ACP medicine, 3rd Edition

Infectious Disease

Mycotic Infections in the Compromised Host

Jo-Anne van Burik MD, FACP1

1Assistant Professor, University of Minnesota Medical School

The author has received grant or research support from Schering-Plough Research Corporation, Inc., Astellas Pharma US, Inc., and Enzon Pharmaceuticals, Inc.; participates in the speakers' bureaus for Schering-Plough Research Corporation, Inc., Pfizer, Inc., and Astellas Pharma US, Inc.; and is a consultant for Schering-Plough Research Corporation, Inc., and Astellas Pharma US, Inc.

December 2005

Opportunistic fungal infections have become increasingly important over the past several decades, paradoxically because advances in medical practice have improved the survival of debilitated and immunosuppressed patients. Opportunistic fungal pathogens may originate as human commensals (e.g., Candida albicans) or have an environmental reservoir (e.g., Aspergillus fumigatus). They may have yeast (budding, unicellular) or mold (branching, tubular hyphal cell) phenotypes. Timely diagnosis of opportunistic fungal infection depends on an understanding of host characteristics, environmental risk factors, clinical presentation, and diagnostic testing. In treatment, correction of predisposing conditions can be as important as the use of antifungal medication. Localized infections may require surgery. Immunocompromised patients require either prophylaxis or early empirical treatment during high-risk periods.

Candidiasis

EPIDEMIOLOGY

  1. albicansis a yeast that is virtually ubiquitous in humans. Acquired at or soon after birth, it becomes part of the normal flora of the gastrointestinal and vaginal tracts. In healthy persons, overgrowth of Candidaat those commensal sites is a common cause of minor skin and mucous membrane infections—notably, oral candidiasis, diaper rash in infants, and vaginal candidiasis in women. In persons with immune system aberrations or iatrogenic factors that predispose to infection, candidal infections can become invasive; the organism may enter the bloodstream and disseminate to normally sterile tissues.
  2. albicanshas the best adherence mechanisms of the various Candidaspecies and is therefore the predominant yeast colonizing the mouth, gut, and vagina. Treatment with systemic antifungal drugs may result in the replacement of C. albicans by other candidal species and their appearance as opportunistic pathogens. This phenomenon has grown with the wider use of such agents. In particular, C. glabrata and C. krusei bloodstream infections have become more common since the introduction of fluconazole in the early 1990s.1,2 Other Candida species regarded as frequent human pathogens include C. parapsilosis, C. tropicalis, C. lusitaniae, C. dubliniensis, and C. guilliermondii.3 C. lusitaniae is notable for resistance to amphotericin. C. parapsilosis is notable for nosocomial transmission from an exogenous source, such as hyperalimentation fluids. In a hospital, a series of infections with the same non-albicans Candida species in several patients over a short period of time suggests a common nosocomial point source.

ETIOLOGY

Candidal infection often reflects a combination of environmental and host defense factors; this is especially true of localized mucocutaneous infection from overgrowth of commensal C. albicans. Wearing diapers or dentures provides an environment conducive to candidal growth, as does antibiotic treatment that reduces the commensal bacteria that normally help keep Candida in check. Host factors include the normal life phases of infancy and pregnancy (especially third trimester) and pathologic conditions such as vitamin deficiencies and malnourishment, diabetes mellitus and other endocrine abnormalities, congenital or acquired defects in cell-mediated immunity, and malignancy. Iatrogenic contributors include radiotherapy, systemic or inhaled steroids, and other immunosuppressive medications.4

PATHOGENESIS

Candida can reach normally sterile tissues through iatrogenic means: contamination of plastic catheters may lead to localized infection, such as peritonitis from peritoneal dialysis catheters and cystitis or upper urinary tract infection from urinary (Foley) catheters.5 Alternatively,Candida may spread from colonized surfaces to contiguous tissues. Depending on the original site, such invasion can lead to esophagitis, sinusitis, mastoiditis, and, in rare cases, primary pneumonia. A breakdown of GI mucosa through damage from cancer chemotherapy, radiation, trauma, or concurrent viral ulcers may allow a commensal Candida strain to gain access to the bloodstream. Tissue abscesses from hematogenous dissemination can form in the lung, brain, liver, spleen, kidney, bone, joints, heart valves, skin, and eye. In short,Candida infections can affect almost every organ system in the body.

DIAGNOSIS

Clinical Manifestations

Oropharyngeal candidiasis

Patients with oropharyngeal candidiasis may complain of sore throat or raw tongue; eating may be so uncomfortable that patients lose weight. Pseudomembranous candidiasis (thrush) presents as loosely adherent white patches and plaques on the buccal mucosa, palate, oropharynx, or tongue. Erythematous candidiasis presents as redness without pseudomembranes. An erythematous, smooth plaque on the dorsal surface of the tongue characterizes median rhomboid glossitis. Angular cheilitis presents as erythema, maceration, and fissuring at the corners of the mouth.

Gastrointestinal candidiasis

Esophageal candidiasis causes painful swallowing, a feeling of obstruction on swallowing, and substernal or retrosternal chest pain. Thrush may also be evident.6 Candidiasis elsewhere in the GI tract presents as pain in the abdominal quadrant where the affected organs are located.

Genital candidiasis

Candidal vaginitis may present as intense pruritus of the vulva and a cervical discharge that can vary from scant to thick and white. There may be edema of the vulva and erythema of the vagina and labia that extends onto the perineum.

Balanitis can begin as itching or burning, with vesicles or white patches on the penis. Plaques may extend onto the thighs, buttocks, and scrotum.

Diaper rash

Candida diaper rash causes itching and maceration in the perianal area that may spread to the entire skin region of diaper contact. Satellite lesions may be present. Girls may have a vaginal discharge.

Hematogenous candidiasis

Patients with hematogenous Candida infection and major organ involvement may have fever, with or without additional manifestations in the organ system involved (central nervous system, lungs, heart, urinary tract, bones, joints, liver, spleen, gallbladder, or eyes). Even in the absence of ocular symptoms, patients with positive blood cultures for Candida should have a dilated eye examination to look for the white cotton ball-like chorioretinitis lesions of hematogenous Candida endophthalmitis, which can result in permanent blindness unless treated appropriately.

Candiduria

A laboratory report of Candida in the urine may represent contamination of the sample by vaginal flora, colonization of a urinary catheter or the lower urinary tract, or infection. Asymptomatic colonization of the lower urinary tract is the most common source of candiduria; treatment is of questionable value in such patients, because the candiduria may resolve without treatment or return despite initially successful treatment.7,8 Systemic antifungal treatment is typically reserved for symptomatic patients and for those who are at increased risk for Candida infection; this population includes recent renal transplant recipients, patients with neutropenia, patients with diabetes, and those undergoing genitourinary tract manipulation.9

Laboratory Tests

Candidal lesions can be so distinctive that diagnosis does not require testing. When the appearance is uncertain, pseudomembranes should be scraped and sent for staining and culture. Fungal forms (4 to 6 µm oval yeast cells, pseudohyphae, and hyphae) can be visualized using 40× to 100× magnification after staining with potassium hydroxide—with or without calcofluor—or with Gram stain. Culture plates specific for yeast include bromocresol green and Sabouraud dextrose agar, although candidal organisms are easily cultured on blood agar. In immunosuppressed patients, endoscopy specimens from esophageal and other GI sites should be submitted for viral culture in addition to fungal culture, because such patients can have concurrent herpesvirus infections.

Diagnosis of hematogenous and major organ candidiasis requires culture of blood, radiographic imaging of the organ system involved, and culture of any localized fluid collections. Blood culture is used for diagnosis of fungemia, catheter-related infection, vascular infection, endocarditis, and liver and spleen infection. Even repeated cultures—both of blood and of biopsy tissue—are often negative in visceral (hepatosplenic) candidiasis, however.10

The current generation of automated blood culture systems has improved the ability to detect Candida, and Candida species are now the fourth most common nosocomial bloodstream isolate. When culture growth is noted, a germ tube test can be performed to distinguish C. albicans from other species of Candida. The organism is inoculated into serum and incubated for 2 to 3 hours at 37° C. If an elongated hypha (a germination tube) is seen extending from the yeast, the species is C. albicans.

Antifungal susceptibility testing should be requested for the first bloodstream isolate from a new infection episode. Susceptibility testing is available for azoles (e.g., fluconazole, voriconazole) but not for echinocandins.

DIFFERENTIAL DIAGNOSIS

In patients with mucocutaneous manifestations that do not fit the classic picture of C. albicans infection, non-albicans candidal species, bacteria, mold, and viruses need to be considered. Bacterial infection is especially likely in patients with findings such as abscesses or fever, whereas viral infection may be present in those with ulcerations of the mucosal surface. Infections in severely debilitated patients may have multiple copathogens. Candidiasis must also be distinguished from noninfectious syndromes such as aphthous ulcers.

TREATMENT

Active Infection

Management of candidal infections should include attempts to correct any factors that can predispose to candidal overgrowth. In some cases, this will involve local measures: with diaper rash, for example, the affected areas should be kept dry. Other cases require general measures, such as tighter control of glucose levels in diabetic patients or minimizing the number and dosage of antibacterial or immunosuppressive medications.

Antifungal drug therapy for candidiasis may be topical or systemic11 [see Table 1]. For mucocutaneous infections in particular, it is important to try topical agents before giving systemic ones. The use of topical agents can prevent the replacement of C. albicans with other candidal strains and the development of drug resistance, and it avoids the side effects of systemic treatment.

