Immunocompromised Hosts

Immunocompromised Hosts David Kramer, M.D.

1

Primary Immunodeficiency Disorders

DISORDER

DEFICIENCY

Humoral Deficiency

Decreased phagocyte efficiency, failure of lysis

Syndromes

and agglutination of bacteria, inadequate neutralization of toxins

Cellular Immunodefi-

Absence or impaired delayed hypersensitivity,

ciency

absent T cell cooperation or function

Neutropenia

Decreased neutrophil numbers

Phagocytic defects

Decreased adhesion, chemotaxis, opsonization, phagocytosis, killing

Complement deficien-

Defective membrane attack mechanisms

When the neutrophil count falls below 500, and especially when it stays that way for days and weeks at a time, the risk of an infectious complication is 40% to 60%, and if the patient remains profoundly neutropenic the risk can actually approach 100%. Within that context, it is also possible to differentiate in this patient population between lower and higher-risk patients according to the duration of their neutropenia. Lower risk patients are being defined as those who are neutropenic for less than 10 days, higher risk for greater than 10 days. Now, in a neutropenic patient, it is important to recognize there are other alterations of the host defense matrix that can alter the risk for developing an infectious complication. So the presence of oral or GI mucositis which intersects the integrity of the integumentary barriers can lead to both colonization and a risk-free infection. These can be influenced by the type and intensity of a chemotherapy that is being administered. They can lead to both new acquisition of organisms, as well as to alterations of the endogenous microflora, which of course contribute to the risk for developing an infectious complication. These risks can be aggravated by indwelling catheters, as well as devices, and further deter by changes in phagocyte function as well as alter cellular and humoral immunity, some of which are the result of a chemotherapy or radiation that is administered and others emanate from underlying diseases.

cies In the 1990s gram-positive organisms predominate, particularly the coagulase, and coagulase negative staphylococci. Staph aureus is certainly a contender for the lead spot in some centers, but virtually in all, coagulase negative staphylococci are number one. It is important to remember that the enterococci has increased in frequency, particularly those that are resistant to vancomycin, and this has become a problem. And this underscores the importance of not overusing vancomycin. There have been tremendous changes in the distribution of gramnegative organisms. Two decades ago, gram-negative organisms dominated the course of the disease in this population. Among the gram-negatives, Pseudomonas aeruginosa was the most noteworthy. In fact, when this organism is present, it still carries a very serious prognosis. In some ways, numerically replacing Pseudomonas are multiply resisting gram-negatives, particularly the betalactamase inducible Enterobacter, Citrobacter, Serratia, which have caused outbreaks and significant infections in some centers treating cancer patients. This patient population like other immunocompromised hosts is vulnerable to a wide array of potential infectious agents, including anaerobes. Those are quantitatively the most numerically significant organisms in our body and the GI tract. They infrequently account for singular infections, but they are part of mixed infections, especially in the oral cavity and the perianal area. Mycobacteria infections, including MTB are seen in cancer patients, albeit infrequently. Among the atypical mycobacteria, chelonei and fortuitum are the cause of the catheter-related infections; and Mycobacteria kansasii is the cause of pneumonic infections. Viruses in this patient population include the herpes virus, simplex, cytomegalovirus, varicella zoster. The respiratory viruses have also emerged as important pathogens, particularly respiratory syncytial virus or parainfluenza virus, adenovirus, especially in patients you

2

Secondary Immunodeficiency Disorders

DISORDER

DEFICIENCY

HIV/AIDS

Altered cellular immunity, dysgammaglobulinemia, phagocytic defects or neutropenia

Cancer

Neutropenia, lymphopenia, humoral deficiencies, altered physical integrity

Immunosuppressive

Impaired cellular immunity and/or neutropenia

therapies Transplantation

Varies with solid organ vs bone marrow and includes deficiencies in cellular and phagocytic immunity

Malnutrition

see in high doses of chemotherapy, or in those undergoing bone marrow transplantation. It is important to include Candida and Aspergillus among the most important of the pathogens. Pneumocystis remains and important cause of infection in patients with cancer, including Hodgkin, and lymphomas, leukemias. Toxoplasmosis can be associated with a meningoencephalitis in this patient population as well as Strongyloides, which can cause hyperinfection syndrome with polymicrobial sepsis as part of its manifestation. In terms of the common sites for infection, the primary portal is the GI tract, but the most important physical sites are the oral cavity, skin, perianal area, and respiratory tract. It is important to remember with this patient population, particularly those who are neutropenic, the signs and symptoms of infection can be subtle and muted. Physical evidence for infection certainly early-on in the course of the disease may not be apparent. And while it is true that fever is usually associated with infection in the neutropenic patient, it is not impossible for a serious infection to occur in a patient who is neutropenic and afebrile. And one syndrome that is particularly notable is that associated with Clostridium septicum, which can cause life-threatening infections with fasciitis, and which may not be associated with fever early in its course in the neutropenic patient.

Impaired cellular immunity, complement activity

3

Other Secondary Immunodeficiency States

•

Indwelling catheters (central venous, urinary catheter, Cerebrospinal fluid)

•

Burns

•

Inhalation Therapies (steroids or contaminated solutions)

•

Surgical Wounds

•

Fistula-sinus communications (neurocutaneous, neuroenteric, otic, facial sinus-meningeal sinus tract, facial sinus fracture)

•

Intravenous drug use

•

Prosthetic devices (cardiac valves, pacemakers)

4

Other Secondary Immunodeficiency States

Malnutrition

Congenital Heart Disease

Cystic Fibrosis

Urinary Tract Anomalies

Diabetes Mellitus

Kartagener syndrome

Nephrotic syndrome

Eczema

Uremia

Protein-losing enteropathy

Cirrhosis, ascites

(lymphangiectasia)

Prolonged Antibiotic Therapy

Chronic blood product

Spinal cord injuries

transfusions

Sickle Cell Anemia Periodontitis

5

Pathogens Associated With Anatomic Disruption

Site

Bacteria

Fungi

Other

Oral cavity

Alpha strap; an-

Candida spp

HSV

Candida spp

HSV, CMV

Candida spp

Strongyloides

aerobic Esophagus

Staph; colonizing bacteria

Lower GI

Enterococci, Enterobacteriaceae Bacteroides, Clostridia

Skin (Catheter)

Staph, Strep,

Candida,

Corynebacteria,

Aspergillus

Bacillus, Atyp

Malassezia

Mycobacteria,

Furfur

Gram-negatives Urinary Tract

Enterococci,

Candida

Enteric Bacteria, Pseudomonas

6

Pathogens Associated with Defects in Cellular Immunity

Bacteria

Fungi

Viruses

Other

Legionella

Cryptococcus

VZV, HSV, CMV,

P. carinii

Nocardia

Histoplasma

EBV, hepatitis

T. gondii

Salmonella

Coccidiodes

Live virus vaccines

Cryptosporidia

Mycobacteria

Candida

vaccinia, measles

Strongyloides

Listeria

7

Pathogens Associated With Humoral, Complement or Reticuloendothelial Defects

Defects

Bacteria

Viruses

Other

Immunoglobulin

S. pneumonia,

Enteroviruses,

Giardia lamblia

abnormalities

Staphylococ-

(Including Po-

cus,

lio)

Hemophilus, Neisseria, Enteric organisms Complement

S. pneumonia,

abnormalities

Staphylococcus, Hemophilus, Salmonella, DF2

Splenectomy

S. Pneumonia,

Babesia

Hemophilus, Salmonella, DF2

8

Clinical Features of Primary Immunodeficiencies – Newborns and Infants

Diagnosis

Clinical Features

DiGeorge syndrome

Hypocalcemia, heart disease, unusual facies

Congenital asplenia

Cyanosis, heart disease, midline liver

Leukocyte adhesion defi-

Delayed umbilical cord separation,

ciency syndrome

leukocytosis, recurrent infectious

SClD (also AIDS)

Diarrhea, pneumonia, thrush, FTT

SCID with GVH

Maculopapular rash, alopecia, lymphadenopathy, hepatosplenomegaly

Wiskott-Aldridge syndrome

Melena, draining ears, eczema

Chediak-Higashi syndrome

Oculocutaneous albinism, recurrent infections, neutropenia

C3 deficiency

Recurrent pyogenic infections, sepsis

Congenital Neutropenias

Chronic gingivitis, recurrent aphthous ulcers, skin infection

9

Clinical Features of Primary Immunodeficiencies – Six Months to Five Years

Diagnosis

Clinical Features

X-linked lymphoproliferative syn-

Severe mononucleosis

drome X-linked agammaglobulinemia

Paralytic disease post immunization

Hyper IgE syndrome

Recurrent skin and systemic staph, coarse facial features

Chronic mucocutaneous candidiasis

Persistent thrush, nail dystrophy, endocrinopathy

Specific granule deficiency

Recurrent skin abscesses

10

Clinical Features and Primary Immunodeficiencies – Older than Five Years

Diagnosis

Clinical Features

X-linked agammaglobulinemia

Progressive dermatomyositis with ECHO encephalitis

Ataxia-telangiectasia

Sinopulmonary Infections, neurological deterioration, telangiectasis

Chronic granulomatous disease

Lymphadenopathy, dermatitis, pyloric-antinial obstruction, pneumonias, small bone osteomyelitis

