AIDS Patients in the Intensive Care UnitL.A

AIDS Patients in the Intensive Care Unit

L. A

-R

, P. R

-S

, J. P

-B

, F. B

-G

Introduction

The first cases of acquired immunodeficiency syndrome (AIDS) were reported in the summer of 1981, in American young homosexual males. Two years later, the virus responsible for the disease, known as human immunodeficiency virus (HIV-1), was identified. Although this agent causes the vast majority of cases, a variant of this virus (HIV-2) was later isolated in patients from or epidemio- logically linked to West Africa. From its onset, the epidemic of HIV/AIDS has shown continuous growth beyond all predictions. According to the Joint United Nations Program on HIV/AIDS (UNAIDS), at the end of 1999, about 56 million people worldwide had been infected, of which, 20 million had died [1]. The problem is particularly worrying in developing countries, where 95% of the HIV-infected people live, especially in Sub-Saharan Africa, with a mean preva- lence of 8.8% in the adult population (it has been estimated that 25.3 million people infected by HIV were living in this area at the end of 2000). In contrast, in North America and Western Europe together, at the end of 2000 the infected population was 1.46 million. In addition, the development of preventive pro- grams and the availability of highly active antiretroviral therapy (HAART) in industrialized countries has determined a change in the pattern of the epidem- ic: not only is the growth of the epidemic slower but survival of infected patients is also increasing. In Spain, according to data from the Health Department (http://www.msc.es/sida), the infection rate has decreased from 187.6 per million in 1994 to 58.9 in 2000.

The HIV/AIDS epidemic is a major health problem, with high morbidity,

mortality, and costs produced by a chronic and ultimately fatal disease. It also

has a great socio-economic impact, since HIV infection affects mainly young

productive adults. Likewise, the disease affects individuals belonging to high

economic and educational classes, at least in the first stages, although later it

persists in the most-vulnerable classes. This epidemic has therefore led to a sig-

nificant reduction in life expectancy, even to the appearance of a negative demographic growth, and to an important decrease of the gross domestic prod- uct in countries with a greater incidence of the disease.

HIV/AIDS and the Intensive Care Unit

Patients with HIV infection are admitted to intensive care units (ICUs) for monitoring and vigilance, or for advanced life support; but a non-negligible number of patients can be admitted to these units due to causes unrelated to the infection. In the last 3 years, only 33% of HIV/AIDS patients were admitted to our unit due to conditions directly associated with the disease, while the other conditions were not associated (trauma, coronary syndromes, drug overdose, etc.) (unpublished data).

The presence of HIV-infected patients in ICUs varies widely depending on the area being considered and the type of hospital [2]. In some units, this group of patients can reach more than 33% of all admissions [3]. Overall, of all HIV-infect- ed patients admitted to a hospital, about 4%–12% will require ICU care [4, 5].

The improvement of preventive and therapeutic options has prolonged the life of HIV/AIDS patients, and has changed the spectrum of diseases that cause hospitalization. At the beginning of the epidemic, more than two-thirds of ICU admissions were due to respiratory failure, especially secondary to Pneumocystis carinii pneumonia (PCP) [6, 7]. However, in the last few years only 38%–49% of admissions were due to respiratory failure [3–5] (Table 1), and 37%–45% of these were caused by PCP [3–5, 8]. Bacterial pneumonia is becoming the leading cause of respiratory failure leading to ICU admission (47%–53%), but other etiologies, such as tuberculosis, toxoplasmosis, or Kaposi sarcoma (KS), still represent a significant minor proportion [3, 8]. Neurological problems (11%–27%), sepsis (10%–15%), and several types of cardiac manifes- tations (5%) are other frequent reasons for ICU admission [3–5, 8].

Toxoplasmosis is the major cause of cerebral dysfunction in this group of

patients (62% of cases of central nervous system disease in the series of

Casalino et al. [3]), although tuberculosis, cryptococcosis, bacterial meningitis,

cerebral lymphoma, or progressive multifocal leukoencephalopathy (PML) are

also reported with variable frequencies [9]. Sepsis and septic shock are mainly

of pulmonary origin and bacterial etiology [10, 11]. In the series of Rosenberg

et al. [11], pneumonia caused 65% of episodes of sepsis, and in 45% of infec-

tions a bacterial agent was identified, although in this study and in others, other

micro-organisms were found, such as P. carinii, Mycobacterium tuberculosis,

cytomegalovirus (CMV), Cryptococcus neoformans, and Toxoplasma gondii. The

most common cardiac manifestations in HIV/AIDS patients are pericarditis,

myocarditis, dilated cardiomyopathy, endocarditis, neoplasms, and cardiac drug toxicity [12]. Some of the most frequent infectious agents associated with cardiac disease are Staphylococcus aureus, Streptococcus viridans, Salmonella, M. tuberculosis, T. gondii, and C. neoformans, and the most common neoplasms are KS and lymphoma [3, 12].