Table 1 Treatment of Infections Caused by Candida Species

Infection

Drug

Dosage

Relative Efficacy

Comments

Denture stomatitis

Fluconazole

100–400 mg p.o. daily for 1–14 days

First-choice agent

Remove dentures at night

Gingivostomatitis

Nystatin

Swish 4–6 ml of 100,000 units/ml q.i.d., or suck 200,000-unit lozenges q.i.d., daily for 2 wk

First-choice topical agent

Clotrimazole

Suck 10 mg troches five times daily for 2 wk

Alternative topical agent

Less bitter than nystatin

Gentian violet

Apply 1% solution to oropharynx once, repeat weekly as needed

Alternative topical agent

Stains tissue

Fluconazole

100–400 mg p.o. daily for 1–14 days

First-choice systemic agent

May lead to replacement ofC. albicans with other Candidastrains

Itraconazole

100 mg p.o., b.i.d., or 200 mg daily of oral solution for 14 days

Alternative systemic agent

Capsule absorption improved by acidic stomach contents

Amphotericin

0.5 mg/kg I.V. daily for 2 wk beyond the last clinical symptoms, then once or twice weekly as maintenance

Alternative systemic agent

Sinusitis/mastoiditis

Fluconazole

400–800 mg p.o. or I.V. daily for 3 wk

First-choice agent

Amphotericin

0.5 mg/kg I.V. daily for 3 wk

Alternative agent

Itraconazole

200 mg p.o. or I.V. twice daily or 400 mg daily of oral solution for 3 wk

Alternative agent

Capsule absorption improved by acidic stomach contents

Pneumonia

Amphotericin

0.5 mg/kg I.V. daily for 2 wk ± 50 mg nebulized daily

First-choice agent

Fluconazole

400–800 mg p.o. or I.V. daily for 2 wk

Alternative agent

Itraconazole

200 mg p.o. or I.V. b.i.d., or 400 mg daily of oral solution for 2 wk

Alternative agent

Capsule absorption improved by acidic stomach contents

Flucytosine

25 mg/kg p.o., q.i.d., for duration of amphotericin therapy

Adjunct to amphotericin

Follow levels and adjust dose for renal insufficiency

Meningitis

 

 

 

Remove foreign bodies

Amphotericin

0.7–1.0 mg/kg I.V. daily for 2–6 wk ± 1 mg intrathecal or intraventricular daily

First-choice agent

Flucytosine

37.5 mg/kg p.o., q.i.d., for duration of amphotericin therapy

Adjunct to amphotericin

Follow levels and adjust dose for renal insufficiency

Fluconazole

400–800 mg p.o. or I.V. daily for duration of risk factors that led to infection

First-choice agent

May be used for maintenance after amphotericin

Brain macroabscess

 

[See Meningitis,above]; continue therapy until lesion has resolved

 

Debulk or drain abscess

Esophageal infection

 

Continue alltherapy for 2 wk after clinical resolution

 

Fluconazole

100–400 mg p.o. daily

First-choice oral systemic agent

Micafungin

150 mg daily I.V.

First-choice I.V. systemic agent

Itraconazole

100–200 mg p.o., b.i.d., or 200–400 mg daily of oral solution

Alternative agent

Capsule absorption improved by acidic stomach contents

Caspofungin

50 mg daily by slow I.V. infusion

Alternative agent

Reduce dose for hepatic insufficiency

Voriconazole

200 mg q. 12 hr p.o.

Alternative agent

Taken ≥ 1 hr before or after meal

Amphotericin

0.5 mg/kg I.V. daily

Alternative agent

Liver/spleen infection

 

 

 

Correct neutropenia

Amphotericin

0.5–1.0 mg/kg I.V. daily until fevers have resolved and lesions appear smaller on CT scan

First-choice agent

Fluconazole

6–12 mg/kg p.o. or I.V. daily for the duration of lesions on serial CT scans

First-choice agent

May be used for maintenance after amphotericin

Spleen infection

 

[See Liver/Spleen Infection, above]

 

May require splenectomy

Peritoneum infection

 

 

 

Remove peritoneal catheter

Amphotericin

0.5–1.0 mg/kg I.V. daily until fevers have resolved and peritoneal fluid appears less infected, for 3–4 wk after last positive culture

First-choice agent

Fluconazole

6–12 mg/kg p.o./I.V. daily until fevers have resolved and peritoneal fluid appears less infected, for 3–4 wk after last positive culture

First-choice agent

May be used for maintenance after amphotericin

Caspofungin

50 mg daily by slow I.V. infusion, for 3–4 wk after last positive culture

Alternative agent

Reduce dose for hepatic insufficiency

Cystitis, uncomplicated

 

 

 

Asymptomatic candiduria may represent colonization or specimen contamination rather than infection, and may not require treatment; remove urinary catheter

Fluconazole

200 mg p.o./I.V. on first day, then 100 mg p.o. daily for 4 more days

First-choice agent

If poor response, rule out fungus ball in renal pelvis

Amphotericin

Bladder irrigation with 5 mg in 100 ml water at 42 ml/hr for 1–2 days, or 0.3 mg/kg I.V. once

Alternative agent

If poor response, rule out fungus ball in renal pelvis

Pyelonephritis

Amphotericin

0.5–1.0 mg/kg I.V. daily for 2 wk, or longer if fevers have not resolved

First-choice agent

Resolve concomitant nephrolithiasis

Voriconazole

6 mg/kg q. 12 hr for first 24 hr, then 3–4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr for 2–4 wk after cultures become negative

First-choice agent

Oral form taken ≥ 1 hr before or after meal

Renal/perinephric abscess

Amphotericin

0.5–1.0 mg/kg I.V. daily until several weeks after scan shows resolution of abscess

First-choice agent

Drain abscess

Voriconazole

6 mg/kg q. 12 hr for first 24 hr, then 3–4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr until several weeks after scan shows resolution of abscess

First-choice agent

Oral form taken ≥ 1 hr before or after meal

Vulva/cervix infection

 

 

 

Stop antibacterial agents

Clotrimazole

One applicator per vagina each evening for 3–7 days

First-choice topical agent

Gentian violet

Apply 0.25%–1% solution to vagina two to three times daily for 3 days

Alternative topical agent

Stains tissue

Fluconazole

100–400 mg p.o. daily for 1–14 days

First-choice systemic agent

Itraconazole

100 mg p.o., b.i.d., or 200 mg daily of oral solution for 14 days

Alternative systemic agent

Capsule absorption improved by acidic stomach contents

Balanitis/balanoposthitis

 

 

 

Reduce predisposing factors

Clotrimazole

1% cream applied twice daily for 1 wk

First-choice topical agent

Fluconazole

Single oral 150 mg dose

First-choice systemic agent

Diaper/perianal rash

 

 

 

Keep affected area dry

Nystatin

Cream or powder applied after every diaper change for 1 wk

First-choice topical agent

Miconazole

Ointment applied after every diaper change for 1 wk

First-choice topical agent

Osteomyelitis/septic arthritis

 

 

 

May require surgery

Amphotericin

0.5–1.0 mg/kg I.V. daily for 4–12 wk

First-choice agent

Follow ESR

Flucytosine

25 mg/kg p.o., q.i.d., for duration of amphotericin therapy

Adjunct to amphotericin

Follow levels and adjust dose for renal insufficiency

Fluconazole

6–12 mg/kg p.o. daily for 1–6 mo

Maintenance

Follow ESR

Endocarditis/pericarditis

 

 

 

May require surgery

Amphotericin

0.5–1.0 mg/kg I.V. daily, often continued for 6–10 wk after corrective surgery

First-choice agent

Follow ESR

Flucytosine

25–37.5 mg/kg p.o., q.i.d., for duration of amphotericin therapy

Adjunct to amphotericin

Follow levels and adjust dose for renal insufficiency

Fluconazole

6–12 mg/kg p.o. daily for 1–6 mo

Maintenance

Follow ESR

Chronic mucocutaneous candidiasis

Ketoconazole

400 mg p.o. daily for 3–9 mo

Take with food

Folliculitis

Fluconazole

100–400 mg p.o. daily for 1–6 wk

First-choice agent

Econazole

1% cream rubbed into affected area twice daily

Adjunctive agent

Ketoconazole

400 mg p.o. daily for 1–6 wk

Alternative agent

Take with food

Itraconazole

200 mg p.o. daily for 1–6 wk

Alternative agent

Paronychia/onychomycosis

 

 

 

Avoid moisture

Fluconazole

6–12 mg/kg p.o. daily for 2–6 mo

First-choice agent

Itraconazole

200 mg p.o. daily for 2–6 mo

Alternative agent

Capsule absorption improved by acidic stomach contents

Keratitis

 

 

 

May require adjunctive penetrating keratoplasty

Natamycin

1 drop 5% suspension every 1–2 hr for first 2 days, then decrease gradually over 3 wk

First-choice agent

Fluconazole

0.2% topical, 1 drop to affected eye q. 5 min for four doses for 4–6 wk

Alternative agent

Endophthalmitis

Amphotericin

Intravitreal 0.005–0.010 mg in 0.1 ml once, with repeat dosing based on ophthalmologic opinion

Ophthalmologist will make decision to use

Advanced vitritis may require systemic amphotericin and/or vitrectomy

Voriconazole

6 mg/kg q. 12 hr for first 24 hr, then 3–4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr; duration determined by ophthalmologist

 

