Timeline for Common Side Effects
Day0 Day10
Day0 Day10 Day20Day20
Elevated amylase & lipase.
Elevated amylase & lipase. CytopeniasCytopenias Clinical pancreatitis
Elevated liver function tests
Elevated liver function tests
Musculoskeletal symptoms
Herpes zoster
Herpes zoster
Headache, fatigue, anorexia, nausea
ECG abnormalities
Figure. 10.19. Chronology of common side eff ects during a 20-day course of parenteral Pentostam
for several days following this localized heat therapy may reduce secondary infection risk.
Th e results of a controlled study in 2002 suggest that oral fl uconazole 200 mg daily for 6 weeks speeds healing in Old World CL. Subsequent experience with this agent, and other azole antifungals, itraconazole, and ketoconazole, has yielded mixed results. Reports of success with systemic azole antifungal treatment of Old World CL have been primarily limited to the L. major species. Liver function screening and monitoring should be performed if these agents are utilized.
Topical paromomycin (aminosidine) formulations, an aminoglycoside antibiotic, hold great promise as an option for uncomplicated cases of Old World CL due to L. major . When the agent is mixed with methylbenzonium chloride, an effi cacy of 74% was reported in the treatment of CL due to L. major ; however, local discomfort can occur. In the United States, a paromomycin sulfate 15% with gentamicin sulfate 0.5% formulation (WR279396) has shown positive responses in healing times and subsequent scar cosmesis in phase II pla- cebo-controlled studies. Owing to its simplicity for both the patient and the provider, coupled with the absence of blister- ing and dyspigmentation that may be seen with Th ermoMed™ or cryotherapy treatments, if a paromomycin formulation of equal or better effi cacy is eventually FDA approved, it would be an attractive alternative to the physical modalities described earlier. Currently in the United States, some pharmacies can compound paromomycin (15% paromomycin phosphate with 10% urea in white soft paraffi n), which can be applied twice daily for 3 to 4 weeks. Compounding pharmacies in the United States can be located at http://iacprx.org/referral_service/ index.html
Aggressive systemic treatment of Old World CL is reserved for specifi c scenarios as outlined in the algorithm. Th e standard for aggressive systemic treatment of Old World CL remains a par- enteral pentavalent antimony (PVA) agent. Pentostam (sodium stibogluconate) is the agent used in the United States. In addi- tion to relatively simple lesions that do not respond to earlier measures, larger Old World CL lesions (>3.5 cm diameter for L. major , >1cm for L. tropica ), numerous lesions, lymphocutaneous
manifestations, and the presence of disease in an immunocom- promised patient all may merit parenteral PVA treatment. Also, patients with “complicated” lesions of the hands and feet, cos- metically conspicuous involvement of areas such as the face, involvement overlying joints or bursa, or the presence of mul- tiple satellite “daughter” lesions are appropriate candidates for PVA treatment.
Pentostam (sodium stibogluconate) is only available in the United States via an approved investigational new drug (IND) protocol within the military (Walter Reed Army Medical Center in Washington D.C., phone 202–782–1663/8691 and Brooke Army Medical Center, San Antonio, TX, phone 210– 916–5554) or the CDC Parasitic Drug Services section (phone 404–639–3670) free of cost to civilian physicians for parasito- logically confi rmed cases. Th e dosage regimen is 20 mg/kg/day for 10 to 20 days, with an overall effi cacy ranging from 45% to 100%. It is recommended that the outpatient administration occur via a steel butterfl y needle inserted into the antecubital vein each day to eliminate the risk of device-related infections. A timeline for the occurrence of side eff ects with this regimen is shown in Figure 10.19 . Common side eff ects are reversible elevations of pancreatic and hepatic enzyme levels, arthralgias, and myalgias. Th e musculoskeletal side eff ects are the most common reason for early discontinuation of therapy. Although severe cardiac problems are rare, note that a >0.5-second pro- longation of the QT interval is an indication to stop therapy temporarily.
