Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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DIABETES MELLITUS, HYPERGLYCEMIA, & THE CRITICALLY ILL PATIENT

597

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Other Complications of Diabetes Mellitus

In addition to disordered glucose control, it is important to

consider the interaction between the complications of diabetes

and unrelated acute illness. Some of the complications are clin-

ically obvious, such as renal failure or nephrotic syndrome with

hypoalbuminemia. Others are less obvious, such as defects in

vision (short of total blindness), which may make it difficult for

the patient to be totally compliant with management.

Renal and retinal complications should be looked for

routinely if the patient is known to have diabetes. However,

the consequences of autonomic neuropathy often are not

addressed in clinical evaluation. In patients with long-

standing diabetes, there may be devastating effects. For

example, orthostatic hypotension is usually not symptomatic

in most patients with autonomic neuropathy yet may

become dramatically important when other causes of

hypotension are present, such as volume depletion, cardiac

disease, or drug-related causes. Another overlooked problem

that can interfere with management is gastroparesis, which

should be considered in patients who are vomiting or have

diabetes that is difficult to control. With this disorder, poor

glucose control results from a lack of coordination between

insulin injection and absorption of meals owing to delay in

food exiting the stomach. Recurrent urinary tract infections

may result from a neurogenic bladder. Lastly, patients with

symptomatic autonomic neuropathy are also at increased

risk for sudden death from cardiorespiratory arrest.

Another not uncommon phenomenon that can cause an

acute problem in patients with long-standing diabetes is the

syndrome of hyporeninemic hypoaldosteronism. This disor-

der is seen commonly in older patients with type 2 diabetes

and mild renal insufficiency. With administration of ACE

inhibitors or in the presence of other acute illness, severe

hyperkalemia may be seen. Hyperkalemia may occur in

patients whose serum potassium concentration may be only

mildly elevated or at the upper limit of normal under usual

circumstances owing to hyporeninemic hypoaldosteronism.

Hermans G et al: Impact of intensive insulin therapy on neuro-

muscular complications and ventilator dependency in the med-

ical intensive care unit. Am J Respir Crit Care Med

2007;175:480–9. [PMID: 17138955].

Van den Berghe G et al: Intensive insulin therapy in the medical

ICU. N Engl J Med 2006;354:449–61. [PMID: 16452557]

Van den Berghe G et al: Outcome benefit of intensive insulin dose

versus glycemic control. Crit Care Med 2003;31:359–66. [PMID:

12576937]

Van den Berghe G et al: Intensive insulin therapy in the critically ill

patients. N Engl J Med 2001;345:1359–67. [PMID: 11794168]

Vanhorebeek I, Langouche L, Van den Berghe G: Tight blood glu-

cose control with insulin in the ICU: Facts and controversies.

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598

Since acquired immunodeficiency syndrome (AIDS) was

first described in 1981, much has been learned about the

spectrum of diseases associated with the progressive

immunosuppression caused by the human immune defi-

ciency virus (HIV). Malignancies and opportunistic infec-

tions are common sequelae of advanced HIV disease, but

HIV also can directly and indirectly affect the pulmonary

circulation, kidneys, heart, brain, and adrenal glands. Sepsis,

respiratory failure, and neurologic complications are com-

mon problems that often require management in the ICU.

The advent of highly active antiretroviral therapy (HAART)

and the success of prophylaxis strategies against several

common opportunistic infections have led to prolonged

survival and improved quality of life of patients with HIV

infection. In turn, the characteristics of patients with HIV

who are admitted to the ICU are changing, with concomi-

tant reconsideration of the benefits of ICU care. However,

widespread use of HAART has led to new problems and

complications of treatment, some of which are serious

enough to warrant ICU admission. The benefits of ICU care

for HIV-infected patients were questioned early in the epi-

demic because of studies reporting poor outcomes for

patients with respiratory failure owing to Pneumocystis

pneumonia (PCP). In the early stages of the HIV epidemic,

respiratory failure owing to PCP was responsible for up to

one-half of ICU admissions for patients with HIV infection,

with a mortality approaching 80–90%. By the mid-1990s,

the incidence of PCP with respiratory failure declined sig-

nificantly, accounting for only 18% of ICU admissions, and

mortality rates were considerably lower (50–60%). A recent

study at a single institution documented improved survival

of HIV-infected patients admitted to the ICU in the current

era, with an overall survival rate to hospital discharge of

71% compared with 31% in the pre-HAART era. However,

other institutions report survival rates in the range of

44–61%. Differences in patient populations, ICU admission

standards, and clinical practices may limit our ability to

draw comparisons across institutions.

With the decline in ICU admissions owing to PCP, the

most common present-day indications for admission of

patients with HIV infection are respiratory failure (42%,

including PCP), sepsis (12%), cardiac causes (10%), and neu-

rologic disease (12%), followed by smaller percentages of

patients requiring postoperative care and those with GI bleed-

ing, metabolic derangements, trauma, and drug overdoses.

End-stage liver disease is an increasingly common cause of

death in HIV-infected patients as deaths from opportunistic

infections decline and the complications of chronic hepatitis C

and B coinfection are seen. Patients may present with compli-

cations of HAART, such as lactic acidosis, impaired glucose

tolerance, hyperlipidemia, adverse drug reactions, and non-

salutory drug interactions leading to toxicities. Thus patients

with HIV infection are admitted to the ICU for a number of

reasons. Below we review the most common conditions neces-

sitating ICU hospitalization among HIV-infected patients.

COMPLICATIONS OF HIV DISEASE: AN

OVERVIEW

The primary cause of immunosuppression in HIV disease is

a progressive decline in the number and percentage of CD4

lymphocytes, resulting in decreased cellular immunity as

well as impairment of B-lymphocyte function. Increased

likelihood of infections caused by bacterial, protozoal,

mycobacterial, fungal, and viral pathogens can occur

throughout the entire course of HIV infection. However,

opportunistic infections and malignancies, certain neuro-

logic disorders, and severe wasting are associated with

advanced HIV infection.

The use of HAART has greatly modified the course of

HIV disease, with substantial declines in HIV-associated

morbidity and mortality. However, HAART regimens are

often complex, consisting of multiple drugs from up to four

different classes of antiretroviral agents; their success

depends on strict compliance with regimens, careful atten-

tion to the effects of food on absorption of antiretroviral

HIV Infection in the

Critically Ill Patient

Mallory D. Witt, MD

Darryl Y. Sue, MD

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HIV INFECTION IN THE CRITICALLY ILL PATIENT

599

drugs, the presence of resistant virus, drug interactions, and

patients’ ability to tolerate adverse effects of the medications.