Finally, during the first stage of the epidemic, the observed mortality among AIDS patients admitted to the ICU was high. Wachter et al. [6] and Schein et al.

[7] reported a mortality of 69% and 77% respectively, which increased to 87%

and 91% in patients who developed acute respiratory failure. These poor out- comes changed physicians’ attitudes to these patients, and it was thought that ICU admission was generally futile and mechanical ventilation was rarely indi- cated. This led to the search for new therapeutic options outside the ICU.

However, introduction of antiretroviral therapy and the availability of better options for prevention and management of opportunistic infection, especially PCP, with the use of co-trimoxazole and corticosteroids, have changed the prognosis and management of HIV/AIDS infection. In several recent series [3–5], in-ICU and in-hospital mortality among HIV/AIDS patients admitted to the ICU ranged between 21% and 24% and between 30% and 39%, respectively.

The 1-year survival was 27%–28% [3, 4, 13]. These rates are comparable to those observed in high-risk non-HIV-infected patients admitted to the ICU (severe sepsis, the elderly, patients needing cardiopulmonary resuscitation, bone mar- row transplantation recipients) [3]. According to these data, admission of HIV/AIDS patients to the ICU should not be considered futile, although more studies are needed to evaluate the impact of HAART.

We must bear in mind that the outcome varies with the cause of ICU admis- sion [3–5, 8, 10, 11]. In-hospital mortality is 44%–93% in patients admitted due Table 1. Reasons for intensive care unit (ICU) admission among HIV/AIDS patients

% of Admissions

Respiratory failure 38.4–49.2

Neurological disease 11.1–26.8

Severe sepsis 10.2–58.1

Gastrointestinal bleeding 6.3–6.5

Cardiac disease 4.5–7.9

Drug overdose 2.3–5.3

Metabolic disturbance 1.6–1.7

Trauma 1.1–2.9

Miscellaneous 2–9.3

a

From references [4–6, 12]. The intervals are the extreme values reflected in the references

to severe sepsis/septic shock, 26%–46% in those with acute respiratory failure, 32%–41% in those with central nervous system dysfunction, and 6%–69% in those with cardiac involvement. Multiple risk factors have been identified in several studies, with independent association with mortality in HIV/AIDS patients admitted to the ICU (APACHE/SAPS scores, need for mechanical ven- tilation, and duration, diagnosis of PCP, patients coming from a hospital ward, serum albumin level less than 25 g/l, CD4+ count less than 50x10

/l, function- al status, weight loss, HIV disease stage, duration of AIDS, etc.) [3–5, 8, 11]

(Table 2). As a general rule, as reported by Casalino et al. [3], short-term in-ICU and in-hospital outcome is determined by the severity of the acute disease and health status prior to admission, whereas long-term outcome depends mainly on those variables reflecting the stage of HIV infection. However, to date, no single factor or combination of factors has been able to reasonably predict after-ICU survival. For example, Nickas and Wachter [4] reported an in-hospi- tal mortality of 39% in a group of patients with very high mortality predicted on a theoretical basis (CD4+ cells count less than 50x10

/l, serum albumin level less than 25 g/l, and mechanical ventilation). Therefore, caution must be used when evaluating these markers for a particular case.

Table 2. Factors influencing in-ICU/in-hospital mortality among HIV/AIDS patients admitted to the ICU (multivariate analysis)

Odds ratio

Functional status (>2) 1.82

AIDS diagnosis in ICU 1.62

AIDS diagnosis prior to ICU 2.63

Time since AIDS diagnosis (>360 days) 1.91

Albumin level 0.39 per 10 g/l increase

Serum albumin <25 g/l 3.06

APACHE II score >17 3.41

APACHE III score >80 3.1

SAPS I score >12 1.62

Mechanical ventilation requirement 4.3–19.2

Acute respiratory distress syndrome in ICU 14.0

Bacterial cause of infection 1.3

Pneumonia 1.9

Pneumocystis carinii pneumonia diagnosis 2.4–4.5

a

From references [4, 5, 9, 12]. Only statistically significant results are presented. Functional

status assessed by a modified Karnofsky index (see reference [4]). The intervals are the

extreme values reflected in the references

Pathogenesis

HIV infection is a consequence of viral infection and replication inside cells bearing CD4+ receptors (CD4+ T lymphocytes and, in minor proportion, macrophages and dendritic cells) and then cell destruction. Besides CD4+, other co-receptors (mainly CCR5 and CXCR4) are needed for virus internaliza- tion [14].

Among all branches of the immune system, T cell-mediated immunity plays a pivotal role in control of HIV infection. However, unlike in other viral infec- tions, the immune response is unable to control the disease [15]. This seems to be due to the defective response of HIV-infected (CD4+) and non-infected (CD8+) T lymphocytes.