C6, C6, C2, C8 deficiency

Recurrent Neisseria meningitis

Common variable immunodefi-

Sinopulmonary infectious,

ciency

malabsorption, splenomegaly, autoimmunity

11

Risk Factors for Infection in Fever and Neutropenia

•

Primary risk factor is the depth and duration of neutropenia - Neurophil counts < 500/mm3 and especially less than 100/mm 3 - 48-60% of neutropenic patients who become febrile have an established or occult infection

•

Duration of neutropenia

•

LOW RISK

HIGH RISK

Duration <10 days

Duration >10 days

Factors which may modify the risk or patterns of infection associated neutropenia -

Oral or GI mucositis

-

Type and intensity of therapy (including transplantation)

-

Endogenous microflora

-

Indwelling catheters (or devices)

-

Altered qualitative phagocytic function

-

Altered cellular or humoral immunity

12

Current Pathogens Associated with Fever and Neutropenia

•

•

•

Gram-positive organisms predominate. -

Coagulase negative Staphylococci are the most frequent

-

S. aureus is second (in some centers MRSA are important)

-

Viridans streptococci comprise up to 39% of bacteremias

-

Enterococci, especially resistant to vancomycin

Risk factors associated with Viridans Streptococci -

Profound neutropenia (PMN's <100/mm3)

-

High-dose cytosine arabinoside

-

Oropharyngeal mucositis

-

Treatment with H2 antagonists

-

Quinolone or trimethoprim-sulfa prophylaxis

Complications include ARDS (3-33%), shock (7-18%), endocarditis (7-8%) and death (6-30%)

13

Current Pathogens Associated with Fever and Neutropenia

•

Among Gram-negatives, P. aeruginosa has declined -

P. aeruginosa was isolated in less than 20 of >1000 episodes of febrile neutropenia during the past decade.

-

However, when infection with Pseudomonas occurs, it still carries a serious prognosis.

•

Multiply-resistant Gram-negatives (especially Enterobacter) have emerged as pathogens at several centers.

14

Current Pathogens Associated with Fever and Neutropenias

•

Anaerobes (as mixed infections) are important in oral cavity and GI infections

•

Mycobacteria, both MTb and atypicals need to be considered

•

Viruses -

Herpes viruses (HSV, CMV, VZV, HHV 6)

-

Respiratory viruses (RSV, PIV, Adenovirus, Measles)

15

Current Pathogens Associated with Fever and Neutropenia

•

•

Fungi (especially in high-risk patients) -

Candida (both acute and chronic infections)

-

Cryptococcus (both CNS and extra-neuronal infections)

-

Aspergillus and Mucor

-

Regional isolates - eg, Fusarium, Trichosporon

Parasitic Infections -

Pneumocystis carinii

-

Toxoplasmosis gondii

-

Strongyloides stercoralis

16

Common Sites of Infection in Fever and Neutropenia

•

Primary portal of entry is usually the GI tract

•

Other important portals and sites include

•

-

Oral cavity - especially periodontal disease

-

Skin - including catheter sites

-

Perianal area

Respiratory tract

17

Initial Evaluation of Fever and Neutropenia

•

Signs end symptoms can be muted and subtle, especially during the early stages of infection in profoundly neutropenic patients

•

Profoundly neutropenic patients can sometimes have a life-threatening infection and yet be afebrile - usually there is a localizing

Underscoring the fact that if there are signs or symptoms that suggest infection, even in the absence of fever, the patient should be treated as if infected. A careful comprehensive physical examination is critical and needs to be repeated frequently. That exam should focus on the specific sites of infection. The most important oral cavity, the lower esophagus, the lungs, perianus, skin, and one should always consider exit sites from catheters. In terms of the initial evaluation of the patient who is a febrile neutropenic, it is safe to say that blood cultures are useful, certainly for screening evaluations, but their yield is relatively low. Only about 10% to 15% of newly febrile neutropenic patients will actually have a bacteremia

symptom that heralds a serious underlying process (eg, C. septicum). •

Careful and comprehensive physical exam should be repeated at least daily

•

Exam should focus specifically on periodontium, pharynx, lower esophagus, lungs, perineum, skin, catheter entry and exit sites

•

Blood cultures - including from catheter (all ports) are important

•

Routine surveillance cultures are not indicated but may be indicated in centers with increased incidence of certain nosocomial infections

•

Other cultures should be guided by signs or symptoms of infection

18

Initial Evaluation of Fever and Neutropenia

•

Initial chest radiographs have a low yield in patients without respira-

Other evaluation techniques: Initial chest x-rays tend to have a lowyield in the absence of pulmonary symptoms. They do serve as valuable baselines for patients who are likely to have prolonged periods of neutropenia. The use of imaging studies, particularly CT and MRI, can be especially helpful in patients with protracted neutropenia who are at-risk for certain sites of infection, particularly in the lungs, liver, and spleen.

tory symptoms. Baseline chest radiographs could prove helpful in patients with high-risk neutropenia •

Imaging studies - ultrasound, CT, MR - can be useful in patients with prolonged neutropenia and/or persistent fever (eg, chest CT for Aspergillus, liver CT/MR for hepatic candidiasis)

19

Initial Management of Fever and Neutropenia

•

Prompt initiation of broad-spectrum therapy when the neutropenic patient becomes febrile, coupled with appropriate modification of the initial regimen

•

There is no "ideal regimen" - variables include the risk status of the patient, local microflora and their sensitivity patterns, toxicity, preference and cost

•

Options, based on current patterns of infection and available antibi-

The most important underlying principle in the management of the cancer patient or neutropenic patient who becomes febrile, is indeed prompt initiation of a broad spectrum antibiotic therapy. This needs to encompass the most common organism, so grampositive and gram-negatives in particular. Having said that, there really is not an ideal regimen. It depends upon the status of the patient, the local microflora, their sensitivity patterns, toxicity, preference, and cost. There are a number of choices that have been advocated, ranging from combination regimens to more simplified approaches. With regard to combination regimens, the standards include third generation cephalosporins coupled with aminoglycosides. The alternatives are single-agents, particularly selective third generation cephalosporins. They should have antipseudomonal activity if they are going to be used as monotherapy, or the carbapenems and the extended spectrum penicillins that have beta-lactamase inhibitors associated with them.

otics -

Combination regimens (eg, third-generation cephalosporin plus aminoglycoside and/or vancomycin)

-

Monotherapy (eg, third generation cephalosporin, carbapenem, extended-spectrum ampicillin/sulbactam)

-

Monobactams for patients with beta-lactam allergy

-

For low-risk patients #

Outpatient parenteral therapy

#

Oral therapy

Outpatient therapy is already being employed in selecting populations, low-risk patients populations who present with fever and neutropenia. If one were to look at all of the data that has been collected, I think you can say that either monotherapy or combination therapy are reasonable choices for the curable management of the febrile neutropenic patient. While aminoglycosides have been part of the regimen in many centers, at least our own experience based upon thousands of episodes of fever and neutropenia, suggest that it is really not necessary to give aminoglycosides early on. Vancomycin should not be employed for empirical therapy. The risk for developing resistant organisms outweighs the benefits for empirical vancomycin. The only settings in which Vancomycin should be employed empirically are those settings that include patients with a clinically obvious catheter site infection, patients with colonization with resistant organisms, an individual who has persistent positive cultures despite appropriate antibiotic therapy, or who presents with hypotension or evidence of cardiovascular impairment. Aside from that, pathogen directed vancomycin is really the way to proceed in this patient population. The reason why Vancomycin became popularized is that indwelling catheters have been increasingly used for the last couple of years in the management of children and adults with cancer. With that has come an increase in the incidence of gram-positive infections. There is no question that placing a catheter in a patient increases the risk for developing a bacteremia and that bacteremia could be due to a coagulase negative or positive staph, it could be due to other gram-positives, gram-negatives, or to a fungi, most notably Candida. The principles of management of these catheters, particularly the subcutaneously planted port, while we generally think of the need to remove these devices, in this clinical setting most of these infections can be treated without device removal. So a simple bacteremia can be treated without device removal. It is important to remember if a double or triple lumen catheter is in place, rotate the antibiotics in each of the ports because colonization can be in

20

Antimicrobial Agents for Fever and Neutropenia

•

•

Antifungal agents -

Amphotericin B - still the gold standard.