Caspofungin

50 mg daily by slow I.V. infusion; duration determined by ophthalmologist

 

Systemic infection

 

 

 

Halt fungemia

Amphotericin

0.5–1.0 mg/kg I.V. daily for 7 days after the last positive blood culture, then switch to fluconazole, 6–12 mg/kg p.o. daily for 7 additional days; fluconazole may be continued longer if neutropenia has not resolved; if theCandida species recovered is resistant to fluconazole, continue amphotericin for a total of 14 days after the last positive blood culture

First choice for patients who are neutropenic, deteriorating, or otherwise unstable

Use lipid formulation, not generic, for patients with nephrotoxicity or infusion toxicity; remove catheters and replace at new sites; check for metastatic lesions (e.g., endophthalmitis)

Fluconazole

6–12 mg/kg I.V. or p.o. daily for 14 days after the last positive culture

First choice for stable patients who are not neutropenic

Remove catheters and replace at new sites; check for metastatic lesions (e.g., endophthalmitis)

Caspofungin

50 mg daily by slow I.V. infusion for 14–28 days after the last positive culture

Alternative agent

Reduce dose for hepatic insufficiency

Voriconazole

6 mg/kg q. 12 hr for first 24 hr, then 3–4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr for 14–28 days after the last positive culture

Alternative agent

Oral form taken ≥ 1 hr before or after meal

Prevention of candidiasis in hematopoietic stem cell transplant recipients

Micafungin

50 mg I.V. daily until 5 days after engraftment

Note: Major pathogens include C. albicans, C. tropicalis, C. parapsilosis, and C. pseudotropicalis. C. lusitaniae and C. guilliermondii are usually resistant to amphotericin. C. glabrata and C. krusei are usually resistant to fluconazole.
ESR—erythrocyte sedimentation rate

When systemic treatment is required, fluconazole is often the drug of choice for C. albicans infections. C. glabrata infections should be considered fluconazole resistant and treated with a different agent until sensitivities are known. Importantly, C. krusei is innately resistant to fluconazole, so infections caused by this organism should be treated with a different agent.

In the first years of the 21st century, several new antifungal agents have gained important roles in the treatment of candidiasis and other fungal infections. Voriconazole, a new triazole with wide-spectrum antifungal activity and high bioavailability, has proved effective as empirical antifungal therapy in patients with neutropenia and persistent fever.12 Caspofungin is the first in a new class of antifungal agents called echinocandins, which inhibit synthesis of an integral component of the fungal cell wall, β-(1,3)-D-glucan. The Food and Drug Administration has approved caspofungin for the first-line treatment of candidemia, esophageal candidiasis, and other Candida infections (e.g., intra-abdominal abscesses, peritonitis, and pleural space infections).13,14 A comparison study found caspofungin to be at least as effective as amphotericin B for the treatment of invasive candidiasis and, more specifically, candidemia.15 Caspofungin is also approved by the FDA for the empirical treatment of presumed fungal infection in febrile neutropenic patients, and it appears to be as effective as, as well as generally better tolerated than, liposomal amphotericin B when used for this purpose.16 Micafungin, the second echinocandin to become clinically available, is approved by the FDA for intravenous treatment of esophageal candidiasis and for Candida prophylaxis in hematopoietic stem cell transplant recipients.17,18

Adjunctive measures are important in controlling severe candidal infections and in boosting the immune function of severely debilitated patients. For patients with catheter-related infections, strong consideration should be given to catheter removal from any affected site (intravascular, genitourinary, and peritoneal) if possible. Neutropenic patients may benefit from colony-stimulating factors or granulocyte transfusions. In patients with a central venous catheter, infections accompanied by tenderness or erythema along the catheter tunnel tract may require surgical debridement of the tract. Macroabscesses may require surgical drainage or debulking. Patients with recurrent positive cultures despite receiving both systemic medication and adjunctive measures should be reexamined clinically and radiologically to look for an occult focus of Candida organisms, such as an infected thrombus or abscess.

Prophylaxis

Secondary pharmacologic prophylaxis for mucocutaneous infection may be started in patients who have experienced several episodes of thrush (in advanced AIDS) or vaginitis (in pregnancy). Profoundly neutropenic patients with sufficient mucosal breakdown to provide portals of entry for Candida into the bloodstream require primary pharmacologic prophylaxis until the mucosal barriers have recovered their protective function. Examples of such mucosal barrier breakdown include, but are not limited to, mucositis during bone marrow transplant procedures, GI graft versus host disease (GVHD), and viral gastroenteritis. Prophylactic medications can be topical or systemic, depending on the site involved and the patient's tolerance of individual agents.

The use of antifungal chemotherapy can shift GI yeast flora from C. albicans to fluconazole-resistant species. For that reason, candidal infections that occur during fluconazole prophylaxis require culture and sensitivity testing to determine definitive treatment.

PROGNOSIS

Fortunately, most candidal infections are readily manageable, provided that further diagnostic investigation (e.g., susceptibility testing and radiography) is pursued for poorly responsive infections. Morbidity and mortality remain highest for patients with hematogenous and major-organ candidiasis.

Cryptococcosis

EPIDEMIOLOGY

Cryptococcus neoformans is a yeast that is widely distributed in nature. Environmental sources of C. neoformans include aged pigeon droppings, pigeon nesting areas, dust, and eucalyptus trees.19 However, most persons exposed to environmental sources of C. neoformansdo not experience symptomatic disease. Suppressed cell-mediated immunity is the most important risk factor for symptomatic infection; currently, AIDS patients with CD4+ T cell counts below 100/mm3 account for 80% to 90% of cases of clinical cryptococcosis. In the United States, the annual incidence of cryptococcosis in AIDS patients decreased substantially during the 1990s, with more than two thirds of cases occurring in patients who did not receive highly active antiretroviral therapy.20 Person-to-person transmission has not been documented other than through transplanted organs.

ETIOLOGY

Cryptococcus infection begins with the inhalation of aerosolized organisms and localized proliferation with pulmonary invasion. In immunocompetent individuals, pulmonary infection may be asymptomatic and resolve spontaneously. Immunocompromised persons may have an acute, symptomatic pulmonary infection, which may disseminate by hematogenous spread—most often to the CNS, but also to the skin, soft tissue, genitourinary tract, bone, or joints. Cryptococcal CNS infection may become symptomatic while pulmonary infection clears because cerebrospinal fluid lacks several soluble anticryptococcal factors that are present in serum, such as complement components. Organ transplant recipients who receive calcineurin inhibitors such as tacrolimus as their primary immunosuppressive agent may be protected from cryptococcal infections, because calcineurin is thought to be a potential virulence factor for the yeast. Moreover, only a minority of cryptococcal infections in organ transplant recipients involve the CNS.21 Rarely, Cryptococcus can be directly inoculated through intact skin as a route of infection.

PATHOGENESIS

  1. neoformansis a round or oval yeastlike structure, 4 to 6 µm in diameter, that grows well at body temperature. A large protective polysaccharide capsule surrounds each cell. The highly negative surface charge may contribute to resistance to leukocyte phagocytosis.

DIAGNOSIS

Clinical Manifestations

CNS infection

Cryptococcosis of the CNS may present as mild and nonspecific complaints, such as persistent headache, nausea, dizziness, ataxia, impaired memory and judgment, irritability, somnolence, clumsiness, confusion, and obtundation. Patients may or may not have fever, and most have minimal or no nuchal rigidity. Papilledema is noted in up to one third of cases and cranial nerve palsies in about one fifth. If the cranial nerves become involved, patients may experience decreased visual acuity, diplopia, facial numbness or weakness, or catastrophic vision loss.22 As the disease progresses, seizures may occur.

Respiratory infection

Pulmonary cryptococcosis may present as cough, dyspnea, blood-streaked sputum, and a dull ache in the chest.

Cutaneous infection

Skin lesions may be single or multiple and commonly begin as painless lesions of the face or scalp. Skin lesions may take the form of erythematous or umbilicated papules, pustules, acneiform lesions, indurated plaques, palpable purpura, soft subcutaneous masses, sinus tracts, cellulitis, vesicles, or large ulcers with undermined edges.

Prostatic infection

The prostate can provide a sequestered focus of active cryptococcosis after therapy for systemic cryptococcal infection. These foci may occur even in patients who did not have prostatic involvement initially, and the foci can be a source of recurrent systemic infection. Prostatic cryptococcosis may present as a peripheral prostatic nodule, but patients often have no symptoms. Diagnosis requires culture of urine obtained after prostatic massage.

Laboratory Tests

Routine blood studies remain normal in cryptococcosis. Lumbar puncture is indicated in immunosuppressed patients with CNS abnormalities; characteristic findings include elevated opening pressure, depressed glucose level, increased protein concentration, and lymphocytic pleocytosis. The latex agglutination test detects antigen in CSF or serum in more than 90% of patients with cryptococcal meningitis, whereas India ink smear of CSF detects cryptococci in 25% to 60%.

In cryptococcal CNS infection, CT or MRI scans of the head may be normal or reveal hydrocephalus, cerebral edema or atrophy, or a focal space-occupying mass lesion. Gelatinous cryptococcal pseudocysts may appear as nonenhancing lesions.

In pulmonary cryptococcosis, chest x-rays most often show one or more circumscribed masses or nodules, often in the upper lobes, without hilar involvement. Less common radiographic patterns include segmental pneumonia, single thick-walled cavities, pleural effusion, and miliary disease.