The average time from HIV infection to the development of AIDS is 8–10 years. However, there is a small proportion of patients not following this usual evolution, and the study of these individuals has been essential for knowledge of the immunity to HIV [14–17]. Asymptomatic patients with a normal CD4+

cell count, a low or undetectable viral burden despite long-term HIV infection, and no treatment are known as non-progressors and represent 5%–10% of HIV-infected patients. In addition, there are some exposed yet uninfected indi- viduals despite repeated exposure to HIV. Finally, those who develop AIDS in the first 5 years after HIV infection are known as rapid progressors.

In the first days to weeks after HIV primary infection, a high level of viremia is observed, together with an important immune system activation, essentially represented by T lymphocytes, with a partial control of viral replication [14, 15]. After a few weeks or months, a rapid decrease in viremia occurs, followed by a return of T lymphocyte count to near-normal levels. The patient enters a prolonged asymptomatic stage with a balance between viral production and destruction, despite detectable viral burden. The progression of the disease is characterized by a continuous increase in viral burden and a decrease in T lym- phocyte CD4+ (T-helper cells) count, and finally, appearance of severe immunosuppression [14, 15, 17].

After activation induced by viral antigens, T cells release several cytokines,

in particular interleukin-2 (IL-2), which in turn stimulate the CD8+ T lympho-

cytes (T cytotoxic cells). These are the effector arm of cellular immunity, with

the ability to recognize and lyze cells expressing foreign proteins. During HIV

infection, HIV-specific CD8+ T lymphocytes proliferate, and these cells, with a

broad spectrum of antiviral activity, play an essential role in controlling the dis-

ease [14, 15]. However, HIV selectively infects and destroys activated CD4+ T

lymphocytes, and this depletion of T-helper cells diminishes the subsequent

immune response. It is well known that CD4+ T lymphocytes are important for

the initiation of the response, for the maintenance of memory and maturation

of the functions of CD8+ T lymphocytes [15, 17].

HIV-specific CD8+ T cells exert a broad spectrum of antiviral activities.

They produce a protein, perforin, which together with the granzymes, are essential for the lysis of infected cells [15]. They influence viral replication through the production of several cytokines. Some of these, such as interfer- on- γ (IFN-γ), inhibit replication, while others, such as tumor necrosis factor- α (TNF-α), can up-regulate HIV replication [15, 16]. They can also interfere with viral replication through the production of chemokines that limit, by competition or down-regulation, interaction of HIV with cell co-receptors [15]. RANTES (regulated on activation normal T expressed and secreted), MIP-1 α (macrophage inflammatory protein), and MIP-1 β block the CCR5 co-receptor. SDF-1 (stromal cell-derived factor) is the natural ligand for CXCR4 co-receptor.

Humoral immunity also plays a role in the defense against HIV, but is not well defined [14]. Although some data support a protective function of anti- HIV antibodies, as in the case of a possible decrease in perinatal transmission in the presence of maternal antibodies [18], or a potential protection of some health care workers by neutralizing antibodies [19], current evidence is not enough to state a crucial importance of humoral immunity in the control of the disease [20, 21]. Antibodies against HIV can be detected 2–3 weeks after the primary infection, but even in their presence, viral replication continues.

Only when the infection is well established, sometimes even in the final stages, are HIV-neutralizing antibodies present [14, 21]. Together with their neutralizing function, they can complement other defensive mechanisms, namely complement and cellular immunity [14, 21].

Finally, several local factors, not well defined yet, are involved in the defense against HIV [14–16]. The presence of sexually transmitted diseases and lack of circumcision are known to be associated with a higher risk of infection. Dendritic cells, which take antigens in the periphery and transport them to lymph nodes, where T lymphocytes are activated, may play a role dur- ing the primary infection of the mucosa. In addition, the presence of CD8+ T lymphocytes and HIV-specific IgA antibodies can also help to control the viral burden in the genital tract.

Despite the deployment of such an important defense system, HIV contin-

ues to replicate and therefore the disease progresses [14–17, 20]. The mecha-

nisms (not well characterized) seem to be multiple, namely mutations in gag,

pol, and env genes, a decrease of HIV-specific CD8+ T lymphocytes due to

clonal deletion, and persistence of the virus in immune-privileged sites (cen-

tral nervous system, eye, testis, dendritic cells, and infected memory T cells).

Antiretroviral Therapy

The introduction of HAART in 1996 has turned HIV infection, formerly a fatal disease, into a chronic process with a survival of several decades. At the end of the 1990s, the mortality of patients with CD4+ counts of less than 100x10

/l was approximately 66% less than in former years [22]. With this type of treatment, based on the use of potent antiretroviral drugs in combination, a favorable response can be elicited in 60%–90% of antiretroviral-naive patients [23].

The main goal of HAART is to achieve a sustained reduction of viral burden to the lowest possible levels and, ideally, a complete viral suppression (HIV-1 RNA plasma levels under detection limits of 50–20 copies/ml). A rapid reduc- tion (a few months) of viral burden under 20 copies/ml is related to a long-term response [24].