Side effects and toxicities of HAART drugs are relatively

common, and changes in doses and/or components of regi-

mens may be necessary. As described below, a number of

antiretroviral agents preclude prescription of other com-

monly used medications, and certain drug-drug interactions

necessitate dose modifications of either or both drugs.

Although the presentation of HIV infection can be highly

variable, a number of general principles can be applied to all

patients. First, the level of immunosuppression must be consid-

ered when evaluating any disorder in an HIV-infected patient.

The likelihood of opportunistic infections and malignancies

increases as the number of CD4+ T-lymphocytes decreases.

In the presence of waning cellular and humoral immu-

nity, reactivation of latent infections may occur. For example,

in the absence of appropriate prophylaxis, one-third of HIV-

infected patients with prior exposure to Toxoplasma (ie, a

positive serum titer of IgG antibody to Toxoplasma) may

develop cerebral toxoplasmosis if they reach a sufficient level

of immunosuppression. In the absence of appropriate anti-

tuberculous prophylaxis, an HIV-infected individual with a

positive tuberculin skin test has a 7–10% chance per year of

developing active tuberculosis compared with an individual

without HIV infection with a positive skin test, who has less

than a 10% lifetime risk. Endemic fungal infections such as

histoplasmosis and coccidioidomycosis may reactivate with

declining immune status, presenting as disseminated infec-

tion. However, the most common infectious agents encoun-

tered in patients with HIV are traditional bacterial

pathogens, leading to pneumonia, bacteremia, and sepsis.

Patients with severe immunosuppression marked by

low CD4 T-lymphocyte counts benefit substantially

from prophylaxis against infections with P. jiroveci and

Mycobacterium avium complex (MAC). Appropriate prophy-

laxis should be given to selected patients, including those

with positive purified protein derivative (PPD) skin tests for

tuberculosis and those with antitoxoplasma antibodies.

Bica I et al: Increasing mortality due to end-stage liver disease in

patients with human immunodeficiency virus infection. Clin

Infect Dis 2001;32:492–7. [PMID: 11170959]

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infection. J Intensive Care Med 2007;22:73–81. [PMID: 17456727]

Huang L et al: Intensive care of patients with HIV infection. N Engl

J Med 2006;355:173–81. [PMID: 16837681]

Khouli H et al: Outcome of critically ill human immunodeficiency

virus-infected patients in the era of highly active antiretroviral

therapy. J Intensive Care Med 2005;20:327–33. [PMID:

16280405]

Morris A et al: Improved survival with highly active antiretroviral

therapy in HIV-infected patients with severe Pneumocystis

carinii pneumonia. AIDS 2003;17:73–80. [PMID: 12478071]

Morris A et al: Current issues in critical care of the human immun-

odeficiency virus–infected patient. Crit Care Med 2006;34:42–9.

[PMID: 16374154]

Mrus JM et al: Impact of HIV/AIDS on care and outcomes of

severe sepsis. Crit Care 2005;9:R623–30. [PMID: 16280060]

Rosen MJ, Narashimhan M: Critical care of immunocompromised

patients: Human immunodeficiency virus. Crit Care Med 2006;34:

S245–50. [PMID: 16917430]

Tedaldi EM et al: Influence of coinfection with hepatitis C virus on

morbidity and mortality due to human immunodeficiency

virus infection in the era of highly active antiretroviral therapy.

Clin Infec Dis 2003;36:363–7. [PMID: 12539079]

Vincent B et al: Characteristics and outcomes of HIV-infected

patients in the ICU: Impact of the highly active antiretroviral

treatment era. Intensive Care Med 2004;30:859–66. [PMID:

14767592]



Severe Complications of Antiretroviral

Therapy

Beginning with zidovudine (azidothymidine [AZT]), anti-

retroviral therapy has been used to slow the progression of

HIV infection. In the mid-1990s, protease inhibitors in com-

bination with other antiretroviral therapy demonstrated

potent effects on HIV, termed highly active antiretroviral

therapy (HAART). Increased availability of new HIV thera-

pies has led to an attendant increase in drug-drug interac-

tions as well as adverse effects of these therapies. Below we

review the serious complications of antiretroviral therapy

that, in some cases, may necessitate ICU admission.

Antiretroviral therapy can be divided into four drug classes:

nucleoside analogue reverse-transcriptase inhibitors (NRTIs),

nonnucleoside reverse-transcriptase inhibitors (NNRTIs),

protease inhibitors (PIs), and fusion inhibitors. These

drugs demonstrate both class and individual adverse drug

reactions as well as important interactions with each other

and with other drugs used to treat heart failure, anxiety,

infection, depression, and hyperlipidemia. Patients admitted

to the ICU with underlying HIV disease may be receiving

antiretroviral therapy that can complicate current manage-

ment or may present with unique adverse reactions to the

medications.

Lactic Acidosis and Hepatic Steatosis

Hyperlactatemia is an uncommon complication of NRTI use

and can be associated with fatal lactic acidosis. Its presenta-

tion may mimic septic or cardiogenic shock, hepatitis, or

drug-induced liver failure. Clinical features include

hepatomegaly, abnormal liver function tests, pancreatitis,

mild to severe lactic acidosis, and evidence of fatty liver on

ultrasound or CT scanning. Many NRTIs have been associ-

ated with this disorder, although stavudine and didanosine,

alone or in combination, are implicated most commonly.

The likely mechanism is inhibition of mitochondrial DNA

synthesis leading to impaired oxidative phosphorylation

with ensuing lactic acidosis and evidence of dysfunction in

the liver as well as other organs.

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CHAPTER 27

600

Hyperglycemia and Other Metabolic

Complications

Glucose intolerance, including hyperglycemia, frank dia-

betes, and even ketoacidosis may occur in some patients,

necessitating ICU admissions. Glucose dysregulation has

been associated with PI use and resulting insulin resistance

after a median of 60 days from initiation of therapy. In some

cases, substitution of an alternative antiretroviral agent leads

to resolution of hyperglycemia.