Antigen titers in either serum or CSF can be used to follow the course of disease, but a lack of standardization among manufacturers of cryptococcal antigen tests means that reliable results can be obtained only if the same kit is used for serial measurements. For definitive diagnosis of cryptococcosis, positive antigen test results must be confirmed by culture. Sputum cultures are often negative, however, and may be falsely positive. Bone lesions appear on radiographic studies as round, lytic lesions.

DIFFERENTIAL DIAGNOSIS

CNS cryptococcosis may resemble coccidioidomycosis, histoplasmosis, tuberculosis, brucellosis, syphilis, viral meningoencephalitis, meningeal metastases, sarcoidosis, and chronic benign lymphocytic meningitis. Cryptococcomas may resemble pyogenic, nocardial, or mold-associated abscesses; tuberculosis; toxoplasmosis; hemorrhage; or lymphoma or other neoplasms. Pulmonary cryptococcosis may be indistinguishable from tuberculosis, histoplasmosis, pneumocystosis, and neoplasm. Cutaneous cryptococcosis may resemble comedones, acne, lipoma, syphilis, tuberculosis, sarcoidosis, molluscum contagiosum, and basal cell carcinoma. Bone lesions resemble those of other mycoses and tuberculosis.

TREATMENT

In patients with cryptococcal CNS infection, therapy begins with intravenous amphotericin B plus oral flucytosine [see Table 2].23 Once the patient is clinically stable and afebrile, which usually takes 2 to 6 weeks to achieve, those agents are replaced with fluconazole. After 8 to 10 weeks of maintenance therapy, fluconazole is continued at a reduced dose for the duration of suppressed cell-mediated immunity, to prevent relapse.24

Table 2 Treatment of Infections Caused by Cryptococcus Species

Infection Site

Drug

Dosage

Relative Efficacy

Comments

CNS

Amphotericin

0.7–1.0 mg/kg I.V. daily for AIDS patients, 0.5–0.8 mg/kg I.V. daily for non-AIDS patients; continue for 2–6 wk

First-choice agent

Continue until patient is stable and afebrile

Flucytosine

37.5 mg/kg p.o., q.i.d., for duration of amphotericin therapy

Adjunct to amphotericin

Adjust dose for renal insufficiency

Fluconazole

6 mg/kg p.o. daily for 8–10 wk, then 3 mg/kg for duration of suppressed cell-mediated immunity

Maintenance/prophylaxis

Pulmonary

Fluconazole

6 mg/kg I.V./p.o. daily for 2–6 mo

First-choice agent

Amphotericin

0.5–1.0 mg/kg I.V. daily for 2–6 wk, then change to fluconazole

Alternative agent

A condition that resembles immune reconstitution syndrome has been reported in organ transplant recipients with C. neoformans infection. Onset of this condition was observed a median of 5.5 weeks after the initiation of antifungal therapy and was marked by worsening of clinical manifestations despite negative cultures for C. neoformans. In some patients, this condition may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy.25

Pulmonary disease from C. neoformans can be treated with amphotericin or fluconazole. Secondary prophylaxis for pulmonary disease is often not indicated in patients whose immunosuppression is not severe.

COMPLICATIONS

Elevated CSF pressure in CNS cryptococcosis is associated with blindness and death. An absolute pressure under 250 to 300 mm H2O can be maintained by removing CSF to decrease pressure by 50%.26 Hydrocephalus can lead to permanent loss of cognitive function even in patients whose infection is considered cured. Relief of hydrocephalus with a shunt is vital to ensure an optimal outcome.27

PROGNOSIS

In CNS cryptococcosis, a good prognosis is associated with normal mental status, a CSF leukocyte level of more than 20 cells/mm3, and a CSF cryptococcal antigen titer of less than 1:1,024. Even in patients who respond to therapy initially, up to 40% may have residual neurologic defects and up to 25% of the 40% may experience relapse.

For HIV-negative patients who had cryptococcosis between 1990 and 1996, overall mortality was 30% and attributable mortality 12%. Significant predictors of mortality included age greater than 60 years, hematologic malignancy, and organ failure.28 For solid-organ transplant recipients, renal failure at the time of hospital admission has been identified as an independent predictor of death.21

Pneumocystosis

EPIDEMIOLOGY

Common and apparently harmless in the lungs of healthy persons, Pneumocystis jiroveci (formerly known as P. carinii) can cause pneumonia in those with prolonged lymphopenia. AIDS patients remain the single largest group at risk, although prophylaxis has markedly reduced the incidence of the disease in that population.29 The risk of Pneumocystis pneumonia (PCP) is also higher in the setting of primary immune deficiencies, severe malnutrition (which accounted for epidemics in Central Europe during World War II), organ transplantation, and long-term corticosteroid treatment with monthly doses above 20 mg of prednisone or the equivalent. For solid-organ transplant (except lung transplant) recipients, the incidence of P. jiroveci pneumonia is highest during the first year after transplantation.30

ETIOLOGY

Once P. jiroveci is inhaled, it attaches to lung epithelial cells. Pulmonary infection focuses on the interstitium and the alveoli.

Uncommonly, P. jiroveci infection spreads beyond the lungs. Patients receiving aerosolized pentamidine as prophylaxis are at risk for upper lung lobe and extrapulmonary disease because this is primarily a topical treatment; the aerosol does not penetrate into the less well ventilated portions of the lungs, and the drug is not absorbed into the circulation. Sites of extrapulmonary involvement include lymph nodes, abdominal organs, bone marrow, eyes, and thyroid.31

PATHOGENESIS

Although Pneumocystis was formerly classified as a protozoan, nucleic acid comparison studies have identified this organism as a fungus. Host immune defects in humoral and cellular immunity allow unchecked replication of the organism. In the absence of CD4+ T cells, alveolar macrophages are unable to contain infection.

DIAGNOSIS

Clinical Manifestations

Most patients with PCP have a fever.32 Tachypnea and tachycardia are common in acutely ill patients. Clinical manifestations may develop insidiously and may not interfere with the person's daily routine initially. Consequently, some patients present with several weeks of pulmonary symptoms, including dyspnea, nonproductive cough, hypoxemia, chest pain, and hemoptysis. Nevertheless, lung auscultation may reveal only scant abnormal findings.33

Laboratory Tests

Chest x-rays show bilateral infiltrates in most patients. Patients who have received aerosolized pentamidine as prophylaxis but experienced breakthrough infection are more likely to have disease confined to the apices.31

Methenamine-silver staining of induced sputum or bronchoscopic alveolar lavage specimens can usually confirm the diagnosis [see Figure 1]. At 4 µm in diameter, the cysts of Pneumocystis are similar in size to the 5 µm cysts of Histoplasma. Pulse oximetry and arterial blood gases are among the methods for testing the level of oxygenation that are used to evaluate disease severity and monitor progression.

 

Figure 1. Cysts of Pneumocystiswhich stain black and measure approximately 4 to 5 µm, are visible on a methenamine-silver stain of a cytospin preparation from a bronchoscopic alveolar lavage fluid sample.

DIFFERENTIAL DIAGNOSIS

Any immunocompromised patient with respiratory symptoms, fever, and an abnormal chest radiograph should be considered to have PCP. Nevertheless, many other infectious agents and noninfectious diseases can mimic PCP.

TREATMENT

Active Infection

The treatment of choice for P. jiroveci infection is high-dose intravenous trimethoprim-sulfamethoxazole (TMP-SMX). Severely hypoxemic patients should receive adjunctive corticosteroid therapy.34 Approximately 25% of patients receiving high-dose TMP-SMX have a poor therapeutic response or hypersensitivity reactions. Alternative treatment regimens include pentamidine, trimethoprim-dapsone, clindamycin-primaquine, trimetrexate-leucovorin, and atovaquone [see Table 3].

Table 3 Treatment and Prophylaxis of Pneumocystis jiroveci Pneumonia

 

Drug

Dosage

Relative Efficacy

Comments

Treatment

 

 

 

All treatments last 21 days

Trimethoprim sulfamethoxazole (TMP-SMX)

Two double-strength tablets p.o., or 5 mg/kg of the trimethoprim component I.V. q. 8 hr

First-choice agent

Rash or fever in 19% of patients

Corticosteroid (oral prednisone or I.V. prednisolone)

40 mg b.i.d. for 5 days, then 40 mg daily for 5 days, then 20 mg daily for 11 days; administer 30 min before TMP-SMX

Adjunctive agent

If arterial oxygen pressure < 70 mm Hg or arterial-alveolar gradient > 35 mm Hg

Pentamidine

4 mg/kg I.V. daily

Alternative agent for severe disease

Trimethoprim-dapsone

Trimethoprim, 5 mg/kg p.o., t.i.d., and dapsone 100 mg p.o. daily

Alternative regimen for mild to moderate disease

Rash or fever in 10% of patients

Clindamycin-primaquine

Clindamycin 300–450 mg p.o., q.i.d., or 600 mg I.V. q. 8 hr, and primaquine base 15 mg p.o. daily

Alternative regimen

Give clindamycin I.V. for more severe infections; rash or fever in 21% of patients

Atovaquone

750 mg suspension p.o., b.i.d.