-

Liposomal formulations of amphotericin B (expensive)

-

Fluconazole

-

Itraconazole

Antiviral agents -

Acyclovir, valacyclovir, famciclovir

-

Foscarnet

-

Ganciclovir

-

Ribavirin

-

Amantadine, rimantadine

only one of them. There are times where it is important to remove catheters. They include patients who have either a tunnel infection, who have persistent positive cultures despite 48 hours of appropriate antibiotic therapy. Some of the bacillus species require catheter removal, even though the organisms are sensitive. Candida is an absolute indication for device removal. Antibiotic therapy can be discontinued in low-risk patients who have evidence of recovery of neutrophil counts and who are afebrile. In those patients, monitoring your outcome is probably all that is needed. On the other hand, for high-risk patients, meaning those with profound neutropenia, and particularly for persistent fever, continuation of antibiotic therapy is necessary and should be coupled with an antifungal and other agents to support the patient during the course of neutropenia. Sites of infection often involve the oral cavity or the esophagus and the lungs, as well as other organ site infections, especially around the perianal area. Cutaneous infections can be caused by a panoply of organisms from bacteria to viruses or fungi. The predominant bacteria that are responsible for cutaneous manifestations of infection are due to staph, strep, Pseudomonas, which is associated with ecthyma gangrenosa. Fungal infections can include a number of cutaneous lesions ranging from pustules associated with disseminated candidiasis. Local signs of necrotizing infection appear with Aspergillus, Mucor or Fusarium. Viral infections can be associated with a number of vesicular and erythematous rashes as well.

21

Initial Management of Fever and Neutropenia

•

Ceftazidime was as effective as piperacillin + tobramycin for overall response (63 vs 61%), including in patients with profound

Pulmonary infections. These are divided into focal versus disseminated infections, according to whether a patient is neutropenic or non-neutropenic. There are a number of non-infectious complications that always need to be considered when you are evaluating a patient who has developed new pulmonary infiltrates. The approach to the management of these patients doesn’t depend upon whether you are dealing with focal consolidation, where one is generally thinking about bacteria or fungi, or a diffuse and interstitial process where one certainly thinks about bacteria, but is more naturally attracted to either pneumocystic or viral infections.

neutropenia -

Infection related mortality was comparable: 6% for ceftazidime vs 8% for piperacillin + tobramycin

-

In terms of other respiratory tract disease, otitis media can be due to common organisms, but they can otitis also be associated with fungi, particularly Aspergillus. When negative infections occur, external otitis can occur.

Adverse events were more common for the combination (20%) than monotherapy (8%) group

22

Initial Management and Subsequent Modifications

•

Either monotherapy or combination therapy permit a highly successful outcome for patients who present with fever and neutropenia

•

Vancomycin is not Indicated for empirical therapy except in centers with high Incidence of MRSA or alpha strep

•

Other situations in which empirical vancomycin might be appropriate Include -

Clinically obvious catheter infection

-

Known colonization with pen/cephalosporin resistant pneumococci

-

Positive blood culture with Gram positive bacteria

-

Hypotension or evidence of cardiovascular impairment

23

Reducing Catheter-related Infections

•

Major problem is bacteremias, especially coagulase-positive staph, other gram positives, gram negatives and Candida. -

Most simple bacteremias can be treated without catheter removal.

-

Need to rotate antibiotics to multiple ports

-

Need to remove catheters for tunnel infections, persistent bacteremias or candidemia

•

Infection be reduced by subcutaneous devices vs externalized devices.

24

Oral Therapy For Low-risk Patients

•

Studies demonstrate a benefit with oral therapy or potentially simplified parenteral therapy (eg, ceftriaxone)

25

Should Antibiotics Be Continued Until Resolution of Neutropenia?

•

Disconnection of antibiotic therapy is feasible for low-risk patients who have evidence of bone marrow recovery, it is not acceptable for patients with persistent profound neutropenia -

In such patients, discontinuation of antibiotics can be associated with significant clinical deterioration

•

For high-risk patients, addition of antibiotics, antifungal and other agents is the rule

26

Initial Management and Subsequent Modifications

•

Modifications are particularly frequent for patients with prolonged neutropenia

•

Modifications represent an important adjunct to therapy rather than a failure of the primary regimen

•

Clinical Events Requiring Modification of Therapy -

Breakthrough bacteremia or fungemia

-

Catheter associated soft tissue infection

-

Severe oral mucositis or necrotizing gingivitis

-

Esophagitis

-

Diffuse or interstitial pneumonitis

-

New pulmonary infiltrate despite antibiotic therapy

-

Perianal tenderness or cellulitis

-

Prolonged or recurrent fever with persistent neutropenia

27

Skin Infections in Fever and Neutropenia

•

Can be caused by bacteria, viruses and fungi

•

Predominant bacteria include staph, strep, Pseudomonas (causing ecthyma gangrenosa - also seen with Aeromonas)

•

Fungal infections include candida (local or disseminated), Aspergillus (at catheter sites or disseminated), Mucor, Fusarium

•

Virus infections can be caused by HSV, VZV (can sometimes be chronic)

28

Pulmonary Infections in Fever and Neutropenia

Pneumonia

Infectious

Non-infectious

Focal consolidation

Gram positive or

Hemorrhage,

(Lobar or segmental)

negative bacteria,

infarction, atelectasis,

Legionella, Anaerobes,

radiation, drug-related,

Mycobacteria, Crypto,

tumor

Histo, Coccidiodes, Aspergillus Diffuse Interstitial

Bacteria, viruses,

Edema, ARDS, Drug-

P. carinii, MTB

related, radiation,

Disseminated fungi,

lymphatic metastasis

Chlamydia, mycoplasma Nodular Infiltrate

Aspergillus, other

(+/- cavitation)

mycoses, Nocardia,

Tumor

Bacteria (Gram positive and negatives, anaerobes), MTB

29

HEENT Infections in Fever and Neutropenia Sinusitis in a patient who is immunocompromised can be caused by a fungal infection, especially Aspergillus or Mucor, which can cause severe infections.

•

Otitis media can be caused by routine bacteria or caused by gram negatives or fungi (Aspergillus)

•

Sinusitis can be recurrent (eg, patients with obstructive tumors)

•

Can also be caused by fungi including Aspergillus, Mucor, Fusarium, Pseudallescheria boydii.

30

Gastrointestinal Tract Infections in Fever and Neutropenia

•

Mucositis/Esophagitis - due to gram-positive, gram-negative and anaerobic bacteria. Candida and viruses (especially HSV, CMV) may be contributing factors.

•

Intraabdominal Infections -

Typhlitis or neutropenic colitis (due to gram negative bacteria, especially Pseudomonas)

-

Clostridial infections (C. perfringens, C. septicum, C. tertium)

-

Pseudomembranous and antibiotic associated colitis (C. difficile)

•

The gastrointestinal tract is the most common port of entry of organs, but there are certain syndromes that are associated with the GI tract that are noteworthy. This includes mucositis and esophagitis, gram-positive and gram-negative infections, as well as anaerobes, but also, especially for esophagitis, Candida and viruses appear. In terms of intraabdominal processes, the syndrome of neutropenic colitis generally presents as right lower quadrant pain, and is generally due to gram negative bacteria, particularly Pseudomonas aeruginosa. It can be rapidly progressive and sometimes needs surgical intervention, although the general approach is to try and treat patients with appropriate antibiotic therapy. Clostridial infection which can be due to Clostridium septicum, but also perfringens and tertium can cause significant infections and with perfringens and septicum, a fasciitis is especially noteworthy. Invasive mycoses are very relevant to the compromised host. Mycoses have emerged as major problems in this patient population. Invariably the Candida stands at the top of the list. Aspergillus, Mucor, Cryptococcus, Fusarium, Trichosporon as well as histo, blasto and cocci.

Hepatosplenic candidiasis

Perianal cellulitis

Candida may cause a broad array of symptoms and syndromes that can occur, from superficial candidiasis to deep infection, and deep infections most importantly disseminated infection. With regard to Candida esophagitis, as I mentioned already, the differential diagnosis includes other organisms, particularly simplex and Cytomegalovirus, as well as bacteria. The diagnosis can only be made by biopsy. Now in many situations biopsy is contraindicated and therefore intervention with either oral therapy, in the form of fluconazole, or systemic therapy, in the form of lower doses of amphotericin, can lead to resolution of this syndrome relatively promptly. Fungemia can be related to catheter-related infections. In the presence of fungemia, devices must be removed. A positive culture for Candida in an immunocompromised patient should always be taken seriously. An effective therapy means, especially if there is a device in place, its removal together with appropriate antifungal therapy. Even with removal of the device, continued shedding of organisms can occur because of the presence of a suppurative phlebitis, which can remain in place even when the catheter is taken out.