Lipid disorders are a growing concern in the setting of

HAART, with elevations in triglycerides, low-density

lipoprotein (LDL), and total cholesterol described. While

hyperlipidemia itself rarely leads to ICU admission, the

potential for accelerated atherosclerosis and coronary artery

disease associated with these lipid disorders is of concern. The

increased risk of cardiovascular disease in HAART-associated

hyperlipidemia is small but measurable. A recent report from

the Data Collection on Adverse Events of Anti-HIV Drugs

study indicated that the incidence of myocardial infarction

increased by an average of 26% per year of exposure to

HAART. A subsequent analysis revealed that over a period of

36,145 person-years of follow-up, 207 patients experienced at

least one cardio- or cerebrovascular event (CCVE). The inci-

dence of the first CCVE was 5.7 per 1000 person-years, with a

relative risk of 1.26 per year of exposure to HAART. The

impact of HAART on atherosclerotic disease is less than that

of hypertension, smoking, and other traditional risk factors;

emphasis on modification of risk factors remains paramount

in patients with HIV disease on HAART.

Pancreatitis can occur in the setting of HIV infection as a

result of antiretroviral and other HIV-related medications and

sometimes can be severe enough to necessitate ICU admission.

Didanosine, stavudine, or a combination of didanosine, stavu-

dine, and hydroxyrea have been implicated most commonly,

but lamivudine, ritonavir, isoniazid, lopinavir/ritonavir,

trimethoprim-sulfamethoxasole, sulfonamides, corticos-

teroids, and pentamidine rarely have been associated with

pancreatitis. Alcohol use as well as gallstones must be consid-

ered in the HIV-infected person presenting with pancreatitis.

Bartlett JG, Gallant JE: 2005–2006 Medical Management of HIV

Infection. Baltimore: Johns Hopkins Medicine, Health

Publishing Business Group, 2005.

Falco V et al: Severe nucleoside-associated lactic acidosis in human

immunodeficiency virus–infected patients: A report of 12 cases

and review of the literature. Clin Infect Dis 2002;34:838–46.

[PMID: 11850865]

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highly active antiretroviral therapy in HIV-1-infected adults.

Am J Med Sci 2004;328:48–56. [PMID: 15254441]

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Pulmonary Complications of HIV Infection

The most common cause of respiratory failure in the pres-

ence of HIV infection is P. jiroveci pneumonia, discussed

below. Other infectious etiologies that may present with

respiratory failure include bacterial pneumonia, endemic

fungal infections such as coccidioidomycosis and histoplas-

mosis, and sepsis.

The likelihood of specific pathogens being responsible for

pulmonary infection depends on several factors, including

the degree of immunosuppression, relevant exposure history,

and receipt of appropriate prophylaxis. For example, pneu-

mococcal pneumonia and tuberculosis may infect patients

irrespective of CD4 count, whereas P. jiroveci is uncommon

with a CD4 count above 200/μL. Second, prophylaxis with

trimethoprim-sulfamethoxazole significantly decreases the

likelihood of PCP as well as cerebral toxoplasmosis. Third, a

history of prior or latent infection may be important, such as

the presence of a positive tuberculin skin test, a history of

exposure to endemic fungi, or prior bacterial pneumonia.

Finally, the pattern on the chest x-ray may provide important

clues, including evidence of localized infection or findings

consistent with disseminated infection.

A. Symptoms and Signs—Important clues to the underly-

ing cause of respiratory failure include the duration of symp-

toms; the quantity and quality of sputum; the presence of

hemoptysis, dyspnea, and cyanosis; recent travel; geographic

place of residence; history of tuberculin skin testing results;

and recent adherence to prophylaxis.

B. Laboratory and Imaging Studies—Evaluation should

include chest x-ray, sputum Gram stain, sputum acid-fast

stain, complete blood count, blood cultures for bacteria,

liver function tests, serum lactate dehydrogenase (LDH),

creatinine, and arterial blood gases. In some cases, addi-

tional studies may be warranted, including serum crypto-

coccal antigen, fungal and mycobacterial blood cultures, and

CD4 count (if not known). Chest CT scan may be helpful to

identify additional foci of infection, verify the presence or

absence of hilar or mediatstinal adenopathy or parenchymal

cavitary lesions, or demonstrate a miliary pattern suggestive

of disseminated tuberculosis or coccidioidomycosis.

Urinary Histoplasma antigen should be measured in patients

from endemic areas or with known or potential exposure. In

the appropriate geographic area or with known or suspected

prior exposure, the presence of antibody to Coccidioides

immitis should be determined, but antibody is absent in up

to 25% of patients with advanced HIV infection and dis-

seminated coccidioidomycosis.

C. Fiberoptic Bronchoscopy—For patients with PCP (see

next), fiberoptic bronchoscopy with bronchoalveolar

lavage is diagnostic, and lavage may be useful for the diag-

nosis of tuberculosis and nontuberculous mycobacterial

infections.

D. Empirical Therapy—If the patient is critically ill, empiri-

cal therapy is indicated before results of laboratory studies

are available. Because bacterial pneumonia caused by

Streptococcus pneumoniae is the most common infection

leading to focal or diffuse infiltrates, antibacterial antibiotics

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HIV INFECTION IN THE CRITICALLY ILL PATIENT

601

should be initiated. For ICU patients, recommended treat-

ment includes a third-generation cephalosporin plus a

macrolide such as azithromycin. Antipseudomonal therapy

should be initiated in the at-risk patient.

The decision to start empirical treatment for PCP depends

on clinical suspicion. Patients likely to have PCP have more

severe hypoxemia, may have diffuse lung disease (although

x-ray abnormalities vary widely), often have elevated serum

LDH, and have a CD4 lymphocyte count under 200/μL.

Treatment should consist of trimethoprim-sulfamethoxazole

unless contraindicated; high-dose corticosteroids are indi-

cated if severe hypoxemia is present (see below).

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P. Jiroveci Pneumonia

ESSENTIALS OF DIAGNOSIS



Nonproductive cough, fever, anorexia, progressive

dyspnea.



Hypoxemia with increased P(A–a)o



Focal, diffuse, or patchy infiltrates on chest x-ray; on

occasion, the chest x-ray appears normal.



Finding of P. jiroveci on bronchoalveolar lavage.

