.
Mario C. Raviglione. Reichman and Hershfield’s Tuberculosis: A Comprehensive, International Approach. 3^rd Edition.
 

References

1.         Hirschtick RE, Glassroth J, Jordan MC, Wilcosky TC, Wallace JM, Kvale PA, Markowitz N, Rosen MJ, Mangura BT, Hopewell PC. Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group. N Engl J Med 1995;333(13):845-51.
2.         Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41(RR-17):1-19.
3.         Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Recomm Rep 2002;51(RR-8):1-52.
4.         Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep 2004;53(RR-15):1-112.
5.         Mofenson LM, Oleske J, Serchuck L, Van Dyke R, Wilfert C. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep 2004;53(RR-14):1-92.

Table 1. HIV/AIDS-associated Pneumonias

Bacteria

Streptococcus pneumoniae

Haemophilus influenzae and other Haemophilus

Staphylococcus aureus

Pseudomonas aeruginosa

Klebsiella pneumoniae

Rhodococcus equi

Mycobacteria

Mycobacterium tuberculosis

Mycobacterium kansasii

Mycobacterium avium complex (MAC)a

Other nontuberculous mycobacteria

Fungi

Pneumocystis jirovecii (formerly carinii)

Cryptococcus neoformans

Histoplasma capsulatum

Coccidioides immitis

Penicillium marneffei

Aspergillus fumigatus and other Aspergillus species

Viruses

Cytomegalovirus (CMV)a

Protozoa

Toxoplasma gondii

Strongyloides stercoralis

aCytomegalovirus (CMV) and Mycobacterium avium complex (MAC) are rarely the cause of pulmonary dysfunction in patients with HIV infection regardless of their CD4 cell count.

 
 

Table 2. CD4 Cell Count Ranges for HIV/AIDS-associated Pneumonias

Any CD4 Cell Count

Upper respiratory tract infection

Acute bronchitis/sinusitis

Bacterial pneumonia (most often Streptococcus pneumoniae, Haemophilus spp.)

Mycobacterium tuberculosis pneumonia

CD4 Cell Count < 200 cells/uL

Pneumocystis jirovecii pneumonia (PCP)

Cryptococcus neoformans pneumonia

Bacterial pneumonia accompanied by bacteremia or septicemia

Extrapulmonary or disseminated M. tuberculosis

CD4 Cell Count < 100 cells/uL

Bacterial pneumonia due to Pseudomonas aeruginosa

Toxoplasma gondii pneumonia

CD4 Cell Count < 50 cells/uL

Histoplasma capsulatum: usually associated with disseminated disease

Coccidioides immitis: usually associated with disseminated disease

Aspergillus species (most often A. fumigatus) pneumonia

Cytomegalovirus pneumonia: usually associated with disseminated disease

Mycobacterium avium complex: usually associated with disseminated disease

 
 

Table 3. Selected Empiric Treatment Regimens for Bacterial Pneumonia, Tuberculosis, and Pneumocystis Pneumonia

Bacterial Pneumonia

Outpatient

            Beta-lactam (oral) plus macrolide (oral) antibiotic OR

            Beta-lactam (oral) plus doxycycline (oral) OR

            Respiratory fluoroquinolone (oral)

 

Inpatient

            Beta-lactam (intravenous) plus macrolide (oral) antibiotic OR

            Beta-lactam (intravenous) plus doxycycline (oral) OR

            Respiratory fluoroquinolone (intravenous)

 

Tuberculosis (standard initial therapy consists of 4 drugs plus vitamin B6)

            INH (isoniazid) AND

            Rifampin AND

            Ethambutol AND

            Pyrazinamide

 

Pneumocystis Pneumonia*

Outpatient

            Trimethoprim-sulfamethoxazole (oral) OR

            Trimethoprim (oral) plus dapsone (oral) OR

            Clindamycin (oral) plus primaquine (oral) OR

            Atovaquone (liquid suspension)

 