Other PVA agents are used around the world, including Glucantime (meglumine antimoniate) in Europe. Although PVA in the form of Pentostam is only delivered intravenously in the United States, intramuscular and intralesional protocols are used in endemic areas. Th e intralesional route is advantageous because of reduced side eff ects and decreased cost, but can be painful.
Amphotericin B deoxycholate therapy, 0.5 to 1 mg/kg/day for 14 to 30 days to a cumulative dose of 1 to 2 gm, is reserved for Old World CL PVA treatment failures. It has a well-doc- umented risk of nephrotoxicity and infusion-related allergic reactions.
Miltefosine, an antineoplastic agent, has been used successfully to treat various forms of leishmaniasis in both hemispheres of the world. In a 2007 comparative study, oral miltefosine, 2.5 mg/kg/ day for 28 days was as successful in treating Old World CL as a PVA agent and no patients showed serious side eff ects.
Published reports of successful treatment of Old World CL with photodynamic therapy have appeared in recent years. A 2006 series of fi ve patients who underwent a regimen of δ-aminolevulinic acid in a water-in-oil emulsion applied to lesions, followed by irradiation once weekly for a month showed excellent results with no scarring (Ghaff arifar). Only mild local infl ammatory reactions occurred at the treated areas.
Other oral agents, including allopurinol, dapsone, rifampi- cin, both oral and intralesionally injected zinc sulfate, and topical imiquimod have been used to treat Old World CL, either alone or in combination with a PVA, with variable results.
Regardless of therapeutic intervention (or noninterven- tion), complete healing and re-epithelialization of lesions with no recurrence 6 months later is considered a clinical cure of CL. In 2007, a systematic review of published randomized controlled trials of Old World CL concluded that studies thus far were highly variable in quality and methods, and provided weak evidence for the treatment of Old World CL. It is clear that well-designed, double-blinded, controlled studies are strongly needed.
Follow-up
Patients should be followed up for up to 6 to 12 months aft er apparent clinical healing. Relapse can occur and is most likely in the fi rst few months aft er initial clearing. Patients should monitor healed sites for evidence of ulceration, scabbing, scaling, indu- ration, new lesions, or increase in scar size. Reactivations oft en occur at sites of trauma of even minimal degree, the Koebner phenomenon (isomorphic response). Because of this, elective surgery and tattoo placements should be delayed for 12 months.
Reinfection from the same species causing Old World CL is unlikely for the remainder of the individual’s lifetime, but occurs in a very small percentage of patients.
A diagnosis of any type of leishmaniasis precludes blood donation in the United States for the remainder of the patient’s life as in the following document:
http://www.militar yblood.dod.mil/librar y/policies/ downloads/03–08.pdf
W E S T E R N H E M I S P H E R E :
C O C C I D I O I D O M Y C O S I S A N D T H E S K I N
Deserts of the New World are the habitat of Coccidioides species, the fungi that cause coccidioidomycosis. Th e organisms live in the soil and produce arthroconidia, which are dispersed by the wind. Suitable hosts, such humans, dogs, and horses, acquire pulmonary infection through the inhalation of the air-borne arthroconidia. Th e infection is virtually always acquired from an environmental source; person-to-person transmission does not occur.
Most cases of coccidioidomycosis are asymptomatic. A minority of patients develop a febrile, infl uenza-like respiratory illness. Extrapulmonary dissemination occurs in <1% percent of patients. Th ough only a relatively small percentage of patients
experience severe symptoms, coccidioidomycosis is nevertheless a signifi cant cause of morbidity, since the infection is so widely prevalent in endemic areas. Occasional deaths do occur, particu- larly in patients with risk factors.