General Considerations

Despite the widespread use of primary and secondary pro-

phylaxis, PCP remains the most common pulmonary infec-

tion associated with respiratory failure in persons with AIDS,

usually occurring in patients with previously undiagnosed

HIV infection or in patients who are nonadherent to prophy-

laxis and HAART. Early recognition and treatment, as well as

the use of adjunctive corticosteroid therapy, have resulted in

improved survival and less morbidity for patients with mod-

erate to severe disease.

Decreased survival of patients with PCP and respiratory

failure has been associated with severity of illness at hospi-

tal admission and prior use of PCP prophylaxis. The para-

dox of decreased survival in the setting of PCP prophylaxis

has been attributed to more severe immunosuppression

leading to failure of prophylaxis or potential resistance to

antibiotics.

Clinical Features

A. Symptoms and Signs—Common symptoms include

nonproductive cough, fever, anorexia, and progressive dysp-

nea. Physical examination may reveal fever, tachypnea,

cyanosis, and oral thrush, with rales and decreased basilar

breath sounds on lung examination.

B. Laboratory Findings—The white blood cell count is typ-

ically low or normal. The CD4 lymphocyte count is typically

less than 200/μL. Patients have moderate to severe hypoxemia

with increased P(

–a)

. Serum LDH is elevated in nearly all

patients.

C. Imaging Studies—The chest radiograph typically

demonstrates bilateral interstitial or alveolar infiltrates,

although virtually every radiographic pattern has been

described. Pleural effusions and mediastinal or hilar

adenopathy typically are absent unless a second pulmonary

process is present.

D. Fiberoptic Bronchoscopy with Bronchoalveolar

Lavage—The diagnosis is confirmed by identifying the

organism using modified Giemsa or methenamine silver

stains or immunofluorescent antibody. In most patients, the

diagnosis is made by bronchoalveolar lavage using fiberoptic

bronchoscopy, which has a sensitivity of 95–98% Some

patients may be too hypoxemic to undergo fiberoptic bron-

choscopy; in such cases, sputum obtained by suctioning from

the endotracheal tube or by expectoration may be stained

and examined for P. jiroveci, but the sensitivity is consider-

ably lower.

Differential Diagnosis

In a patient with known or suspected HIV infection and res-

piratory failure with pulmonary infiltrates consistent with

PCP, the differential diagnosis includes bacterial and viral

pneumonia, tuberculosis, other opportunistic infections

(including fungal pneumonia), congestive heart failure with

pulmonary edema, and acute respiratory distress syndrome

(ARDS).

Treatment

Patients with hypoxemic respiratory failure from PCP gener-

ally are managed in the same way as patients with ARDS.

Patients will require oxygen supplementation and may

require endotracheal intubation and mechanical ventilation.

A. Antipneumocystis Therapy—

1. Trimethoprim-sulfamethoxazole (TMP-SMX)—This

agent remains the treatment of choice for patients with PCP.

It is given as a fixed combination that delivers 15 mg/kg per

day of trimethoprim in divided doses every 8 hours intra-

venously or orally for 21 days. Side effects include fever, a

spectrum of exfoliative skin eruptions, eosinophilia,

leukopenia, thrombocytopenia, nausea, vomiting, and hepa-

titis. The dose must be decreased if the creatinine clearance is

less than 40 mL/min.

2. Pentamidine isethionate—This drug may be given to

patients with moderate to severe PCP who are unable to take

TMP-SMX because of serious allergic reactions. It is

administered a dose of 4 mg/kg per day intravenously for

21 days. However, serious side effects including renal insuf-

ficiency, pancreatitis, and orthostatic hypotension limit its

utility. Hypoglycemia may occur during or after treatment

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CHAPTER 27

602

and is exacerbated by renal insufficiency. Serum glucose

should be monitored at least every 8 hours. In some

patients, hypoglycemia may be followed by protracted

hyperglycemia requiring insulin. If any of these side effects

occur, an alternative treatment must be chosen.

3. Clindamycin and primaquine—Clindamycin, 600 mg

intravenously or 300–450 mg orally every 6 hours, can be

given with primaquine, 30 mg base orally once daily, for 21

days. Side effects include pseudomembranous (Clostridium

difficile) colitis, rash, hemolytic anemia in persons deficient

in glucose-6-phosphate dehydrogenase, liver function test

abnormalities, and methemoglobinemia.

4. Dapsone and trimethoprim—Dapsone is given in a

dosage of 100 mg orally once daily along with trimethoprim,

15 mg/kg per day in three or four divided doses, for 21 days.

Side effects include hemolytic anemia in patients with

glucose-6-phosphate dehydrogenase deficiency, methemo-

globinemia, liver function test abnormalities, rash, fever,

leukopenia, and thrombocytopenia.

5. Atovaquone—Atovaquone may be administered in

patients allergic to or unable to tolerate the preceding regi-

mens. It is given as a suspension of 750 mg twice daily by oral

administration for 21 days.

B. Corticosteroids—In patients with PCP who present with

respiratory failure of moderate to severe degree, adjunctive

therapy with corticosteroids is indicated. Corticosteroids

reduce the incidence of severe respiratory failure and

decrease mortality in patients with severe hypoxemia.

Candidates for corticosteroids have a P(

–a)

greater than

35 mm Hg or a Pa

less than 70 mm Hg. Such patients

should be given prednisone, 40 mg orally twice daily for

5 days, 40 mg orally once daily for 5 days, and then 20 mg

orally once daily for the remainder of the 21-day course of

treatment. To achieve maximum benefit, prednisone should

be started within 72 hours of beginning therapy. In patients

unable to take oral medications, intravenous methylpred-

nisolone can be substituted using the same dosage regimen.

C. Follow-up Care—Response to therapy typically occurs

within 2–7 days, marked by improvement in gas exchange

and decrease in fever. For patients who initially respond to

therapy and then develop fever, a search for another source

of infection should be undertaken. Drug fever, often

caused by TMP-SMX, should be considered when no other

pathogens are recovered and the patient is improving

clinically.

Twenty-one days of antipneumocystis therapy should be

followed by secondary prophylaxis with TMP-SMX, one

tablet (double-strength) orally three times per week. In

patients unable to tolerate TMP-SMZ, acceptable alternative

prophylactic regimens include dapsone, atovaquone, and

other agents.



Pulmonary Infection with Mycobacterium

Tuberculosis

ESSENTIALS OF DIAGNOSIS



Fever, night sweats, weight loss, cough, hemoptysis.