Current recommendations to start treatment for HIV infection are mainly based on viral burden and CD4+ T lymphocyte level [22, 23, 25]. However, all symptomatic patients should be treated, regardless of the viral burden or CD4+

T cell level. Patients with CD4+ cells less than 200x10

/l, even if asymptomatic, should also be treated. Treatment can be postponed in asymptomatic patients with CD4+ levels greater than 350x10

/l. In asymptomatic patients with CD4+

levels between 200 and 350x10

/l, the decision to treat should be based on the rate of lymphocyte decrease, viral burden, and the preference of the patient. Sex is not a determinant of decision to treat.

Three groups of antiretroviral agents are currently in use, exerting activity on two HIV enzymes (reverse transcriptase and protease). The first group is that of the nucleoside reverse transcriptase inhibitors (NRTIs), comprising DDI, 3TC, D4T, DDC, and AZT. Another group is the non-nucleoside reverse transcriptase inhibitors (NNRTIs), including delavirdine, efavirenz, and nevi- rapine. The last group, the protease inhibitors (PIs), includes amprenavir, indi- navir, nelfinavir, ritonavir, and saquinavir.

Current recommendations for initial combination antiretroviral therapy are the following [22, 23, 25]: two NRTIs plus one PI; two NRTIs plus one NNRTI;

two PIs plus one or two NRTIs; one PI plus one NNRTI, with or without one or

two NRTIs; three NRTIs. Regimens including PIs have the advantage of a high

potency and the evidence of long-term efficacy (more than 3 years). However,

there are also several drawbacks, such as their complexity, their toxic effects

(metabolic, cardiovascular, etc.), and the possible appearance of cross-resist-

ance within PIs, thus limiting the use of these drugs in future regimens. Non-PI

combinations offer the advantage of sparing the most potent drugs; however,

although initial efficacy seems to be similar, it has not been proved in the long term; in addition, resistance can appear more rapidly, and their toxic effects are not negligible. Therefore, treatment must be individualized, taking into consid- eration the advantages and disadvantages for each particular case.

Despite the efficacy of the treatment, HIV replication in latently infected rest- ing T lymphocytes and other long-lived cell populations has been demonstrat- ed. Even in patients with an undetectable viral burden for a long time, plasma HIV-1 RNA rebounds can occur after interruption of antiretroviral therapy [23, 25]. Thus, it seems unlikely that antiretroviral therapy alone can eradicate HIV.

Current research is directed at the design of more potent drugs, with less toxicity, which are better tolerated, and also with different targets (fusion inhibitors). At the same time, much work is in progress to increase the activity of antiretroviral therapy (hydroxyurea, cyclosporine) and to improve immuni- ty against HIV (cytokine therapy, vaccines) [22, 25].

Opportunistic Infections

The introduction of HAART with at least three antiretroviral drugs has result- ed in a major change in the prognosis and management of HIV infection. The incidence of some opportunistic infections (OI), such as PCP, disseminated Mycobacterium avium complex (MAC), or CMV, has been drastically reduced.

Similarly, a decrease has been observed in other conditions, for which no effec- tive treatment was available, such as KS, PML, and cryptosporidiosis [26].

OI are present in patients not receiving HAART or in those with failure of

therapy. Likewise, immediately after starting antiretroviral therapy, a paradoxi-

cal increase of OI is observed, because the immune system has not yet recovered

or due to the appearance of the so-called immune reconstitution syndrome

(IRS). It has been reported that in some cases 2 weeks are enough to recover the

immune response against OI [27]. IRS especially presents in severely immuno-

suppressed patients in the first 12–16 weeks after starting HAART, and is char-

acterized by a severe inflammatory response. With effective antiretroviral ther-

apy, with an adequate immunological and virological response, IRS determines

the presence of clinical manifestations in patients with latent infections or a

paradoxical deterioration of a patient with an OI under treatment. This syn-

drome has been reported in CMV, MAC, and M. tuberculosis, among others, as

well as with PML and KS [28]. Treatment for IRS is not well defined, but steroids

or non-steroidal anti-inflammatory drugs can be useful in severe cases, togeth-

er with HAART and the corresponding etiological therapy for OI [26, 28]. In the

rest of the chapter we shall review some of the OI that can cause admission to

ICU among AIDS patients.

P. carinii

This is an eukaryotic micro-organism considered to be a fungus closely related to Ascomycetes. At present, several lines of evidence suggest that re-infection is a major cause of PCP in immunosuppressed individuals [29], presenting typi- cally as a pneumonia in HIV-infected patients, while extrapulmonary disease is generally associated with the use of prophylactic inhaled pentamidine [30]. The risk of PCP markedly increases with CD4+ counts of less than 200x10

/l (rela- tive risk 4.9 versus CD4+ count greater than 200x10

/l) [31].