31

Assessment of High-risk Patients with Persistent Fever

•

Frequent meticulous physical examination is essential

•

Consider ultrasound of liver/spleen (especially in patients with persistent fever who are recovering their white count)

•

Consider chest CT in patients with persistent fever/neutropenia who become candidates for empirical antifungal therapy

32

Fungal Infections and Immunocompromised Hosts

•

Invasive mycoses are major problems for immunocompromised hosts

•

Candida is the most common

•

Depending on the host and geographic location, other important mycoses can include Aspergillus, Mucor, Cryptococcus, Fusarium, Blastomycetes, Coccidioides

33

Fungal Infections and Phagocytic Deficiencies

Disorder

Deficit

Infections

Chronic

Impaired production of

Invasive Aspergillosis

Granulomatous

oxidative metabolites

Disease Myeloperoxidase

Defective Intracellular kill-

Deficiency

ing

Granulocyto-

Quantitative deficit of

Candidiasis, invasive

penia

phagocytes

Aspergillosis

Candidiasis

Zygomycosis, Trichonosporosis, Fusariosis, Pseudallescheriasis Corticosteroid

Impaired phagocytosis

invasive Aspergillosis,

therapy

of conidia by

Candidiasis,

macrophages

Zygomycosis

and defective damage to hyphae by neutrophils

34

Fungal Infections and Altered Cellular Immunity

Disorder

Deficit

Infections

Severe Combined

Depletion of T- and B-

Candidiasis,

Immunodeficiency

cell precursors

Cryptococcosis

DiGeorge syndrome

Thymic hypoplasia

Candidiasis, Cryptococcosis, Histoplasmosis

Chronic

Impaired recognition or

Mucosal candidiasis

Mucocutaneous

T-cell response to

Candidiasis

Candida antigens

Acquired Immune

Defective cell-mediated

Mucosal candidiasis,

Deficiency Syn-

and humoral immunity;

Cryptococcosis,

drome

impaired neutrophil

Aspergillosis,

function

Histoplasmosis, Coccidioidomycosis

35

Candidiasis

•

More than 80 species, less than 10 of which are medically important

•

C. albicans is responsible for >60% of candidiasis

•

Colonization is 25-70% -

5-15% of newborns to first week, increasing to 46% by 18 months

•

Major sites include oral cavity, GI tract, and vagina

Other clinically relevant species of Candida -

C. tropicalis - a cause of disseminated infection in compromised hosts.

-

C. parapsilosis - second to C. albicans as a cause of endocarditis.

-

C. glabrata - rare cause of endocarditis and disseminated infection in compromised hosts and catheter associated fungemia. Resistant to azoles.

-

C. lusitaniae - can be a cause of fungemia and deep infection. Resistance to amphotericin B reported.

The diagnosis of disseminated candidiasis is still a challenge. The best technique available to us is the lysis centrifugation, a technique that has permitted us to make the diagnosis of candidemia in close to 60% to 70% of the patients, as compared to about 20% of the patients who do not have blood cultures but the lysis centrifugation technology. Newer techniques, and particularly non culture-dependent techniques like enolase or arabinitol and PCR, are still experimental and not part of any standard regimen. The clinical presentation in this patient population of disseminated candidemia rests on the presence of fever. That may be all you have. So persistent fever of babies may be the only symptom of disseminated candidiasis. If one does have evidence of skin lesions, particularly papules or chronic lesions that are available for biopsy, that can help you to diagnose infection earlier on. Myositis can be part of this syndrome, so muscle pain, in addition to fever in a neutropenic patient is suggestive of disseminated candidiasis. The sites of dissemination include many organs from the skin to the kidneys, lungs, GI tract, liver, spleen, and the central nervous system. Very similar to what one sees in neonatal candidiasis. The drug of choice is a polyene, particularly amphotericin. Either amphotericin B or, depending upon the setting, the liposomal or lipid associated formulation of amphotericin. The duration of therapy really depends upon whether or not there is evidence of organ infection. In the absence of organ infection, treating a patient or a child for between 30 to 40 mg/kg and in an adult for one-half to a gram of amphotericin is appropriate therapy. If there is evidence of organ infection, higher doses and longer courses are needed. This syndrome is characterized by new or persistent fever, the presence of abdominal pain, or right upper quadrant tenderness, an elevated alkaline phosphatase and leukocytosis. The clinical presentation includes “bulls eye” lesions on either ultrasound or CT and the MR scan, which may be the most sensitive way of diagnosing this syndrome. These lesions are generally not visible in children with neutropenia, so if you had a patient who was surveyed during the time they had neutropenia, they had a negative CT or MR scan and is still febrile at the time of resolution of neutropenia, it would be important to go back and repeat those studies. Definitive diagnosis requires biopsy because blood cultures will often be negative. Therapy can require protracted courses of antibiotics with either amphotericin or fluconazole. And if one is using amphotericin on very long courses in high doses, 5FC may also be necessary. Lipid-associated formulations of amphotericin may allow for a greater degree of dose intensity. Cryptococcus. This is much more of a problem in adult HIV patients and adult cancer patients. Cryptococcus can be a problem in children as well. It can be associated with primary infection of the lungs, characterized by a diffuse miliary disease, which can be rapidly progressive in a child with cancer, leading to death if not recognized and treated. The most common manifestation of Cryptococcus is Meningoencephalitis, which often is indolent and can be associated with headaches, nausea, dizziness and irritability. A heightened index of suspicion for the diagnosis is essential because fever is generally low-grade. Patients can deteriorate quite rapidly and have a high degree of mortality.

36

Candidiasis Ecology

•

Nuchal rigidity is rare. There often is evidence of increased intracranial pressure, as well as cranial nerve palsies. The differential diagnosis includes a variety of different meningoencephalides and the CSF is a critical part of the evaluation, particularly looking for Cryptococcal antigen which can be found in large numbers of patients.

Other clinically relevant species of Candida -

C. kruesei - a cause of breakthrough infection in patients receiving fluconazole

-

C. guillermondii

-

C. kefyr (C. pseudotropicalis)

•

Lacks an apparent sexual life cycle

•

Changes in colony morphology can occur during sequential episodes of infection

•

Two major serotypes - A and B -

•

Higher prevalence of B serotype in immunosuppressed patients

Numerous environmental sources, including soil, water, plants, foods and beverages

37

Candidiasis: Laboratory Diagnosis

•

Characteristic features include budding yeast cells, pseudohyphae, or hyphae in tissue. Yeast cells and pseudohyphae commonly measure 3-5 um in diameter

•

C. glabrata has smaller yeast forms and does not produce pseudohyphae or hyphae

•

Wet mount (KOH) or fluorescent microscopy with calcofluor wet specimens

•

Organisms well demonstrated with Gram, Giemsa or Wrights stains

38

Candidiasis: Laboratory Diagnosis

•

Blood cultures are optimized with lysis centrifugation (Isolator), also planted on Sabouraud's agar (with antibiotics but without cycloheximide)

•

Cultures from other clinical sites should be placed on Sabouraud's agar and incubated at 300C. Culture plates should be held for 2-3 weeks

•

Candida produces white to cream-colored colonies

39

Candidiasis: Clinical Syndromes

•

•

Superficial Candidiasis -

Skin, hair, nails, mucous membranes

-

Ocular candidiasis

Deep Candidiasis -

Esophagitis

Arthritis

-

GI/Peritonitis

Osteomyelitis

-

Respiratory tract

Endophthalmitis

-

Urinary tract

CNS

-

Acute Hematogenously disseminated

-

Chronic disseminated (hepatosplenic)

-

Suppurative phlebitis

-

Endocarditis

-

Neonatal candidiasis

40

Ocular Candidiasis

•

Keratoconjunctivitis due to Candida is a complication of the longterm use of steroid eye drops

•

Other risk factors include breaks in the corneal epithelium

•

Characterized by cheesy discharge in the conjunctival sac

41

Candida Esophagitis

•

At risk populations include patients with congenital or acquired immunodeficiency disorders, cancer patients, mechanical problems (achalasia, peptic esophagitis)

•

May be asymptomatic or associated with burning retropharyngeal chest pain

•

May or may not be associated with oral lesions

•

Typical lesions are white mucosal plaques, generally in the distal third of the esophagus. Lesions can be edematous and hemorrhagic

•

Differential diagnosis includes H. simplex, CMV, bacteria

•

Diagnosis can only be confirmed by biopsy

•

Therapy -

Topical - clotrimazole is best

-

Oral - ketoconazole or fluconazole

-

Systemic #

Low-dose amphotericin (0.1 mg/kg/d for 5 days)

#

Conventional amphotericin (0.5-1.0 mg/kg/d)

#

Liposomal amphotericin (for recalcitrant or resistant organisms)

42

Gastric Candidiasis

•

Stomach is second to esophagus as a site for GI candidiasis

•

Lesions may involve the intestine and, in the case of leukemia patients, may be deeply invasive and serve as a nidus for dissemination

43

Candida Peritonitis

•

Peritonitis can occur with peritoneal dialysis (risk is 7%) or postoperatively

•

Symptoms include abdominal pain, with or without nausea, vomiting or low-grade fever

•

Dialysate should be examined microscopically and cultured

•

Peritoneal fluid should be examined, especially in the post-op patient

•

Therapy -

It is prudent to remove the device

-

Approximately 25% can be cured without catheter removal

-

If dissemination has occurred, amphotericin should be administered

-

Although amphotericin can be added to the dialysate or infused, it is associated with pain and can lead to fibrosis

-

Recommendations are for IV amphotericin + oral 5 FC.

