INFECTIOUS DISEASE BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

VIDEO LECTURE

 

MYCOLOGY - CHAPTER SEVEN 

OPPORTUNISTIC MYCOSES  

Dr Art DiSalvo

 

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Opportunistic mycoses are infections due to fungi with low inherent virulence which means that these pathogens constitute an almost limitless number of fungi.  These organisms are common in all environments.  

The disease equation: 

Number of organisms  x  Virulence  = Disease  

Host resistance  

With opportunistic infections, the equation is tilted in favor of "disease" because resistance is lowered when the host is immunocompromised. In fact, for the immunocompromised host, there is no such thing as a non-pathogenic fungus.

The fungi most frequently isolated from immunocompromised patients are saprophytic (i.e. from the environment) or endogenous (a commensal).  The most common species are Candida species, Aspergillus species, and Mucor species.

The upward trend in the diagnoses of opportunistic mycoses reflects increasing clinical awareness by physicians, improved clinical diagnostic procedures and better laboratory identification techniques. Another important factor contributing to the increasing incidence of infections by fungi that have not been previously known to be pathogenic has been the rise in the number of immunocompromised patients who are susceptible hosts for the most uncommon agents. Patients with primary immunodeficiencies are susceptible to mycotic infections particularly when cell-mediated immunity is compromised. In addition, several types of secondary immunodeficiencies may be associated with an increased frequency of fungal infections.

When a fungus is isolated from an immunocompromised patient, the attending physician has to distinguish between: 

  • Colonization (which is of no major concern)

  • Transient fungemia (often involving C. albicans

  • Systemic infection. 

A great deal of clinical judgment is required to reach these conclusions, which imply important therapeutic decisions.  

The diagnosis of opportunistic infections requires a high index of suspicion.  Without this curiosity, the clinician may not consider mycotic infections in the compromised patient because:  

  • Patients present with atypical signs and symptoms

  • Unusual histopathology

  • The fungus may have an unusual organ affinity

  • The etiological agent may be considered a saprophyte or contaminant

  • The systemic mycoses may occur outside the known endemic area

  • The serologic response may be suppressed

Causes of immunodeficiency commonly encountered are:  

  • Malignancies (Leukemias, lymphomas, Hodgkin's Disease).
    In one study of cancer patients, fungal septicemia and pneumonias accounted for almost a third of deaths.  

  • Drug therapies.  Anti-neoplastic substances, steroids, immunosuppressive drugs.

  • Antibiotics. Over-use or inappropriate use of antibiotics can also contribute to the development of fungal infections by altering the normal flora of the host and facilitating fungal overgrowth or by selecting for resistant organisms.

Therapeutic procedures can predispose for fungal infections:    

  • Solid Organ and Bone Marrow transplantation  

  • Open heart surgery

  •  Indwelling catheters (urinary, I.V. drugs or parenteral hyperalimentation).  In cases of fungemia, the contaminated catheter must  be removed before starting anti-fungal therapy.

  • Artificial heart valves can be colonized by a variety of infectious agents, including Candida species. In a case of infection of an artificial heart valve, antifungal treatment is only efficient if the infected valve is replaced.

  • Radiation therapy.  

 

 

Other factors associated with increased frequency of mycotic infections are:

  •  Severe burns  

  •  Diabetes  

  • Tuberculosis  

  •  I.V. drug use  

  • AIDS.    Virtually all AIDS patients will have a fungal infection sometime during the course of disease.  