Alternative agent for mild to moderate disease

Take with food; less effective than TMP-SMX but fewer side effects

Trimetrexate-leucovorin

Trimetrexate, 45 mg/m2 I.V. daily; leucovorin, 20 mg/m2 q. 6 hr for 3 days after trimetrexate

Alternative regimen

Prophylaxis

 

Discontinue when CD4+ cell count > 200/mm3 for 3 mo

 

 

TMP-SMX

One double-strength or single-strength tablet, minimum three times per week but usually taken daily

First-choice agent

Provides cross-protection for toxoplasmosis and some bacteria

Dapsone

100 mg p.o. daily

Alternative agent

Well tolerated if glucose-6-phosphatase levels are normal

Pentamidine

300 mg in 6 ml sterile water by aerosol every 4 wk

Alternative agent

Breakthrough disease occurs in upper lung lobes

Atovaquone

1,500 mg p.o. daily

Alternative agent

Take with food

Dapsone-pyrimethamine-leucovorin

Once weekly: dapsone, 200 mg p.o.; pyrimethamine, 75 mg p.o.; leucovorin 25 mg p.o.

Alternative regimen

Provides cross-protection for toxoplasmosis

Prophylaxis

Primary prophylaxis is indicated for HIV and organ transplant patients whose CD4+ T cell count is below 200/mm3, and secondary prophylaxis is indicated for those with a history of PCP. In HIV-infected patients who respond to highly active antiretroviral therapy, primary and secondary Pneumocystis prophylaxis can be safely discontinued once the CD4+ T cell count has remained above 200/mm3 for more than 3 months.35

TMP-SMX is the first choice for pharmacologic prophylaxis. Along with helping prevent PCP, TMP-SMX has the added benefit of providing protection against toxoplasmosis, salmonellosis, Haemophilus infection, and staphylococcal infection.36 The dosage for TMP-SMX prophylaxis is specific to different immunocompromised patient populations.

There is a significant incidence of adverse reactions to TMP-SMX (rash, nausea, and, in rare cases, myelosuppression or cholestasis). However, because of its superior efficacy and low cost, desensitization should be attempted before switching to a second-choice agent in patients who experience side effects from TMP-SMX [see Table 4]. Other options for prophylaxis include dapsone, aerosolized pentamidine, atovaquone, and trimetrexate37 [see Table 3]. Breakthrough infection with P. jiroveci may occur despite prophylaxis, especially in patients who have unrecognized poor compliance with a regimen of TMP-SMX or high-dose dapsone (100 mg daily).

Table 4 Desensitization of Adult Patients with Sulfa Allergy*

TMP-SMX Preparation

Day

Dose (ml)

SMX Equivalent (mg)

Pediatric oral suspension (40 mg/200 mg per 5 ml), 1 ml diluted with 9 ml normal saline, to equal 4 mg SMX/ml

1

0.25

1

2

0.5

2

3

1

4

4

2

8

5

4

16

Pediatric oral suspension, full strength

6

0.5

20

7

1

40

8

2

80

9

4

160

Single-strength tablet

10–30

One tablet

400

*This is only one of numerous sulfa desensitization regimens. Many hospital pharmacies have their own regimen and will provide the patient with a kit containing premeasured doses, if the physician writes a prescription for sulfa desensitization.
Note: If the patient has had no reaction after 30 days of continuous therapy, the full dose can be given.
TMP-SMX — Trimethoprim-sulfamethoxazole

PROGNOSIS

Prognosis is related to the degree of hypoxemia at presentation, degree of infiltrates on chest radiographs, elevated lactate dehydrogenase level, the presence of copathogens, prior lung damage, se verity of the underlying disease, and general markers of debility. Spontaneous pneumothorax is associated with a poor prognosis.

Aspergillosis

Aspergillus is an environmental saprobe whose spores (conidia) readily become airborne. Conidia of A. fumigatus, the principal Aspergillusspecies involved in human infection, are the ideal size for deposition into lungs and sinuses, with a diameter of 2 to 5 µm. Aspergillusthrives in wet areas such as crawl spaces, basements, and water-treatment facilities. Renovations may result in the release of spore-bearing dust. Potted plants and marijuana have been suggested as sources of spores.

After it is inhaled, Aspergillus can cause a localized infection that may result in allergic or invasive disease. Allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis are the two major clinical variants.

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

Epidemiology

ABPA affects patients with a hypersensitive immune status, such as those with atopy, asthma, extrinsic alveolitis, and cystic fibrosis.38Genetic determinants of immune response are thought to help explain why ABPA develops in only some patients with those conditions. ABPA is equally distributed between males and females with asthma and probably also in those with cystic fibrosis. Diagnosis is usually made in the late teenage years or in the 20s.

Etiology

In susceptible individuals, exposure to Aspergillus antigens causes the formation of IgE antibodies directed at the antigen. Reexposure will then result in mast cell degranulation and eosinophilic infiltration, with wheezing and fleeting pulmonary infiltrates.

Pathogenesis

Aspergillus does not invade tissue in ABPA; rather, it colonizes pulmonary secretions. The severity of ABPA probably varies with the intensity of exposure to spores, the species of Aspergillus involved, and the immune status of the host. Initially, fungal spores are trapped within thick bronchial mucus. As the fungus proliferates, the bronchi fill with mucus and become dilated; fungal hyphae can be identified in mucoid impactions. ABPA has been divided into five stages [see Table 5]. Patients do not necessarily progress through these stages in linear fashion.39

Table 5 Clinical Stages of Allergic Bronchopulmonary Aspergillosis

Stage

Clinical Findings

IgE Level

Eosinophilia

Aspergillus fumigatusPrecipitating Antibodies

Chest Films

I - Active

Asthma

Extremely elevated

Extreme

Present

Infiltrates

II - Remission

Normal

Below active levels but not normal

None

± Slightly elevated

Clear

III - Exacerbation

Asthma

Twice normal

Extreme

Not followed

Infiltrates

IV - Corticosteroid dependent

Tapering steroid therapy worsens asthma

Usually elevated but may be normal

Not followed

Central bronchiectasis

V - Fibrotic

Dyspnea, cyanosis, rales, clubbing, cor pulmonale

Not followed

Fibrosis

Note: IgE levels and eosinophilia are less often followed in patients with stage IV or V disease.

Diagnosis

Clinical manifestations

Patients with ABPA may have cough, wheezing, expectoration of sputum containing brown plugs, fever, weight loss, dyspnea, malaise, pleuritic chest pain, sweats, and hemoptysis.

Lung auscultation in patients with active, recurrent, or corticosteroid-dependent disease (stages I, III, or IV) gives variable results, ranging from normal to localized rales in areas of consolidation to wheezes. In fibrotic disease (stage V), patients may have digital clubbing or cyanosis.

Laboratory tests

Primary criteria for a diagnosis of ABPA include episodic bronchial obstruction (asthma), immediate skin reactivity to A. fumigatus antigen, precipitating antibodies against A. fumigatus antigen, increased total serum IgE concentration (> 1,000 ng/ml), history of transient or fixed pulmonary infiltrates, peripheral blood eosinophilia, and central bronchiectasis. Secondary criteria include A. fumigatus in sputum, history of expectoration of brown plugs or flecks, and late skin reactivity to Aspergillus antigen. Eosinophilia has diurnal variation and may decrease with steroid use or during remission (stage II). Pulmonary function tests are useful in defining the stage of disease and underlying asthmatic activity.

Differential Diagnosis

Allergic bronchopulmonary syndromes can be triggered by molds other than A. fumigatus. Allergic fungal sinusitis is histologically identical to ABPA; if it is caused by A. fumigatus, the serologic findings will be positive in the absence of asthma and lower respiratory findings.

Treatment

Active infection

ABPA is treated with systemic cortico steroids supplemented with oral itraconazole [see Table 6]. Itraconazole reduces the burden of colonizing fungal organisms, thereby decreasing chronic antigen stimulation, permitting a lower corticosteroid dose, and decreasing future recurrences of ABPA.40,41,42 Measures of clinical response can be followed serially and include decreasing serum IgE concentration, improvement in exercise tolerance and pulmonary function, and resolution of pulmonary infiltrates.

Table 6 Treatment of Disease Caused by Aspergillus Species

Disease

Drug

Dosage

Relative Efficacy

Comments

Allergic bronchopulmonary aspergillosis

Corticosteroid (prednisone)

0.5 mg/kg daily for 2 wk, then 0.5 mg/kg every other day for 3 mo, then taper to discontinuance over another 3 mo

First-choice agent

Follow serum IgE monthly

Itraconazole

200 mg p.o., b.i.d., for 4 mo

Adjunctive agent

Capsule absorption improved by acidic stomach contents

Invasive aspergillosis

Voriconazole

6 mg/kg q. 12 hr for first 24 hr, then 4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr, treat for minimum of 12 wk

First-choice agent

Oral form taken ≥ 1 hr before or after meal

Caspofungin

70 mg I.V. loading dose, then 50 mg I.V. daily; treat for minimum of 12 wk

Alternative agent

Reduce dose for hepatic insufficiency

Amphotericin

1.0–1.5 mg/kg I.V. daily for 2–12 wk, then switch to maintenance therapy

Alternative agent

Use lipid formulation, not generic, for patients with nephrotoxicity or infusion toxicity

Itraconazole

200–300 mg p.o., b.i.d., for 2–12 mo or duration of clinical disease

Maintenance or alternative agent

Solution has better bioavailability than capsule; document blood levels

Corticosteroid-dependent (stage IV) patients will have disabling wheezing and dyspnea after oral corticosteroids are tapered or stopped. Patients with fibrotic disease (stage V) require supplemental oxygen and moderate doses of alternate-day prednisone.