Inpatient

            Trimethoprim-sulfamethoxazole (intravenous) OR

            Pentamidine (intravenous) OR

            Clindamycin (intravenous) plus primaquine (oral)

* Persons with PCP who have moderate to severe disease should also receive adjunctive corticosteroids (e.g., prednisone)

HIV / AIDS intensive care

Author : Laurence Huang, M.D. Professor of Medicine University of California San Francisco Chief, HIV/AIDS Chest Clinic San Francisco General Hospital

2008-07-28

Introduction

Combination antiretroviral therapy has changed human immunodeficiency virus (HIV) infection and the acquired immune deficiency syndrome (AIDS) from a uniformly fatal disease to a chronic disease that cannot currently be cured but can successfully be treated with medications. The effectiveness of these medications and the promise of newer medications have created an optimistic long-term prognosis for persons with HIV/AIDS. This optimism may play a role in decisions regarding the use of intensive care and intensive care unit (ICU) management. Although the guiding principles of all ICU management pertain to critically ill persons with HIV/AIDS, antiretroviral therapy and unresolved questions regarding its use in the ICU add an additional level of complexity to already complicated patients. This article provides an overview of the spectrum of diseases in persons with HIV/AIDS that require intensive care, as well as predictors of outcome. The article focuses on some of the challenging issues associated with the intensive care of these individuals, including legal statutes concerning HIV testing and disclosure, the administration of antiretroviral medications, important potential drug-drug interactions with common ICU medications, and current controversies surrounding antiretroviral therapy use in the ICU.  

HIV electron micrograph. Source : CDC

Spectrum of diseases in the ICU: past, present, and future

Early in the HIV/AIDS epidemic, respiratory failure due to Pneumocystis pneumonia (PCP) accounted for up to 84% of ICU admissions for persons with HIV/AIDS. Experience treating persons with PCP and intensive care of these patients was limited and the mortality rates were extraordinarily high, ranging from 62% to 94%. Against the backdrop of AIDS, at the time an untreatable and fatal disease, physicians and patients alike questioned the appropriateness of intensive care for persons with HIV/AIDS, especially those with PCP. A majority of physicians surveyed during 1984-85 felt that mechanical ventilation (the use of a ventilator to mechanically assist or replace spontaneous breathing when patients cannot do so on their own) was rarely or never indicated for an AIDS patient with PCP and respiratory failure. Less than 20% of 188 patients with AIDS surveyed in an outpatient setting during 1985 stated that they would want intensive care in the event of both severe memory loss and PCP-associated respiratory failure.

The pessimism surrounding intensive care for persons with HIV/AIDS lessened during the late 1980s to mid 1990s because of groundbreaking, but incremental advances in HIV care. The first class of antiretroviral medication – nucleoside reverse transcriptase inhibitors – was developed and antiretroviral monotherapy produced short-term reductions in the incidence of AIDS and opportunistic infections. Prophylaxis regimens prevented new and recurrent opportunistic infections. The treatment and management of PCP and other opportunistic infections improved. Trimethoprim-sulfamethoxazole and pentamidine, the mainstays of PCP treatment, were joined by several new regimens as effective PCP therapies. Adjunctive corticosteroid treatment significantly decreased the rates of respiratory failure and mortality associated with PCP. These advances created a more optimistic sense regarding the overall care – and by extension the intensive care of persons with HIV/AIDS, setting the stage for the current era.

By 1996, a new class of antiretroviral medication - HIV protease inhibitors - combined with nucleoside reverse transcriptase inhibitors to usher in the present era in HIV medicine. AIDS incidence and mortality decreased dramatically in areas of the world with access to these medications; and hospital admissions for persons with HIV/AIDS declined in parallel. Although no national surveillance databases exist to track persons with HIV/AIDS receiving intensive care, studies from San Francisco and Paris indicate that ICU admissions also decreased after combination antiretroviral therapy was incorporated into clinical practice. At San Francisco General Hospital, the annual number of ICU admissions for persons with HIV/AIDS has decreased from 111 per year (1992-1995) to 88.5 per year (1996-1999) to 62 per year (2000-2004). Annual ICU admissions for persons with HIV/AIDS at Bichat-Claude Bernard University Hospital in Paris have decreased from 94.5 per year (1995-1996) to 79 per year (1998-2000).