Certain fungi may be frequently associated with some of the predisposing factors listed above. However, any one of the ubiquitous saprophytes (most of which do not cause disease in immunocompetent hosts) as well as occasional pathogens may cause disease in these patients.  

biofilm1.jpg (82985 bytes)  Figure 1.
A biofilm consisting of various bacteria (b) and yeast (y) strains colonizing an indwelling, silicone rubber voice prothesis after being placed for 3 to 4 months in a laryngectomized patient. The image was taken by scanning electron microscopy. Scale bar: 5 m.
Henny C. van der Mei, E.P.J.M. Everaert, H. J. Busscher. University of Groningen and the MicrobeLibrary
 

Biofilm Formation

It has long been recognized that in patients with a microbial infection, any artificial device  such as an indwelling catheter or prosthetic valve, must be removed before antibiotic therapy is effective.  The foreign body will act as a nidus, seeding the infection if it remains present.  The exact mechanism is not clear.  A biofilm is a microcolony of organisms which adhere to a surface (catheter, implant, or dead tissue) and which resist removal by fluid movement and have a decreased susceptibility to antimicrobials (figure 1).  This biofilm phenomenon, which occurs on the rocks in a stream, was first recognized as a public health problem in water pipes and was regarded as a source of coliform  contamination of drinking water.  Recent work in clinical microbiology has shown that these organisms develop a resistance to therapy because they are contained in a matrix which acts like a tissue to and becomes a barrier to antibodies, macrophages and antimicrobial agents.

Candida species readily form biofilms and are the most prevalent organism isolated from catheters.
 

 

malassezia.jpg (61660 bytes)  Figure 2
Scanning Electron Micrograph of Malassezia furfur
CDC/Janice Carr

tinea versicolor.jpg (50788 bytes)  Figure 3
Tinea Versicolor on chest.

CDC/Dr. Gavin Hart

oralthrush.jpg (76389 bytes) Figure 4
 Oral thrush. Aphthae. Candida albicans.
CDC

CLINICAL PRESENTATION  

In immunosuppressed patients, common fungal infections may have an unusual presentation because of:

  • Atypical signs and lesions.    
    Malassezia furfur (Figure 2) usually causes a rather benign and self-limited disease in normal hosts (Tinea versicolor) (figure 3), but in immunocompromised patients may show a rash with disseminated disease and sepsis.  This organism requires long-chain fatty acids for growth.  Patients receiving parenteral fat emulsions for nutrition become a walking petri plate. 

     

  • Unusual Organ affinity.  
    Candida (figure 5) may invade liver, heart valves; Oral thrush (figure 4) occurs in people who are relatively immunocompetent while esophageal candidiasis occurs in those patients who are immunologically compromised.  Cryptococcus may cause pulmonary, cutaneous and cardiac (figure 5A) infections.  
     

  • Infections with systemic dimorphic fungi occurring outside endemic areas. These factors complicate the diagnosis and management of these diseases.
     

  • Unusual Histopathology.  
    Even the inflammatory reaction may be different in biopsy specimens.  The normal host reaction to fungal invasion is usually pyogenic or granulomatous.  In the immunodeficient host, the inflammatory reaction is necrotic.  

 

 

candidaalbicans.jpg (29923 bytes)  Figure 5
Candida albicans showing germ tube production in serum. Gram stain.
CDC/Dr. Lucille K. Georg

Figure 5A
Cryptococcus: Cardiac infection
Dr Arthur DiSalvo

 

cryptococcus.jpg (92906 bytes)  Figure 6.
Histopathology of lung shows widened alveolar septum containing a few inflammatory cells and numerous yeasts of Cryptococcus neoformans. The inner layer of
the yeast capsule stains red.
CDC/Dr. Edwin P. Ewing, Jr.

coccidio1.jpg (48932 bytes) Figure 7.
 Histopathology of coccidioidomycosis of lung showing spherule with endospores of Coccidioides immitis. FA stain. Endospores, not spherule wall, are stained
CDC

coccidio2.jpg (42009 bytes)  Figure 8.
Bar graph showing reported cases of coccidioidomycosis in California by year, 1986-1992. Epidemiology, surveillance.
CDC

histo1.jpg (44102 bytes)  Figure 9.
Histiocyte containing numerous yeast cells of Histoplasma capsulatum. Tissue smear, Giemsa stain  CDC

histo2.jpg (38268 bytes) Figure 10.
Computed tomography scan of lungs showing classic snowstorm appearance of acute histoplasmosis CDC

blasto1.jpg (48328 bytes)  Figure 11.
Smear from foot lesion of blastomycosis showing Blastomyces dermatitidis yeast cell undergoing broad-base budding. 
ASCP/Atlas of Clinical Mycology II / CDC

