paracoccidioidomycosis
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Paracoccidioidomycosis (PCM), also known as South American blastomycosis, is a
fungal infection Fungal infection, also known as mycosis, is disease caused by fungi. Different types are traditionally divided according to the part of the body affected; superficial, subcutaneous, and systemic. Superficial fungal infections include common ti ...
that can occur as a mouth and skin type, lymphangitic type, multi-organ involvement type (particularly lungs), or mixed type. If there are
mouth ulcer A mouth ulcer (aphtha) is an ulcer that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by many different mechanisms, but usually there is no serious underlying cause ...
s or skin lesions, the disease is likely to be widespread. There may be no symptoms, or it may present with
fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, sepsis,
weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
, large glands, or a large liver and spleen. The cause is fungi in the genus '' Paracoccidioides'', including ''
Paracoccidioides brasiliensis ''Paracoccidioides brasiliensis'' is a dimorphic fungus and one of the two species that cause paracoccidioidomycosis (the other being ''Paracoccidioides lutzii).'' The fungus has been affiliated with the family Ajellomycetaceae (division Ascomyco ...
'' and '' Paracoccidioides lutzii'', acquired by breathing in fungal spores. Diagnosis is by sampling of
blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...
,
sputum Sputum is mucus that is coughed up from the lower airways (the trachea and bronchi). In medicine, sputum samples are usually used for a naked eye examination, microbiological investigation of respiratory infections and cytological investigations ...
, or
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
. The disease can appear similar to
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
,
leukaemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
, and
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
Treatment is with
antifungals An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...
;
itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth ...
. For severe disease, treatment is with
amphotericin B Amphotericin B is an antifungal medication used for serious mycosis, fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candida infections, candidiasis, coccidioidomy ...
followed by itraconazole, or
trimethoprim/sulfamethoxazole Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazo ...
as an alternative. It is
endemic Endemism is the state of a species being found in a single defined geographic location, such as an island, state, nation, country or other defined zone; organisms that are indigenous to a place are not endemic to it if they are also found elsew ...
to Central and South America, and is considered a type of
neglected tropical disease Neglected tropical diseases (NTDs) are a diverse group of tropical disease, tropical infections that are common in low-income populations in Developing country, developing regions of Africa, Asia, and the Americas. They are caused by a variety ...
. In Brazil, the disease causes around 200 deaths per year.


Signs and symptoms

Asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...
lung infection is common, with fewer than 5% of infected individuals developing clinical disease. It can occur as a mouth and skin type, lymphangitic type, multi-organ involvement type (particularly lungs), or mixed type. If there are
mouth ulcer A mouth ulcer (aphtha) is an ulcer that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by many different mechanisms, but usually there is no serious underlying cause ...
s or skin lesions, the disease is likely to be widespread. There may be no symptoms, or it may present with
fever Fever, also referred to as pyrexia, is defined as having a body temperature, temperature above the human body temperature, normal range due to an increase in the body's temperature Human body temperature#Fever, set point. There is not a single ...
, sepsis,
weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
, large glands, or a large liver and spleen. Two presentations are known, firstly the
acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse eff ...
or subacute form, which predominantly affects children and young adults, and the chronic form, predominantly affecting adult men. Most cases are infected before age 20, although symptoms may present many years later.


Juvenile (acute/subacute) form

The juvenile, acute form is characterised by symptoms, such as fever, weight loss and feeling unwell together with
enlarged lymph nodes Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In cli ...
and enlargement of the liver and spleen. This form is most often disseminated, with symptoms manifesting depending on the organs involved. Skin and
mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
lesions are often present, and bone involvement may occur in severe cases. This acute, severe presentation may mimic
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
,
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
or
leukaemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
.


Adult (chronic) form

The chronic form presents months to years after the initial infection occurs and most frequently presents with dry cough and shortness of breath. Other symptoms include excess salivation,
difficulty swallowing Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or liqui ...
, and difficulties with voice control. Upper respiratory tract mucosal lesions may be present, as well as increased mucus production and coughing up blood. Both pulmonary and extrapulmonary involvement is common. Up to 70% of cases have mucosal involvement, with lesions often found in the mouth,
oropharynx The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its struct ...
,
larynx The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
, and palate. Classic lesions are superficial painful granular
ulcer An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing o ...
s, with small spots of bleeding.