Over the past decade, a new clinical spectrum of intensive care for persons with HIV/AIDS has emerged. Respiratory failure remains the most common ICU indication but the proportion of ICU admissions due to respiratory failure has declined. At Beth Israel Medical Center (New York), respiratory failure accounted for 22% of HIV-associated ICU admissions from January through June 2001 compared to 54% a decade earlier. PCP and other AIDS-associated illnesses are no longer the most common indication for ICU admission. At San Francisco General Hospital, PCP has decreased from 84% (1981-1985) to 20% (1992-1995) to 14% (2000-2004) of the ICU admissions for persons with HIV. At Bichat-Claude Bernard University Hospital, the proportion of persons with HIV/AIDS admitted to the ICU for AIDS-associated diseases decreased significantly from 58% (1995-1996) to 37% (1997-June 1999) (p<0.001). The declines in PCP and AIDS-associated illnesses have been partially offset by increases in persons with HIV/AIDS being admitted to the ICU with pulmonary, cardiac, gastrointestinal, renal, and metabolic illnesses, which may or may not be related to underlying HIV disease.Because there are now six distinct classes of antiretroviral medications that dramatically improve the prognosis for persons with HIV/AIDS – and because the future likely has an even greater promise – there will be an even greater clinical spectrum of intensive care for persons with HIV/AIDS. Increases in both cardiopulmonary diseases and malignancies are anticipated with an aging HIV population that is living longer due to the effectiveness of these medications. End stage liver disease secondary to viral hepatitis has emerged as a frequent cause of morbidity and mortality in the HIV population; these patients may increasingly require intensive care unless current therapies for hepatitis improve significantly. 

The overall improved prognosis of persons with HIV/AIDS also has led to more aggressive management of other medical conditions in persons with HIV infection, including coronary artery bypass as well as liver, renal, and heart transplantation at selected specialty centers. As these procedures become more widespread in persons with HIV infection, clinicians will face a new wave of challenges related to the intensive care of these complex patients.

Finally, without dramatic changes in health care access and the stigma associated with HIV disease, HIV-associated illnesses will remain a primary cause for ICU admission at institutions that serve vulnerable populations and at those institutions who care for HIV-infected émigrés from parts of the world where HIV/AIDS prevalence is high.

What are the most common conditions that require intensive care?

The general conditions that require intensive care in persons with HIV/AIDS are similar to those in the general population, but the specific causes for these conditions may differ.

Respiratory conditions. Since the beginning of the HIV/AIDS epidemic, respiratory failure has been the most common indication for ICU admission among persons with HIV/AIDS. However, the proportion of ICU admissions due to respiratory failure has declined and the underlying causes of respiratory failure have changed. Earlier in the HIV/AIDS epidemic, respiratory failure was often due to PCP or another HIV-associated pneumonia (infection of the lungs). Currently, PCP and other infectious pneumonias are less common and non-infections conditions (e.g., chronic obstructive pulmonary disease, COPD, lung cancer) appear to be more common. The decline in AIDS deaths and resulting increased survival, the high proportion of cigarette smoking in persons with HIV/AIDS, and emerging data that underlying HIV infection itself may be an independent risk factor for COPD and lung cancer are postulated explanations for these observations.

Sepsis. Sepsis (infection that has spread into the bloodstream) is increasingly common among persons with HIV/AIDS admitted to the ICU, and its mortality rate has been reported to be as high as 68%. Most often, bacterial pathogens are the cause of the sepsis. More deaths in persons with HIV/AIDS have been attributed to sepsis in the present era than in the earlier eras. The precise explanation for this observation is unclear but the increase in drug resistant bacteria (e.g., drug resistant Streptococcus pneumoniae [DRSP] and mythically-resistant Staphylococcus aureus [MRSA]) is a concern in persons with HIV/AIDS as well as in the general population.

