Current Diagnosis & Treatment in Infectious Diseases

Section VI - Histoplasma Capsulatum

77. Fusarium, Penicillium, Paracoccidioides, & Agents of Chromomycosis

Michael R. Keating MD

FUSARIUM INFECTION

Essentials of Diagnosis

  • Worldwide geographic distribution.
  • Mold, septate hyphae 3–8 µm in diameter.
  • A rare infection in severely immunocompromised patients.
  • Blood cultures often but not always positive.
  • No serologic tests available.
  • Cutaneous involvement is common feature.

General Considerations

  1. Epidemiology.Fusariumspp. is an emerging fungal pathogen. Although long recognized as a cause of local infection involving nails, traumatized skin, or the cornea (eg, in contact lens wearers), deep or disseminated infection was not described until the mid 1970s. Despite its worldwide distribution and its frequent recovery from soil and vegetative material, infection is quite rare. Only ~ 100 cases involving invasive disease in immunosuppressed patients have been described in the medical literature.

Most cases of serious disease occur in patients with hematologic malignancy and chemotherapy-induced neutropenia. Profound neutropenia and prolonged neutropenia increase the risk for infection. The respiratory tract is the most common portal of entry leading to infection, but other sites of acquisition include a disrupted skin barrier, the digestive tract, and a central venous catheter. Fusarium onychomycosis also appears to be a potential source of disseminated infection in at-risk patients.

  1. Microbiology.Fusariumspp. are filamentous fungi that are soil saprophytes and plant pathogens. The hyphae range in size from 3 to 8 µm and are generally septate. Growth from clinical specimens usually occurs after 4–5 days of incubation in the laboratory (Figure 77-1). Dichotomous branching is common, and branches usually occur at an angle of 45°. Consequently, Fusarium spp. are indistinguishable from Aspergillus spp. (see Chapter 75) when seen in tissue. Although there are many different species, human disease appears to be limited to F oxysporum, F solani, F moniliformie, and F proliferatum. Like other filamentous fungi, the different Fusarium spp. may be identified by the distinguishing characteristics of their fruiting bodies and microconidia.
  2. Pathogenesis.The clinical pathogenic pattern of infection caused by Fusariumspp. is very similar to that of Aspergillus infection. Although much rarer than invasive aspergillosis, the same pathogenic mechanisms that allow A conidia to invade tissue contribute to the development of Fusarium infection. Alteration in macrophage function by steroid therapy and neutropenia allow the Fusarium microconidia to replicate unimpaired in host tissue. Angioinvasion leads to early dissemination particularly to skin structures. The reason for the marked propensity to disseminate to skin is unknown. Colonization with Fusarium spp. without infection is common, particularly among burn patients.

Clinical Findings

  1. Signs and Symptoms.Invasive fusariosis usually develops with the abrupt onset of high spiking fevers (Box 77-1). Although myalgias are a common feature, infection of muscle is uncommon but has been reported. Focal symptoms may depend on the site of infection. Shortness of breath, cough, and hemoptysis are present in patients with pulmonary involvement. Central venous catheter infection may be associated with tunnel tract tenderness or exudation.

Physical findings are also dependent on the extent of invasive disease and sites of dissemination. Almost 80% of patients will have cutaneous involvement. Typically, this will begin as a erythematous indurated maculopapular lesion, which will enlarge and eventually ulcerate, leaving a nodular lesion with a necrotic, often black center (Figure 77-2). Multiple lesions are commonly seen and may resemble ecthyma gangrenosum. Localization to the extremities is most common. Primary cutaneous fusariosis may present with a single necrotic skin lesion. Multiple skin lesions suggest disseminated disease. A rhinocerebral form of infection has been described that is indistinguishable from rhinocerebral mucormycosis or aspergillosis.

  1. Laboratory Findings.Neutropenia is usually present at the onset of the signs and symptoms of infection, but there are no other commonly associated hematologic or chemistry abnormalities. Blood cultures are positive in 60% of patients with invasive fusariosis, which is in marked distinction to invasive aspergillosis, where blood cultures are negative. The reason for this difference is unknown. There are no serological tests available for diagnosing Fusarium infection.
 