History
Since the initial description of coccidioidomycosis in 1892, the skin has provided particularly important clues to the diagnosis. Th e fi rst reported case was discovered as the result of striking cuta- neous manifestations. Th e patient, an Argentine soldier, presented with cutaneous nodules that clinically resembled tumor-stage mycosis fungoides. Skin biopsy revealed distinctive organisms, which are now known to be the fungal spherules of Coccidioides . In the 1930s, the skin provided another clue to a milder expression of the disease. At that time in the San Joaquin Valley of California, erythema nodosum was considered an important sign of “Valley Fever,” a self-limited respiratory illness caused by coccidioidomy- cosis. Over the past half-century, as the desert Southwest trans- formed into a popular destination for tourism and for migration, coccidioidomycosis became an increasingly important disease. In current times, cutaneous signs continue to be exceedingly useful clues to the diagnosis of coccidioidomycosis.
Epidemiology
Coccidioides species are found in arid regions of the New World from the western United States to Argentina. Areas with hot, dry summers, few winter freezes, low annual rainfall, and alkaline soil are particularly suitable for growth of the organism within the soil. Central and southern Arizona and the San Joaquin Valley of southern California have the highest incidence rates of coccid- ioidomycosis in the world. In California, the species Coccidioides immitis is identifi ed as the causative organism. Outside California, the species Coccidioides posadasii (sometimes designated C. immi- tis var . posadasii ) is responsible for nearly all infections. Both spe- cies produce clinically similar signs and symptoms.
In endemic areas, exposure to air-borne dust is a well- documented risk factor for infection. Clusters of cases have been associated with archeological excavations and with military exer- cises. Epidemics have occurred in association with dust storms, earthquakes, and droughts. Over the past decade, Arizona has been experiencing an epidemic attributed to a prolonged drought. From 1996 to 2006, the incidence in Arizona increased more than four-fold.
Both healthy and immunosuppressed patients are at risk for coccidioidomycosis. Occasionally, severe infections can develop even in healthy persons with no risk factors. Risk factors for severe disease and dissemination include genetic predisposi- tion, immunosuppression, or pregnancy. Filipinos and African- Americans appear to be genetically predisposed to a markedly increased risk of severe coccidioidomycosis. Immunosuppressed patients, including acquired immunodefi ciency syndrome (AIDS) patients and transplant recipients, have a particularly high risk of fulminant disease and dissemination.
Diagnosis
Th e lungs are the primary site of infection in nearly all cases. Chest radiographs commonly show pulmonary infi ltrates,
Table 10.1: Cutaneous Manifestations of Coccidioidomycosis
Reactive skin lesions (without organisms) Erythema nodosum
Acute exanthem
Erythema multiforme-like eruptions Sweet’s syndrome
Interstitial granulomatous dermatitis Skin lesions with identifi able organisms Disseminated cutaneous coccidioidomycosis Primary cutaneous coccidioidomycosis
Figure 10.20. Erythema nodosum. Tender red subcutaneous nodules developed on the legs 1 week aft er the onset of pulmonary coccidioidomycosis.
lung nodules, hilar lymphadenopathy, and/or pleural eff usion. Excluding the respiratory system, the skin is the most common organ to demonstrate clues to the diagnosis of coccidioidomyco- sis. Th e organisms may be directly identifi able within the skin, or the skin may display important reactive signs of the pulmonary infection ( Table 10.1 ).
Erythema Nodosum
Erythema nodosum is one of the most common and character- istic manifestations of coccidioidomycosis. Women are more likely than men to develop erythema nodosum in association with the infection. One to three weeks aft er the onset of the ill- ness, patients present with tender red subcutaneous nodules, most oft en involving the legs ( Fig. 10.20 ). Skin biopsies demon- strate a septal granulomatous panniculitis with no evidence of organisms. Erythema nodosum appears to refl ect a strong cell- mediated response against the pulmonary infection and thus is believed to be associated with a generally good prognosis. Th e tender nodules resolve spontaneously as the pulmonary symp- toms subside.