Neurologic conditions. The spectrum of neurological conditions that require intensive care for persons with HIV/AIDS includes all the causes seen in the general population (e.g., stroke) in addition to HIV-associated opportunistic infections and neoplasms. The main HIV-associated neurological opportunistic infections include Cryptococcus neoformans meningitis (inflammation of the meninges, the protective membranes covering the central nervous system) and Toxoplasma gondii encephalitis (inflammation of the brain). Worldwide, neurological presentations of Mycobacterium tuberculosis (TB) are an important consideration. The main HIV-associated neurological neoplasm is primary central nervous system (CNS) lymphoma. In one study, neurologic diagnoses accounted for 12% of the ICU admissions and had a 75% survival rate in the combination antiretroviral therapy era. A study of neurological causes of ICU admission in the U.S. found that Cryptococcal meningitis, Toxoplasma encephalitis, and progressive multifocal leukoencephalopathy (PML) had decreased, but the incidence of ischemic stroke, hemorrhagic stroke, and primary CNS lymphoma had increased.

Cardiac conditions. The classic and modifiable risk factors for atherosclerotic cardiovascular disease include hypertension, diabetes, dyslipidemias (usually hyperlipidemia or elevated levels of lipids), and cigarette smoking. In general, the risk of these conditions and therefore the risk of acute coronary events (e.g., acute myocardial infarction, also known as an MI or, more commonly, a heart attack) increase as age increases. Thus, increases in atherosclerotic cardiovascular disease and acute coronary events in persons with HIV/AIDS may result from these individuals living longer and developing the conditions associated with increased risk for MI. However, antiretroviral therapy is also associated with a host of atherogenic complications, including dyslipidemias, insulin resistance, and diabetes. Several studies suggest that antiretroviral therapy may have contributed to the increasing rates of cardiovascular disease in persons with HIV/AIDS, although traditional risk factors also remain important factors. Persons with HIV/AIDS may also develop HIV-associated cardiomyopathy (disease of the heart muscle, which results in decreased cardiac function) or HIV-associated pulmonary arterial hypertension (high blood pressure in the pulmonary arteries, the blood vessels that carry blood from the heart to the lungs) that may require intensive care.

Gastrointestinal and liver conditions. Gastrointestinal (GI) bleeding may require intensive care if the bleeding is severe and if the person’s blood pressure is unstable. Often the causes of upper GI bleeding in persons with HIV/AIDS are similar to those found in the general population (e.g., peptic ulcer, duodenal ulcer). The causes of lower GI bleeding are also similar to those found in the general population (e.g., diverticular disease) but HIV-associated conditions such as cytomegalovirus (CMV) colitis are important considerations.

End stage liver disease secondary to viral hepatitis has emerged as a frequent cause of morbidity and mortality among persons with HIV/AIDS. Furthermore, several antiretroviral medications for HIV are also active against hepatitis B virus (HBV), so decisions about antiretroviral therapy are intertwined with those regarding hepatitis therapy. If antiretroviral therapy is initiated in a person with untreated HIV and HBV infections, clinicians can co-treat HBV by selecting two or more of these HBV-active medications as components of the person’s HIV regimen. Persons receiving concurrent HIV and HBV therapy who are admitted to the ICU should have these therapies continued if possible, as severe flares of the underlying hepatitis B have been reported after discontinuation of therapy.

Renal Disease. End stage renal disease (ESRD or kidney failure) secondary to HIV-associated nephropathy (a type of kidney disease known as HIVAN), hepatitis B or C co-infection, diabetes and/or hypertension is now a frequent cause of morbidity and mortality among persons with HIV/AIDS. Because HIV infection itself appears to be the cause of HIVAN and may contribute to other renal diseases (e.g., immune-complex glomerulonephritides), persons with HIV/AIDS and HIVAN should be treated with combination antiretroviral therapy, which may slow the progression of disease.