44

Urinary Tract Candidiasis

•

Urinary Tract accounts for 49% of nosocomial candida infections. Candida is the causative organism in 7%

•

Risk factors include indwelling catheter and predisposing illnesses (eg, diabetes mellitus, immunosuppression)

•

Symptoms of lower tract infection (dysuria, frequency) and fungus galls or bezoars (primarily in diabetics) may occur

•

Colony counts >104 suggest the diagnosis

•

Removal of the catheter may ameliorate symptoms

•

Therapeutic recommendations include instillation of amphotericin B (which can be painful) to fluconazole -

Note that ketoconazole is not excreted into the urine in an active form

•

Because of the high volume of blood flow, the kidney is commonly involved in disseminated candidiasis

•

Ascending infection can be associated with obstruction, renal stones, nephrostomy tubes, ureteral stents or with diabetes

•

Symptoms can be indistinguishable from bacterial pyelonephritis -

Persistent fever in a patient receiving broad-spectrum antibiotics

-

Blood cultures are positive in <50%, even with disseminated candidiasis

45

Urinary Tract Candidiasis

•

Microabscesses are primarily in the renal cortex

•

Candiduria is helpful but not definitive -

Presence of hyphae is not necessarily indicative of invasive disease

•

Imaging studies (CT, MR) may reveal evidence of abscesses, often in association with lesions elsewhere

•

-

Lesions may not be apparent during neutropenia

-

Can be found in intravenous drug users

Intravenous amphotericin in the recommended therapy -

Short courses have been used, although longer courses are preferred for proven renal abscesses

-

Fluconazole has also been used

46

Bone And Joint Candidiasis

•

Prosthetic and rheumatoid joints can be infected hematogenously or during surgery

•

Arthritis can occur in neonates or neutropenic patients

•

Symptoms are indolent, and joint fluid is variable

•

Osteomyelitis is generally hematogenous, clinically indolent, and most commonly involves the lumbar vertebrae

•

Therapy includes surgical debridement and intravenous amphotericin B

47

Catheter-associated Candidiasis

•

Fungemia is a sequelae of intravascular catheters in immunocompetent and immunosuppressed hosts

•

Positive cultures should never be ignored. In neutropenic patients they often signify disseminated infection.

•

Effective therapy mandates removal of the catheter and systemic therapy

•

Suppurative phlebitis can cause of treatment failure and may require surgical therapy

48

Candida Endocarditis and Pericarditis

•

Subacute endocarditis can occur following candidemia, especially in patients with valvular defects or prosthetic devices -

Lesions can become large and result in embolic phenomena

-

Transesophageal echo is necessary if transthoracic echo is negative

•

Pericarditis is a rare complication

•

Surgery plus amphotericin B is necessary

49

CNS Candidiasis

•

Risk group includes neonates, neutropenic patients, complicated neurosurgery or VP shunts

•

Presentation is generally indolent

•

CSF profile includes pleocytosis, increased protein and low glucose

•

Can be accompanied by microabscesses, granuloma or vascular lesions

•

Amphotericin + 5 FC is recommended

•

Long-term adverse sequelae (including aqueductal stenosis) is common

50

Candida Endophthalmitis

•

10-37% of adults with candidemia develop endophthalmitis

•

Only one eye is involved in 50%

•

Onset may be acute or delayed, and symptoms are indolent

•

Small, sharply outlined lesions in the posterior pole are most common. Lesions may be absent during neutropenia.

•

Lesions may disappear or enlarge to rupture into vitreous and anterior chamber

•

Therapy includes systemic amphotericin + 5 FC -

Role of fluconazole is investigational

51

Acute Disseminated Candidiasis

•

Diagnosis is often made postmortem and premortem blood cultures are positive in <60-70% -

Newer diagnostics (PCR) are specific but several lack optimal specificity and are experimental

•

Clinical presentation consists of persistent fever, sometimes with evidence of shock and DIC

•

-

Skin lesions include papules with gray necrotic centers

-

Myositis may be an accompanying symptom

Sites of dissemination includes skin, kidneys, lungs, GI tract, liver, spleen, CNS, eyes, thyroid, joints.

•

Therapy includes prompt initiation of amphotericin B, 1 mg/kg/d, optimally in combination with 5 FC

•

Duration of therapy depends on the organs that are involved and duration of immunosuppression

52

Chronic Disseminated Candidiasis Hepatosplenic Candidiasis

•

Primarily found in patients who were neutropenic, but rarely diagnosed during neutropenia

•

Multisystem granulomatous disease

•

Syndrome consists of -

New or persistent fever at recovery from neutropenia

-

Some patients have abdominal pain or RUQ tenderness

-

Elevated alkaline phosphatase

-

Leukocytosis

-

Bulls eye lesions on ultrasound, CT or MR

53

Chronic Disseminated Candidiasis Hepatosplenic Candidiasis

•

Imaging lesions are generally not positive during neutropenia

•

Diagnosis requires biopsy of lesions

•

Biopsy cultures are often negative

•

Therapy requires a long course of amphotericin B with 5 FC -

Treatment continues until resolution of lesions or dense granulation

-

Liposomal formulations of amphotericin may be more beneficial

-

Continuation therapy with fluconazole

54

Cryptococcosis: Epidemiology and Ecology

•

C. neoformans is the only species known to cause human infection -

Monomorphic yeast, 4-6 um in diameter

•

Has a worldwide prevalence

•

AIDS has changed the frequency of this infection -

Rare in pediatric AIDS (<1%)

-

Incidence in children with cancer is 0.5%

•

Infection follows inhalation into lungs

•

Exposure to pigeon excreta is the source of human exposure

•

-

Isolated in <1% of soil samples but >50% of pigeon droppings

-

Human-to-human transmission not reported

Major risk groups include patients with cancer, acquired or congenital immunodeficiency disorders, transplant patients

55

Cryptococcosis: Pathogenesis

•

Following inhalation, a primary pulmonary complex is formed that either heals or progresses

•

The capsule can inhibit phagocytosis

•

Cellular defenses are the most important. Patients with altered T helper numbers or function are most vulnerable.

56

Cryptococcosis Diagnosis

•

Direct examination of CSF, urine, sputum or pus (digested with 10% NaOH) can be positive with India ink prep

•

Histopathology sections can be stained with mucicarmine to demonstrate yeast with capsules

•

Latex agglutination detection of polysaccharide capsule has a sensitivity >90% -

Suitable only for serum and CS

-

Should contain a control for RF, a source of false positives in CSF

-

False positives can occur with Trichosporon beigelii

•

Lumbar CSF titers are higher than those of ventricular fluid

•

Lysis-centrifugation methodology is most sensitive and rapid -

Cultures may take from 1-21 days (mean 3 days)

•

Grows well on Sabouraud agar (without cycloheximide)

•

Niger seed agar is effective for urine and sputum samples from AIDS patients

•

Rapid urease test is helpful since >90% of isolates show urease activity within 15 min

57

Cryptococcosis Clinical Manifestations

•

Lungs are the site of entry

•

Patients with chronic lung disease may have asymptomatic colonization.

•

Previously normal patients have a self-limited pneumonia, sometimes with cavitations.

•

Diffuse miliary disease can rarely occur with disseminated disease.

•

Localized nodular infiltrates can occur, which can be confused with tumor nodules, especially in non-neutropenic cancer patients

58

Cryptococcosis Meningoencephalitis

•

Most common clinical manifestation and major cause of death

•

Can be rapid or indolent -

Indolent cases are characterized by headache, nausea, dizziness, irritability, impaired cognition, ataxia that progresses to lassitude, blurred vision and coma. Fever is often low grade.

-

Acute cases may deteriorate and die within 2 weeks. These patients become somnolent and nauseated with headache.

•

Nuchal rigidity is rare

•

Signs of increased ICP are more common

•

Cranial nerve palsy can occur

•

Differential diagnosis includes aseptic meningitis or brain tumor

•

Lumbar CSF has increased opening pressure. Cryptococcal antigen -

In rapidly progressing cases, the CSF antigen (or India ink) is positive without other abnormalities

59

Cryptococcosis Clinical Manifestations

•

Skin lesions are most common around the face and can be pustular or ulcerative and occur in 10% of patients with cryptococcosis

•

Skeletal lesions occur in 5% and may be confined to a single lesion, most commonly involving the vertebrae.