Prophylaxis

Serum IgE levels should be monitored monthly for 2 years and then every 2 months in patients who have had ABPA. Pulmonary function tests should be performed annually. An increase in serum IgE above remission levels should prompt an evaluation for exacerbation.

INVASIVE ASPERGILLOSIS

Epidemiology

Invasive aspergillosis typically occurs during periods of immune suppression, including neutropenia, treatment of GVHD, and treatment of threatened rejection in transplant recipients. Other factors that may predispose immunosuppressed patients to invasive infection include diminished cough reflex, impairment of mucociliary function, and ischemic damage in the perioperative period or at surgical sites. Except in outbreaks, the incidence of invasive aspergillosis should not be higher than 10% to 15%, even in high-risk patients.

Etiology

In bone marrow transplant recipients, invasive aspergillosis has two distinct periods of onset. The first peak, termed early disease, occurs at a median of 16 days after transplantation, when recipients of both autologous and allogeneic bone marrow have absolute neutropenia and lymphopenia, allowing any form of silent colonization to develop rapidly into invasive and often fatal disease. The second peak, late disease, occurs at a median of 96 days. Late disease develops indolently in recipients of allogeneic bone marrow who have recovered from absolute neutropenia but remain immunosuppressed43 [see Figure 2]. Risk factors for early aspergillosis include allogeneic and especially unrelated donors, male gender, summer season, and transplantation outside of laminar airflow rooms. Risk factors for late aspergillosis are construction in the vicinity of the hospital, acute GVHD, and corticosteroid therapy. The risk for both early and late disease is higher with older age and increasing severity of the underlying oncologic condition. The 1-year survival estimate for bone marrow transplant patients with invasive aspergillosis is less than 10%.

 

Figure 2. Aspergillus infection during the first 6 months after bone marrow transplantation has a bimodal distribution. The first peak (early disease) occurs at a median of 16 days. Early disease is associated with profound neutropenia and develops rapidly. The second peak (late disease) occurs at a median of 96 days. Late disease is associated with corticosteroid use and develops indolently.43

Pathogenesis

Along with A. fumigatus and A. flavus, emerging species involved in invasive aspergillosis include A. terreus, A. nidulans, A. niger, A. glaucus, A. versicolor, and A. ustus. Sinusitis or pneumonia accounts for 90% of invasive disease and develops after inhalation ofAspergillus spores in patients with prolonged neutropenia or other intense forms of immunosuppression.44 Aspergillus spores can also enter the body after direct inoculation through intact skin or ingestion. Intestinal Aspergillus infection has led to fatal GI bleeding in severely immunocompromised patients. For that reason, health-food supplements made from natural substances that are not quality controlled for mold spores are contraindicated in immunocompromised patients. Dissemination of invasive disease can occur either as contiguous extension (such as erosion of paranasal sinus infection into the brain) or by hematogenous spread after the organism erodes into blood vessels.

Diagnosis

Clinical manifestations

Symptoms and signs of invasive aspergillosis reflect the sites of infection.45 Patients with pulmonary disease may have fever, dyspnea, tachypnea, cough, brown sputum, pleuritic chest pain, hemoptysis, wheezing, and rhonchi. Sinus infection may present as headache and sinus pressure or tenderness. Cutaneous disease may present as skin lesions (with or without eschar) at the site of primary inoculation or, in the case of secondary dissemination, in multiple noncontiguous sites. Invasive GI disease may present as abdominal discomfort or distention, peritonitis, small bowel obstruction, or melena; it can involve the liver, spleen, appendix, or peritoneum or cause bowel infarction. Liver transplant recipients are at particular risk for Aspergillus infection of the abdominal suture line or peritoneum.

Laboratory tests

CT scans of the lungs and sinuses should be done in all patients suspected of having an invasive mold infection. Air crescents or so-called ground-glass halos around lung lesions on CT are considered pathognomonic for invasive aspergillosis. Patients with indeterminate pulmonary abnormalities (e.g., new infiltrates or nodules) should undergo bronchoscopy unless the lesions are peripheral. Transbronchial biopsy is performed with bronchoalveolar lavage if the platelet count and bleeding time indicate a low risk of bleeding. A patient with a solitary unilateral pulmonary nodule should undergo CT-guided fine-needle aspiration or in toto resection if the nodule is discrete and large enough.46 CT or MRI scan of the head should be performed before surgical resection to confirm a lack of hematogenous dissemination.

Lung transplant recipients are at risk for localized infection of the bronchial anastomosis, which can result in circumferential anastomotic dehiscence with herniation of perianastomotic fat.47 In the early stages of tracheobronchitis, onset of pulmonary symptoms may precede the appearance of radiographic abnormalities. Bronchoscopy will reveal lesions of the mainstem and segmental bronchi. Although most of the lesions are ulcerative, other lesions such as plaquelike lesions, pseudomembranes, or nodules occasionally develop. Disease can vary from localized tracheobronchitis discovered incidentally to extensive bronchial obstruction contributing to respiratory failure.

Opacified sinuses and sinuses containing air-fluid levels should be cultured by an otolaryngologist. However, sinuses showing mucosal thickening and viscous air-fluid levels are inflamed and provide low yields upon culture. If cultured by swab rather than by aspiration or biopsy, they have a predictably low yield of pathogens. If a CT scan demonstrates bony erosion of sinus walls, bone biopsy samples should be taken and examined histopathologically.

Although the diagnostic tests used on a given specimen depend on the body site from which the specimen was taken, specimens are usually submitted for culture, cytology, and histopathologic evaluation. Recovery of the organism in culture and demonstration of hyphae invading tissue make the diagnosis definitive. Growth occurs after 2 to 14 days of incubation. Hyphal cells or cell fragments should be visible with hematoxylineosin or methenamine-silver staining. Typical Aspergillus hyphal cells have frequent septations and join at 45° angles (dichotomous branching).

An enzyme-linked immunosorbent assay for the detection of Aspergillus galactomannan antigen in serum is commercially available, and has become an important tool for the early diagnosis of invasive aspergillosis.48 In one study, the test had a sensitivity of 75% and a specificity of 100%.49 The assay is increasingly being used on specimens of body fluids other than serum, including urine, bronchoalveolar lavage fluid, and CSF.50

Differential Diagnosis

Although invasive aspergillosis is the most common cause of pulmonary nodules in immunocompromised patients, in at least 10% of such cases the pathogen (or copathogen) will be a non-Aspergillus fungus or a bacterium (e.g., Nocardia, Legionella, or atypical Mycobacterium). Other conditions that must be excluded are septic emboli, pulmonary edema, diffuse alveolar hemorrhage, drug reactions, acute respiratory distress syndrome, idiopathic pneumonia syndrome, and bronchiolitis obliterans.

Treatment

Active infection

The recommended agent for treatment of invasive aspergillosis is voriconazole.51,52

An alternative regimen is amphotericin B, either conventional or lipid formulations, in dosages equivalent to 1 mg/kg/day of standard amphotericin B. Caspofungin is approved by the FDA for patients who fail to tolerate or to improve with standard therapy (salvage treatment) [see Table 6].53,54 Adjunctive measures include colony-stimulating factors, surgical resection of unilateral pulmonary nodules (in patients with no evidence of CNS dissemination), and granulocyte transfusions.

Prophylaxis

Environmental and pharmaceutical prophylaxis options are used in patients who are profoundly neutropenic for 3 weeks or longer, because in such patients, invasive aspergillosis occurs with 5% to 10% frequency and mortality is high. Environmental prophylaxis includes high-efficiency particulate air (HEPA) filtration for allogeneic hematopoietic stem cell transplant recipients, rather than laminar airflow; in addition, severely immunocompromised patients should use high-efficiency respiratory-protection devices (e.g., N95 respirators) when they leave their rooms if dust-generating activities are ongoing in the building.55

Pharmacologic antimold prophylaxis is not standardized. In a 2004 clinical trial comparing micafungin with fluconazole for fungal prophylaxis during the preengraftment period of hematopoietic stem cell transplantation, there was a trend toward fewer Aspergillus infections in micafungin-treated patients during the study period (one infection versus seven infections, P = 0.08).18 Some centers begin pharmacologic prophylaxis at or before the onset of neutropenia in select patient populations.

Secondary prophylaxis should be started at the onset of neutropenia in patients with a history of aspergillosis who are entering major periods of immunosuppression, such as hematopoietic stem cell transplant recipients.56 Voriconazole and caspofungin have been replacing amphotericin B for secondary prophylaxis in these patients; the lower toxicity of these agents permits wider use of drug prophylaxis, but the agents are being used in off-label fashion. Adjunctive measures such as nonmyeloablative conditioning procedures and granulocyte transfusions may be used.57 In general, however, granulocyte transfusions are not effective for secondary prevention of fungal infection during profound neutropenia.

Prognosis

In the 1990s, the overall case-fatality rate for aspergillosis was 58%. Mortality was highest (> 85%) in bone marrow transplant recipients and patients with CNS or disseminated aspergillosis.43,44 Death often results from the erosion of blood vessels by fungal invasion, with massive hemoptysis or other fatal hemorrhage.

Zygomycosis

EPIDEMIOLOGY

The agents of zygomycosis (a broad term that includes the better-known mucormycosis) cause disease that closely resembles invasive aspergillosis. However, this group of organisms is taxonomically different, belonging to the phylum Zygomycota. The principal pathogens include Rhizopus, Mucor, and Rhizomucor; occasional pathogens include Absidia, Cunninghamella, Mortierella, Saksenaea, Cokeromyces, andApophysomyces.