What are the predictors of outcome?

Mortality in the ICU is related to the reason for ICU admission. Thus, predictors of outcome depend on the specific reason for ICU admission.

The highest mortality rates reported for persons with HIV/AIDS who require intensive care are respiratory failure and sepsis. If respiratory failure is due to PCP, mortality remains nearly 50% and is increased if accompanied by PCP-associated pneumothorax (collapsed lung) where mortality is greater than 90%. Sepsis mortality rates from 50% to 68% have been reported. For persons with HIV/AIDS who require intensive care for other HIV-associated conditions, the reported mortality is generally lower, below 50%. Furthermore, persons with HIV/AIDS who are admitted to the ICU for a non-HIV-related condition may have better outcomes than those who are admitted for a condition related to underlying HIV. In a study from San Francisco, patients admitted with a non-AIDS-associated diagnosis had a significantly higher odds of surviving than patients admitted with an AIDS-associated condition (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5-5.8, p = 0.002). In a study from New York, ICU admission with an HIV- associated illness was independently associated with increased mortality (OR 4.2, 95% CI 2.0-9.0, p < 0.001).

Mortality in the ICU is also related to the severity of the acute illness. Predictors of increased hospital mortality include the need for mechanical ventilation and disease severity (as assessed by scoring systems such as the Simplified Acute Physiology Score I [SAPS I], and the Acute Physiology and Chronic Health Evaluation II [APACHE II] score). ICU mortality has also been related to the preadmission health status of the patient. Patients with a decreased serum albumin level or a history of weight loss may have a higher mortality. In general, the CD4 cell count and the plasma HIV RNA level are inaccurate predictors of ICU or hospital mortality. However, long-term mortality after ICU admission is related to the underlying severity of HIV disease. Compared to earlier eras, long-term survival following ICU discharge is improved in the current combination antiretroviral therapy era.

Does the intensive care management of persons with HIV/AIDS differ from that of persons without HIV/AIDS?

As a general rule, the cardinal principles of ICU management are the same in persons with and without underlying HIV/AIDS. The first principles involve the “ABCs”: A = secure an airway (often by endotracheal intubation, which involves placing a breathing tube into the trachea to provide a means of mechanical ventilation); B = ensure adequate breathing; C = ensure adequate circulation and delivery of oxygen to vital organs. There are, however, unique features of intensive care for persons with HIV infection that are important to understand.

HIV testing in the ICU

Persons with risk factors for HIV infection may be admitted to the ICU without a prior (or recent) HIV test. In many cases, knowledge of the person’s HIV status may influence the specific diagnoses being considered (since certain diagnoses only occur in persons who have HIV) and, therefore, in these situations an HIV test could provide valuable clinical information. In the current era, up to 40% of persons with underlying HIV are unaware of their HIV infection at the time of ICU admission.

Nevertheless, HIV testing and test disclosure requirements were originally established to protect persons with HIV. In the ICU, these requirements may present inadvertent legal barriers that discourage, or even prevent HIV testing when a patient cannot provide their own consent. Because of these barriers, the intensivist may be forced to defer HIV testing until the patient recovers. Each state and the District of Columbia have specific legislation regarding HIV testing; an up-to-date compendium of each state’s HIV testing laws is available at http://www.ucsf.edu/hivcntr/StateLaws/I

Antiretroviral therapy in the ICU

Currently, there are six distinct classes of antiretroviral medication: nucleoside reverse transcriptase inhibitors, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 antagonists, and integrase inhibitors. Once initiated, strict adherence to combination antiretroviral therapy is recommended. The benefits of adherence to antiretroviral therapy include maximal and continued suppression of HIV viral replication, decreased rates of drug resistance, and increased survival. However, the use of antiretroviral therapy in critically ill persons with HIV presents distinct issues related to drug delivery, absorption, dosing, drug-drug interactions, and antiretroviral-associated toxicities. Some issues are unique to critically ill persons with HIV; others pertain to all persons with HIV but are especially important in the ICU. As a result, it may be difficult or impossible to continue antiretroviral therapy in a critically ill patient with HIV.