•

Ocular lesions include papilledema, optic atrophy, extraocular motor palsy.

•

It usually can not be detected in the urine, although it frequently is isolated from urine in patients with disseminated disease.

•

Cryptococcus can also be associated with -

Pyelonephritis

-

Prostatitis

-

Adrenal cortical lesions

-

Endocarditis

-

Hepatosplenic disease

-

GI and GU tract involvement

60

Cryptococcosis Treatment

•

•

Standard therapy for meningoencephalitis -

Amphotericin B, 0.5 mg/kg/d for 6 weeks plus

-

5-flucytosine, 100 mg/kg in 4 divided doses for 6 weeks

Patients with HIV who develop meningitis require maintenance therapy with fluconazole

•

Death can occur in up to 15%. Poor prognosticators include rapid disease progression, increased ICP at diagnosis, poor CSF response.

61

Aspergillosis Aspergillus: Aspergillus is the fungal organism we prefer not to see in the immunocompromised host, fumigatus and flavus species are the major ones that are encountered. A. niger is usually a saprophyte and not associated with significant infection. It is the one that you see in fungus balls, and that usually is a non-invasive syndrome.

•

More than 135 species and 18 varieties exist -

16 species and 1 variety have been associated with human disease #

A. fumigatus is most common cause of invasive and noninvasive disease worldwide

#

Invasive forms of aspergillus include both pulmonary and nonpulmonary manifestations. The non-pulmonary manifestations include involvement of a variety of different organ systems, but the most common one is the pulmonary disease and the most common port of entry is through the upper airway. The disease that one is most concerned about is the localized and then disseminated forms of pulmonary aspergillus.

A. flavus is second, causing disease in immunosuppressed hosts

#

A. niger is usually saprophytic

#

A. niger and A fumigatus are common cause of a "fungus ball"

62

Aspergillosis Epidemiology and Ecology

•

Most species are found in soil, various food products, cotton and organic debris

•

A. fumigatus grows well at temperatures >550C and compost piles are an excellent media

•

Moldy grains are source of Aspergillus spores

•

Hospital sources (eg, fireproofing material) have been contaminated with A. flavus. Also, potted plants, hospital construction.

•

Spores can be inhaled or contaminate wound surface

•

Invasive disease has been reported in -

2% of patients undergoing renal transplantation

-

4-17% of patients undergoing liver transplantation

-

Aspergillus is the most common fungal pneumonia in organ transplant patients

-

Invasive disease occurs in 5-20% during chemotherapy-induced granulocytopenia or bone marrow transplantation

63

Aspergillosis Epidemiology and Ecology

•

Risk factors for infection following BMT -

Age greater than 30 years

-

HLA match and presence of GVHD

-

Conditioning regimen - T cell depletion, steroids

-

Duration of neutropenia

•

CGD patients are vulnerable to Aspergillus

•

HIV patients can also develop aspergillosis

64

Aspergillosis Pathogenesis

•

Usual portal of entry is the respiratory tract. Less common are GI tract and traumatized skin

•

Initial control is by the pulmonary macrophages

•

Some conidia can be carried by macrophages to the RE system and can be associated with dissemination

•

Corticosteroids are a major risk factor for infection

•

Neutropenia or neutrophil dysfunction contribute

•

Fungus ball is a large mycelial mass growing in cavities in the upper lobe of the lungs or sinuses. Fungus balls are not associated with invasive disease

65

Aspergillosis Pathogenesis and Pathology

•

Invasive aspergillosis is characterized by hyphal invasion of blood -

Infection spreads hematogenously as well as by contiguity.

-

In patients with CGD, vascular invasion is not apparent but a massive inflammatory response is evident

66

Aspergillosis Laboratory Diagnosis

•

Morphology of A. fumigatus and A. niger is distinct enough so that positive identification can be made on histological appearance

•

Aspergillus grows well on conventional media -

Sabouraud's and malt extract with antibiotics are used

-

Cycloheximide should be avoided

67

Aspergillosis Clinical Manifestations

•

Allergy to Aspergillus antigen causes allergic bronchopulmonary aspergillosis

•

Saprophytic colonization of air spaces -

Otomycosis

-

Fungus ball of paranasal sinus

-

Endobronchial colonization

-

Fungus ball of the lung

68

Aspergillosis Clinical Manifestations

•

Keratitis or endophthalmitis can occur from trauma or surgery.

•

Otomycosis is colonization of the external auditory canal -

Greenish-black or fuzzy growth on cerumen

-

Can become invasive in severely compromised hosts

69

Aspergillosis Clinical Manifestations

•

Fungus balls of the paranasal sinus or lung represents saprophytic colonization without invasion -

Maxillary sinus is most common but other sinuses can be involved

-

The fungus ball itself can contribute to obstruction but not bony erosion

-

In the lung, a fungus ball usually occurs in a preexisting cavity. Hemoptysis is a complication

70

Aspergillosis Clinical Manifestations

•

•

Invasive Pulmonary Aspergillosis -

Symptoms can be subacute to acute, nearly always with fever

-

Cough, pleuritic pain and hemoptysis in neutropenic patients

-

Can be more indolent in CGD, and fever may be absent

In immunosuppressed hosts, radiograph shows single or multiple round or infarct-like lesions, sometimes with cavitation or hemorrhage -

CT is more sensitive

-

Infection follows or co-exists with a bacterial (Pseudomonas) or viral (CMV) infection

•

Invasive Pulmonary Aspergillosis -

Vascular invasion causes infarction of distal tissues

-

Pulmonary infection crosses contiguous tissues - through the diaphragm into the stomach or liver; into the pericardium, heart or SVC

-

Hematogenous infection occurs in a third of cases

-

Cavitation, sometimes associated with neutrophil recovery, can sometimes be accompanied by massive hemoptysis

71

Aspergillosis Clinical Manifestations

•

Invasive Sinus Infection -

May be acute or chronic

-

Acute infection is associated with fever and may be accompanied by symptoms of sinusitis or rhinitis, lesions over the nose or sinus area, necrotic lesions of the turbinates or hard palate

-

Can spread to contiguous tissues including orbit or brain

-

Most frequently associated with prolonged neutropenia

-

Sensitivity of repeated nasal cultures is 50%

72

Aspergillosis Clinical Manifestations

•

CNS is most common site for disseminated disease -

•

Cutaneous lesions can occur at sites of trauma or catheter insertion. -

•

Can consist of single or multiple lesions

Can also be consequence of disseminated infection

Endocarditis can be a consequence of cardiac surgery or can occur with iv drug use -

•

Cardiac lesions can also occur with disseminated infection

GI involvement can include an ulcerative esophagitis or lesions in the stomach, small and large intestine. A Budd-Chiari syndrome has been described in association with Aspergillus.

•

Osteomyelitis of the ribs and vertebrae can occur -

Direct extension from lung lesions

-

As part of hematogenous infection

Fungus balls. In the lungs of patients they generally don’t represent invasive disease, but they can be seen in other sites as well. One can see evidence of fungus balls in the sinuses as well. Hemoptysis is something that can occur. A saprophytic form of fungus balls can occur as an isolated lesion. Some have advocated surgical removal of those lesions prior to the administration of chemotherapy. Surgery doesn’t, however, play a role in invasive aspergillus. It is interesting to note that early on the symptoms can be subjective and vaguely associated with fever. Cough and pleuritic pain suggests the presence of aspergillus pneumonia. In immunosuppressed hosts the chest radiograph can sometimes show anything from single to multiple round lesions. These can sometimes look like tumor nodules, but they can undergo evolution rather rapidly as well because hemorrhage can occur into them. A plain chest x-ray may be negative for aspergillus but the CT scan may reveal sites of infection. Invasive aspergillus is really an angioinvasive disease, and vascular invasion is what leads to an infarction of tissues and the pulmonary infection really follows the tissue, so that you can see an extension of this disease contiguously through the lung planes through the diaphragm and into the liver and spleen and all the way down to the kidneys. Hematogenous spread can occur although positive blood cultures often don’t. And one can see cavitation of lesions at times of recovery of neutrophils. The syndrome of rhinocerebral disease or invasive sinus infection is as important with aspergillus as it is with Mucor. This can be both acute and chronic. Acute infection is associated with fever and can be associated with a bit of an eschar around the anterior nares, which can spread rapidly through the cribriform plate into the brain. This is a very severe infection and in order to treat this, surgical therapy in tandem with systemic amphotericin or other antifungal agents is essential. The central nervous system is the most common site of disseminated disease and can consist of both single as well as multiple lesions, and one can see cutaneous lesions. These can be part of a systemic syndrome or can be secondary to local inoculation. Local inoculation from environmental sources, particularly around catheter sites can be associated with aspergillus. The treatment is with a combination of amphotericin, sometimes in association with surgery. Itraconazole has been employed. The problem with itraconazole is that it is imperfectly absorbed in this patient population. It is not adequate first-line therapy. Surgery has been used to extricate both central nervous system as well as sinus infections. Its role in pulmonary disease is largely restricted to the solitary cavitary lesions in which hemoptysis is a risk factor, but it really doesn’t make a difference on indications throughout the basic disease because the extension of the disease is simply too much.