Chest radiograph showing focal infiltrates with cavita-

tion (CD4 lymphocytes >500/μL); focal or generalized

infiltrates (CD4 lymphocytes <500/μL); hilar and medi-

astinal lymphadenopathy.



Positive sputum for acid-fast bacilli or positive culture

for M. tuberculosis. Positive acid-fast stain or culture

from nonpulmonary site.

General Considerations

Tuberculosis (TB) is common in HIV-infected individuals

and in some cases may be associated with respiratory failure

or multiorgan dysfunction severe enough to warrant ICU

admission. TB occurs at all stages of HIV disease, even when

cell-mediated immunity is relatively intact, as measured by

CD4 count. Both primary infection and reactivation occur

with great frequency in this highly susceptible population.

The clinical presentation of tuberculosis in the presence of

underlying HIV infection may be atypical. Rather than the

cavitary lesions or upper lobe and apical disease usually seen

in immunocompetent, HIV-negative hosts, chest x-ray find-

ings may include infiltrates located in the middle and lower

lung zones, interstitial infiltrates, and hilar adenopathy; up to

25% of patients may have a normal chest x-ray. Disseminated

tuberculosis with lymphatic, bone marrow, and liver involve-

ment is significantly more common in persons with HIV

infection than in those with normal immune function.

Mycobacterial blood cultures are positive much more fre-

quently in HIV-infected patients. The tuberculin skin test

(PPD) is unreliable as a marker of tuberculous infection

because of its low sensitivity in HIV-infected patients.

Clinical Features

A. Symptoms and Signs—Patients with tuberculosis and

HIV infection may present with fever, productive cough,

shortness of breath, night sweats, lymphadenopathy, and

weight loss similar to that observed in non-HIV-infected

patients. Alternatively, symptoms may be minimal. Physical

examination findings include fever, loss of lean body mass,

and abnormal lung findings; some patients may have lym-

phadenopathy and/or hepatosplenomegaly.

B. Laboratory Findings—Liver function tests may be

abnormal in patients with tuberculosis, especially with dis-

seminated disease; elevated alkaline phosphatase, LDH, and

γ-glutamyl transpeptidase suggest granulomatous hepatitis.

Anemia is frequently present, and pancytopenia may be

present if there is bone marrow involvement.

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HIV INFECTION IN THE CRITICALLY ILL PATIENT

603

Smears for acid-fast bacilli from sputum and culture of

sputum for mycobacteria are the key to diagnosis. Three or

more sputum samples should be submitted for stain and cul-

ture. If the patient is unable to produce adequate sputum for

sampling, sputum can be induced by administering

aerosolized hypertonic saline. Negative acid-fast smears do

not exclude tuberculosis; in select patients, empirical treat-

ment should be continued until cultures are negative. In

patients undergoing fiberoptic bronchoscopy with bron-

choalveolar lavage for diagnosis of PCP, fluid also should be

sent for acid-fast staining and mycobacterial culture, even if

prior sputum specimens have been negative. Urine cultures

and blood isolators for mycobacteria may be positive. Drug

susceptibility studies should be done on all M. tuberculosis

isolates because drug-resistant strains are not uncommon in

many areas.

In patients suspected of having disseminated tuberculo-

sis, bone marrow or liver biopsy, punch biopsy of suspicious

skin lesions, and in some cases lumbar puncture may assist in

making the diagnosis.

C. Imaging Studies—Virtually any chest x-ray pattern can

be seen in tuberculosis with HIV infection, from classic api-

cal fibronodular infiltrates with cavitation to normal lung

parenchyma. A radiographic pattern consistent with primary

tuberculous infection is seen more often with HIV infection,

consisting of middle to lower lung field infiltrates, sometimes

with hilar adenopathy. Disseminated tuberculous infection

may be accompanied by a miliary pattern on chest x-ray.

Treatment

Patients with HIV infection and tuberculosis with suscepti-

ble strains of M. tuberculosis usually are treated successfully

with conventional antituberculous drug regimens. The ideal

duration of therapy is not known. The initial use of rifampin,

isoniazid, ethambutol, and pyrazinamide is recommended if

organisms are likely to be sensitive. If multidrug-resistant

tuberculosis is suspected, five- and six-drug regimens should

be considered. Absorption of antituberculous drugs may be

impaired in critically ill patients, and administration of par-

enteral agents may be necessary. Liver aminotransferase lev-

els should be monitored because isoniazid, rifampin, and

pyrazinamide are hepatotoxic. Tuberculosis and HIV coin-

fection is an indication for instituting directly observed ther-

apy (DOT) of tuberculosis.

A. Isoniazid, Rifampin, Pyrazinamide, and Ethambutol—

This combination of drugs is highly effective against suscep-

tible tuberculous organisms. The duration of treatment in

the HIV patient consists of 2 months of all four drugs fol-

lowed by 18 weeks of isoniazid and rifampin. Isoniazid is

given in a dosage of 300 mg orally or intramuscularly daily.

Common side effects include hepatitis, peripheral neuropa-

thy from pyridoxine deficiency, alteration in sensorium,

fever, and rash. Patients receiving isoniazid should be given

pyridoxine, 50 mg daily.

The usual dose of rifampin is 600 mg/day orally or intra-

venously. Side effects include hepatitis, discoloration of

urine, rash, fever, and alteration in other drug levels (eg, oral

contraceptives, warfarin, corticosteroids, digoxin, and

methadone). Pyrazinamide is given as 15 mg/kg orally daily.

Elevation of aminotransferases, hepatitis, hyperuricemia,

and arthralgias may be seen as side effects of this drug.

Ethambutol is given orally at a dosage of 15 mg/kg per day.

Ethambutol is generally well tolerated, but loss of color

vision or visual acuity may occur.

Rifampin is contraindicated in patients receiving PIs, such

as indinavir and ritonavir, and some NNRTIs, such as nevi-

rapine and delavirdine, because of significant drug interac-

tions. Rifabutin may be substituted for rifampin to minimize

drug interactions with PIs and NNRTIs. Dose modifications

of antiretrovirals and rifabutin may be needed.

