Deep fungal infections

1. Deep fungal infections
Dr. Rahul pratap s chouhan

3. Subcutaneous mycoses
• They are sporadically occurring infections
• caused by fungi present in the natural environment that are
directly inoculated into the dermis or subcutaneous tissue
through a penetrating injury.

4. Classification:
• The most common are
1. Sporotrichosis
2. Mycetoma
3. Chromoblastomycosis
• Rarer infections are
4. Phaeohyphomycosis
5. Lobomycosis
6. Rhinosporidiosis
7. Subcutaneous mycosis caused by Conidiobolus or
Basidobolus

5. 1. Sporotrichosis(Rose gardener’s disease)
• This is an acute or chronic fungal infection caused by Sporothrix
schenckii (Dimorphic fungus) and closely related species.
• It occurs in both temperate and tropical zones.
• It occurs sporadically in North, South and Central America,
sub‐Saharan Africa, India, Egypt, Japan and Australia.
• It may occur in groups occupationally exposed to the organism, such
as workers using straw as packing material, forestry workers or
gardeners.
• It can occur at any age.

6. • There are different clinical variants seen in immunocompromised
patients and those with HIV/AIDS.
• In most cases of cutaneous sporotrichosis the fungus is introduced
into the skin or mucous membrane by trauma, as in a minor puncture
wound caused by a thorn or a splinter, or perhaps an insect bite.
• It is not contagious, although transmission has been recorded from
cats.
• Systemic sporotrichosis is rare, and the portal of entry is thought to
be the lung in these cases.
• The incubation is usually 8–30 days.

7. Clinical features
• The initial presentation of sporotrichosis is a single papule at a site of
injury, m/c on the hand.
• The lesion then becomes eroded or ulcerated with purulent drainage, but it
is generally not painful.
• Additional lesions appear weeks later, typically developing as dermal and
subcutaneous nodules and ulcers along the path of lymphatic drainage
(often up the arm). This is the well-known “sporotrichoid” pattern.
• The involved lymphatic vessels may become fibrosed.
• Lesions of “fixed” cutaneous sporotrichosis can have a granulomatous
appearance, often with ulceration, while disseminated lesions typically
present as subcutaneous nodules.

9. Pathology
• Histologically, suppurative and granulomatous inflammation is found
in the dermis and subcutis.
• The causative organisms are rarely evident; staining with fluorescent-
labeled antibodies may aid in recognition of the sparse cigar-shaped
yeast forms.
• Asteroid bodies are often seen.
• When numerous fungi are present (e.g. in an immunocompromised
host), budding yeast and cigar-shaped organisms can often be
visualized with PAS or silver stains.

11. Treatment
• Itraconazole (100–200 mg/day) for 3–6 months as the treatment of
choice for lymphocutaneous or fixed cutaneous sporotrichosis(Based
upon multicenter, non-randomized trials and case series, the Mycoses
Study Group of the Infectious Diseases Society of America has
recommended). The drug is generally safe and well tolerated, and the
relapse rate is low.
• Amphotericin B may be indicated in severe or disseminated disease.

12. • Oral saturated solution of potassium iodide (SSKI) has been used with
success. Although neither fungistatic nor fungicidal, SSKI is thought
to affect the host’s immune reaction to the organism. Its cost is low,
but it has a bitter taste as well as potential side effects including
iododerma, gastrointestinal upset, and thyroid suppression.
• Topical therapy is not effective.