73

Aspergillosis Treatment

•

Drug of choice is amphotericin B at 1-1.5 mg/kg/d -

Little data exist regarding combination regimens

-

Liposomal preparations are being explored

-

Itraconazole has been used for continuation therapy

74

Aspergillosis Treatment

•

Surgery is used to extirpate CNS and sinus lesions

•

Role for pulmonary lesions is limited to

•

-

Solitary cavitary lesion refractory to medical therapy

-

Hemoptysis from a solitary cavity

-

Contiguous invasion of esophagus, ribs or pericardium

Leukocyte transfusions have been employed in CGD

75

Mucormycosis

•

The causative agents are members of the Zygomycetes (class) and Mucorales (order) -

The agents responsible for most invasive infection include: Rhizopus, Absidia, Mucor and Cunninghamella #

Other members of this order also cause infection, including: Saksenaea, Apophysomyces, Syncephalastrum, Cokeromyces, although not necessarily invasive disease

76

Mucormycosis Epidemiology and Ecology

•

Distribution is worldwide. Organisms found in decaying vegetables,

Mucor does just about everything that aspergillus can do only more so because it is more recalcitrant to intervention. The agents of Mucor responsible for invasive disease include Rhizopus, Absidia, Mucor and Cunninghamella. There are other members of this family that can also be associated with significant disease, particularly in the upper airway and around the sinuses. The syndrome with Mucor looks like aspergillus but is even more recalcitrant to treatment and that is the rhinocerebral syndrome with again extension through the ethmoid sinuses through the cribriform plate, and into the brain.

compost piles, soil, old bread •

Nosocomial infections can occur (e.g., Elastoplast) but is less common than with Aspergillus

•

Major risk factors for infection include diabetes, malignancy, organ transplantation, chronic liver or kidney disease, burns or other disruptions of physical defense barriers

77

Mucormycosis Pathogenesis and Pathology

•

Portal of entry is respiratory, GI or skin

•

Diabetic ketoacidosis predisposes to progressive nasal and cerebral mucormycosis

•

Neutropenia, or altered phagocytic function (e.g., steroids) contrib-

Pneumonia can occur with Cryptococcus and can be rapidly progressive, can be associated with both cavitation and can, on rare occasions, be associated with exsanguinating hemoptysis. These are very serious infections. Treatment of cranial, facial mucormycosis is a combination of both surgical debridement as well as antifungal therapy. Less common fungi can cause notable infection in this patient population, depending upon the region that one is in. This includes Trichosporon which is a yeast that is commonly associated with white piedra, but it can be associated with fungemia and disseminated infection. A fact that is interesting to note and important to note is that it shares cross reactivity with cryptococcal antigens, so cryptococcal antigen positivity doesn’t always mean Cryptococcus. It could be Trichosporon. It responds poorly to amphotericin B.

ute. •

Hallmark is vascular invasion by hyphae leading to thrombosis and infarction. Thrombosis may occur in large as well as small vessels.

•

Spread can be contiguous or hematogenous

Fusarium, which is a plant pathogen, can cause disseminated infection usually beginning on the skin or muscles and associated with fungemia. Pseudallescharia boydii mimics aspergillus and Mucor in its appearance and profile and it is important to think about and diagnose because it tends to be resistant to amphotericin, but is sensitive to miconazole. Bipolaris as well as Penicillium marneffei can cause serious infection both in cancer as well as HIV patients. Bone marrow and in solid organ transplant patients. If one looks at the patient population undergoing bone marrow transplantation, one can begin to categorize the likelihood of infection based upon where one is in the course of post-transplant. Early on bacterial infections during the neutropenic phase are very similar to what one sees in the neutropenic cancer patient who wasn’t receiving bone marrow transplantation. And similarly, fungal infections can occur in the same manner. What is different in this patient population is the time of onset on various viral infections. With herpes simplex appearing early, Cytomegalovirus occurring generally between 30 and 60 days post-transplant and Varicella zoster generally after that, more particularly after about 100 days. So if one looks at the evaluation of the patient undergoing bone marrow transplantation, the pretreatment evaluation largely centers on screens for those organisms that are likely to cause problems, including Cytomegalovirus, the Epstein-Barr virus, herpes simplex, hepatitis. One looks for evidence of any kind of organ involvement and of course for the presence of ova and parasites. Here particularly, Strongyloides, in the presence of immunosuppressive therapy, can be associated with a hyperinfection syndrome that includes polymicrobial bacteremia as well as pneumonic infiltrates.

During the early period, that is before the engraftment transplantation, the patterns of infection are largely that related to fever and neutropenia. And the other infections that one thinks about are herpetic gingivostomatitis; Largely this is a reactivation infection and generally prevented by the use of prophylactic acyclovir. The fungal infections are very similar to those that occur in the setting of fever and neutropenia. Hemorrhagic cystitis can occur in this patient population. Here, one thinks about particularly adenovirus as well as cytomegalovirus. During the new period following transplantation,

78

Mucormycosis Laboratory Diagnosis

•

which is during the early engraftment phase, Pneumonitides can occur, and there is a difference depending upon whether the patient has undergone allogeneic versus autologous bone marrow transplantation. In the setting of allogeneic bone marrow transplantation, the syndrome of interstitial pneumonia largely associated with CMV as well as graft versus host disease is manifest. And when it occurs it carries with it a very high degree of morbidity and mortality.

Histologically mucor can be recognized by their broad (7-15 um) hyphae and lack of regular septations. Unlike the regular dichotomous branching of Aspergillus.

•

Mucorales grow rapidly on most mycological media (without cycloheximide)

79

Mucormycosis Clinical Manifestations

•

Rhinocerebral syndrome is most common in uncontrolled diabetics or patients with cancer.

•

Infection is acute and rapidly progressive.

•

Extension from ethmoid sinus to the orbit is frequent, resulting in loss of ocular movement, proptosis and involvement of CN III, IV and V.

•

Extension to dura and brain with embolization of distal brain tissue may occur.

•

Pneumonia is accompanied by fever and rapidly progresses

•

Infiltrates progress rapidly with apparent cavitation

•

Hemoptysis can occur, and may be massive

•

Infection of the bronchus or trachea can occur independently of pneumonitis

•

Cutaneous mucormycosis occurs at sites of trauma, iv sites or post-op sites -

Skin lesions are generally single, begin as erythematous, indurated cellulitis but develop central black necrosis

•

GI lesions arise in 7% - the stomach is most common followed by the colon. GI lesions can serve as a nidus for dissemination

•

CNS involvement can be by direct extension or hematogenous spread

•

-

Local extension is mostly from ethmoid sinus

-

Hematogenous disease is mostly from a pulmonary focus

Cardiac mucormycosis is rare, but endocardial vegetations have been described

80

Mucormycosis Treatment

•

Craniofacial mucormycosis without extension to the brain or carotid artery can respond to surgical debridement, control of the underlying disease and amphotericin B

•

Treatment of pulmonary disease or disseminated infection in compromised hosts is very disappointing, even with higher doses of amphotericin or liposomal preparations

81

Less Common Pathogens

•

Trichosporon beigelii, a yeast that causes white piedra, can cause fungemia and disseminated disease

•

-

Shares cross reactivity with Cryptococcal antigen

-

Responds poorly to amphotericin

Fusarium, a plant pathogen, can cause disseminated infection in immunocompromised hosts -

Generally begins with skin lesion or invasion through impaired integument with dissemination

82

Less Common Pathogens

•

Pseudallescheria boydii mimics Aspergillus in its appearance and clinical manifestations. Notable for its resistance to amphotericin B. It is sensitive to miconazole.

•

Bipolaris, Wangiella and Exserohilum are agents of Phaeohyphomycosis. Can cause cutaneous, pulmonary, CNS and disseminated infections

•

Penicillium marneffei presents with disseminated infection in cancer and AIDS patients. Histopathologic lesions resemble histoplasmosis

83

Special Considerations in Bone Marrow Transplant Patients

•

Pretreatment evaluation -

Serology for CMV, EBV, HSV, Hepatitis B, Serology, RPR, HIV

-

Chemistries including hepatic enzymes, renal function, CBC

-

Stool for ova and parasites

-

PPD

-

Chest radiograph

84

Special Considerations in Bone Marrow Transplant Patients

•

Early Period (Before Engraftment) -

Fever and neutropenia may occur, which is similar to cancer patients

-

Herpetic Gingivostomatitis caused by reactivation

-

Fungal infections - similar to those in fever/neutropenia

-

Hemorrhagic cystitis (adenovirus, CMV, Papovavirus, HSV, bacteria, chemotherapy, GVH

•

Middle Post-transplant Period (Early Engraftment) -

Pneumonitis - due to infectious and non-infectious causes #

Infections - especially CMV.