Different populations are at risk for zygomycosis at different sites. Cutaneous infection most often develops in patients who are severely ill from trauma; only 50% have systemic immunocompromising disease. Conditions that increase risk for pulmonary, rhinocerebral, and disseminated zygomycosis include poorly controlled diabetes (particularly ketoacidosis) and immunosuppression (e.g., neutropenia, sustained immunosuppressive therapy, or long-term prednisone use). Iron overload, such as that from repeated dialysis or blood transfusions, increases susceptibility to zygomycosis because iron is an essential element for the growth and metabolism of Zygomycetes. Infection may occur in patients receiving the iron chelator deferoxamine to reduce iron overload, because Zygomycetes can readily use iron even when it is bound to deferoxamine.

Persons at risk for zygomycosis of the GI tract are those with some form of severe protein-calorie malnutrition, such as uremia, kwashiorkor, or chronic diarrhea. In the United States, a Mucor liver abscess developed in a transplant recipient who consumed health-food supplements made from natural substances that were not quality controlled for mold spores.58

ETIOLOGY

Cutaneous infection usually occurs by traumatic inoculation; it is preceded by skin trauma in greater than 80% of cases. Sources of trauma have included surgery, burns, motor vehicle accidents, knives, and even insect bites. A well-publicized series of infections occurred between 1978 and 1980 from elasticized surgical dressings that were found to be contaminated with Rhizopus.59

Pulmonary, rhinocerebral, and disseminated zygomycosis are acquired via airborne spores deposited in the nasal turbinates or pulmonary alveoli. GI tract disease follows ingestion of fungal spores in moldy food.

PATHOGENESIS

Onset of cutaneous infection usually occurs a few days after the initiating trauma. The pace of cutaneous illness varies: necrosis may spread slowly over weeks, resembling an arterial insufficiency ulcer, or progress rapidly over days, resembling synergistic gangrene. Secondary cutaneous dissemination is unusual, except perhaps in burn victims.

Infection that starts as colonization in the nasal turbinates or paranasal sinuses may extend contiguously. When infection extends directly along veins that drain the orbit and facial tissues, cavernous sinus thrombosis results. With posterior extension, frontal lobe necrosis with brain abscess ensues. Zygomycetes can also enter the CNS by hematogenous spread.

DIAGNOSIS

Clinical Manifestations

Cutaneous disease can occur anywhere on the body, but it is most often found on the extremities.60 Cutaneous lesions are usually characterized by central dermal necrosis surrounded by a margin of red-to-purple edematous cellulitis, sometimes with bullae indicating epidermal necrosis. Mold may be visible on the edge of a wound. If dermal necrosis is present, pain is common. Fever may be present or absent.

Pulmonary disease typically displays the usual pneumonia symptoms of fever, dyspnea, pleuritic chest pain, hoarseness, and gross hemoptysis. Rhinocerebral disease may begin with fever, leukocytosis, ketoacidosis, facial pain, sinus drainage, or headache. A black eschar on the nasal or palatal mucosa should immediately raise suspicion for rhinocerebral disease. With orbital extension, clinical findings may include orbital swelling or cellulitis, extraocular muscle paresis, proptosis, and chemosis.

Rhinocerebral disease may result in cranial nerve abnormalities, most commonly a seventh-nerve palsy. In patients with cavernous sinus thrombosis, venous engorgement from outflow obstruction is noted in the retina, conjunctiva, and eyelid. Paresis of cranial nerves III, IV, and VI may result in diplopia. Less often, proptosis, meningeal irritation, epistaxis, and involvement of cranial nerve V may occur.

Laboratory Tests

Most patients with pulmonary or disseminated disease will have abnormal chest imaging results, but there is no specific radiographic appearance or lobar predilection. In neutropenic patients with early disease, chest films may show little infiltrate, perhaps because these patients may lack inflammatory cells to cause infiltrate. If pulmonary disease progresses to tissue necrosis and hemorrhage, however, the radiographic changes will become obvious.

A CT scan of the head is indicated in patients with clinical signs of rhinocerebral disease. Scans may show bone destruction, a brain infarct, or a space-occupying brain lesion and can be used to guide surgical intervention.

Definitive diagnosis is made by recovery of Zygomycetes in culture. Growth occurs after 2 to 5 days of incubation. Wound surfaces can be swabbed for fungal culture, but specimens should also be taken from rapidly spreading infections, nonwound cutaneous lesions, and lesions such as a black eschar on the hard palate or nasal mucosa.

Specimens should be immediately examined with potassium hydroxide, calcofluor white stains, or both. Histologic studies should be done by using hematoxylin-eosin and methenamine-silver staining. In cutaneous disease, hyphae are seen in the middle of an acute neutrophilic infiltrate. Zygomycetes hyphal cells should have infrequent septations, be of variable diameter, join at 90° angles, and twist in ribbonlike fashion upon one another. In the uncommon instance where all those histologic findings are obvious, a tentative pathologic diagnosis of Zygomycetes infection can be made. However, the usual situation is that the tangle of fungal hyphae cannot be distinguished fromAspergillus.

Histology may be the only basis for diagnosis, however, given that Zygomycetes grow less frequently in culture than other filamentous molds. One reason is that Zygomycota mold cells are large, because they have few or no septations (i.e., they are pauciseptate or aseptate). Consequently, when the microbiology technologist uses a razor blade to mince tissue being prepared for fungal culture, one slice through the cell wall can lead to leakage of cytoplasm and death, leaving no intact cells for growth. Homogenization of tissue submitted for culture also leads to a high rate of false negative results.

DIFFERENTIAL DIAGNOSIS

Cutaneous zygomycosis can look like ecthyma gangrenosum, which is more often caused by Aspergillus and Pseudomonas. Pulmonary zygomycosis should be differentiated from aspergillosis, pneumonia caused by other less common bacteria and molds, and pulmonary embolism. Rhinocerebral zygomycosis can resemble orbital tumors, cavernous sinus thrombosis from Staphylococcus infection, or aspergillosis.

TREATMENT

Active Infection

Zygomycosis is currently treated with maximal-dosage intravenous amphotericin, 1.0 to 1.5 mg/kg daily for 2 to 12 weeks or for the duration of clinical disease. In addition to intravenous infusions, intracavitary or topical amphotericin may be required for CNS disease; topical amphotericin can be applied to cutaneous disease. Posaconazole, an orally administered triazole, is effective against zygomycosis61but is not yet approved by the FDA.

Treatment should include adjunctive measures such as debridement of any adherent mycelial masses at accessible sites of infection. Debridement should be repeated as often as every other day until cultures of the debrided tissues are negative. Some patients may be candidates for granulocyte transfusions or hyperbaric oxygen.

Prophylaxis

Pharmacologic prophylaxis of zygomycosis infections is unusual because the frequency of infection with this group of organisms is low even in high-risk patient groups. Additionally, the medication for prophylaxis is intravenous amphotericin, which is toxic and is expensive when the lipid formulations are used; however, posaconazole may have a role in the future. Topical or systemic preemptive therapy may be appropriate for individual patients, such as burn victims in whom surveillance cultures of wounds demonstrate fungal hyphae.

PROGNOSIS

Hosts with zygomycoses may not be as immunocompromised as hosts with some of the more common opportunistic mold infections; hence, zygomycoses may be associated with better survival.

Fusariosis

EPIDEMIOLOGY

Fusarium is a soil-borne mold that can cause human disease if a portal of entry is available, such as skin, nails, the airways, or the eyes. Species responsible for the majority of human disease are F. solani, F. moniliforme, and F. oxysporum. The number of organisms and the depth of penetration may determine the course of infection. Eye infection can occur after contamination of soft-contact-lens paraphernalia through inadequate washing of soil-borne spores from the hands or contamination of the lens during use; under windy conditions, aerosolized spores can be blown into the eye.

The single most important host risk factor for invasive fusariosis in immunocompromised patients is neutropenia.62,63 Good clinical outcomes have clearly been linked to recovery from neutropenia, and fatal relapse of disease has been linked to recurrent neutropenia.64 Other immune system defects linked to infection include heatstroke, systemic corticosteroid use, and topical steroid use at the site of colonization.65

Some Fusarium species produce secondary metabolites called mycotoxins. Under favorable environmental conditions, those species can grow on grains and contaminate them with mycotoxins. Consumption of mycotoxin-laden foodstuffs can result in both infection and poisoning—especially in malnourished persons, who have enhanced susceptibility to the toxin. An important historical example is an outbreak of toxic alimentary aleukia that occurred in the Soviet Union at the end of World War II. Starving people harvested grains that had been left in the fields over the winter and had become heavily contaminated with Fusarium mycotoxin. Those who ate more than 2 kg of food made from the grains suffered an illness that progressed from mucosal inflammation to pancytopenia to mucosal necrosis with fatal bacterial infection. Hundreds of thousands of people died of the illness.

ETIOLOGY

Opportunistic Fusarium infection begins by colonization of broken skin, the upper airways, sinuses, or conjunctivae. Reported causes of skin-barrier breakdown include catheters (central venous and peritoneal dialysis), burns, trauma, surgical procedures (coronary bypass), and denuding of skin from infection (as from varicella). When the host has an immune system defect, tissue inflammatory reactions at the site of colonization are reduced, enabling the organism to grow and spread.