13. 2. Chromoblastomycosis (Chromomycosis, Cladosporiosis ,
Verrucous dermatitis, Phaeosporotrichosis , Pedroso’s disease)
• It presents as a “verrucous dermatosis” and is caused by several genera of
dematiaceous (pigmented) fungi.
• Typically chronic in nature, an expanding verrucous plaque on the lower, or
• occasionally upper, extremity is the classic presentation.
• There are six fungi that are responsible for the vast majority of cases:
Fonsecaea pedrosoi, Fonsecaea compacta, Fonsecaea monophora,
Phialophora verrucosa, Cladophialophora carrionii, and Rhinocladiella
aquaspersa.
• The clinical presentation and colonial morphologies of each of these fungi
are very similar, and differentiation is based on microscopic and conidial
characteristics.
Amphotericin B, given intravenously and titrated up to 1
mg/kg/day,

14. Epidemiology and pathogenesis
• It is most commonly found in tropical and subtropical climates and
occasionally in temperate zones such as the US, Europe, and Canada.
Farmers, miners, and others working in rural areas are at increased
risk.
• Men 20–60 years of age are most often affected, probably due to
increased occupational exposure, which accounts for up to 90% of
cases.
• The fungi responsible for causing chromoblastomycosis are found in
the soil and in decaying plants and wood.
• The disease is typically contracted from trauma to the lower
extremities, including from not wearing shoes. As a result, the
organism is introduced into the dermis or subcutis via implantation.

15. Clinical features
• The disease usually presents as a papule or nodule on the leg, which
progresses to form a verrucous or granulomatous plaque (Fig. 77.22).
• The lesion may appear annular as the central portion resolves with
scarring.
• Several lesions may coalesce to form a multi-nodular mass, or
multiple lesions may exist as discrete islands scattered within
unaffected skin.
• It is thought that autoinoculation from scratching may be responsible
for the spread of infection.
• Typically, only one extremity is affected.
• A subcutaneous nodule or mass is occasionally the presenting lesion.
There are usually no constitutional symptoms.

17. Pathology
• Histologic findings- Pseudoepitheliomatous hyperplasia, intraepidermal
abscesses, and suppurative and granulomatous inflammation within the
dermis.
• Pathognomonic round, pigmented “Medlar bodies” or sclerotic bodies,
which are 6 to 12 microns in diameter and said to resemble “copper
pennies”, are present in the dermis, both extracellularly and within giant
cells.
• Detection of organisms via PCR of tissue samples has been reported for
the more common species.

19. Treatment
• Itraconazole alone (200–400 mg/day) administered for at least 6
months may have cure rates of up to 80–90%.
• 5-Flucytosine combined with either intravenous amphotericin B or an
oral triazole has been reported to be efficacious.
• In a small series, oral terbinafine (500 mg/day) given for at least 7
months was effective.
• Successful treatment with voriconazole or posaconazole has also
been described.

20. • For small lesions, surgical excision can be attempted together with
systemic antifungal treatment.
• Other treatment considerations include cryosurgery and the addition
of antibiotics if the lesion is secondarily infected.
• Some authors have advocated heat therapy based on evidence that
the causative organisms will not grow at high temperatures.

21. 3. Mycetoma (Madura foot, Maduromycosis)
• “Madura foot”, is a Greek term for “fungal tumor”.
• It is a granulomatous infection of dermal and subcutaneous tissue
that may extend to muscle or even bone.
• Mycetoma is differentiated from other mycoses by its characteristic
draining sinuses containing grains (sclerotia, sulfur granules) and local
edema.
• It is endemic to tropical and subtropical climates.
• Actinomycotic mycetoma is more prevalent in Central and South
America, while eumycotic mycetoma is more common in Africa.
• The typical patient is a man between 20 and 50 years of age.

22. • Three different subtypes exist:
• (1) actinomycotic mycetoma– caused by filamentous aerobic and
anaerobic organisms, e.g. Nocardia brasiliensis, Actinomadura
madurae;
• (2) eumycotic mycetoma– caused by true fungi
• (3) botryomycosis – caused by true bacteria, e.g. Staphylococcus
aureus, Pseudomonas spp.

23. Pathogenesis
• In most cases, causative organisms are acquired from the soil via direct
inoculation into the skin, leading to a dermal and subcutaneous fungal
infection.
• Deeper invasion to muscle or bone can subsequently occur.
• This process may occur rapidly or over many years.
• Sometimes, multiple sites of involvement appear in the vicinity of the original
lesion, likely due to multiple injuries rather than contiguous spread of disease.
• Lack of protective footwear, malnutrition, and exposed cuts and abrasions are
risk factors for infection.