Drug delivery. Frequently, critically ill patients are unable to take medications by mouth. As a result, these patients often receive important therapies intravenously, via an intravenous catheter. Delivery of antiretroviral therapy in a person who is unable to take medications by mouth is complicated since all of the currently approved antiretroviral medications are dispensed as capsules or tablets except for enfuvirtide (administered via subcutaneous injection). Several antiretroviral medications are available as an oral solution but only zidovudine has an intravenous formulation. For medications without an intravenous or oral solution, the capsules can be opened and the tablets can be crushed and re-constituted for delivery via a feeding tube (a tube placed into the stomach for delivery of oral medications and nutrition). However, it is unclear whether the levels of the antiretroviral medications that are achieved through this approach are sufficient to suppress HIV viral replication. In addition, extended release and enteric-coated formulations should never be crushed as this will destroy the enteric coating and result in decreased plasma levels of the antiretroviral medication.

Drug absorption. In order to inhibit HIV viral replication, antiretroviral medications must be sufficiently absorbed to achieve certain levels in the bloodstream. Critical illness may complicate the absorption of oral medications and several factors can contribute to variations in the absorption of antiretroviral medications. For example, some antiretroviral medications require the interruption of continuous enteral feeding (delivering liquid nutrients directly to the GI tract) for optimal absorption, while other antiretroviral medications should be taken with food to minimize adverse effects. In addition, H₂-blockers and proton pump inhibitors, used for stress ulcer prevention, are contraindicated with certain antiretroviral medications.

Drug dosing. The dose of many antiretroviral medications must be adjusted in persons with kidney or liver impairment. Since critically ill patients often have either kidney or liver impairment and the degree of impairment can change rapidly (within hours), the correct dosing of antiretroviral medications can be challenging. Low levels of these medications may increase the risk of drug resistance while high levels may result in increased side effects and drug toxicity.

Drug-drug interactions and antiretroviral-associated toxicities. Many antiretroviral medications have important drug-drug interactions with other medications. These interactions involve other HIV-associated medications and common ICU medications. In some instances, the concurrent use of these medications is contraindicated and may result in life-threatening side effects or toxicities. In other cases, medications may be used concurrently but their use requires close monitoring. The Department of Health and Human Services “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents” maintains up-to-date tables of important drug-drug interactions and drugs with overlapping toxicities to guide clinical care (http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf).

Should antiretroviral therapy be used in critically ill persons with HIV/AIDS?

There are no randomized clinical trials that address the question of whether to use antiretroviral therapy for clinically ill persons with HIV/AIDS; therefore,  there is no precise answer.. However, there are compelling arguments for and against using antiretroviral therapy in the ICU. The relative risks and benefits of using antiretroviral therapy in a critically ill individual should be weighed carefully.

Arguments for antiretroviral therapy in the ICU. Antiretroviral therapy improves immune function; with the therapy CD4 cell counts (cells that defend the body against HIV and opportunistic infections) rise, and plasma HIV RNA falls. Although the short-term impact of increasing the CD4 cell count and decreasing the plasma HIV RNA level on ICU mortality is unclear, improving immune function with antiretroviral therapy could be beneficial. In persons with HIV, improving their immune function with antiretroviral therapy reduces the risk of HIV-associated opportunistic infections and malignancies. This could contribute to reductions in additional HIV-associated complications that increase mortality in critically ill persons. The lower toxicity associated with the newer antiretroviral medications and combinations further strengthen the argument for their use in the ICU. For patients already receiving antiretroviral therapy, discontinuing therapy could result in the selection of drug-resistant virus.

Arguments against antiretroviral therapy in the ICU. The considerable issues related to drug delivery, absorption, dosing, drug-drug interactions, and antiretroviral-associated toxicities combine to indicate that the use of antiretroviral medications is associated with significant risks to patients who are already in a life-threatening condition and cannot afford additional complications. Immune reconstitution syndromes (see below) could result in clinical worsening of an already critical disease and the threat of this syndrome may make physicians reluctant to initiate antiretroviral therapy in the ICU.

