**6. Zygomycosis**

166 Immunodeficiency

**Figure 3.** Grocott's methenamine silver (GMS) stained tissue section of lung showing fungal balls of

Diagnostic criteria for ABPA in persons with CF were revised by the Cystic Fibrosis Foundation. ABPA is considered a definite diagnosis requiring treatment if the following are noted: (1) clinical deterioration, including cough, wheeze, increased sputum production, diminished exercise tolerance, or diminished pulmonary function; (2) total serum IgE level greater than 1000 IU/mL or a greater than 2-fold rise from baseline; (3) positive serology results for *Aspergillus* (*Aspergillus* precipitins or *Aspergillus* -specific IgG or IgE); and (4) new infiltrates on chest radiographs or CT scans. Treatment for ABPA is also recommended in patients with CF who have new radiographic findings and symptoms and a change in

Definitive diagnosis of invasive aspergillosis or chronic necrotizing *Aspergillus* pneumonia

In the appropriate clinical setting of pulmonary infiltrates in a patient who is neutropenic or immunosuppressed, visualization of the characteristic fungi using Gomori methenamine silver stain or Calcofluor or a positive culture result from sputum, needle biopsy, or bronchoalveolar lavage (BAL) fluid should result in the prompt institution of therapy. This is especially important after bone marrow transplantation because a positive *Aspergillus* culture result from sputum has a 95% positive predictive value for invasive disease. However, a negative fungus result from culture of sputum or BAL fluid does not exclude pulmonary aspergillosis because *Aspergillus* is cultured from sputum in 8-34% of patients and from BAL fluid in 45-62% of patients eventually found by biopsy or autopsy to have

An assay to detect galactomannan, a major component of the *Aspergillus* cell wall, is available. Patients who are at high risk, such as those who have received stem cell transplants or who have prolonged neutropenia, may be screened for the development of invasive *Aspergillus* infection by monitoring serum galactomannan levels weekly.The presence of an elevated galactomannan level in BAL fluid may also be helpful in the diagnosis of pulmonary aspergillosis in patients in whom compatible radiographic changes

hyphae of *Aspergillus fumigatus.* (Courtesy: www.mycology.adelaide.edu.au)

baseline IgE level to greater than 500 IU/mL [79].

invasive disease [80].

depends on the demonstration of the organism in tissue [76].

Zygomycosis is an infection caused by fungi in the orders Mucorales and Entomophthorales. The Mucorales order contains 2 families exist—Mucoraceae and Cunninghamellaceae. Mucormycosis is another common name applied to this same group of diseases. This designation reflected the predominance of the Mucorales in causing disease in humans. However, this term ignored the role of the Entomophthorales (*Conidiobolus* species and *Basidiobolus* species). The currently accepted designation is zygomycosis, reflecting all disease processes caused by the members of the class Zygomycetes. During the past decade, the Zygomycetes have emerged as common causes of invasive fungal infections [87].

The pathogens that cause zygomycosis are commonly found in the environment on fruit, on bread, and in soil and are common components of decaying organic debris. These organisms are ubiquitous and generally saprophytic, rarely causing disease in immunocompetent hosts, but they are the third-most-common cause of invasive fungal infection in immunocompromised patients, especially stem cell transplant recipients and patients with underlying hematologic malignancies [88].

Fungal Infections in Immunosuppressed Patients 169

• Stem cell transplantation

• Solid organ transplants

• Severe and prolonged neutropenia

• Metabolic acidosis • Deferoxamine therapy

• Intravenous drug use

• Penetrating trauma (rare)

disease and save more lives.

• Steroid use

• Renal failure • Peritoneal dialysis

• Burns

benefit [93].