24. Clinical features
• The foot is the most common site of infection, followed by the hand,
trunk, and scalp.
• Involvement is typically unilateral and begins as a painless papule.
• Once the subcutaneous tissues are infected, there is swelling and eventual
formation of purulent draining sinuses.
• The drainage contains the characteristic grains, which represent compact
masses of fungal colonies and vary in size from minute to almost a
centimeter in diameter.

25. • Invasion of deeper tissues then ensues, and sometimes cavities are
formed within involved bone.
• This disease is generally asymptomatic.
• All three subtypes can have a similar clinical presentation.

26. Pathology
• Pseudoepitheliomatous hyperplasia is a common histologic finding that
accompanies suppurative and granulomatous inflammation of the dermis
and subcutis as well as fibrosis.
• The characteristic grains represent tightly packed colonies of organisms.
Estimation of the diameter of the filaments comprising the grain as
compared to the size of the nuclei of surrounding inflammatory cells allows a
distinction between eumycotic (thicker filaments) and actinomycotic (thin,
fine filaments) mycetomas.
• Special stains, e.g. methenamine silver, Brown–Brenn, can aid in
distinguishing the subtype.

28. Treatment
• Eumycotic mycetoma must be diagnosed early and surgically excised
(including a large margin of normal surrounding tissue) before the
underlying bone becomes involved (Best outcome).
• Once the lesion has been excised, systemic antifungal therapy is
administered.
• Amphotericin B is not very effective.
• Depending upon the particular fungus, itraconazole, fluconazole,
voriconazole, posaconazole, ketoconazole, and terbinafine have been used
to treat eumycotic mycetomas.
• The medical treatment of actinomycotic mycetoma consists primarily of
streptomycin or amikacin plus either trimethoprim–sulfamethoxazole or
dapsone; therapy is continued for months to years.

29. 4. Lobomycosis (Keloidal blastomycosis, Lacaziosis,
Lobo’s disease)
• It is a chronic fungal infection characterized by cutaneous nodules
that resemble keloids.
• The causative organism, Lacazia loboi (previously known as Loboa
loboi).
• Lobomycosis occurs in Central and South America and has been linked
to contact with dolphins and a marine environment as well as soil and
vegetation in rural areas.
• Infection typically occurs after minor trauma and most often affects
men.

30. Clinical features
• It presents as asymptomatic, firm, keloid-like nodules that favor the
distal extremities, ears (especially the helices), and face but can also
affect the trunk.
• The lesions enlarge slowly over years, forming broad, multinodular
plaques that may have a smooth surface or (occasionally) a verrucous
appearance and ulceration.

31. Pathology
• Histologic evaluation shows highly characteristic chains of
thickwalled, yeast-like cells (known as “brass knuckles”) with
intercellularbridges.
• PAS or silver stains highlight these organisms, which can also be
identified in scrapings from the surface of skin lesions.
• Additional findings include a dermal granulomatous infiltrate and
either atrophy or pseudoepitheliomatous hyperplasia of the
epidermis.

33. Treatment
• Surgical excision or cryosurgery.
• Antifungal medications are typically ineffective.
• Clofazamine and itraconzole may be of some benefit for patients with
widespread disease.

34. Systemic mycoses
• Fungal infections that involve deep structures, and that have the
propensity to disseminate, usually via the bloodstream, from the
original focus of infection.
• They include two main groups of disease: the endemic mycoses and
the opportunistic systemic mycoses.

35. Pathophysiology
• Endemic mycoses are usually acquired via inhalation of the causative
organisms.
• In many cases, infections are asymptomatic and the primary infection
can only be detected in retrospect by a positive skin test, as in
tuberculosis.
• The main endemic mycoses are histoplasmosis (classic and African
types), blastomycosis, coccidioidomycosis, paracoccidioidomycosis
and infection caused by Talaromyces (previously Penicillium)
marneffei.