B. Other Antituberculous Drugs—Patients in the ICU who

cannot tolerate or absorb oral medications may be given

intravenous isoniazid and rifampin; intravenous amikacin

and a fluoroquinolone should be added to optimize antimy-

cobacterial therapy. The usual dose for amikacin is 7.5 mg/kg

every 12 hours intravenously or intramuscularly. Serum lev-

els should be monitored to avoid nephrotoxicity. Side effects

may include renal failure, ototoxicity, and rarely, neuromus-

cular blockade. Dose adjustment for impaired renal function

is necessary. Fluoroquinolone dosing varies depending on

which agent is selected. Common side effects include GI

intolerance, rash, and altered sensorium. The dose is

decreased in patients with renal function abnormalities.



Bacterial Pneumonia

At all stages of HIV disease, bacterial pathogens are the most

common cause of community-acquired pneumonia. In fact,

bacterial pneumonia occurs approximately 25-fold more fre-

quently among HIV-infected adults than in the general com-

munity, with an inverse relationship between CD4 counts

and incidence. Among the bacterial pathogens, the pneumo-

coccus is particularly important: Infection with S. pneumo-

niae occurs approximately 100 times more frequently than in

the HIV-uninfected host, with increased incidence in the set-

ting of smoking and low CD4 counts. Recurrence rates for

pneumococcal pneumonia are high, ranging from 6–24%.

The presentation of pneumococcal pneumonia in the HIV-

infected patient is similar to that in the immunocompetent

host, with abrupt onset fever, chills, cough and pleuritic

chest pain. S. pneumoniae bacteremia in the setting of HIV

infection occurs in up to 90% of patients and may be the key

to diagnosing a community-acquired pneumonia because

the sensitivity of sputum Gram stain and culture is 50% or

less. Radiographic findings of pneumococcal pneumonia

consist of the characteristic lobar or bronchopneumonia.

Haemophilus influenzae, Legionella pneumophila, and

Mycoplasma pneumoniae are also seen in the setting of HIV

infection. Hospitalized or neutropenic patients are at



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604

increased risk for infection with Staphylococcus aureus,

including methicillin-resistant S. aureus (MRSA), and gram-

negative aerobic bacilli, including Pseudomonas aeruginosa,

especially in the ICU setting. Bacterial infections may occur

alone or, less commonly, may complicate an opportunistic

infectious process such as PCP. Unusual bacteria may be

responsible for pneumonia, including Rhodococcus equi, an

aerobic intracellular gram-positive coccobacillus causing

cavitary lung disease.

For patients admitted to the ICU with community-

acquired pneumonia, recommended initial therapy includes

a third-generation cephalosporin (eg, ceftriaxone, 2 g intra-

venously once daily) plus azithromycin, 500 mg intra-

venously once daily, unless there is suspicion of Pseudomonas

infection (substitute a β-lactam with antipseudomonal effi-

cacy such as ceftazidime or piperacillin-tazobactam).

Aviram G, Fishman JE, Boiselle PM : Thoracic infections in human

immunodeficiency virus/acquired immune deficiency syn-

drome. Semin Roentgenol 2007;42:23–36. [PMID: 17174172 ]

Blumberg HM et al: American Thoracic Society/Centers for

Disease Control and Prevention/Infectious Diseases Society of

America: Treatment of tuberculosis. Am J Respir Crit Care Med

2003;167:603–62. [PMID: 12588714]

Frieden TR et al: Tuberculosis. Lancet 2003;362:1858–9. [PMID:

13678977]

Klugman KP et al: HIV and pneumococcal disease. Curr Opin

Infect Dis 2007;20:11–5. [PMID: 17197876]

Lopez-Palomo C et al: Pneumonia in HIV-infected patients in the

HAART era: Incidence, risk and impact of the pneumococcal

vaccination. J Med Virol 2004;72:517–24. [PMID: 14981752]

Thomas CF Jr, Limper AH: Pneumocystis pneumonia. N Engl J Med

2004;350:2487–98. [PMID: 15190141]

Wolff AJ, O’Donnell AE: HIV-related pulmonary infections: A

review of the recent literature. Curr Opin Pulm Med 2003;9:

210–4. [PMID: 12682566]

OTHER INFECTIOUS CAUSES OF PNEUMONIA

AND RESPIRATORY FAILURE



Fungal Pneumonia

Fungal pneumonias should be considered in patients with

pulmonary infiltrates, negative cultures and smears for

mycobacteria, negative stains and cultures for bacteria, and

clinical progression with antibacterial treatment. Fungal

infection also may present as a disseminated process with

multiorgan involvement. Tissue biopsies and serologic tests

are most helpful because growth of fungal pathogens in cul-

ture is slow, sometimes on the order of weeks.

A. Cryptococcal Pneumonia—Since advanced HIV disease

is the primary risk factor for cryptococcal infections in most

of the world, the incidence of cryptococcal infections has

declined significantly in countries with access to HAART. The

lung is the most common portal of entry for the organism,

after which asymptomatic colonization or life-threatening

pneumonia can occur. In the presence of an advanced

immunocompromised state, cryptococcal pneumonia may

progress rapidly, with dissemination from the lung to blood-

stream, skin, and/or meninges. Most patients with AIDS and

cryptococcal pneumonia are symptomatic, with fever,

malaise, cough, dyspnea, and weight loss. Radiographic find-

ings include diffuse interstitial opacities, focal infiltrates, alve-

olar infiltrates, pleural effusions, and cavitary lesions.

Diagnosis is made by isolation of Cryptococcus neoformans

from sputum, bronchoalveolar lavage fluid, or pleural fluid or

by the presence of a positive cryptococcal antigen in bron-

choalveolar lavage fluid. Lumbar puncture must be per-

formed to rule out CNS cryptococcal infection even if

patients are asymptomatic because concomitant CNS

involvement is present in approximately 90% of patients with

AIDS and cryptococcal pneumonia. The serum cryptococcal

antigen is an insensitive test in the absence of disseminated

disease and may be negative in the patient with isolated cryp-

tococcal pneumonia. Patients with respiratory failure attrib-

uted to cryptococcal pneumonia should undergo evaluation

for PCP as well; in some cases, both pathogens may be pres-

ent. Mortality for those with respiratory failure from crypto-

coccal pneumonia is very high despite aggressive treatment.