Cause

Paracoccidioidomycosis is caused by two species of fungi that can exist as a mold or yeast depending on temperature, ''P. brasiliensis'' and ''P. lutzii''. In protected soil environments, near water sources, that are disturbed either naturally or by human activity, ''P. brasiliensis'' has been epidemiologically observed (although not isolated). A known animal carrier is the
armadillo Armadillos (meaning "little armored ones" in Spanish) are New World placental mammals in the order Cingulata. The Chlamyphoridae and Dasypodidae are the only surviving families in the order, which is part of the superorder Xenarthra, along wi ...
. In the natural environment, the fungi are found as filamentous structures, and they develop infectious spores known as
conidia A conidium ( ; ), sometimes termed an asexual chlamydospore or chlamydoconidium (), is an asexual, non-motile spore of a fungus. The word ''conidium'' comes from the Ancient Greek word for dust, ('). They are also called mitospores due to the ...
. Human to human transmission has never been proven.


Mechanism

Primary infection, although poorly understood due to lack of data, is thought to occur through inhalation of the
conidia A conidium ( ; ), sometimes termed an asexual chlamydospore or chlamydoconidium (), is an asexual, non-motile spore of a fungus. The word ''conidium'' comes from the Ancient Greek word for dust, ('). They are also called mitospores due to the ...
through the respiratory tract, after inhaling fungal conidia produced by the mycelial form of ''P. brasiliensis''. This occurs predominantly in childhood and young adulthood, after exposure to agricultural activity. Infection may occur through direct skin inoculation, although this is rare. After inhalation into the
alveoli Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit. Uses in anatomy and zoology * Pulmonary alveolus, an air sac in the lungs ** Alveolar cell or pneumocyte ** Alveolar duct ** Alveolar macrophage * ...
, there is rapid multiplication of the organism in the lung tissue, sometimes spreading via the venous and lymphatic systems. Approximately 2% of people develop clinical features after the initial asymptomatic infection. The type of immune response determines the clinical manifestation of the infection, with children and
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
co-infected individuals most commonly developing the acute/subacute disseminated disease. Most of those infected develop a Type 1 T-cell (Th1) mediated immune response, resulting in
fibrosing alveolitis Idiopathic pulmonary fibrosis (IPF), or (formerly) fibrosing alveolitis, is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar tissue. It is ...
and compact granuloma formation that control fungal replication, and latent or asymptomatic infection. It then is thought to remain dormant in residual lung lesions and
mediastinal The mediastinum (from ) is the central compartment of the thoracic cavity. Surrounded by loose connective tissue, it is an undelineated region that contains a group of structures within the thorax, namely the heart and its vessels, the esophagu ...
lymph nodes. A deficient Th1 cell response results in the severe forms of the disease. In these individuals, granulomas do not form, and the affected person develops Th2 and Th9 responses, resulting in activation of
B lymphocytes B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
, high levels of circulating antibodies, eosinophilia, and
hypergammaglobulinemia Hypergammaglobulinemia is a medical condition with elevated levels of gamma globulin. It is a type of immunoproliferative disorder. Types Hypergammaglobulinemia is a condition that is characterized by the increased levels of a certain immunogl ...
. Lung involvement subsequently occurs after a dormant phase, manifesting in upper respiratory tract symptoms, and lung infiltrates on imaging. The commonest, chronic form, is almost certainly a reactivation of the disease, and may develop into progressive scarring of the lungs (pulmonary fibrosis). It can cause disease in those with normal immune function, although immunosuppression increases the aggressiveness of the fungus. It rarely causes disease in fertile-age women, probably due to a protective effect of
estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
.


Diagnosis

More than 90% of cases can be diagnoses with direct
histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
examination of tissue, such as sputum, bronchial lavage fluid, exudates and
biopsies A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a diseas ...
.
Histopathological Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...
study with Gomori methenamine silver (GMS) stain or hematoxylin and eosin ( H&E) stain revealing large yeast cells with translucent cell walls with multiple buds. In the juvenile form, lung abnormalities are shown in high-resolution CT scans of the lungs, whereas in the chronic form plain X-rays may show interstitial and alveolar infiltrates in the central and lower lung fields. Culture of ''P. brasiliensis'' takes between 20 and 30 days, requiring multiple samples and culture media. Initial culture can occur at room temperature, however after growth is noted, confirmation occurs by incubating at to 36-37 degrees to transform the fungus into yeast cells.
Antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
detection is useful both for acute diagnosis and monitoring. Gel immunodiffusion is commonly used in endemic areas, diagnoses 95% of cases with high specificity.
Complement fixation The complement fixation test is an immunological medical test that can be used to detect the presence of either specific antibody or specific antigen in a patient's serum, based on whether complement fixation occurs. It was widely used to diagnos ...
allows for a measure of severity of cases by quantifying the antibody level, and is thus useful for monitoring treatment response. It is however only sensitive for 85% of cases, and cross-reacts with '' H. capsulatum.''