Figure 77-1. Laboratory specimen of Fusarium spp. showing characteristic hyphae elements and typical spindle-shaped fruiting bodies (×800).

  1. Imaging.The chest roentgenogram in a patient with pulmonary involvement may show nonspecific infiltrates, nodular lesions, or cavitary lesions. With rhinocerebral infection, opacification of one or all the sinus cavities and destruction of bony structures can best be imaged with computed tomography. A bone scan may be helpful to determine if there is bone involvement underlying extensive cutaneous involvement.
  2. Differential Diagnosis.In addition to invasive fusariosis, the differential diagnosis of persistent neutropenic fever includes invasive aspergillosis and other infection with opportunistic filamentous fungi. Although Candida, Aspergillus, and Rhizopusspp. are all capable of causing similar skin lesions in disseminated invasive disease, Fusarium spp. are the most likely of these organisms to do this. Histologically and clinically, fusariosis resembles invasive aspergillosis and infection due to Pseudoallescheria boydii (see Chapter 75).
 

Figure 77-2. Photograph of a typical cutaneous lesion of Fusarium infection on the scalp of a neutropenic patient after allogeneic bone marrow transplantation.

  1. Complications.Widespread or metastatic cutaneous involvement can develop from a single primary focus of infection. Disseminated disease may involve the heart, liver, kidneys, spleen, brain, and other vital organs.

BOX 77-1 Fusariosis in Adults and Children

More Common

· High fever, acute onset

· Myalgias

· Shortness of breath, hemoptysis, cough

· Cutaneous involvement

· Positive blood culture

Less Common

· Rhinocerebral infection

· Central nervous system involvement

· Intra-abdominal organ involvement

Diagnosis

The diagnosis is confirmed by the recovery of Fusarium isolates from blood or biopsy specimens. Skin lesions developing in the setting of new fever in a neutropenic patient should be biopsied for histopathology and culture. The recovery of Fusarium spp. from sputum can suggest the diagnosis in the appropriate host with a syndrome compatible with invasive fusariosis; however, colonization of the respiratory tract can occur with this organism.

Treatment

Amphotericin B is the treatment of choice (Box 77-2). Response to therapy is usually poor, and in vitro susceptibility testing suggests that more than half of the strains tested are resistant to amphotericin B. It is unknown if the lipid preparations of amphotericin B offer any therapeutic advantage, but patients have been successfully treated with lipid preparations of amphotericin B. The use of granulocyte colony stimulating factors and granulocyte transfusions has been reported to be effective in some patients. Fusarium spp. are uniformly resistant to 5-flucytosine. The role of treatment with azoles is unknown. The most important factor contributing to successful treatment is recovery of neutropenia.

Prognosis

Invasive fusariosis is a lethal disease. The overall mortality rate according to the medical literature is > 70%.

BOX 77-2 Treatment of Fusariosis in Adults and Children

First Choice

Amphotericin B, 1–1.5 mg/kg/d until neutropenia resolved and full response

Second Choice

Lipid preparation of amphotericin B (dose dependent on specific preparation)

Comment

· Treatment with granulocyte colony stimulating factor and granulocyte transfusion should be considered

· Many strains are amphotericin B resistant

· Recovery of neutropenia is critical

 

Prevention & Control

Because the skin and nails are potential portals of entry, before chemotherapy-induced neutropenia, patients with significant onychomycosis should be evaluated by a dermatologist for Fusarium infection (Box 77-3). Futhermore, high-risk neutropenic patients with skin trauma and contamination should be carefully examined for potential inoculation with Fusarium spp. This may need to include biopsy and culture.

PENICILLIUM INFECTIONS

Essentials of Diagnosis

  • Penicillium marneffeiinfection found in both immunocompetent and immunosuppressed patients.
  • P marneffeifound in Southeast Asia and southern China.
  • Mold, septate hyphae 1.5–5 µm in diameter.
  • May be cultured from a variety of specimens including blood.
  • Penicilliumspp. other than P marneffei occur worldwide.
  • Infection with Penicilliumspp. is rare; occurs in immunosuppressed patients.