PATHOGENESIS

The mold form of Fusarium consists of septate hyphae with branches at acute angles. Growth of hyphae in skin lesions may result in subcutaneous granulomas. Once infection has penetrated into the lumen of blood vessels, hyphae can disseminate through the body to produce embolic infection whose hallmark is necrotic skin lesions and, less often, endophthalmitis or brain abscess.66

DIAGNOSIS

Clinical Manifestations

Manifestations of focal Fusarium infection vary with the organ involved. Keratitis presents as a corneal ulcer; if therapy is delayed, infection may progress to endophthalmitis. Primary cutaneous infections present in many forms, including ulcers, necrosis, pustules, vesicles, painful nodules, mycetomas, and pannic ulitis. Onychomycosis presents as a milky-white area in the nail, which may spread until the entire nail becomes opaque; the free border of the nail may become thickened.

With disseminated infection, secondary cutaneous lesions may be the first characteristic finding. These may take the form of multiple erythematous subcutaneous nodules, painful lesions with progressive central infarction, or target lesions with ecthyma gangrenosum-like centers surrounded by a rim of erythema.67

Laboratory Tests

Fusarium is the only opportunistic mold that can be easily recovered from the bloodstream; blood cultures will be positive in 40% to 60% of patients with disseminated infection. Many clinical laboratories identify Fusarium to only the genus level; speciation would not alter the prognosis or treatment. Patients with fever and neutropenia should have cultures of blood, as well as biopsy and culture from any body sites suspicious for infection. Because Fusarium often colonizes nonsterile tissues, the mycologic data should be combined with histopathologic data to distinguish colonization from tissue infection. Biopsies of suspicious skin lesions should be taken from the center of the lesion and should extend to subcutaneous fat, because mold organisms easily invade blood vessels of the dermis and subcutis, resulting in an overlying ischemic cone. Part of the biopsy specimen, or a second biopsy specimen, should be sent for culture.

DIFFERENTIAL DIAGNOSIS

In addition to Fusarium, a variety of other organisms can be responsible for new skin lesions in an immunocompromised host; these includeAspergillus, other molds, Pseudomonas, and varicella.

TREATMENT

Fusarium species are relatively resistant to treatment with antifungal agents, and sensitivity testing for Fusarium is not standardized. Fluconazole, itraconazole, and 5-fluorocytosine have no activity against Fusarium species, and amphotericin, ketoconazole, miconazole, and terbinafine have limited activity.

Active Infection

Invasive disease is usually treated with high-dose systemic amphotericin [see Table 7]. Topical amphotericin or nystatin cream is sometimes added to the systemic amphotericin regimen in attempts to increase local delivery of drug. Voriconazole is approved by the FDA for salvage therapy for Fusarium infections. Corneal ulcers caused by Fusarium infection are treated with topical amphotericin or natamycin.

Table 7 Treatment of Infections Caused by Fusarium Species

Infection Site

Drug

Dosage

Relative Efficacy

Comments

Invasive fusariosis

 

 

 

Surgery may be needed

Amphotericin

1.0–1.5 mg/kg I.V. daily for 2–12 wk

First-choice agent

Use lipid formulation, not generic, for patients with nephrotoxicity or infusion toxicity

Voriconazole

6 mg/kg q. 12 hr for first 24 hr, then 4 mg/kg q. 12 hr; when oral medication tolerated, 200 mg p.o., q. 12 hr; continue treatment for several months, or for minimum 2 wk after recovery from neutropenia, with resumption if patient becomes neutropenic again after an infection

Alternative agent

Oral form taken ≥ 1 hr before or after meal

Keratitis/corneal ulcer

Natamycin 5% suspension

1 drop q. 1–2 hr for first 2 days, then decrease gradually over 3–6 wk

First-choice agent

May require surgery

Skin lesions (as part of invasive disease)

 

 

 

Treat primarily as invasive disease; continue topical therapy until lesions are dry scabs

Nystatin

Cream twice daily to affected areas

Adjunct to I.V. amphotericin

Amphotericin

Topical compound twice daily to affected areas

Adjunct to I.V. amphotericin

Compound locally

Because outcome is clearly linked to recovery from neutropenia, adjunctive measures are essential.64 Colony-stimulating-factor injections and neutrophil transfusions have been used to increase the neutrophil count. Further episodes of electively induced myelosuppression should be avoided because there is a high incidence of recurrence and multiple-organ failure in patients with subsequent neutropenic episodes.

Surgical treatment has an important role in the management of localized infection; examples include enucleation of an affected eye, wide excision, and nail removal. In an extreme situation, amputation of a limb can be used to cure fusarial soft tissue infections.

Prophylaxis

Prevention of primary Fusarium infection involves the same environmental measures that would be used to prevent other mold infections in patients at risk. In general, patients with chronic neutropenia or those about to receive myelosuppressive therapy should wash their hands regularly and avoid contact with soil or inhalation of dust. Myelosuppressive therapy should be given in an inpatient environment with air filtration to reduce the number of aerosolized spores.

Secondary prophylaxis is required when a patient with known recent Fusarium infection has an episode of neutropenia. A systemic antifungal agent with activity against Fusarium is used at treatment doses. Efforts to shorten the duration of neutropenia with colony-stimulating factors are sometimes employed. The use of neutrophil transfusions as secondary prophylaxis for patients without fever or skin lesions is difficult to justify and is rarely done.

Infection by Dematiaceous Fungi

EPIDEMIOLOGY

Dematiaceous fungi live in soil and rotting wood. Current taxonomy has more than 100 species of dematiaceous fungi spread out among more than a dozen different families, falling under several classes and orders. All contain melanin pigment in the walls of hyphae or spores, resulting in a color that is dark brown, greenish gray, or black. They are an important group of opportunists, because some species have a tendency to cause CNS infection.68 Species that appear to be particularly neurotropic include Cladophialophora, Cladosporium, Bipolaris, Exserohilum, Dactylaria, Exophiala, and Fonsecaea.

Most reports of infection by dematiaceous fungi emphasize cerebral disease in an immunocompromised patient.69 However, there is a growing literature describing these infections in specific at-risk patient populations (such as solid-organ-transplant recipients) and in immunocompetent patients, who may experience nasal polyps and an obstructive fungal ball destroying the sinuses.70,71

ETIOLOGY

Injury to the skin can implant dematiaceous fungus in subcutaneous tissues; inhalation of spores can cause a minimal infection in the lung or sinuses. Sinus infection can erode through bone into the brain, or unrecognized pulmonary infection can metastasize to the brain.

PATHOGENESIS

Primary cutaneous disease usually exhibits one of three histopathologic patterns: solid granulomas, stellate abscesses, or cavitary lesions. Cystic lesions probably start as solid granulomas, which undergo focal necrosis to form stellate abscesses. The abscesses can then coalesce into a unilocular fluctuant abscess.

DIAGNOSIS

Clinical Manifestations

Dematiaceous fungi cause primarily skin and soft tissue infections.70 Analogous syndromes seen in tropical and subtropical areas of the world include mycetoma (tumorous growth of the skin with tissue granules) and chromoblastomycosis (verrucous skin infection with sclerotic bodies). Immunocompetent persons develop an asymptomatic initial lesion: a discrete, well-encapsulated, erythematous to flesh-colored plaque or nodule. The nodule center tends to become necrotic, forming a localized, encapsulated abscess. In immunocompromised persons, subcutaneous lesions may not encapsulate and may spread contiguously or systemically.

Systemic infections may present as unexplained fever during neutropenia that persists despite administration of broad-spectrum antibiotics. Metastatic disease may involve the lungs, joints, esophagus, heart, peritoneum, or bone, but the favored site is the CNS.

Laboratory Tests

Histopathology and culture of a tissue specimen are generally necessary to identify an infection as dematiaceous. Fungi are visible in cells lining an abscess, in the lumen of an abscess, or free in the granulation tissue of a cyst wall. The fungi appear as yeastlike cells that can be solitary or arranged in short chains, pseudohyphal-like fungal elements, or septate hyphae of varying lengths. The hyphae may differ fromAspergillus, Fusarium, or the Zygomycetes by having thicker walls, irregular diameter, variable branching, or constrictions at the septations. Because the degree of visible pigment can vary between patients infected with the same species, a melanin stain such as Masson-Fontana can be used to reveal cell wall pigment in tissue sections.

In patients with CNS involvement, dematiaceous infection often presents as rim-enhancing brain abscesses on CT scan.

DIFFERENTIAL DIAGNOSIS

On histopathologic examination, the septate fungal hyphae of dematiaceous fungi bear close resemblance to Aspergillus. The pathologist will usually label such specimens as Aspergillus-like, because less than 0.1% of them will culture out as a dematiaceous fungus. The Masson-Fontana melanin stain can discriminate dematiaceous fungus from Aspergillus but is rarely used in histopathology laboratories, so the distinction is usually made by culture.

TREATMENT

Complete surgical excision appears critical in the management of cutaneous lesions. If the entire lesion is removed in an immunocompetent host, antifungal therapy may not be needed. Disseminated disease requires systemic antifungal medication, sometimes combined with surgery. Amphotericin, 0.8 to 1.2 mg/kg I.V. daily for 2 to 12 weeks, is typically used, but the choice of medications should be evaluated on an individual basis. The new triazoles and echinocandins may come to replace amphotericin for this purpose.72

The duration of therapy is determined by the immune competence of the host, the site and extent of involvement, disease responsiveness, and the susceptibility of the organism. Neutrophil transfusions may be added for patients with systemic infection and low levels of circulating neutrophils, but no controlled studies of this approach have been performed.

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Editors: Dale, David C.; Federman, Daniel D.