Acute Exanthem
An acute exanthem commonly occurs very early in the course of the illness, oft en within the fi rst 48 hours. In some cases, the onset even precedes the development of respiratory symptoms. Th e generalized eruption may be morbilliform, macular, papu- lar, urticarial, or target-like ( Fig. 10.21 a & b). Th e acute exan- them closely resembles an allergic drug reaction, erythema multiforme, a viral exanthem, or generalized allergic contact dermatitis. Associated pruritus ranges from being minimal to severe. An enanthem sometimes accompanies the eruption. Skin biopsies demonstrate a nonspecifi c pattern of spongiotic derma- titis or mild interface dermatitis. Th e exanthem persists for days or weeks, and then subsides spontaneously. Desquamation of the palms ensues in some cases. Because the acute exanthem occurs so early in the course of the illness, the initial Coccidioides serol- ogies may be falsely negative. Serologic testing may be repeated in 2 weeks, if necessary, to allow time for seroconversion.
Erythema Multiforme-like Eruptions
For many decades, erythema multiforme has been cited as a common reactive manifestation of coccidioidomycosis; how- ever, review of the literature fails to reveal histopathologic
(A)
(B)
Figure 10.21. A & B. Th e acute exanthem of coccidioidomycosis. Th e
(A)
(B)
Figure 10.23. A & B. Interstitial granulomatous dermatitis associ- ated with pulmonary coccidioidomycosis. A. Scattered smooth red papules developed on the extremities on the fi rst day of fever in this
elderly man. B. Edematous pink papules on the back. Th e patient’s
cutaneous eruption was the fi rst sign of illness in this otherwise asymptomatic woman with coccidioidomycosis.
confi rmation of the association. Both the acute exanthem and Sweet’s syndrome may produce annular or target-like lesions, which clinically mimic erythema multiforme. Cases previ- ously designated as erythema multiforme may actually have represented examples of these other two entities. Regardless of whether true erythema multiforme is associated, erythema multiforme- like eruptions (with annular or target-like fea- tures) remain an important clinical clue to the diagnosis of coccidioidomycosis.
Sweet’s Syndrome
Sweet’s syndrome (acute febrile neutrophilic dermatosis) is associated with a variety of underlying systemic disorders. Only recently has this eruption been recognized as a reactive mani- festation of pulmonary coccidioidomycosis. Despite the pau- city of reported cases, Sweet’s syndrome is a common reactive manifestation of the infection in the experience of the author. Early in the course of the illness, patients present with painful edematous red papules and plaques, oft en with pustular features ( Fig. 10.22 ). Annular and target-like lesions are sometimes evi- dent. Fever and peripheral blood leukocytosis are frequently associated. Skin biopsies reveal marked subepidermal edema and dense neutrophilic dermal infi ltrates with abundant leuko- cytoclastic debris. In skin biopsy specimens, no organisms are identifi able by microscopy or by culture. Th e cutaneous signs and symptoms resolve as the pulmonary symptoms improve. Recognition of underlying coccidioidomycosis is particularly important, so that patients do not receive inappropriate treat- ment with immunosuppressive therapies. Th ough idiopathic Sweet’s syndrome is frequently treated with systemic corticos- teroids, such immunosuppressive therapies are best avoided in patients with coccidioidomycosis.
Interstitial Granulomatous Dermatitis
An immunologically induced granulomatous dermatitis occurs in association with a variety of underlying systemic diseases, such as systemic vasculitides, connective tissue diseases, lym- phoproliferative disorders, and infections. In such cases, the granulomatous infl ammation appears to be a reactive phe- nomenon, occurring in the absence of detectable organisms. Histopathologically (and sometimes clinically) the eruptions resemble granuloma annulare or necrobiosis lipoidica. In a recent case series of fi ve patients, interstitial granulomatous der- matitis was described as a reactive manifestation of pulmonary coccidioidomycosis. Despite the small number of reported cases, this eruption appears to be a relatively common manifestation of coccidioidomycosis in the experience of the author. Early in the course of the illness, patients develop scattered plaques and coalesc- ing papules on the trunk and extremities ( Fig. 10.23 a & b). Skin biopsies reveal interstitial granulomatous dermal infi ltrates,
Figure 10.22. Sweet’s syndrome associated with pulmonary coccidioidomycosis. Edematous plaques accompanied the patient’s respiratory symptoms on the fi rst day of illness.
which resemble granuloma annulare. In contrast to typical idiopathic granuloma annulare, neutrophils, karyorrhectic debris, and subepidermal edema may also sometimes be conspic- uous. Th e eruption resolves as the pulmonary symptoms subside. Reactive granulomatous dermatitis must be distinguished from disseminated infection by microscopic examination and culture of skin biopsy specimens.