The course of the disease is generally insidious and the usual symptoms include fever, dry cough, and dyspnea. The characteristic radiographic findings of PCP are fine, bilateral perihiliar interstitial shadowing. However, chest radi- ographs can be normal or reveal pneumothorax, solitary nodules, or upper lobe shadowing. Use of inhaled pentamidine as prophylaxis has been associated with atypical radiographic findings [29]. High-resolution computed tomography (CT) is more sensitive than plain chest films for the diagnosis of PCP, with the typical findings being a mosaic pattern of ground-glass shadowing.

The gold standard for the diagnosis of PCP is detection of the micro-organism in respiratory tract samples. Since P. carinii cannot be cultured, diagnosis is made through direct observation of the organism by light microscopy or using mono- clonal antibodies techniques. Fibrobronchoscopic bronchoalveolar lavage (BAL), with a diagnostic confirmatory rate of 79%–98%, is the reference technique for collecting samples [31], and when combined with transbronchial biopsy has a diagnostic yield near to 100% [32]. Induced sputum is an alternative to BAL, with a sensitivity of 55%–95% [31]. Studies based on induced sputum show a low sen- sitivity and poor diagnostic yield. In addition, use of the polymerase chain reac- tion (PCR) offers the possibility of improving the yield of non-invasive samples.

However, PCR at present can only be considered a research tool, and it remains to be determined whether it will prove more cost-effective than BAL.

The main prognostic marker in PCP is blood oxygen level at the time of diagnosis. Patients with a PO

less than 70 mmHg or an alveolar-arterial gradi- ent greater than 35 mmHg have an elevated risk of death, and their condition must be considered as moderate to severe.

The treatment of choice in all cases of PCP is trimethroprim-sulfamethoxa-

zole (TMP-SMX) for 21 days [29, 32, 33] (Table 3). If a favorable response is

observed, therapy can be continued via the oral route. Adverse events are fre-

quent (rash, fever, liver enzyme elevation, neutropenia, thrombocytopenia, ery-

thema multiforme, or renal toxicity), precluding treatment in 25%–50% of

patients [32]. Given the high therapeutic efficacy of TMP-SMX, treatment must

be continued as long as side effects are of moderate intensity, and desensitiza-

tion is recommended in cases of hypersensitivity. When side effects are severe,

alternative treatments include IV pentamidine and IV trimetrexate plus folinic

acid (Table 3). Pentamidine can produce hypoglycemia, pancreatitis, diabetes

mellitus, pancytopenia, hypotension, and renal failure. Adverse effects of trime- trexate include fever, rash, leukopenia, and liver enzyme elevations [33].

Impairment or oxygenation is frequently seen within the first 3–5 days of therapy for PCP. Use of corticosteroids has proved to decrease mortality, dete- rioration of oxygenation, and respiratory failure in patients with moderate- to-severe PCP, when started in the first 72 h of antimicrobial therapy [34].

Table 3. Treatment and prophylaxis of opportunistic infections in persons infected with human immunodeficiency virus (PIs protease inhibitors, NNRTIs non-nucleoside reverse transcriptase inhibitors)

Pneumocystis carinii pneumonia

• Co-trimoxazole 160/800 mg/day

• CD4+ <200 cells/mm

• Oropharyngeal candidiasis

• History of Penumocystis carinii pneumonia Toxoplasmosis • Co-trimoxazole

160/800 mg/day

• CD4+ <100 cells/mm

• History of toxoplasmic encephalitis

Cryptococcal meningitis

• Fluconazole 100-200 mg/day

• History of cryptococal meningitis

Cytomegalovirus disease

• Ganciclovir 5 mg/kg per 12 h ≥ 3–6 weeks

• History of cytomegalovirus disease

• Consider for CMV seropositi- ve with CD4+ < 50 cells/mm

Tuberculosis • Isoniazid ≥ 9 months • Positive tuberculin skin test

Mycobacterium avium complex

• Clarithromycin or azithromycin

• CD4+ < 50 cells/mm

cont. ➝

Infection Prophylaxis Indications for prophylaxis

The recommended dose is 40 mg prednisone (or equivalent) every 12 h on days 1 through 5, 40 mg/day on days 6 through 10, and 20 mg/day on days 11 through 21. It has been shown that steroid therapy is associated with a higher rate of herpetic mucocutaneous infections and oral thrush lesions, but not with other OI.

Some alternative treatments are dapsone or dapsone plus pyrimethamine Severe disease

• Co-trimoxazole (trimethoprim component 15–20 mg/kg per day IV, divided in 3-4 doses) ≥ 21 days

• Adjuvant high-dose steroids Mild-to-moderate disease

• Co-trimoxazole (trimethoprim component 12–15 mg/kg per day PO) ≥ 21 days (IV, PO)

• Sulfadiazine 4–6 g/day plus pyremethamine 100–200 mg loading dose, then 50–100 mg/day plus folinic acid 10 mg/day ≥ 6–8 weeks

First choice

Treatment

Alternative regimens

• Clarithromicyn 500 mg/12 h plus ethambutol 15 mg/kg per day ± rifabutin 300 mg/day