Although mild to moderate cryptococcal pneumonia

alone can be treated with fluconazole, HIV-infected patients

with severe cryptococcal pneumonia admitted to the ICU

should receive amphotericin B, 0.7–1 mg/kg per day intra-

venously, with or without flucytosine, 100 mg/kg daily, until

symptoms are controlled, followed by fluconazole, 200–400

mg/day indefinitely or until immune restoration with

HAART has been well established. This regimen is optimal

for CNS disease as well, except that amphotericin B and

flucytosine are given for at least 2 weeks.

B. Other Fungal Pneumonias—Endemic mycoses caused

by such fungi as Histoplasma capsulatum and Coccidioides

immitis usually present in patients with advanced immunod-

eficiency as a disseminated process of which pulmonary dis-

ease is one component. Fever, cough, and progressive

dyspnea are common and may be accompanied by signs and

symptoms of sepsis or other organ system involvement.

Chronic or subacute pneumonia caused by C. immitis can

occur in up to 10% of AIDS patients living in endemic areas

such as Arizona and the San Joaquin Valley of California.

However, use of HAART has been associated with a decline in

the incidence of HIV-associated coccidioidomycosis. Any radi-

ographic findings may be present on chest x-ray, including

cavities, interstitial or lobar infiltrates, nodules, and pleural

effusions. Disseminated coccidioidomycosis is associated with

advanced immunosuppression. Sputum, bronchoalveolar

lavage fluid, and/or bronchial washings should be sent for fun-

gal stains and culture. Complement fixation titers greater than

1:16 are diagnostic of disseminated coccidioidomycosis but

may be insensitive in HIV-infected patients; up to 25% of

patients will have no detectable anticoccidioidal antibodies.

Intravenous amphotericin B, 0.5–1 mg/kg per day, should be



HIV INFECTION IN THE CRITICALLY ILL PATIENT

605

used for initial treatment of pulmonary disease to a total

dose of 30–40 mg/kg, followed by fluconazole at 200

mg/day orally. Patients with suspected dissemination

should undergo lumbar puncture to look for meningitis

because high-dose fluconazole is the preferred treatment

for meningitis caused by C. immitis.

Pneumonia owing to Histoplasma was seen in up to 15%

of AIDS patients living in endemic areas in the pre-HAART

era, although it is significantly less common today.

Dissemination occurs in patients with advanced disease and

low CD4 lymphocyte counts. Chest x-ray findings are non-

specific, with diffuse infiltrates, nodules, focal infiltrates, cav-

ities, and hilar adenopathy noted. Urine Histoplasma

polysaccharide antigen assay is moderately sensitive

(50–70%) in cases of pneumonia, with a sensitivity of 90% in

the setting of disseminated disease. Histoplasma serum and

bronchoalveolar lavage antigen, serologic studies, the pres-

ence of intracellular organisms on peripheral blood smear

(30% sensitivity for disseminated Histoplasma infection),

and tissue biopsy may be helpful in diagnosis. Cultures of

blood, respiratory tract secretions, bone marrow, or

biopsy specimens are positive in 85% of patients but require

2–4 weeks to grow. In severe or disseminated disease for

patients in the ICU, intravenous amphotericin B should be

given initially (for 3–14 days depending on response), fol-

lowed by itraconazole, 200 mg orally twice daily indefinitely.

Invasive and obstructing aspergillosis has been described

rarely in patients with HIV infection and advanced immun-

odeficiency. Factors predisposing to Aspergillus infection

include corticosteroid use, neutropenia, pneumonia caused

by other pathogens, marijuana smoking, and use of broad-

spectrum antibiotics. Chest x-ray abnormalities may include

focal infiltrates, cavities, pleural-based densities, or diffuse

infiltrates. Because Aspergillus organisms may colonize

patients without causing infection, sputum culture and

staining may be unreliable. A tissue biopsy showing

Aspergillus in tissue or invading blood vessels is the most reli-

able diagnostic test. Voriconazole is the treatment of choice

for invasive aspergillosis, at a dose of 6 mg/kg intravenous

every 12 hours × 2 doses, followed by 4 mg/kg intravenous

every 12 hours for at least 1 week, then 200 mg bid.

Alternative agents include intravenous amphotericin B, as

well as itraconazole for prolonged treatment in milder cases if

there has been a good clinical response to initial treatment.



Kaposi Sarcoma

The incidence of Kaposi sarcoma (KS) has declined dramat-

ically in the HAART era, with a concomitant decline in the

incidence of pulmonary KS. Studies from the pre- and early

HAART era described an incidence of pulmonary involve-

ment in approximately 35% of patients with HIV-associated

KS, with a higher proportion found at autopsy. Clinically

symptomatic pulmonary KS is seen most often with

advanced HIV disease and can progress to respiratory failure.

Most but not all pulmonary KS occurs in the presence of

concomitant mucocutaneous lesions. Patients typically pres-

ent with nonproductive cough, dyspnea, and sometimes

fever, with chest pain and hemoptysis less commonly

reported. Chest x-ray abnormalities typically include bilat-

eral middle-lower lung opacities with a central or perihilar

distribution; infiltrates may be interstitial or nodular or may

appear as linear perihilar densities. Kerley B lines, intratho-

racic adenopathy, and pleural effusions are seen less com-

monly. Abnormal gas exchange, hemoptysis, and

superinfection with bacteria may occur. The diagnosis of

pulmonary KS is usually established by fiberoptic bron-

choscopy. Bronchoalveolar lavage should be performed to

rule out other opportunistic pathogens because pulmonary

KS is often seen in conjunction with PCP or other oppor-

tunistic infections. Response of KS to chemotherapy or radi-

ation therapy generally was poor in the pre-HAART era;

however, potent antiretroviral therapy in conjunction with

daunorubicin, liposomal doxorubicin, or paclitaxel may

arrest or even reverse the course of pulmonary KS.

Chiller TM, Galgiani JN, Stevens DA: Coccidioidomycosis. Infect

Dis Clin North Am 2003;17:41–57. [PMID: 12751260]

Mocroft A et al: The changing pattern of Kaposi sarcoma in

patients with HIV, 1994–2003. Cancer 2004;100:2644–54.

[PMID: 15197808]

Perfect JR, Casadevall A: Cryptococcosis. Infect Dis Clin North Am

2002;16:837–74. [PMID: 12512184]

Wheat LJ, Kauffman CA: Histoplasmosis. Infect Dis Clin North

Am 2003;17:1–19. [PMID: 12751258]



Sepsis In HIV-Infected Patients

ESSENTIALS OF DIAGNOSIS



Fever or hypothermia, hypotension, hyperventilation,

change in mental status.