#

Other Important pathogens include RSV, adenovirus, PIV, Influenza, PCP

-

Noninfectious causes Include alveolar hemorrhage, radiation/drug damage, edema, vascular disease

•

Late Post-transplant Period -

Other pathogens that can occur in this setting include the common respiratory viruses, and there have been in bone marrow transplant settings particular outbreaks and significant morbidity associated with these respiratory viruses. Once again, always important to take into account that non-infectious complications can occur, including alveolar hemorrhage that is putatively non-infectious. During the late period the patient who has undergone bone marrow transplantation, after about say 100 days, bacterial infections can occur especially due to the encapsulated organisms of which Strep pneumoniae dominating the situation, and Varicella zoster reactivation becoming important at this point in time. With regard to those patients who have undergone solid organ transplantation, here too one can break them down according to early, middle and late. They include bacterial infections, fungal infections, and virus infections, and they are differentially distributed according to where one is in the period post-transplant and according to the type of transplantation which has been done. Patients who have renal transplant are most susceptible to septicemia and pyelonephritis, and patients who have undergone liver transplants are most responsible to various enteric organisms, as well as to ascending cholangitis. Those who have undergone intestinal transplantation as you might imagine are most susceptible to bacterial infections, especially with GI flora. The bacterial and fungal infections in patients undergoing heart, cardiac transplantation are notable. Indeed, infections occur commonly in this patient population 20% to 40% of the time. Respiratory tract disease is the most important single organ. Mediastinitis can occur, and both staph and gram negatives can be the offending organisms. For the patients undergoing heart-lung transplants, pneumonitis is the most common site of an infection, especially with gram negative organisms.

Bacteremias due to encapsulated organisms (especially S. pneumoniae)

-

Varicella-Zoster infections occur in 25-40% and can become disseminated

-

Hepatitis - due to both infectious and noninfectious causes

85

Special Considerations in Solid-organ Transplant Patients

•

Important risk factors include -

Site of the transplant (and risk for site-specific infections)

-

Underlying disease and its predisposition to infection (eg, CF)

-

Status of underlying disease and degree of malnutrition

-

Age and age-specific pathogens (RSV in children vs Cryptococcus in adults) #

-

Primary vs reactivation infections

Acquisition of infection from the donor organ (e.g., CMV, EBV,

With regard to viral infections in patients undergoing solid organ transplantation, Cytomegalovirus tops the list. It is typically acquired from donor organs; therefore, screening becomes important in the setting of the symptoms and can be manifest between one to three months following the transplantation. Symptoms can include fever, as well as hematological abnormalities. Infection can be disseminated with visceral involvement. Culture and histological findings are important as well as antigen detection techniques to assess the risk for infection. Other viral organisms that occur in solid organ transplantations, including the Epstein-Barr virus. This can have a broad range of activities from nonspecific to lymphoproliferative disorders. A lymphoproliferative syndrome associated with EBV can occur and treatment for that is actually donor lymphocytes. Adenovirus is an important infection both in solid organ as well as allogeneic and autologous bone marrow transplantation. It occurs often as well in patients undergoing liver transplantation and has a high degree of morbidity.

Toxoplasma, Hepatitis B, C, HIV) -

Intraoperative course (especially ischemia, duration)

-

Post-transplant immunosuppression - use of steroids vs cyclosporine, tacrolimus (FK 506)

-

Prolonged use of catheters

-

Nosocomial exposures and infection

86

Special Considerations in Solid-organ Transplant Patients

Early Period (0-1

Middle Period (1-6

Late Period (> 6

Month)

Month)

Months)

Bacterial Infectious

Viral Infections

Viral infections

Grim negatives

CMV (especially

EBV

Pseudomonas

seronegative recipient

VZV

(especially CF)

from + donor

Community-acquired

Gram positives

EBV

Bacteria

Fungal Infections

VZV

Pseudomonas (CF)

Viral infections

P. carinii pneumonia

Gram negatives

HSV

Toxoplasmosis (espe-

(small bowel trans-

Respiratory

cially heart)

plant)

Bacteria

Fungal

Pseudomonas (CF)

Aspergillus (lung with

Gram negatives (small

chronic rejection

bowel tx)

87

Special Considerations in Solid-organ Transplant Patients

•

Bacterial and Fungal Infections -

Renal Transplants: Septicemia and Pyelonephritis is common. Pneumonia occurs in 10-25%

-

Liver Transplants: Enteric organism account for 50%. Ascending cholangitis is a common infection

•

Intestine: Bacterial infections appear to be common

Bacterial and Fungal Infections -

Heart Transplants: Infections account for 20% of acute and 40% of late deaths.

•

-

Respiratory tract is most common site

-

Mediastinitis can be a problem

-

Staph and gram negatives are problematic

Heart-Lung Transplants -

Pneumonia is most common site of infection, especially with gram negatives. Can be difficult to distinguish from rejection.

-

Particular problem with CF patients

88

Special Considerations in Solid-organ Transplant Patients

•

Viral Infections -

CMV is most common

-

Typically acquired from donor organ reactivation refection; tends to be less severe

-

Symptoms manifest at 1-3 months and include fever, hematologic abnormalities

-

Can include disseminated infection with visceral involvement

-

Culture and histological findings can be important in diagnosis

-

EBV can have a broad range of disease from nonspecific to lymphoproliferation and lymphoma. Incidence of EBV lymphoproliferation may be 20% by 7 years after liver transplantation - however, this may become altered with immunosuppressive regimen.

-

Adenovirus follows 10% of liver transplants (nonspecific to GI symptoms, cystitis or necrotizing hepatitis/pneumonitis)

89

Infection Prevention Strategies

•

Antibiotic Prophylaxis -

Oral nonabsorbable antibiotics

-

Selective decontamination

Prophylaxis. It is going to be recommended that Trimethoprim sulfa be restricted to Pneumocystis prophylaxis. They are not being employed for broad bacterial prophylaxis. Empirical therapy should be avoided and absolutely avoided for heparin solutions to try to prevent bacterial infections. Fluconazole can be used and employed successfully in patients undergoing bone marrow transplantations, but the data is restricted to employing it in other settings. An antibacterial regimen is initiated around the time of the transplantation, and particularly ganciclovir for CMV and trimethoprim sulfa for Pneumocystis.

# Trimethoprim-sulfamethoxazole # Quinolones # Antifungal prophylaxis

•

-

Antiviral prophylaxis

-

Antiparasitic prophylaxis

IDSA recommendations -

Trimethoprim/sulfa: Indicated for P. carinii prophylaxis

-

Quinolones: Not recommended for routine prophylaxis because of increasing resistance

-

Vancomycin strongly discouraged

-

Fluconazole - may have some efficacy in bone marrow transplant patients - but not recommended for routine use

90

Prophylaxis after Solid Organ Transplant Pittsburgh Children's Regimen

Regi-

Kidney

Liver

Heart

Lung

Intestine

Cefazolin

Amp+

Cefazolin

Clinda+

Amp+

Ceftaz

cefo

Ganc

Ganc

men Periopera-

Cefo

tive CMV

Ganc

Ganc

Ganc

MG P. ca-

T/S

T/S

T/S

T/S

T/S

rinii

91

Prevention Strategies

•

Strategies for Improving Host Defenses -

Cytokines and Immunomodulating agents

-

Active and Passive Immunization

-

#

Immunoglobulins

#

Monoclonal antibodies

Combination Therapy

92

Biologicals in the Clinic

•

Hematopoietic cytokines - Colony Stimulating Factors (GM, G, M-CSF and SCF)

•

Interleukins (IL-1, I L-2, IL-3, IL-6, IL-11, IL-12)

•

Tumor necrosis factor

•

Immunization (active and passive)

93

ASCO Clinical Practice Guidelines for Colony Stimulating Factors

•

Colony Stimulating Factors are recommended to -

Reduce likelihood of febrile neutropenia when expected incidence is >40%

-

After episode of fever and neutropenia in prior cycle when the intent is to not reduce dose-intensity.

•

After high-dose therapy with autologous bone marrow

Not clearly recommended -

At the onset of fever and neutropenia unless high likelihood for septic complications

-

Use in AML should be with caution

-

CSFs should not be used concurrently with chemotherapy or radiation, or to support increasing close intensity

94

Is There a Value to Cell Replacement Therapy?

•

Neutrophil transfusions -

Impact on children with CGD

-

Lack of impact on patients with neutropenia

95

Biologicals: Indications

•

Who should receive biologicals -

Not for low-risk patients

-

Appropriate for high-risk patients when there is a potential for benefit based on ASCO guidelines

-

Role as an adjunct to the management of fever and neutropenia is not established

-

Role for documented infections is not yet established

96

97