36. 1.Histoplasmosis( Darling’s disease, Cave disease , Ohio
valley disease, Reticuloendotheliosis)
• It is caused by the dimorphic fungus Histoplasma capsulatum var.
capsulatum.
• H. capsulatum is found in the soil in warm, moist climates, particularly the
Mississippi, Ohio, and St Lawrence river valleys in the US and Canada.
• Between 80% and 90% of persons from endemic areas may exhibit positive
histoplasmin skin testing.
• Birds, fowl, and bats are significant reservoirs for histoplasmosis. Because
the feces of these animals contain the organisms, the areas in which they
live can harbor infectious fungal spores. Caves, schoolyards, construction
sites, unoccupied buildings, and chicken coops tend to be high-risk areas.

37. Pathogenesis
• It is caused either by inhalation of H. capsulatum or, rarely, by direct cutaneous
inoculation of the fungus.
• Immunocompetent hosts can acquire the disease, but immunocompromised
hosts have a higher risk of dissemination.
• Clinical presentations include acute and chronic pulmonary histoplasmosis,
disseminated histoplasmosis, and primary cutaneous histoplasmosis.
• In disseminated histoplasmosis, the most common sites of involvement (after the
lung) are the spleen, lymph nodes, bone marrow, and liver; calcifications within
the lymph nodes, lungs, and spleen can serve as evidence of prior infection.
• Cutaneous manifestations most commonly result from disseminated disease.
• In Severe disseminated histoplasmosis there is impaired interferon-γ responses
due to mutations in IFNGR1 or STAT1, which encode interferon-γ receptor 1 and
signal transducer and activator of transcription 1, respectively.

38. Clinical features
• The skin lesions of histoplasmosis are nonspecific, making the diagnosis
virtually impossible with physical examination alone.
• When chronic disseminated histoplasmosis occurs in
immunocompetent hosts, the most common mucocutaneous finding is
oral ulcers but occasionally nodules and vegetative plaques are also
seen.
• Disseminated histoplasmosis in immunocompromised hosts (including
those with HIV infection) can present with mucocutaneous erosions or
ulcers as well as multiple erythematous papules or nodules with scale
or crust.
• In African histoplasmosis, a variant caused by H. capsulatum var.
duboisii, most patients present with mucocutaneous, subcutaneous,
and bone lesions.

39. Pathology
• Biopsy specimens demonstrates characteristic intracellular yeast
forms surrounded by a rim of clearing.
• Histiocytes and giant cells are the host cells in histoplasmosis, which
is in the differential diagnosis of “parasitized macrophages”.
• For easier identification of the fungi, tissue may be stained with PAS
or methenamine silver.

41. Treatment
• In primary, self-limited, asymptomatic histoplasmosis, treatment may
not be necessary.
• In symptomatic or disseminated disease, systemic antifungal therapy
is required.
• Amphotericin B, given intravenously and titrated up to 1 mg/kg/day,
is currently the most effective therapy and should be used initially for
severe disease, followed by itraconazole.
• In immunocompetent hosts with mild to moderate, stable disease,
itraconazole (200–400 mg/day) is the treatment of choice.
• HIV-infected patients with disseminated histoplasmosis require
lifelong maintenance therapy with itraconazole after initial treatment
with amphotericin B (if required for severe disease).

42. 2.Blastomycosis (North American blastomycosis
,Gilchrist’s disease)
• Blastomyces dermatitidis is a dimorphic fungus and the causative agent of
blastomycosis.
• This disease is endemic to North America, particularly the Mississippi and Ohio
river valleys, Great Lakes region, and southeastern states.
• All ages and genders affected
• Adult men are most likely to develop systemic infection, and children are more
likely to develop acute pulmonary blastomycosis rather than chronic or
cutaneous disease.
• The soil is an important source of infection, making those who have occupations
with frequent outdoor exposure at higher risk than the remainder of the
population.
• Blastomycosis also rarely occurs in other regions of the world, including Africa
and India.