**7. Conclusion** 

• Poorly controlled diabetes mellitus, either type 1 or type 2 • Hematologic malignancy (eg, leukemias, lymphomas)

Unfortunately, findings from laboratory studies are nonspecific for zygomycosis. Diagnosis requires a high index of suspicion, a host with appropriate risk factors, and evidence of tissue invasion with the characteristic appearance of broad nonseptate hyphae with right-angle branches. No serologic tests are available, and blood cultures are of no

Opportunistic fungal infections of the body which occur almost exclusively in debilitated patients whose normal defence mechanisms are impaired. The organisms involved are cosmopolitan fungi which have a very low inherent virulence. The increased incidence of these infections and the diversity of fungi causing them, has paralleled the emergence of Acquired Immune Deficiency Syndrome (AIDS), more aggressive cancer and posttransplantation chemotherapy and the use of antibiotics, cytotoxins, immunosuppressives, corticosteroids and other macro disruptive procedures that result in lowered resistance of the host allowing fungi to invade tissues and produce pathological changes that can cause death. Compromised immunity is the most important predisposing factor for clinically significant fungal infections. Neutrophil deficiency as a result of bone marrow suppression or damage is frequently associated with such infections. Different fungi infect humans and may live in extracellular tissues and within phagocytes. Therefore, the immune responses to these microbes are often combinations of the responses to extracellular and intracellular bacteria. However, less is known about antifungal immunity than about immunity against bacteria and viruses. This lack of knowledge is partly due to the paucity of animal models for mycoses and partly due to the fact that these infections typically occur in individuals who are incapable of mounting effective immune responses. Improved diagnostic methods have been developed for an early diagnostic of opportunistic mycosis in order to control the

Fungi are ubiquitous in the natural world, often found in association with plants, mammals, and insects. Accordingly, humans are continually exposed to multiple genera of fungi via various routes, including the respiratory and gastrointestinal routes, which allow the possibility of colonization. Depending on the interaction between host mucosal defense mechanisms and fungal virulence factors, colonization may be transient or persistent, or local disease may ensue [89].

Overall, *Rhizopus* species from the Mucoraceae family are the most commonly identified etiologic agents of zygomycosis in humans. Of the *Rhizopus* species, the most common agent associated with zygomycosis is *Rhizopus arrhizus* (*Rhizopus oryzae*), followed by *Rhizopus rhizopodiformis*. Other causes include *Mucor* species, *Cunninghamella bertholletiae, Apophysomyces elegans, Absidia* species, *Saksenaea* species, *Rhizomucor pusillus, Entomophthora* species, *Conidiobolus* species, and *Basidiobolus* species [90].

Zygomycosis caused by *R arrhizus* is acute and rapidly fatal despite early diagnosis and treatment. These organisms have a particular predilection for invading major blood vessels, with ensuing ischemia, necrosis, and infarction of adjacent tissues, resulting in the production of black pus. Persons at particular risk include those with granulocytopenia and acidosis. For unknown reasons, the Zygomycetes have a propensity to affect patients with acidosis, particularly those with diabetes. They also infect patients with acidosis secondary to renal insufficiency, diarrhea, and aspirin intake. Patients who are receiving glucocorticoids or deferoxamine and those who have undergone splenectomy also are at risk [90].

The overall mortality rate associated with zygomycosis is approximately 50% and has remained at this level for the past 50 years. Rhinocerebral zygomycosis carries a mortality rate of approximately 85%. Mortality rates are very high because, by the time zygomycosis is suspected and diagnosed, it has frequently spread diffusely and caused extensive tissue destruction. However, the risk of mortality varies depending on the characteristics of the host, the type of infection, the site of infection, and the use of surgical intervention. In general, antifungal therapy and surgical management independently decrease the likelihood of death [91].

Zygomycosis manifests as a spectrum of diseases, depending on the portal of entry and the predisposing risk factors of the patient. The 5 major clinical forms include rhinocerebral zygomycosis, pulmonary zygomycosis, abdominopelvic and gastric (gastrointestinal) zygomycosis, primary cutaneous zygomycosis, and disseminated zygomycosis [91].