Differential diagnosis

The disease can appear similar to
tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
,
leukaemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
, and
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...


Treatment

Both ''P. brasiliensis'' and ''P. lutzii'' are
in-vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology and ...
susceptible to most antifungal agents, unlike other
systemic Systemic fundamental to a predominant social, economic, or political practice. This refers to: In medicine In medicine, ''systemic'' means affecting the whole body, or at least multiple organ systems. It is in contrast with ''topical'' or ''loc ...
fungal infections. Mild and moderate forms are treated with
itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mouth ...
for 9 to 18 months, as this has been shown to be more effective, has a shorter treatment duration and is more tolerated. Acidic beverages have been shown to reduce absorption of itraconazole. Co-trimoxazole is a second line agent, and is preferred for those with brain involvement, and during pregnancy. For severe cases, intravenous treatment with
amphotericin B Amphotericin B is an antifungal medication used for serious mycosis, fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candida infections, candidiasis, coccidioidomy ...
is indicated, for an average of 2 to 4 weeks.
Prednisolone Prednisolone is a steroid medication used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthrit ...
prescribed at the same time may reduce inflammation during treatment. Patients should be treated until stabilisation of symptoms, and increase in body weight. Advice in regards to nutritional support, as well as smoking and alcohol intake should be provided.
Adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androge ...
, if found, is treated with corticosteroids. Clinical criteria for cure includes the absence or healing of lesions, stabilisation of body weight, negative as well as negative autoantibody tests. There is insufficient data to support the benefits of above drugs to treat the disease.


Epidemiology

Paracoccidioidomycosis is endemic in rural areas of Latin America, from southern Mexico to Argentina, and is also found in Brazil, Colombia, Venezuela, Ecuador and Paraguay. An epidemic outbreak has never been observed. It has the highest prevalence of all systemic mycoses (fungal infections) in the area. As many as 75% of people in endemic areas have been estimated to be infected with the asymptomatic form (up to 10 million people), with 2% developing clinically significant disease. Morbidity and mortality is strongly associated with patient's socioeconomic background, with most adult patients being male agricultural workers. Other risk factors include smoking, alcohol use, HIV co-infection or other immunosuppression. 80% of reported cases are in Brazil, in the southeast, midwest, and south, spreading in the 1990s to the Amazon area. Most of the remaining infections are in Argentina, Colombia and Venezuela. Most epidemiological reports have focused on '' P. brasliensis,'' with '' P. lutzii'' epidemiology poorly understood as of 2015. Rising cases have been linked to agriculturalization and deforestation in Brazil, urbanisation to peripheral city areas with poor infrastructure, as well as increased soil and air humidity. One Brazilian indigenous tribe, the Surui, after changing from subsistence agriculture to coffee farming showed higher infection rates than surrounding tribes. There have also been reports in non-endemic areas with the rise of eco-tourism, in the United States, Europe and Japan. All reported cases were returned travellers from endemic regions.


History

Lutz-Splendore-de Almeida disease is named for the physicians
Adolfo Lutz Adolfo Lutz (6 October 1855 – 18 December 1940) was a Brazilian physician, father of tropical medicine and medical zoology in Brazil, and a pioneer epidemiologist and researcher in infectious diseases. Life Lutz was born in Rio de Janeiro, on ...
, Alfonso Splendor (1871–1953), an Italo-Brazilian Parasitologist and Floriano Paulo de Almeida (1898–1977), a Brazilian Pathologist specializing in Pathologic Mycology (Study of Infectious Fungi), who first characterized the disease in Brazil in the early 20th century.


See also

* North American blastomycosis


References


External links

{{Mycoses Animal fungal diseases Mycosis-related cutaneous conditions Tropical diseases Fungal diseases