BOX 77-3 Control of Fusariosis

Prophylactic Measures

· Evaluate patients with significant onychomycosis for fusarium infection prior to chemotherapy

· High-risk patients with skin trauma and contamination should be examined for inoculation with Fusarium spp.

Isolation Precautions

None

General Considerations

  1. Epidemiology.Penicilliumspp. are ubiquitous in nature and may be recovered with ease from a variety of sources within the hospital environment. These molds commonly contaminate clinical specimens and cause contamination in the laboratory. Colonization of nonsterile anatomical sites in humans is common. In most cases where Penicillium spp. are recovered from clinical specimens, they represent colonization. Nevertheless, colonization must be distinguished from the possibility of invasive disease.

Unique among the Penicillium spp., P marneffei is an endemic mycosis that is found in Southeast Asia and southern China. Most of the cases in the world literature have been reported from these areas; however, an increasing number of cases have been reported among individuals, particularly those with AIDS, who have traveled to or resided in the endemic parts of Southeast Asia and southern China. In Thailand, penicilliosis is the third most common opportunistic infection in patients with AIDS. Little is known about the environmental reservoir of P marneffei. Infection is acquired via inhalation, inoculation of the skin, and possibly ingestion. Person-to-person transmission does not occur. There is a marked predominance of male cases (~ 90%).

  1. Microbiology.Penicilliumspp. are among the most common filamentous fungi found in nature. These blue-green molds grow rapidly in the mycology laboratory and produce fine septate hyphae with 1.5–5 µm wide elements. In tissue specimens, the mycelial elements are somewhat larger at 15–20 µm in width and exhibit branching at ~ 45° angles. One of the Penicillium spp., P marneffei, is unique because of its dimorphic characteristic. In tissue specimens, it grows as a small yeast cell that resembles Histoplasma capsulatum. In the laboratory, P marneffei will grow as a mold with hyphal characteristics similar to the other Penicillium spp. The species may be distinguished by their characteristic conidia forms. Except for P marneffei, the Penicillium spp. are rarely speciated by mycology laboratories.
  2. Pathogenesis.Infection caused by Penicilliumspp. other than P marneffei occurs almost exclusively among profoundly immunosuppressed patients and is exceedingly rare. Penicillium spp. lack the necessary virulence factors to commonly cause human infection, and only in the setting of extreme immunodeficient states can invasive infection occur.

In contrast, P marneffei is capable of causing infection in both immunocompetent and immunocompromised patients. In immunocompetent patients, P marneffei infection may resemble histoplasmosis with a granulomatous reaction involving the reticuloendothelial system. The organism is capable of surviving within macrophages. On occasion, a more suppurative reaction can occur in immunocompetent patients, resulting in abscess formation in various organs, especially the lung, skin, liver, and subcutaneous tissues. P marneffei infection in immunosuppressed patients can be granulomatous or necrotizing and is likely to disseminate.

Clinical Findings

  1. Signs and Symptoms.Infections caused by Penicilliumspp. other than P marneffei are very rare, and recovery of Penicillium spp. from clinical specimens will almost always represent colonization; however, in the severely immunocompromised host, repeated recovery may represent opportunistic infection. Isolated case reports of invasive penicilliosis, including prosthetic valve endocarditis, peritonitis, endophthalmitis, and infections at other sites, have been reported in the literature.

The most common presentation of P marneffei infection is chronic illness with fever and weight loss (Box 77-4). A nonproductive cough is frequently present. Other specific symptoms may be present depending on the extent of infection. Because skin involvement occurs in nearly two-thirds of patients, skin lesions are usually present and are most commonly found on the face, upper trunk, and arms. They are papular in appearance and resemble molluscum contagiosum. Generalized lymphadenopathy is also often present. Hepatosplenomegaly may be detected on abdominal examination and is more common in children.

  1. Laboratory Findings.Anemia is the most common laboratory abnormality present and is found in approximately three-quarters of patients. Blood cultures are positive in over half of patients. There are currently no serological tests to diagnose P marneffeiinfection.
  2. Imaging.In patients with pulmonary involvement, the chest x-ray may show multiple infiltrates, abscesses, and cavitation. Hilar involvement may be present, but there is usually no hilar calcification.
  3. Differential Diagnosis.P marneffeimay closely resemble tuberculosis, particularly in patients with HIV infection. The disease also closely resembles histoplasmosis and cryptococcosis as it occurs in HIV-infected patients.