43. Pathogenesis
• The lungs are typically the first site of infection, via inhalation of
organisms.
• In contrast to infections with other dimorphic fungi, secondary
• cutaneous dissemination is a common occurrence and may even be
the
• first sign of disease. Cutaneous manifestations are sometimes seen in
• the absence of overt pulmonary disease. Primary cutaneous
blastomycosis
• is uncommon and results from direct inoculation of the skin from
• trauma, such as in the laboratory.

44. Clinical features
• The most common cutaneous findings are papulopustules and well demarcated
verrucous plaques with scale-crust and pustules within their borders.
• Central ulceration, and more advanced disease may have an appearance similar
to pyoderma gangrenosum.
• The number of lesions can vary from one to several, and they tend to occur on
exposed skin.
• Healing begins centrally and is followed by cribriform scarring.
• Mucous membrane involvement
• Pulmonary infection is subclinical in up to 50% of patients with inhalation
blastomycosis.
• Bone involvement may occur and presents as osteomyelitis with rare extension
to muscle; genitourinary disease is uncommon.

45. Pathology
• Histologic examination of skin lesions demonstrates
pseudoepitheliomatous hyperplasia, suppurative and granulomatous
inflammation, and round yeast forms with characteristic broad-based
budding and thick, double-contoured walls.
• This budding pattern helps to differentiate blastomycosis from other
fungal infections.
• Methenamine silver and PAS staining allow better visualization of the
fungi within giant cells and neutrophilic abscesses.
• Similar budding yeast forms can be seen in sputum samples.

47. Treatment
• Amphotericin B, given intravenously and titrated up to 1 mg/kg/day,
• In mild to moderate non-CNS disease, itraconazole (200–400 mg/day)
is the treatment of choice.
• Fluconazole (400–800 mg/day), voriconazole, and posaconazole are
alternative medications.
• Ketoconazole is no longer routinely used.
• Occasionally, surgical treatment is indicated.

48. 3.Coccidioidomycosis(Valley fever, Desert rheumatism,
San Joaquin valley fever, California disease)
• Coccidioidomycosis is caused by two dimorphic and highly virulent pathogens
that are closely related, Coccidioides immitis and C. posadasii.
• Coccidioidomycosis occurs predominantly in the summer and fall in the
southwestern US, northern Mexico, and Central and South America;
• C. immitis is found primarily in California and C. posadasii elsewhere
• within these regions. The arthroconidia of Coccidioides spp. are inhaled
• via dust particles. Primary infection of the respiratory tract shows no
• gender or age preference, but disseminated disease is more common in
• Mexicans (5×), African-Americans (25×) and Filipinos (175×). Immunosuppressed
• states (e.g. HIV infection) and pregnancy also predispose
• to dissemination; Caucasian women are most likely to have more
• limited disease.

49. Pathogenesis
• C. immitis and C. posadasii are thought to be the most virulent of all
• fungi66. Infectious arthroconidia are inhaled and cause pulmonary
• infection in the vast majority of people living in endemic areas. The
• infection is asymptomatic in ~60% of affected individuals, while the
• remainder develop flu-like symptoms several weeks after exposure67.
• Dissemination to the skin and other organs can occur and depends on
• host factors (see above). Of note, similar to histoplasmosis, severe disseminated
• disease has been associated with an impaired interferon-γ
• response due to mutations in IFNGR1 or STAT1. Rarely, primary cutaneous
• coccidioidomycosis results from direct inoculation of the organism
• into the skin.