• Ganciclovir 5 mg/kg per 12 h ≥ 3–6 weeks • Foscarnet 60 mg/kg per 8 h ≥ 3–6 weeks

• Ganciclovir plus foscarnet Induction

• Amphotericin B 0.7–1 mg/kg per day (IV) plus flucytosine 75–100 mg/kg per day ≥ 2–3 weeks Consolidation

• Fluconazole 400 mg/day ≥ 8 weeks Patients without PIs or NNRTIs

• Isoniazid 300 mg/day ≥ 24 weeks (PO, IM) plus rifampin 600 mg/day ≥ 24 weeks (PO, IV) plus pyrazinamide 30 mg/kg per day ≥ 8 weeks ± ethambutol 15–25 mg/kg per day (IM, IV) or streptomycin 15 mg/kg per day (IM, IV)

Patients on PIs or NNRTIs

• Isoniazid 300 mg/day plus rifabutin 150–450 mg/day plus ethambutol 15–25 mg/kg per day plus pyrazinamide 25 mg/kg per day

• Fluconazole 800 mg/day ≥ 10–12 weeks

• Fluconazole 800 mg/day plus flucytosine 100 mg/kg per day ≥ 6 weeks

• Lipid formulations of amphotericin B 3–6 mg/kg per day ≥ 6–10 weeks

• Itraconazole 400 mg/day ≥ 10–12 weeks

• Clindamycin 600 mg/6h (IV, PO) plus pyremethamine 50 mg/day plus folinic acid 10 mg/day ≥ 6–8 weeks

• Clarithromycin 1 g/12 h or azithromycin 1,200–1,500 mg/day or atovaquone 750 mg/8 h

plus pyremethamine 50–100 mg/day (PO) plus folinic acid 10 mg/day ≥ 6–8 weeks

• Pentamidine isethionate 4 mg/kg per day IV

• Trimetrexate 45 mg/m

per day IV and folinic acid 80 mg/m

per day

• Dapsone 100 mg/day plus trimethroprim 20 mg/kg per day PO

• Clindamycin 600 mg/8 h plus primaquine 15 mg daily PO

• Atavaquone 750 mg/12 h PO

Table 3 cont.

and leucovorin, or aerosolized pentamidine, or atovaquone. The outcome of PCP is better in HIV-infected patients than in those with other forms of immunosuppression; however, mortality of patients needing mechanical venti- lation is still high, ranging from 56% to 75% [35, 36]. In patients with respira- tory failure, non-invasive ventilation with continuous positive airway pressure may be a good alternative approach to avoid risks associated with mechanical ventilation [29, 36].

Prophylaxis against P. carinii with TMP-SMX is indicated in patients with CD4+ count of less than 200x10

/l, or a history of oropharyngeal candidiasis, or prior episodes of PCP [37] (Table 3).

Cryptococcal Disease

C. neoformans usually enters the host through the respiratory route. This agent may affect almost any organ, such as the skin or the lungs, although it has a def- inite predilection for the central nervous system. Cryptococcal disease rarely occurs in patients with CD4+ counts greater than 100x10

/l. From a clinical point of view, cryptococcal pneumonia, which can precede disseminated dis- ease, has no specific features. Likewise, cryptococcal meningitis is not always associated with a clear meningeal syndrome, and can frequently present with mild malaise, fever, and headache [38]. Encephalitis syndrome is generally due to intracranial hypertension and is a marker of poor outcome. In the AIDS patient with cryptococcal meningitis, the usual findings are a weak inflamma- tory response in the cerebrospinal fluid (CSF), large fungal burden, and few mass lesions [39].

Etiological diagnosis can be achieved by several methods. On the one hand, direct examination of urine, BAL, biopsy specimens, and, especially, the CSF with India ink smears has a good sensitivity. On the other hand, detection of cryptococcal antigen in serum or CSF allows a rapid diagnosis in the majority of cases. Given the sensitivity near to 100%, a negative serum cryptococcal anti- gen virtually rules out the disease [40, 41]. Finally, C. neoformans can be isolat- ed from cultures of blood, CSF, urine, respiratory or biopsy samples, and can be cultured on most fungal media.

Initial or induction treatment of cryptococcal meningitis should include a

combination of IV amphotericin B (0.7–1 mg/kg per day) and oral flucytosine

for 2–3 weeks [28, 38, 41] (Table 3). Use of smaller doses of amphotericin B is

associated with lower rates of survival and CSF sterilization [28]. At the same

time, association of flucytosine significantly increases the odds of CSF sterili-

zation and decreases relapses in the maintenance stage, with an acceptable rate

of adverse effects, although a clear effect on mortality has not been proven [28,

40]. In refractory cases, intrathecal administration of amphotericin B can be

considered [41]. After these 2 weeks, a consolidation treatment with flucona-

zole must be administered for 8 weeks, or until CSF cultures are negative. On the other hand, if conventional amphotericin B cannot be given, we can use some of the following alternatives, although current experience is smaller [28, 38, 41]: high-dose fluconazole, fluconazole plus flucytosine, or lipid formula- tions of amphotericin B (Table 3). A relapse rate of 37% has been reported in AIDS patients with cryptococcal meningitis, in which no maintenance therapy was given after control of acute infection. Thus, treatment with life-long flu- conazole is recommended. This regimen has been shown to be superior to those using itraconazole or amphotericin B [41].