BOX 77-4 Penicillium marneffei Infection in Adults and Children

More Common

· Chronic illness

· Fever

· Weight loss

· Cutaneous involvement

· Generalized lymphadenopathy

· Anemia

· Positive blood culture

Less Common

· Diarrhea

· Pericarditis

· Bone and joint involvement

· Central nervous system involvement

Diagnosis

The diagnosis of invasive disease by Penicillium spp. other than P marneffei must be based on histologic evidence of tissue invasion and recovery of the organism from tissue culture. In addition, recovery from a sterile body fluid such as blood or synovial fluid is suggestive of infection but must be interpreted with caution in view of the frequency with which Penicillium spp. contaminate laboratory specimens.

Infection with P marneffei occurs only in people who have lived or traveled in the endemic areas of Southeast Asia and southern China. An exposure history is critical in considering the diagnosis. Blood cultures will establish the diagnosis, but other specimens including bone marrow, skin, abscess fluid, lymph nodes, sputum, and others may yield the organism. P marneffei must be distinguished from Histoplasma capsulatum, which it closely resembles in the laboratory.

Treatment

The drug of choice for treatment of P marneffei infection is amphotericin B, although in vitro resistance has been described (Box 77-5). The addition of 5-flucytocine appears to enhance the efficacy of amphotericin B therapy especially in more severe cases. Itraconazole also appears to be highly active against the organism; however, it should be reserved for indolent cases or for use following an initial response to amphotericin B. A standard course of therapy is 2 weeks of amphotericin followed by 6 weeks of itraconazole. Relapse rarely occurs in immunocompetent patients but is common among AIDS patients. Chronic maintenance therapy with itraconazole is indicated in patients with AIDS.

BOX 77-5 Treatment of Penicillium marneffei Infection in Adults and Children

First Choice

· Amphotericin B, 0.5–1.0 mg/kg/d for 2 wk, followed by 6 wk of itraconazole, 200 mg daily in adults or 3–5 mg/kg daily in children

Second Choice

· Itraconazole, 200 mg daily in adults or 3–5 mg/kg daily in children for 2 months

Comment

· 5-flucytosine, 100–150 mg/kg in 4 divided doses daily, may be given in addition to amphotericin

· More severe cases may need a more prolonged course of amphotericin ± 5-flucytosine

· Chronic maintenance therapy is indicated in patients with AIDS

Prognosis

With early diagnosis and initiation of appropriate fungal therapy, the prognosis is very good; however, among patients in whom the diagnosis is delayed, the mortality rate is high.

Prevention & Control

Because very little is known about the environmental niche of P marneffei, there are no recommendations or guidelines for prevention and control of this infection.

PARACOCCIDIOIDOMYCOSIS

Essentials of Diagnosis

  • Patients usually immunocompetent.
  • Patients in endemic areas with chronic pulmonary and mucotaneous lesions involving the mouth, nose, larynx, and face; regional or diffuse lymphadenopathy.
  • Found in Latin America, from Mexico to Argentina.
  • Dimorphic fungus: yeast form in tissue specimens and at 37°C; mold form when grown at room temperature in the laboratory.
  • Thick-walled yeast, 4–40 µm, with multiple buds when seen in tissue specimens.
  • Complement fixation or immunodiffusion.

General Considerations

Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis. Also known as South American blastomycosis, it is the most prevalent systemic mycosis found in Central and South America and is the most common endemic mycosis in this area.

  1. Epidemiology.Paracoccidioidomycosis is acquired only in Central and South America and ranges from Mexico to Argentina. Most cases occur in Brazil, and fewer cases are seen in Colombia, Venezuela, Ecuador, and Argentina. In other Latin American countries, it is considered rare. It has never been reported in Belize, Nicaragua, Suriname, French Guiana, Guyana, Chile, or any of the Caribbean islands. Cases reported in nonendemic areas such as North America and Europe have occurred in patients who have traveled to or lived in the endemic areas. Within the geographic range for P brasiliensis, there is considerable variability in endemicity. It is commonly found in tropical or subtropical forests, where there are mild temperatures with little seasonal variation and very high humidity. The precise ecological niche in the environment has not been established. Soil has been postulated to be the reservoir.