Immune reconstitution syndrome (IRS), immune reconstitution inflammatory syndrome (IRIS)

The immune reconstitution syndrome (IRS), also referred to as the immune reconstitution inflammatory syndrome (IRIS), is a serious, potentially life-threatening syndrome that can develop in persons with HIV who start on combination antiretroviral therapy. The syndrome results from an antiretroviral therapy-mediated improvement in the person’s immune system that results in an increased inflammatory response against infections. The improved immune function can develop even before the CD4 cell count has risen. IRS has been described with virtually all HIV-associated opportunistic infections but appears to be most common in persons with Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus (CMV), Pneumocystis, and endemic fungi. IRS can present in one of two ways. First, IRS can “unmask” a previously undiagnosed opportunistic infection. More commonly, IRS paradoxically worsens a known opportunistic infection occurring in persons who are started on combination antiretroviral therapy at the same time or soon after treatment for the opportunistic infection.

The presentation of IRS depends on the underlying opportunistic infection. Respiratory failure secondary to IRS is most common in tuberculosis and PCP. Paradoxical worsening in these cases presents with fevers, cough, dyspnea (shortness of breath), hypoxemia (low levels of oxygen), and new or worsened chest x-ray findings. Antiretroviral regimens should be continued in persons with IRS whenever possible. (IS THE IMPLICATION HERE THAT WHILE THERE IS QUESTION ABOUT INITIATING THE THERAPY, CONTINUATION MAKES SENSE? PLEASE CLARIFY.) Care is supportive (SPECIFIC MEANING HERE?), and corticosteroids can be used in severe presentations, particularly in cases of PCP. Because this syndrome can be difficult to distinguish from acute opportunistic infections or other causes of respiratory deterioration, it is imperative that other causes of respiratory failure are sought before assigning a diagnosis of IRS. Thus, the diagnosis of IRS is one of exclusion.

Conclusion

HIV/AIDS has been transformed from a uniformly fatal disease to a chronic disease that cannot currently be cured but can be successfully treated with antiretroviral medications. As a result, intensive care for persons with HIV/AIDS is appropriate for most patients. However, the intensive care of these patients is complex and questions regarding the use of antiretroviral therapy in the ICU remain unanswered. Although the future holds promise, continued advances in our understanding in this area are needed to obtain the greatest benefit for the most critically ill.  

More information

Web Resources

Department of Health and Human Services AIDS Info: http://aidsinfo.nih.gov/

Department of Health and Human Services AIDS Info (current Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents): http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

Department of Health and Human Services Centers for Disease Control and Prevention (HIV/AIDS): http://www.cdc.gov/hiv/

Department of Health and Human Services Centers for Disease Control and Prevention (Global HIV/AIDS): http://www.cdc.gov/nchstp/od/gap/default.html

The National Institutes of Health Office of AIDS Research (OAR): http://www.oar.nih.gov/

University of California San Francisco HIV InSite: http://hivinsite.ucsf.edu/

 

Books

Raphael Dolin, Henry Masur, and Michael Saag. AIDS Therapy. 3^rd Edition.

 

References

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Halpern, SD. HIV testing without consent in critically ill patients. Jama 2005;294(6):734-737.

Huang L, Quartin A, Jones D, Havlir DV. Intensive care of patients with HIV infection. N Engl J Med 2006;355(2):173-81.

Morris, A, Wachter, RM, Luce, J, Turner, J, and Huang, L. Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. Aids 2003;17(1):73-80.

Morris A, Masur H, Huang L. Current issues in critical care of the human immunodeficiency virus-infected patient. Crit Care Med 2006;34(1):42-9.

 

Wachter RM, Luce JM, Hopewell PC. Critical care of patients with AIDS. JAMA 1992;267(4):541-7.