Elevation of intracranial pressure (opening pressure greater than 200 mm H

O, with the patient in the lateral decubitus position) is a common finding in cryptococcal meningitis. In the series of Graybill et al. [39], it was present in 75% of patients, and in 27% it was greater than 350 mmH

O. The presence of obstructive hydrocephalus and focal neurological lesions was uncommon. It is thought that this hypertension can be secondary in part to an impairment of CSF reabsorption in arachnoid villi, due to high levels of fungal polysaccharide antigen or the presence of the micro-organism itself. It was also observed that survival of patients with pressure lower than 250 mmH

O was significantly greater than of those with higher pressure [39]. Thus, routine measurement of baseline opening pressure is recommended in every patient after ruling out the presence of space-occupying lesions [28, 41]. If pressure is normal, lumbar puncture should be repeated after 2 weeks of therapy. In patients with elevated pressure, it should be reduced by 50% through CSF evacuation, repeating punc- tures daily to keep the pressure within the normal range. If this procedure is not enough, a lumbar drainage or a ventriculo-peritoneal shunt can be used.

Steroids have not shown a clear benefit in this setting and therefore are not rec- ommended [28, 39, 41].

Early initiation of appropriate therapy for cryptococcal meningitis improves associated mortality and morbidity. In recent series, mortality was 6%–9% [39, 40], which is markedly lower than previously reported (14%–25%) [38, 41].

Finally, primary prophylaxis with fluconazole only reduced the risk of cryp- tococcosis, but not mortality, in patients with CD4+ counts of less than 50x10

/l.

Therefore, given the risk-benefit ratio, its use is discouraged [28, 37, 38, 41].

Toxoplasmosis

Most cases are due to reactivation of a latent infection. The prevalence varies with geographic location, being more frequent in southern Europe than in northern Europe and the United States (15%–50% versus 5%–10%) [42]. Like cryptococcal disease, this OI is characteristic of advanced stages of immuno- suppression. Cerebral toxoplasmosis is the most common manifestation of T.

gondii infection, presenting in up to 40% of patients with a CD4+ count of less

than 100x10

/l in 18 months of follow-up [42]. Likewise, it is still the most com- mon cause of AIDS-related focal brain lesions. The clinical picture is not spe- cific, and presents generally as malaise, headache, and focal neurological signs.

The diagnosis can only be confirmed by demonstration of the parasite and the typical lesions in the central nervous system (CNS) by means of stereotactic brain biopsy [43]. Although the procedure has a low morbidity and mortality, it is not always indicated, as a reasonable presumptive diagnosis will allow the institution of therapy on most occasions [28, 44]. Several methods are available for this purpose, such as imaging techniques, serology, and PCR testing, where- as culture is not usually performed in clinical practice as it is difficult, slow, and has a low sensitivity [42]. Toxoplasmosis is the most common cause of ring- enhancing lesions on contrast computed tomography brain scans, generally presenting as multiple lesions, in contrast to lymphoma, which usually presents as a unique lesion that often crosses the midline. Nuclear magnetic resonance (NMR) can be more sensitive than CT for identifying multiple cerebral lesions [45]. Similarly, brain thallium-201 single-photon emission computed tomogra- phy (SPECT) can contribute to the differential diagnosis of brain lesions [26], especially when combined with serum toxoplasma IgG (sensitivity and speci- ficity >80%) [46]. Toxoplasma serology has great diagnostic accuracy, as less than 5% of infected patients have a negative test, and thus, alternative diagnoses must be considered in toxoplasma-seronegative patients [42]. Finally, serial determination of PCR for T. gondii in CSF can be an important aid for the diag- nosis, if samples are collected before the 1st week of therapy (sensitivity 50%–65%, specificity 96%–100%, positive predictive value 100%, negative pre- dictive value 92%–97%) [42]. In addition, the possibility of also detecting CMV, JC virus (etiology of PML), and Epstein-Barr virus (primary CNS lymphoma) among others by PCR, will often allow a diagnosis with a minimally invasive approach [44].

Therefore, in those patients with advanced HIV disease and ring-enhancing lesions on contrast CT brain scans, which are toxoplasma seropositive and have not received correct toxoplasmosis prophylaxis, empiric treatment for T. gondii infection should be started. Clinical improvement is usually observed in 1 week and a radiological response in 2 weeks. Thus, in cases with a favorable response, CT/NMR should be repeated after 14 days of treatment. In contrast, if improvement is not observed, or imaging tests are not characteristic of this infection, an alternative diagnosis should be sought, even with brain biopsy.