Nearly 95% of the cases of paracoccidioidomycosis occur in males. It is also unusual in adolescents and children. There is evidence that estrogen has an inhibitory effect on conidia of P brasiliensis, and this may explain the difference in incidence among the sexes. Inoculation of the skin was once thought to be the portal of entry; however, the evidence now suggests respiratory acquisition. There is no evidence of person-to-person transmission.

  1. Microbiology.P brasiliensisis a dimorphic fungus. In clinical specimens, it appears as a thick-walled yeast that ranges in size from 4 to 40 µm. Multiply budding yeast cells (the so-called “pilot wheel” or “mariner's wheel” cells) may be seen from tissue specimens and are a characteristic feature (Figure 77-3). In the laboratory, when this yeast is grown on enriched media at 37°C, colonies will appear in 5–10 days. In contrast, when grown at room temperatures (19°–28°C), the mycelial form or mold will grow in 20–30 days. The thin septate hyphae can develop a variety of conidia, but induction of conidial growth can be difficult and unequivocal identification of P brasiliensis requires documentation of dimorphic growth in the laboratory.
  2. Pathogenesis.After the conidia of P brasiliensisare inhaled, fungal growth begins within the alveoli and small airways of the lungs. The yeast stimulates a vigorous neutrophilic and then macrocytic response. Spread to regional lymph nodes usually occurs early in infection. At the same time, more widespread dissemination may occur, particularly to the reticuloendothelial system. Depending on the host response, the infection may be controlled, may become clinically apparent, or may become dormant. The inflammatory response seen is a mix of granulomatous, suppurative, and necrotizing. Host response and the status of the immune system are critical determinants in the expression of disease. Both humoral and cellular immune responses are required to control the infection. Although serious infection has been reported with increasing frequency in recent years in patients with AIDS or other forms of severe immunosuppression, it is not a common opportunistic infection in these patients despite its endemic nature. The widespread use of prophylactic trimethoprim-sulfamethoxazole in AIDS and transplant patients may explain the relatively infrequent occurrence in these patients.
 

Figure 77-3. Laboratory specimen demonstrating the multiply budding yeast cells characteristic of P brasiliensis. The same morphology may also be seen in tissue specimens (×400).

Clinical Findings

  1. Signs and Symptoms.The manifestations of infection with P brasiliensisrange from asymptomatic or subacute to chronic and focal to disseminated. Although all patients are presumed to have a pulmonary portal of entry, and 80% will have evidence of pulmonary infection, not all will have symptoms that suggest respiratory disease. The majority of patients present with symptoms involving mucosal surfaces of the mouth, nose, or larynx; a variety of cutaneous lesions; or general or localized lymphadenopathy. Symptoms will vary by the extent of involvement, and sites may include the liver, spleen, central nervous system, gastrointestinal tract, and bones. Of note, like H capsulatum, P brasiliensis has a particular propensity to involve the adrenal glands. Most patients with any evidence of disseminated disease will have some degree of adrenal involvement; however, overt Addison's disease is very uncommon.

Patients with respiratory symptoms will present with cough, purulent sputum production, and dyspnea (Box 77-6). Fever may or may not be present. Many patients will have nonspecific constitutional symptoms such as weight loss, weakness, and malaise. Mucocutaneous involvement is characterized by ulcerations in the mouth, cheilosis, and dysphagia.

On physical examination, the pulmonary findings are often less prominent than would be expected based on the radiographic findings. Examination of the mouth may reveal polymorphic ulcerations. The lips may be indurated and painful. Lymphadenopathy is often present, and spontaneous drainage commonly occurs. A variety of cutaneous lesions may be seen including abscesses, nodules, papules, ulcers, and verrucous lesions. It is very common for pulmonary, mucocutaneous, and lymph node involvement to coexist in the same patient.