Most persons who develop zygomycosis are immunocompromised, although 15-20% of patients have no evidence of any underlying condition at the time of the diagnosis.Thus, sporadic cases in immunocompetent hosts are not uncommon. The most common risk factors include the following [91, 92] :


risk [90].

of death [91].

factors include the following [91, 92] :

underlying hematologic malignancies [88].

species, *Conidiobolus* species, and *Basidiobolus* species [90].

local disease may ensue [89].

immunocompromised patients, especially stem cell transplant recipients and patients with

Fungi are ubiquitous in the natural world, often found in association with plants, mammals, and insects. Accordingly, humans are continually exposed to multiple genera of fungi via various routes, including the respiratory and gastrointestinal routes, which allow the possibility of colonization. Depending on the interaction between host mucosal defense mechanisms and fungal virulence factors, colonization may be transient or persistent, or

Overall, *Rhizopus* species from the Mucoraceae family are the most commonly identified etiologic agents of zygomycosis in humans. Of the *Rhizopus* species, the most common agent associated with zygomycosis is *Rhizopus arrhizus* (*Rhizopus oryzae*), followed by *Rhizopus rhizopodiformis*. Other causes include *Mucor* species, *Cunninghamella bertholletiae, Apophysomyces elegans, Absidia* species, *Saksenaea* species, *Rhizomucor pusillus, Entomophthora*

Zygomycosis caused by *R arrhizus* is acute and rapidly fatal despite early diagnosis and treatment. These organisms have a particular predilection for invading major blood vessels, with ensuing ischemia, necrosis, and infarction of adjacent tissues, resulting in the production of black pus. Persons at particular risk include those with granulocytopenia and acidosis. For unknown reasons, the Zygomycetes have a propensity to affect patients with acidosis, particularly those with diabetes. They also infect patients with acidosis secondary to renal insufficiency, diarrhea, and aspirin intake. Patients who are receiving glucocorticoids or deferoxamine and those who have undergone splenectomy also are at

The overall mortality rate associated with zygomycosis is approximately 50% and has remained at this level for the past 50 years. Rhinocerebral zygomycosis carries a mortality rate of approximately 85%. Mortality rates are very high because, by the time zygomycosis is suspected and diagnosed, it has frequently spread diffusely and caused extensive tissue destruction. However, the risk of mortality varies depending on the characteristics of the host, the type of infection, the site of infection, and the use of surgical intervention. In general, antifungal therapy and surgical management independently decrease the likelihood

Zygomycosis manifests as a spectrum of diseases, depending on the portal of entry and the predisposing risk factors of the patient. The 5 major clinical forms include rhinocerebral zygomycosis, pulmonary zygomycosis, abdominopelvic and gastric (gastrointestinal)

Most persons who develop zygomycosis are immunocompromised, although 15-20% of patients have no evidence of any underlying condition at the time of the diagnosis.Thus, sporadic cases in immunocompetent hosts are not uncommon. The most common risk

zygomycosis, primary cutaneous zygomycosis, and disseminated zygomycosis [91].


Unfortunately, findings from laboratory studies are nonspecific for zygomycosis. Diagnosis requires a high index of suspicion, a host with appropriate risk factors, and evidence of tissue invasion with the characteristic appearance of broad nonseptate hyphae with right-angle branches. No serologic tests are available, and blood cultures are of no benefit [93].

#### **7. Conclusion**

Opportunistic fungal infections of the body which occur almost exclusively in debilitated patients whose normal defence mechanisms are impaired. The organisms involved are cosmopolitan fungi which have a very low inherent virulence. The increased incidence of these infections and the diversity of fungi causing them, has paralleled the emergence of Acquired Immune Deficiency Syndrome (AIDS), more aggressive cancer and posttransplantation chemotherapy and the use of antibiotics, cytotoxins, immunosuppressives, corticosteroids and other macro disruptive procedures that result in lowered resistance of the host allowing fungi to invade tissues and produce pathological changes that can cause death. Compromised immunity is the most important predisposing factor for clinically significant fungal infections. Neutrophil deficiency as a result of bone marrow suppression or damage is frequently associated with such infections. Different fungi infect humans and may live in extracellular tissues and within phagocytes. Therefore, the immune responses to these microbes are often combinations of the responses to extracellular and intracellular bacteria. However, less is known about antifungal immunity than about immunity against bacteria and viruses. This lack of knowledge is partly due to the paucity of animal models for mycoses and partly due to the fact that these infections typically occur in individuals who are incapable of mounting effective immune responses. Improved diagnostic methods have been developed for an early diagnostic of opportunistic mycosis in order to control the disease and save more lives.