The treatment of choice is a combination of pyrimethamine plus sulfadi-

azine for 6–8 weeks [26, 28, 42], adding folinic acid to avoid hematological tox-

icity of pyrimethamine (Table 3). In case of intracranial hypertension/mass

effect, corticosteroids should be added. In patients with poor tolerance to sul-

fadiazine, some alternatives are pyrimethamine and folinic acid plus clin-

damycin, or pyrimethamine and folinic acid plus azithromycin or clar-

ithromycin or atovaquone. After initial therapy, suppressive therapy should be continued life long with pyrimethamine and folinic acid plus sulfadiazine (or clindamycin if there is sulfadiazine intolerance) (Table 3).

Primary prophylaxis with TMP-SMX is indicated in toxoplasma-seropositive patients with CD4+ counts less than 100x10

/l [26, 28, 37, 42]. Possible alterna- tives are dapsone plus pyrimethamine and folinic acid, or atovaquone.

Mortality from cerebral toxoplasmosis is 5%–20% despite treatment, and approximately half of the patients experience neurological sequelae [42].

Recurrent toxoplasmosis, altered mental status, severe focal signs at the initia- tion of therapy, and treatment non compliance are markers of a poor outcome.

Bacterial Infections

These constitute an important cause of morbidity and mortality in HIV-infect- ed patients, and their relative importance is increasing due to prophylaxis against opportunistic agents. In a study of 398 AIDS patients, 42% developed bacterial infections [47]. In another review of 126 deaths of HIV-infected patients, bacterial infections accounted for 30% of all causes of fatality [48].

The most frequent infections in AIDS patients are sinusitis, pneumonia, skin and soft tissue infections [47]. There are several explanations for their high incidence, including defects in humoral immunity such as mucosal IgA defi- ciency, impairment of neutrophil chemotactic and phagocytic activity, and decrease of bacterial clearance on the part of the macrophages [47]. In addition, in advanced stages of AIDS, there is a high frequency of neutropenia secondary to drug toxicity (TMP-SMX, gancyclovir, antiretroviral drugs, etc.), OI, or bone marrow failure caused by HIV [48]. In this group of neutropenic patients with bacterial infections, use of granulocyte colony-stimulating factor (G-CSF) reduces mortality.

Streptococcus pneumoniae, Haemophilus influenzae, Salmonella spp., Pseudomonas aeruginosa, and Staphylococcus aureus are the bacteria usually involved. Some others, observed less frequently are Rhodococcus equi, Nocardia asteroides, Campylobacter, and Bartonella [47].

Bacterial pneumonia in these patients is generally caused by S. pneumoniae

and H. influenzae. The clinical presentation is similar to that of immunocom-

petent patients, although H. influenzae pneumonia can occasionally mimick

PCP. Legionella is an uncommon etiology, whereas P. aeruginosa, S. aureus, and

aerobic gram-negative bacilli can be responsible in late stages of HIV infection

[26, 48]. It should be noted that pneumococcal pneumonia is associated with

bacteremia in 60% of cases, and 89% of pneumococcal bacteremias have a

pneumonia as an initial manifestation.

On the other hand, incidence of bacteremia among AIDS patients is also higher than in the general population; the usual agents are S. pneumoniae, S.

aureus, S. epidermidis, P. aeruginosa, H. influenzae, and Salmonella spp.

Pneumonia, followed by gastrointestinal infection and catheters, is the most fre- quent source [48]. Treatment of bacterial infection is not different in AIDS patients from immunocompetent patients.

Other Infections

Mycobacterial diseases [Mycobacterium tuberculosis, Mycobacterium avium complex (MAC)] are other OI that have experienced a resurgence with the AIDS epidemic. The progression rate of tuberculosis from latent infection to active disease is higher in the HIV-positive population (10% each year versus 5% after 2 years) [49]. The evolution is different depending on the country being ana- lyzed. In Spain, tuberculosis still represents 40% of the initial AIDS-defining diseases, whereas MAC disease is of minor relevance [26, 28, 49]. These diseases, especially MAC, appear in stages of severe immunosuppression (CD4+ count less than 50x10

/l). The clinical presentation is generally atypical, as fever of unknown origin, extrapulmonary manifestations, or even as an immune recon- stitution syndrome [26, 28, 49]. Pulmonary disease is generally seen in patients with higher CD4+ counts [28, 49]. A high index of suspicion is necessary, as diagnosis can be difficult. Tuberculosis skin testing can be negative in up to 40% of individuals with the disease [26, 28, 49]. Introduction of clarithromycin and azithromycin has produced a major change in treatment/prophylaxis of MAC disease [26, 28] (Table 3). Therapy for tuberculosis in AIDS patients does not differ significantly from that in the general population [28, 49, 50] (Table 3). However, it is necessary to know the frequent interactions of tuberculostat- ic agents with antiretroviral drugs, which may force changes in therapy, such as substituting rifampin for rifabutin, among others [28, 49, 50].

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