  1. Laboratory Findings.Direct examination of sputum or lymph node drainage with a potassium hydroxide smear may reveal the yeast forms. Culture of sputum or drainage will also be positive. Blood cultures may be positive in disseminated disease, particularly among children and young adults. Serologic tests will be positive in most patients with infection.
  2. Imaging.The chest x-ray will generally show diffuse bilateral interstitial and alveolar infiltrates. Less frequently encountered findings include multiple nodules, cavitation, and hilar lymphadenopathy. Calcification occasionally occurs but not as frequently as in histoplasmosis or tuberculosis.
  3. Differential Diagnosis.Tuberculosis may coexist with paracoccidioidomycosis in as many as one-quarter of the cases, and care must be taken to distinguish two diseases that can resemble each other. The differential diagnosis also includes histoplasmosis, blastomycosis, lymphoma, leishmaniasis, leprosy, and malignancies.
  4. Complications.Chronic untreated pulmonary disease may lead to fibrosis, pulmonary hypertension, and cor pulmonale. Chronic symptomatic adrenal insufficiency is a rare complication of disseminated disease, but adrenal function may recover after long-term antifungal therapy.

BOX 77-6 Paracoccidioidomycosis in Adults and Children

More Common

· Chronic illness

· Fever

· Mucocutaneous involvement (mouth, nose, larynx)

· Cutaneous involvement

· Lymphadenopathy

· Pulmonary involvement

Less Common

· Hepatosplenic disease

· CNS involvement

· Bone and joint involvement

· Arteritis

Diagnosis

The diagnosis of paracoccidioidomycosis can be suspected when an appropriate clinical syndrome occurs in a patient who has lived or traveled in Latin America. Given the syndrome's strong propensity to become dormant and remain so for years, even a remote history of exposure in the endemic area can be considered significant. The presence of multiply budding yeast cells on direct examination of sputum or pus is presumptive evidence of paracoccidioidomycosis. These cells may also be seen on histologic examination of a lymph node or other tissue. Definitive diagnosis requires culture from sputum, pus, blood, or a biopsy specimen. Serologic tests will be positive in 95% of cases by the immunodiffusion test and 80–95% by complement fixation. The skin test for paracoccidioides is of no help diagnostically and is suitable only for epidemiological investigation.

 

Treatment

The azoles are now considered the treatment of choice for paracoccidioidomycosis (Box 77-7). In clinical trials, 95% of patients responded to a standard ketoconazole regimen, and 8% of patients relapsed. Itraconazole may be superior to ketoconazole, but there is less experience with this agent. A similar response rate has been observed but with a lower relapse rate. Similar findings have been noted with fluconazole.

Paracoccidioidomycosis can also be treated with sulfonamides. Although the response rate is excellent, there is a relapse rate of ~ 15%. Therapy with sulfadiazine can be instituted and continued for 4 weeks until a clear clinical response is detected. The maintenance dose is continued for 3–5 years. Amphotericin B can be used in life-threatening infections or in patients who are intolerant of or have failed sulfonamide therapy. Azole therapy should follow amphotericin therapy for several months. Trimethoprim-sulfamethoxazole can be substituted for sulfadiazine in both the initial and maintenance phases of therapy and should be given lifelong in AIDS patients with a history of paracoccidioidomycosis.

Prognosis

The prognosis for paracoccidioidomycosis is excellent when the diagnosis is established early in the course of the disease and therapy is promptly instituted. In patients with advanced disease and a wasting syndrome characterized by weight loss, fatigue, and malnutrition, the prognosis is less favorable but is enhanced by aggressive supportive care, including nutritional repletion, correction of anemia, and bed rest.

BOX 77-7 Treatment of Paracoccidioidomycosis in Adults and Children

First Choice

· Ketoconazole, 400 mg/d for adults or 5–10 mg/kg daily for children, for 6–18 months or itraconazole, 100 mg/d for adults or 3–5 mg/kg daily in children, for 6 months

Second Choice

· Amphotericin B, 0.5–1.0 mg/kg/d, total cumulative dose of 1–3 g in adults or 25–30 mg/kg in children

· Sulfadiazine, 2–6 g/d in adults or 120–150 mg/kg in children, for 4 wk followed by 500 mg/d in adults or 25–50 mg/kg/d in children, for 3–5 y

Comment

· If amphotericin B is used as initial therapy, itraconazole or sulfadiazine should be given as maintenance therapy, as above

