Cutaneous Protothecosis

Localized infection of the skin is most common and typically results from primary inoculation through a wound or abrasion. In immunocompromised individuals, infection with Prototheca can become widespread. Currently, six species are included in the genus Prototheca: Prototheca wickerhamii, Prototheca zopfii, Prototheca blaschkeae, Prototheca cutis, Prototheca ulema, and Prototheca stagnora. The first four species are known to cause infections in humans, most commonly P wickerhamii. Prototheca infections have also been reported in cattle, cats, and dogs, with boxer dogs being the most represented canine breed noted to have cutaneous Prototheca infection.[1]

Prototheca is an achlorophyllic variant of the green alga Chlorella. The organism is ubiquitous but especially prevalent in aqueous environments. Infection usually results from inoculation into the dermis or subcutis by a penetrating injury associated with contaminated or swampy water. Traumatic inoculation with no water exposure has also been reported.[2] Infection has also been described as a complication following surgery.[3, 4] Person-to-person transmission has not been reported, but Prototheca has been cultured from underneath fingernails as well as from other cutaneous sites in healthy individuals.

When healthy individuals become infected, the organism has low virulence and may remit on its own without treatment. Reported cases of protothecosis are more commonly described in patients who are immunosuppressed, have a hematologic malignancy, or a history of organ transplantation. The more widespread use of immunosuppressive drugs also increases the risk of protothecosis infections.[5] Of all possible immunosuppressants, glucocorticoids, whether topically applied, taken orally, or locally injected, are the most specifically associated with the onset of protothecosis.[6] In healthy individuals, the infection is localized and curable, but cases of disseminated disease in individuals who are severely immunocompromised can be fatal. Cases of disseminated disease have involved the blood, the peritoneum, the GI tract, the liver, and the meninges.

Infection is usually caused by P wickerhamii. Less commonly, infection occurs with P zopfii. Prototheca is ubiquitous in the environment. It has been cultured from a wide variety of aqueous sources, including lakes, streams, ponds, and even tap water. Prototheca species have also been cultured from animal feces, soil, and a variety of other sources.

This organism is widely encountered in the environment, but it does not produce infection in most individuals. Most reported cases have occurred in patients who are severely immunosuppressed (eg, long-term immunosuppression for organ transplantation,[7, 8] autoimmune disease, graft versus host disease, chemotherapy or radiation therapy,[9] AIDS/HIV infection,[10, 11, 12] diabetes mellitus,[13] chronic renal failure, or Cushing disease). Another association reported included hypogammaglobulinemia (most likely resulting from common variable immunodeficiency.[14]

Frequency

United States

Protothecosis is a rare infection, with the majority of reports involving the skin and nails.[15] Most cases in the United States are from the Southeast, although cases from virtually all geographic regions have been reported.

International

Protothecosis is seen worldwide, with cases reported on every continent except Antarctica.[6]

Race

No racial predilection is noted.

Sex

No sexual predilection is evident.

Age

Protothecosis typically affects those older than 30 years or elderly persons, although pediatric cases have been reported.

Patients with localized disease have an excellent prognosis and can expect cure. The prognosis of patients with severe disease and immunosuppression is poor.

Localized infection

In immunocompetent individuals, the infection usually remains confined to the skin at the site of inoculation. Olecranon bursitis can develop from protothecosis. Rarely, tenosynovitis can occur secondary to protothecosis and has been reported following injection of a sclerosing agent for varicose vein treatment.[16] Infection of a corneal graft has been reported.[17] Biological agents are being used with increased frequency, and it is important to note that cutaneous protothecosis has been noted in the setting of ustekinumab therapy for psoriasis.[18]

Systemic infection

Rare cases of systemic infection occur almost exclusively in patients who are severely immunocompromised, as in patients receiving chemotherapy, or immunosuppressed patients, such as those on infliximab. Involvement of the meninges has been reported in a few cases of patients with AIDS.

Immunocompromised patients as well as healthy individuals should avoid bathing or swimming in swampy or stagnant bodies of water. Individuals diagnosed with prothecosis should undergo evaluation for underlying immunosuppression if an obvious predisposing factor is not already known.

The classic history is that of trauma (eg, abrasion or cut) to the skin and subsequent exposure to contaminated water. Occupations that may predispose individuals to infection with Prototheca species include rice farmers, anglers, aquarium staff, and handlers of raw seafood.[6] In severely immunocompromised individuals, cutaneous lesions can be widespread, and the algae can be present in the blood.

The skin is the most common site of infection, followed by the periarticular bursae (typically causing olecranon bursitis). The extremities are the most common sites of cutaneous involvement.