 

Examples of variations from standard fungal clinical presentation, diagnosis and treatment

  •    Cryptococcosis  (figure 6)

Studies show that from 10 % to 30 % of AIDS patients have cryptococcal meningitis and they will require maintenance therapy with fluconazole for the remainder of their life.  Fluconazole penetrates the cerebro-spinal fluid

Mortality:         

Without treatment            100% 
With treatment                  20%

Relapse :        

Non-AIDS patients  15-20%
AIDS patients               50%

With relapse there is 60% mortality.

 

  • Sporotrichosis

Co-infection with other fungi is frequent  

  • Coccidioidomycosis   (figure 7 and 8)

Mycelial forms seen in tissue. Occurs in patients outside the endemic area. Patients require fluconazole or itraconazole maintenance therapy.
  

  • Histoplasmosis (figure 9 and 10)

All cases are disseminated.  
Relapse rate is > 50%
  and the infection is rapidly fatal in 10% of patients. It occurs in patients outside the endemic area and they require fluconazole or  itraconazole maintenance therapy  

  • Blastomycosis (figure 11)

More frequently disseminated.  All patients have done very poorly.  

There has been one report on 15 cases of blastomycosis in AIDS patients.  Six patients (40%) had CNS involvement.  Usually CNS disease only occurs in 3-10% of the patients.

  •   Aspergillosis

Mortality: 

With amphotericin B              72% 
Without amphotericin B          90%      

  • Penicillium marneffei

This is a dimorphic fungus that produces a red pigment and reproduces by fission.  It requires amphotericin B therapy and oral itraconazole maintenance.

  •   Pneumocystis carinii (now renamed Pneumocystis jiroveci)  (figure 12)

  This was formerly thought to be a protozoan.  Presently it is believed to be a fungus.  

 

pneumocyst.jpg (29590 bytes) Figure 12.
 Pneumocystis jiroveci is an important cause of opportunistic respiratory tract infections in immunocompromised patients, particularly AIDS patients. This
image depicts P. jiroveci from bronchial washings of an AIDS patient. Mouse monoclonal antibodies against P. jiroveci are labeled with a fluorescent tag.  The labeled Pneumocystis organisms fluoresce bright apple green against a red background.  
  Lewis Tomalty, Gloria J. Delisle Queens University, Ontario and the MicrobeLibrary


  P. marneffei is endemic to Southeast Asia, where it is one of the more common HIV-related opportunistic infections.
Dr Art DiSalvo

pneu1.jpg (48209 bytes)  Cysts of Pneumocystis jiroveci in smear from bronchoalveolar lavage. Methenamine silver stain.
Dr. Russell K. Brynes/CDC

pneu2.jpg (120076 bytes) 
Histopathology of lung shows alveolar spaces containing exudates characteristic of infection with Pneumocystis carinii  CDC/Dr. Edwin P. Ewing, Jr.

   

Some common associations between fungal organisms and disease conditions

Cryptococcus neoformans   Candida albicans   Candida (Torulopsis) glabrata   Zygomycetes   Aspergillus species  
Diabetes mellitus Prolonged antibiotic therapy Cytotoxic drugs Diabetes mellitus Leukemias
Tuberculosis Prolonged intravenous catheters Immunosuppression Leukemias Corticosteroid therapy
Lymphoma Prolonged urinary catheters Diabetes mellitus Corticosteroid therapy Tuberculosis
Hodgkin's disease Corticosteroid therapy Hyperalimentation Intravenous therapy

Immunosuppression

 

Corticosteroid therapy Diabetes mellitus Intravenous catheters Severe burns I.V. drug abuse
Immunosuppression Hyperalimentation      
  Immunosuppression      

 

 

 

"Only the prepared mind can help the impaired host."  Dr. Libero Ajello, Opportunistic Fungal Infections.  Proceedings of the Second International Conference. Charles C.Thomas, 1975.  P. 31-35.

 

 

 

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