· Trimethoprim-sulfamethoxazole may be substituted for sulfadiazine and should be given as lifelong maintenance therapy in patients with AIDS

· Fluconazole may be as effective as itraconazole

Prevention & Control

Prophylactic trimethoprim-sulfamethoxazole will prevent primary or relapse paracoccidioidomycosis (Box 77-8)

CHROMOMYCOSIS

Essentials of Diagnosis

  • Patients are usually immunocompetent.
  • Found worldwide but usually in tropical or subtropical areas.
  • Mold in culture; forms sclerotic body or muriform cell in tissue.
  • Infection results from direct inoculation from contaminated soil or vegetative substances.
  • Chronic indolent cutaneous verrucous lesions, most often on the feet.

General Considerations

Chromomycosis, also known as chromoblastomycosis, is a chronic subcutaneous infection caused by several different fungi. Although rarely seen in the United States, it is common worldwide.

  1. Epidemiology.Chromomycosis occurs worldwide but is most frequently encountered in tropical and subtropical regions. The most common occurrence is in barefoot individuals, particularly among agricultural workers. The organisms causing chromomycosis are found commonly in soil, rotting wood, and decaying vegetation. Infection follows only after traumatic exposure to soil or other material, and person-to-person transmission does not occur.
  2. Microbiology.A variety of different agents is capable of producing the clinical syndrome chromomycosis. The most common is Fonsecaea pedrosoi. Others that may be encountered include Fonsecaea compactum, Cladosporium carrionii, Phialophora verrucosa, Botryomyces caespitosus, Rhinocladiella aquaspersa, Exophiala spinifera, and E jeanselmei. These fungi share a number of characteristics. Most are exceedingly slow growing and require 4–6 weeks in the mycology laboratory before growth may be encountered on culture plates. The colonies tend to be dark green to brown or black in color, and the hyphae are septate. Speciation can be difficult and requires an experienced mycologist.
  3. Pathogenesis.After an incubation period of several weeks following traumatic subcutaneous inoculation, clinical infection begins. Histologically, there is a pyogranulomatous reaction and significant pseudoepithelial hyperplasia yielding the characteristic verrucoid appearance. Sclerotic bodies, also known as muriform cells, are the characteristic histologic finding. These are actually brown, round, fungal elements that are thick-walled and septated. Their presence on histologic examination is pathonomonic. Occasionally, there may be associated branched septated hyphae adjacent to the muriform cells.

BOX 77-8 Control of Paracoccidioidomycosis

Prophylactic Measures

Trimethoprim-sulfamethoxazole

Isolation Precautions

None

Clinical Findings

  1. Signs and Symptoms.Chromomycosis is a chronic skin and soft tissue infection that may develop over months, years, or decades (Box 77-9). Frequently, patients seek medical attention for cosmetic reasons after years of infection. The feet are the most common location after inoculation from being barefoot. The hands, arms, and legs may also be involved. Typically, a lesion will start as a papule and slowly enlarge to develop into a nodule or plaque (Figure 77-4).

Different morphologic forms of infection have been described. The verrucous form has a bulky, wartlike appearance and can be very disfiguring. It is often described as cauliflowerlike in appearance. Ulceration, crusting, and bacterial superinfection are common. The annular form tends to be more flattened with a slowly advancing edge of infection with central healing and scarring. This form is more likely to lead to lymphedema, which in its extreme manifestation may resemble elephantiasis. Infection remains localized with satellite lesions and only rarely disseminates.

  1. Laboratory Findings.Blood chemistries and cell counts are usually normal in patients with chromomycosis.
 

Figure 77-4. Annular crusted-type chromomycosis involving the hand of a patient.

  1. Imaging.Plain film roentgenograms of affected sites will show only soft tissue changes. Bony involvement is rarely seen.
  2. Differential Diagnosis.A wide variety of infections can cause a syndrome similar to that of chromomycosis. Blastomycosis, sporotrichosis, and mycetoma are other fungal infections that may present as chronic skin and subcutaneous infection. Yaws, tertiary syphilis, leishmaniasis, tuberculosis, and infection with atypical mycobacterium are other possibilities. Carcinoma, on rare occasion, may resemble chromomycosis.