Patients typically have an isolated, ill-defined plaque or nodule (see the image below). Large eczematous plaques, pustular lesions, and cutaneous ulceration have also been reported. The lesions may be atrophic, herpetiform, verrucous, or hypopigmented. Bullous lesions may occur with subsequent rupture, drainage, and crusting. Lesions with the appearance of apple jelly have been reported. Erythema and pain may occur. In patients who are immunocompetent, the lesions may be more subtle, with papules or plaques with mild erythema that have been stable for long periods.

Patients with olecranon bursitis have swelling, mild erythema, and, occasionally, drainage in the vicinity of the elbow. In cases of meningeal involvement, patients may have meningeal signs of headache, nuchal rigidity, and photophobia.

Failure to eradicate protothecosis may result in an expanded area of skin infection. Rare cases have progressed to disseminated infection, typically in patients who are severely immunocompromised.

A diagnosis of protothecosis can be made based on findings from either biopsy or culture. Prototheca species readily grow on Sabouraud glucose agar. Smooth, white-to-beige colonies typically demonstrate growth within 48 hours at room temperature. Prototheca species may also be cultured on blood agar, heart-brain infusion agar, or beef infusion broth. Commercial assays that rely on the unique components of the cell wall are also available for identification of Prototheca species. It should be noted that certain selective fungal media commonly used to isolate dermatophytes may contain inhibitors such as cycloheximide, which can inhibit the growth of Prototheca.

Protothecosis is a rare infection, often involving individuals who are immunocompromised. An immune status evaluation may be judicious in patients presenting with this disorder.

Prototheca-ID is a web-based application that can assist with speciation of Prototheca isolates.[20]

No other tests are necessary; however, electron microscopy reveals a double-layered cell wall without chloroplasts. These features differentiate Prototheca organisms from other types of algae. In addition, commercial yeast identification systems, such as API 20C and VITEK 2 systems can identify Prototheca. Newer techniques such as the use of matrix-assisted laser desorption ionization time-of-flight mass spectometry (MALDI-TOF MS) can also be used to rapidly identify P wickerhamii.[8]

Protothecosis demonstrates morula formation. Typically, the sporangia are 3-30 µm in diameter[6] either outside of the macrophages or within the macrophages. They are best visualized with special stains (eg, periodic acid-Schiff, Gomori methenamine-silver) that are used to highlight fungi. The diagnostic feature of P wickerhamii is the presence of sporangia with a central, rounded endospore surrounded by a corona of molded endospores. The appearance of the sporangia is diagnostic, and it is described as moruloid, daisylike, spokelike, and frambesiform. See the histology slides below.

Histopathologic findings range from minimal inflammation to severe granulomatous inflammation with areas of necrosis. The dermis may contain a variety of inflammatory cells such as lymphocytes, eosinophils, neutrophils, plasma cells, and multinucleate giant cells within the dermis. Prototheca are seen either singly or in clusters within interstitial connective tissue, granulomas, and necrotic foci.

The principal histopathologic differential diagnosis is coccidioidomycosis, which also shows a thick, refractile wall. However, the spherules are typically larger and always show smaller endospores (2-4 µm).

Protothecosis can be difficult to eradicate. Reports describe successful treatment of localized disease with ketoconazole, itraconazole, and fluconazole.[21] Voriconazole is also effective.[22] Surgical removal of isolated lesions in combination with antifungal therapy (eg, with azoles) is effective in immunocompetent individuals. Also reported is dual use of local thermal application as an adjunct to azole therapy.[23] An increasing number of reports indicate that itraconazole 200 mg/day for 2 months can be helpful in some adults.[24]

Surgical excision is the treatment of choice in all cases amenable to excision. In addition, debridement for necrotic ulcerative lesions may be warranted. Management of olecranon bursitis should consist of bursectomy.

Although not a true fungal disease, treatment with antifungals is effective and may be used in conjunction with surgical excision. When a patient shows resistance to one antifungal, susceptibility testing may be helpful to direct treatment.[22]

Class Summary

These agents exert a fungicidal effect by the following mechanisms: altering the permeability of the fungal cell membrane, altering RNA and DNA metabolism, and causing intracellular accumulation of peroxide.

Itraconazole (Sporanox)

Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Voriconazole (Vfend)

Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Fluconazole (Diflucan)

Fluconazole is a synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. It has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. It is available as tabs for oral administration, as a powder for oral suspension, and as a sterile solution for IV use. Fluconazole has fewer adverse effects and better tissue distribution than older systemic imidazoles.

It can be used in severe or life-threatening infections in patients intolerant of amphotericin B, and it may be used for maintenance after a course of amphotericin B in coccidioidal meningitis. It penetrates well into cerebrospinal fluid. Metabolic clearance is prolonged in patients with renal dysfunction.

Amphotericin B (AmBisome)

Amphotericin B is for use in disseminated disease. It is produced by a strain of Streptomyces nodosus and can be fungistatic or fungicidal. Amphotericin B binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.