Clinical manifestations and diagnosis of acute/subacute paracoccidioidomycosis

INTRODUCTION — Paracoccidioidomycosis is a systemic endemic mycotic disease caused by thermally dimorphic fungi of the genus Paracoccidioides. Two species are recognized to cause paracoccidioidomycosis: Paracoccidioides brasiliensis and Paracoccidioides lutzii. The fungus has a geographic distribution limited to Central and South America, where paracoccidioidomycosis is the most frequent systemic endemic mycosis.

The clinical manifestations and diagnosis of acute/subacute (juvenile) paracoccidioidomycosis will be reviewed here. The clinical manifestations and diagnosis of chronic paracoccidioidomycosis, as well as the mycology, epidemiology, and treatment of paracoccidioidomycosis are discussed separately. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis" and "Mycology and epidemiology of paracoccidioidomycosis" and "Treatment of paracoccidioidomycosis".)

CLINICAL MANIFESTATIONS — Only a minority of patients (<5 percent) eventually develop clinically manifested disease. Following inhalation, Paracoccidioides typically causes asymptomatic pulmonary infection that may be detected by a positive paracoccidioidin intradermal test. If the infection is not contained by the host, the disease may evolve into one of two patterns: the acute/subacute form, which can appear as early as 45 days after an exposure [1]; or the chronic form, which represents reactivation of the primary infection and is most common [2]. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis".)

Acute/subacute paracoccidioidomycosis (also known as juvenile paracoccidioidomycosis) is almost always observed in children, adolescents, and adults under 30 years of age, and represents fewer than 10 percent of cases [3,4]. In children, it affects both sexes in equal numbers. This is in contrast to the chronic form, which is much more frequent in adult men. (See "Mycology and epidemiology of paracoccidioidomycosis", section on 'Epidemiology'.)

Signs and symptoms — Dissemination of infection to the reticuloendothelial system results in lymphadenopathy, hepatosplenomegaly, and/or bone marrow dysfunction (eg, aplastic anemia) [5,6]. Constitutional signs such as fever and weight loss are also seen. Less common features include bone and skin involvement (picture 1). In contrast to the chronic form, lung involvement is very unusual with the acute/subacute form.

Superficial lymph node involvement is most common in the cervical, axillary, and inguinal regions, and draining fistulae may develop (picture 1 and picture 2). Enlarged abdominal lymph nodes often cause diffuse abdominal pain and occasionally compression of various structures such as the biliary tract (jaundice), and intestines (partial obstruction, malabsorption).

A single-center retrospective study reported the clinical manifestations of 141 pediatric patients (<15 years old) with paracoccidioidomycosis. Generalized lymphadenopathy was the most frequent clinical manifestation (87.2 percent) followed by fever (75.2 percent), weight loss (64.5 percent), adynamia (34 percent), pallor (25.5 percent), hepatomegaly (23.4 percent), splenomegaly (19.1 percent), and skin lesions (16.3 percent) [6].

Laboratory abnormalities — In a study of 63 children with paracoccidioidomycosis, the following laboratory abnormalities were observed [5]:

●Anemia – 90 percent

●Hypergammaglobulinemia – 89 percent

●Eosinophilia – 76 percent

●Hypoalbuminemia – 73 percent

●Hyperbilirubinemia – 44 percent

●Mildly elevated transaminases – 20 percent

Clinical course — The course of acute/subacute paracoccidioidomycosis is generally more severe than the chronic form [3,5,7]. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Clinical manifestations' and "Treatment of paracoccidioidomycosis", section on 'Prognosis'.)

The clinical course progresses rapidly, and if left untreated, the patient's condition becomes seriously compromised within weeks to a few months [7]. In one study that followed 141 patients, there were eight deaths (5.7 percent); serum albumin was a predictor of survival, as almost all patients with a baseline serum albumin value ≥2.18 g/dL survived [6]. Sequelae in patients with acute paracoccidioidomycosis are infrequent and are mostly related to malabsorption from fibrosis of mesenteric lymph nodes.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of acute/subacute paracoccidioidomycosis includes lymphoma and systemic infections associated with generalized lymphadenopathy, hepatosplenomegaly, fever, weight loss and anemia. Infections that may have a similar clinical presentation include disseminated histoplasmosis, tuberculosis, syphilis, cat scratch disease, and a mononucleosis-like syndrome lasting more than 4 weeks (eg, Epstein-Barr virus, cytomegalovirus, Toxoplasma gondii). Primary human immunodeficiency virus (HIV) infection should also be considered in patients with risk factors.