BOX 77-9 Chromomycosis in Adults and Children

More Common

· Chronic infection

· Foot involvement

· Cauliflowerlike appearance

Less Common

· Hand, arm, leg involvement

· Marked lymphedema

· Dissemination (very rare)

Diagnosis

The diagnosis of chromomycosis requires scraping or biopsy. The presence of the characteristic sclerotic body is diagnostic. These are easily seen with a KOH stain, particularly when collected from verrucous form of infection. Annular infections tend to have a lower number of organisms and may require biopsy. Scrapings and biopsy specimens submitted to culture should be held in the mycology laboratory for ≥4–6 weeks to allow sufficient time for growth to occur. There are no serological tests to assist in the diagnosis of mucormycosis.

Treatment

Treatment of chromomycosis is difficult, and failure to achieve a cure is common (Box 77-10). Early, localized infection can be treated with wide surgical excision. Cryotherapy with liquid nitrogen has also been successful in eradicating early infection.

More established infection will require antifungal therapy; 5-flucytosine has been extensively used.


Many cases will have partial response, but relapse is common, and resistance develops frequently. Retreatment with 5-flucytosine is usually unsuccessful because resistance develops. The role of the azoles in the treatment of chromomycosis continues to evolve. Ketoconazole is ineffective. Both itraconazole and fluconazole have been used with some success. The optimal duration of therapy has not been established, and failures and relapses are common. Amphotericin B has been tried in resistant cases but is generally not recommended. Terbinafine has been used in a very small number of patients with promising results. More experience with this agent is needed before it can be recommended. The optimal therapeutic approach to chromomycosis remains to be determined.

BOX 77-10 Treatment of Chromomycosis in Adults and Children

First Choice

· Wide surgical excision or cryotherapy with liquid nitrogen

Second Choice

· Itraconazole, 100 mg/d × 18 mo; for children, 5–6 mg/kg/d

· 5-Flucytosine, 100–150 mg in 4 divided doses/d × ≥18 mo; for children, 50–150 mg/kg/d

Comment

· Terbinafine may be an option; more data needed

· Results with fluconazole have been disappointing but 400 mg/d is an option; for children, 3–6 mg/kg/d

· Failure to respond to antifungal therapy is often seen

BOX 77-11 Control of Chromomycosis

Prophylactic Measures

· Foot infection can be prevented by wearing shoes.

· At-risk individuals (eg, agricultural workers) should minimize trauma to hands and extremities.

Isolation Precautions

None

Prognosis

Untreated chromomycosis leads to a disfiguring, slowly enlarging lesion. Elephantiasis can develop as a result of the disruption and obstruction of lymphatics.

Prevention & Control

Chromomycosis of the feet can be prevented by wearing shoes (Box 77-11). Agricultural workers and other at-risk individuals should attempt to limit trauma to their hands and extremities. Because the organisms causing this infection are ubiquitous in soil and vegetative material, control efforts directed at reducing or eradicating the organisms are impractical.

REFERENCES

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Goldani LZ, Sugar AM: Paracoccidioidomycosis and AIDS: an overview. Clin Infect Dis 1995;21:1275. (Discussion of the clinical manifestation and treatment of Paracoccidioidomycosis in patients with AIDS.)

Manns BJ et al: Paracoccidioidomycosis: case report and review. Clin Infect Dis 1996;23:1026. (Report of a fatal case of paracoccidioidomycosis that occurred > 15 years after the patient left the endemic area, with a succinct review of key features of paracoccidioidomycosis.)

Martino P et al: Clinical patterns of Fusarium infections in immunocompromised patients. J Infect 1994;28(Suppl 1):7. (Large series of patients with Fusarium infection and comprehensive literature review focusing on clinical aspects.)

Patterson TF et al: The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection. Mycoses 1990;33(6):297. (Discussion of the epidemiological aspects of both nosocomial and community-acquired Pseudallescheriasis.)

Perfect JR, Schell WA: The new fungal opportunists are coming. Clin Infect Dis 1996;22(Suppl 2):S112. (Nice summary of emerging fungal pathogens including Penicillium marneffei, Fusarium spp., and Pseudallescheria boydii.)

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