Complications of organ failure, such as alteration in gas

exchange, renal insufficiency or failure, lactic acidosis,

disseminated intravascular coagulation, or liver failure.



Bacteremia, fungemia, or features arousing a high clin-

ical suspicion of infection.



Previous evidence or suspicion of bacterial, fungal, or

mycobacterial infection may be helpful in differential

diagnosis.

General Considerations

Sepsis was discussed in Chapter 15. Important considerations

in patients with HIV infection include the potential for oppor-

tunistic and/or unusual microbial organisms to be involved

and differences in diagnostic strategy and empirical therapy.

Because HIV infection is associated with disruption of

both cellular and humoral immunity, disseminated infection



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606

occurs in a substantial proportion of patients, with the rate

of dissemination proportionate to the degree of immuno-

suppression. Furthermore, phagocytic cell dysfunction and

skin and mucosal membrane disruption increase the likeli-

hood of organism translocation. Compared with age-

matched cohorts, bacteremia is more commonly seen in

HIV-infected patients with an identified focal bacterial infec-

tion. In addition, M. tuberculosis is more likely to disseminate

to multiple organs and causes active disease more often in

patients with HIV infection and immunosuppression.

Treatment with various medications used to treat HIV and

its complications, including zidovudine, trimethoprim-

sulfamethoxazole, pyrimethamine, and valganciclovir—and

even HIV itself—may cause neutropenia.

A. Bacterial Sepsis—Most of these infections are associated

with an identifiable source, such as the lungs, GI tract, uri-

nary tract, CNS, or an intravascular catheter. Clinically silent

sites of bacterial infection include the sinuses, prostate, bil-

iary tract, skin and soft tissues, endocardium, and GI tract.

The most common gram-positive organism responsible for

bacteremia is S. pneumoniae, whereas Escherichia coli is the

most common gram-negative organism found in blood, sug-

gesting that common infections such as pneumonia and uri-

nary tract infection are still the most likely sources of

bacterial infection. Neutropenia should alert one to the pos-

sible presence of P. aeruginosa and staphylococci, both com-

munity- and hospital-acquired. In particular, P. aeruginosa

infection is reported to be increasing in incidence, with risk

factors including neutropenia, antibiotic use, corticosteroid

use, and low CD4 lymphocyte count.

Infection with MRSA is increasingly common among

patients with HIV infection, typically causing multiple skin

and soft tissue abscesses but sometimes with accompanying

bacteremia and/or sepsis. Community-acquired strains of

MRSA are more susceptible to antibiotics than their nosoco-

mial counterparts, with sensitivity to vancomycin, TMP-

SMX, and in some cases clindamycin. Sepsis may be caused

by enteric diarrhea-associated pathogens and Listeria.

B. Disseminated Mycobacterial Infections—A subacute

course of fever, weight loss, night sweats, cough, headache, or

lymphadenopathy suggests a fungal or mycobacterial

pathogen. The initial symptoms are often nonspecific and

the clinical picture benign, but patients may present late,

with a clinical picture consistent with sepsis. Findings sug-

gestive of disseminated fungal or mycobacterial infections

include hepatosplenomegaly, lymphadenopathy, and the

presence of skin or oral lesions. There may be laboratory

findings of pancytopenia (bone marrow infiltration) and ele-

vated LDH and alkaline phosphatase levels.

Tuberculosis can present as a widely disseminated

process. The clinical picture is characterized by weight loss,

anorexia, and fever and sometimes by cough, dyspnea, and

night sweats. Disseminated tuberculosis may be associated

with tuberculous meningitis, necessitating a lumbar puncture

if clinical suspicion of meningeal involvement exists.

Disseminated MAC infection is a late sequela of HIV infec-

tion and is seen in patients with CD4 lymphocyte counts of

less than 50/μL. The clinical picture is similar to that of late-

stage tuberculosis and is also associated with severe diarrhea.

The course is protracted, and the diagnosis is often made by

demonstration of the organisms in the blood using the lysis-

centrifugation method or on tissue biopsy. MAC grows in

approximately 3–6 weeks and can be identified using a DNA-

specific probe.

C. Disseminated Fungal Infections—C. neoformans, C.

immitis, and H. capsulatum are primarily acquired through

the respiratory tract and are hematogenously disseminated

to multiple organs. Because of impaired cellular immunity,

infections with these organisms may progress rapidly in

HIV-infected persons. Progressive disseminated histoplas-

mosis is characterized by an initial mild course with minimal

symptoms of 4–5 weeks’ duration, followed by a syndrome of

hypotension, disseminated intravascular coagulation, renal

insufficiency, severe pancytopenia, abnormal liver function

tests (especially LDH), and respiratory failure. CNS involve-

ment is common. Intracellular organisms may be seen on the

peripheral blood smear. Early initiation of amphotericin B

therapy is critical while awaiting diagnostic studies.

Disseminated coccidioides infection presents in a similar

manner. Diagnosis and treatment of coccidioidomycosis are

discussed in the section on pulmonary infection in HIV-

infected patients.

Although oral and esophageal candidiasis occurs with

great frequency in patients with symptomatic HIV infection,

disseminated candidiasis is rare except in the usual settings of

intravascular catheters, broad-spectrum antibiotics, or intra-

venous hyperalimentation.

Clinical Features

A. Symptoms and Signs—In addition to features that may

localize the primary site of infection, additional information

useful for planning empirical therapy include the travel his-

tory, tuberculin skin test status, history of exposure to or pre-

vious infection with mycobacteria or endemic fungi, and

recent use of antibiotics. Besides the primary infection site,

examination should focus on potential sites of dissemina-

tion, including a careful funduscopic examination, inspec-

tion of skin and mucous membranes, and a search for

lymphadenopathy and hepatosplenomegaly.

B. Laboratory and Imaging Studies—This should include

initially a complete blood count, peripheral blood smear

(intracellular Histoplasma organisms may be seen occasion-

ally), blood cultures (two sets each for aerobic and anaerobic

bacteria); liver function tests: LDH; urinalysis; chest x-ray;

and creatine kinase.

Any potential site of infection should be cultured for

suspected pathogens. Special culture techniques, such as

urine culture after prostatic massage or aspiration of skin