50. Clinical features
• Symptomatic primary inhalation coccidioidomycosis typically presents
• as a flu-like syndrome with fatigue, anorexia, fever, cough, and pleuritic
• chest pain. The cutaneous manifestations can occur alone or in combination
• with the above symptoms and are grouped into four
• patterns: • papules, pustules, plaques, abscesses, and sinus tracts favoring the
• face (Fig. 77.29A,B) • ulcerations • toxic erythema presenting as a diffuse macular eruption early
in
• the disease course and sometimes mimicking contact dermatitis • hypersensitivity reactions such
as erythema multiforme and
• erythema nodosum.
• In HIV-infected patients, the papules may resemble molluscum contagiosum.
• Bone and meningeal involvement can also occur, presenting as
• osteomyelitis and meningitis, respectively.

51. Pathology
• Biopsy specimens of specific lesions (types 1 and 2 above) reveal
characteristic endospore-containing spherules that measure 30–60
microns when mature.
• PAS and methenamine silver stains are helpful in identifying
immature spherules.
• A suppurative granulomatous reaction with histiocytes, lymphocytes,
and giant cells typically surrounds the spherules and released
endospores.

53. Treatment
• Systemic antifungal therapy is required for severe or disseminated disease.
• Amphotericin B is the most effective medication, and the intravenous dose
for severe disease is 1.0–1.5 mg/kg per day (higher dose for patients with
AIDS).
• Chronic disseminated disease requires prolonged therapy with itraconazole
(400 mg/day) or, in the case of meningitis, fluconazole.
• Voriconazole and posaconazole, which have in vitro activity against
coccidioidomycosis equal or superior to that of itraconazole, have been
used successfully (alone or in combination with liposomal amphotericin B)
to treat disseminated disease.
• Ketoconazole is no longer routinely used.

54. 4.Paracoccidioidomycosis(South American
blastomycosis,Brazilian blastomycosis)
• Paracoccidioidomycosis is caused by the dimorphic fungus
Paracoccidioides brasiliensis.
• It is endemic to the Central and South American countries of Brazil,
Argentina, Venezuela, Ecuador, and Colombia.

55. Pathogenesis
• P. brasiliensis is a dimorphic saprophyte that is found in the soil.
• In most cases, infection occurs via inhalation of the conidia from the
environment.
• Pulmonary disease ensues and can be followed by dissemination to
the skin, mucous membranes, gastrointestinal tract, spleen, adrenal
glands, and lymph nodes.

56. Clinical features
• In many patients, the primary pulmonary disease is subclinical to mild.
• When progressive disseminated disease occurs, mucocutaneous involvement is
commonly seen.
• Lesions are often painful and ulcerative or verrucous; they are typically found on
the face and in the nasal and oral mucosae.
• The ulcerations are referred to as “moriform stomatitis”.
• Lymphangitic spread may occur, resulting in cervical lymphadenopathy.
• Another clinical presentation is that of primary mucocutaneous
paracoccidioidomycosis. This frequently has an intraoral and perioral distribution
due to trauma from chewing contaminated sticks and leaves.
• Granulomatous lesions are typically seen. Primary cutaneous
paracoccidioidomycosis can also occur via direct inoculation of the skin, resulting
in the development of a verrucous papule or plaque or cutaneous ulceration.

58. Pathology
• The histologic features of paracoccidioidomycosis resemble those of
Blastomycosis.
• Pseudoepitheliomatous hyperplasia is accompanied by suppurative
and granulomatous inflammation.
• Yeast forms are found within and outside of giant cells. Large, thick-
walled organisms with multiple narrow-based buds may be seen,
leading to an outline that resembles a “mariner’s wheel”.

59. Treatment
• Amphotericin B, systemic azoles, and sulfonamides.
• Prolonged therapy is generally required.
• In disseminated disease, systemic therapy with amphotericin B or an
azole antifungal is indicated.
• Itraconazole is a preferred treatment because it provides reasonable
efficacy and side-effect profile, as well as low potential for recurrent
disease.
• Treatment with voriconazole can also be effective.
• Attempts to modulate the immune system via peptides derived from
the P. brasiliensis 43 kDa glycoprotein have been described.