DIAGNOSTIC TESTS — The diagnosis of paracoccidioidomycosis is based upon the microscopic visualization of fungal elements suggestive of Paracoccidioides spp and/or by culturing this fungus from clinical specimens [4]. Serologic testing can be useful both for diagnosis and for monitoring the response to therapy [8]. The tests used to diagnose acute/subacute paracoccidioidomycosis are identical to those used for chronic paracoccidioidomycosis, and are discussed in detail separately. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Diagnosis'.)

EVALUATION — Acute/subacute paracoccidioidomycosis should be considered in children or young adults (<30 years old) with the following clinical presentation (or a combination of them):

●Fever

●Weight loss

●Localized or generalized superficial lymphadenopathy

●Hepatosplenomegaly

●Abdominal masses (lymph nodes) with or without compressive manifestations

●Signs of bone marrow failure (especially anemia)

Approach to diagnosis — The diagnosis of paracoccidioidomycosis is sought in patients who present with suggestive epidemiological and clinical findings. A typical example would be a child or adolescent from a rural area who presents with fever, weight loss, and diffuse lymphadenopathy. The diagnosis of the acute/subacute form of paracoccidioidomycosis is most often established by direct examination and culture of material obtained by aspiration of enlarged superficial lymph nodes, as well as by results of serologic tests.

The initial evaluation should include all of the following:

●Imaging of affected areas to determine the extent of lymph node involvement (including the presence of compressive manifestations). All patients should be evaluated by abdominal ultrasound or abdominal computed tomography (CT). Chest CT is usually not performed and is important only if signs and symptoms suggest lung involvement (rare) or mediastinal lesion (eg, compression of superior vena cava). Gallium-67 scans may be of help in revealing bone lesions [9].

●Direct examination and culture of specimens obtained by aspiration or biopsy of enlarged lymph nodes are routinely performed.

●Serologic testing (preferably by quantitative immunodiffusion). Antibody titers in the serum (by immunodiffusion) are usually high (≥1:32) in patients with acute paracoccidioidomycosis. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Serologic tests'.)

In addition, patients should be assessed for the presence and severity of bone marrow failure, and nutritional status. Additional tests may be indicated depending on the presence of clinical findings suggestive of involvement of other organs (eg, central nervous system, gastrointestinal tract, adrenal, bone, joints).

IMMUNOCOMPROMISED HOSTS — Paracoccidioidomycosis in HIV-infected patients has some features in common with the acute/subacute form of the disease, such as widespread involvement and rapid progression [10]. In addition, patients with paracoccidioidomycosis and HIV may present with simultaneous lung involvement and generalized lymphadenopathy, making it difficult to differentiate between acute and chronic forms [11]. Chronic paracoccidioidomycosis in immunocompromised hosts is discussed in a separate topic review. (See "Clinical manifestations and diagnosis of chronic paracoccidioidomycosis", section on 'Immunocompromised hosts'.)

SUMMARY AND RECOMMENDATIONS

●Paracoccidioidomycosis is a systemic endemic mycotic disease caused by the thermally dimorphic fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii, which have a geographic distribution limited to Central and South America. (See 'Introduction' above.)

●Paracoccidioides typically causes asymptomatic pulmonary infection. However, if the infection is not contained by the host, the disease may evolve into one of two patterns: the chronic form, which represents reactivation of the primary infection, and the acute/subacute form. (See 'Clinical manifestations' above.)

●Acute/subacute paracoccidioidomycosis (also known as juvenile paracoccidioidomycosis) is almost always observed in children, adolescents, and adults under 30 years of age, and represents fewer than 10 percent of all cases of paracoccidioidomycosis. (See 'Clinical manifestations' above.)

●In acute/subacute paracoccidioidomycosis, dissemination of infection to the reticuloendothelial system results in lymphadenopathy, hepatosplenomegaly, and bone marrow dysfunction (eg, aplastic anemia). Constitutional signs such as fever and weight loss are common. (See 'Signs and symptoms' above.)

●The diagnosis of paracoccidioidomycosis is based upon the microscopic visualization of fungal elements suggestive of P. brasiliensis and/or by culturing this fungus from clinical specimens. Serologic testing can be useful both for diagnosis and for monitoring the response to therapy. (See 'Diagnostic tests' above and 'Approach to diagnosis' above.)