Disseminated Infection
In nearly all cases, the lungs are the primary site of infection in coccidioidomycosis. In less than 1% of cases, dissemination to other organs occurs. Th e skin is the most common site of dis- semination. Other important sites of involvement include the meninges and bones. Disseminated skin lesions usually arise within the fi rst few weeks or months of the illness. Most patients with disseminated infection have fever and appear acutely ill. Occasionally, however, patients may present with disseminated skin lesions aft er an apparently asymptomatic primary lung infection. In the skin, the clinical appearance of disseminated lesions is strikingly diverse. Solitary or multiple papules, nodules,
verrucous plaques, and abscesses may occur ( Fig. 10.24a & b ). In the skin, the organisms sometimes establish a chronic nidus of infection, which persists despite the apparent resolution of the pulmonary infection. Unusual cases of disseminated coc- cidioidomycosis may resemble tumor-stage mycosis fungoides, lepromatous leprosy, or lupus vulgaris.
Skin biopsy confi rms the diagnosis. Histopathologic exami- nation frequently reveals pseudoepitheliomatous hyperplasia and ulceration. A granulomatous and/or suppurative infl ammatory infi ltrate fi lls the dermis. Eosinophils are sometimes numerous. Th e organisms are usually evident in standard H&E-stained sec- tions. Special fungal stains, such as methenamine silver stain or periodic acid-Schiff (PAS) stain, may also assist in revealing the organisms. In tissue sections, the spherules of Coccidioides sp are usually readily distinguished from other fungi because of their large size (10 to 80 microns). Mature spherules of Coccidiodes sp contain numerous distinctive endospores ( Fig. 10.25 ). In some cases, immature Coccidioides sp spherules on the smaller end of the spectrum may be diffi cult to diff erentiate from Blastomyces or Cryptococcus . For such cases, in situ hybridization is available to diff erentiate these three diff erent fungi. Culture is also a useful technique for confi rmation of disseminated coccidioidomyco- sis. Cultured skin biopsy specimens commonly yield growth of Coccidioides sp in as early as 2 to 5 days.
Primary Cutaneous Coccidioidomycosis
Primary cutaneous coccidioidomycosis is much rarer than dis- seminated skin lesions. Th e literature contains only approxi- mately 20 reported cases. Primary cutaneous infection may occur by direct inoculation into the skin through a splinter injury, laceration, or other trauma. Multiple cases have occurred among agricultural workers and laboratory technicians. Th e infection typically presents as an ulcer or nodule at the site of inoculation. In a pattern resembling sporotrichosis, secondary foci of infection sometimes arise along the distribution of lym- phatics. Fever and regional lymphadenopathy may be associated. Th e microscopic appearance is identical to that of disseminated (A)
(B)
Figure 10.24. A & B. Disseminated coccidioidomycosis. A. Ulcerated plaques on the forehead in an otherwise healthy patient with no risk factors. B. Red-brown nodules and scar-like plaque involving the axilla in an immunosuppressed patient taking prednisone.
Figure 10.25. Skin biopsy specimen confi rming disseminated coc- cidioidomycosis (hematoxylin-eosin, 400x). Coccidiodes sp spherules
of varying sizes (small arrowheads). Th e largest spherule (large
coccidioidomycosis. Clinical correlation is needed to distinguish a primary cutaneous infection from a disseminated infection.
Serologic testing
Serologic testing is an important tool in establishing the diagnosis of coccidioidomycosis. Both qualitative and quantita- tive serologic tests are commonly used. One of the most widely