**4. Clinical manifestations of H. capsulatum in HIV-infected patients**

For primary histoplasmosis, the forms of disease depend on the degree of host immunosuppression and the yeast inoculum. Persons with higher CD4 + T-cell count, under cART, exposed to H. capsulatum could have no symptoms or develop an acute mild form of illness more often not recognized if the patients are not living in an endemic area. In this type of patients, the disease is restricted to the lungs as in general population but occurs in less than 5% of the cases [18]. On the opposite side, HIVinfected patients with scarce immunity (CD4 counts < 150 cells/mm3 ) and not taking ART to develop progressive disseminated histoplasmosis. This is the most common profile of histoplasmosis, described in up to 95% of cases [62]. This pathway is common to exogenously acquired histoplasmosis as well as to reactivation and is determined by the hematogenous dissemination through the reticuloendothelial system (RES) that is containing parasitized macrophages. The term PDH describes the constant growth of organism in multiple organs rich in mononuclear phagocytes after the yeasts migrate from the lungs [45]. In endemic area, it is impossible to differentiate the reinfection to reactivation of dormant endogenous foci. Due to defective T-cell immunity in AIDS, reactivation seems to be the common pathway to histoplasmosis; however, autopsies series performed in the 1950s showed that although H. capsulatum is present in the lymph nodes, the cultures performed from these sites were sterile [45]. Thus, in endemic areas this evidence supports reinfection or progression of unrecognized histoplasmosis.

Depending on the degree involvement of RES and the underlying immune condition, different types of infection have been described. The acute disseminated form in AIDS patients is characterized by a high degree of RES involvement with closely packed macrophages engorged with yeast form [63] and have severe clinical implication as sepsis-like syndrome with septic shock, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation, neurological, hepatic, and renal involvement. Several cases of reactive hemophagocytic syndrome have been described [64] with bone marrow biopsy demonstrating the presence of histiocytes phagocytosing erythrocytes with poor outcome. Fever, weight loss, lymphadenopathy, hepatosplenomegaly, vomiting, and diarrhea are present as liver, spleen, bone marrow, and gastrointestinal tracts are the most commonly involved sites. Oropharyngeal and gastrointestinal mucosal ulcers are rarely present [63], but cutaneous lesions are described especially in Latin American late-diagnosed cases (66% versus up to 10% in the United States) [65]. The biopsy from cutaneous lesions (multiple disseminated papules, plaques, nodules, and pustules) could provide a simple and rapid diagnosis showing H. capsulatum yeasts intra- and extracellularly. CNS involvements such as encephalopathy, acute meningitis, or encephalitis are demonstrated in acute aggressive form of DPH with poor outcome [66]. Other atypical manifestations are described in acute form as chorioretinitis, colonic masses or anal ulcers, and pericarditis [45]. Acute disseminated forms rapidly evolve to death if untreated; therefore, rapid diagnosis and initiation of intravenous fungicidal therapy are required.

The second form of manifestation is subacute disseminated histoplasmosis, with a moderate involvement of the RES and also a moderate degree of macrophages parasitization [63]. Subacute or intermediate form is correlated with a longer interval of time when symptoms are present, in consequence a later presentation in the medical system. Manifestations are related to the development of focal lesions in various organs and associate with fever, weight loss, and weakness. Almost 25% of the patients have focal lesions in different organ systems, including gastrointestinal tract, endovascular, CNS, and adrenal glands [45, 63]. Gastrointestinal tract is commonly

affected in subacute form, in addition to hepatic and splenic involvement. Lesions could be observed from the oropharynx to anus [67], but autopsies series demonstrate that the most affected parts are the colon and cecum followed by the terminal ileum with unique or multiple, deep, or diffuse ulcerations that lead to perforation or strictures, polypoid, and nodular masses that are complicated with obstruction. Symptoms frequently present in AIDS patients are: diarrhea, crampy abdominal pain, and tenderness in association with fever. Ascites, lower intestinal bleeding, and intestinal obstruction of the ileum are rare. In case of severe diarrhea, signs of malabsorption are present. Endoscopic examination especially of the right colon with subsequent biopsies could establish the diagnostic of PDH and exclude other AIDSassociated opportunistic infections (gastrointestinal tuberculosis and CVM colitis), cancers (Kaposi sarcoma and adenocarcinoma), idiopathic inflammatory bowel disease (ulcerative colitis and Crohn disease), and sarcoidosis. Systematic colonic biopsies must be performed in HIV-seropositive patients who have unexplained GI tract pathology because it can establish diagnosis in up to 89% of cases [68].

Endovascular forms of subacute PDH are represented by endocarditis on native or prosthetic valves, infection of abdominal aortic aneurysms, or prosthetic vascular grafts. These manifestations are rare, but in HIV patients who develop embolic phenomena in context of negative blood culture and extended vegetations on the left-sided valves (aortic valve), clinician must consider histoplasmosis.

Central nervous system (CNS) is involved in subacute PDH under several forms: subacute or chronic meningitis, diffuse encephalitis, cerebritis, focal granulomatosis lesions of the brain or spinal cord, and stroke due to fungi emboli [69, 70]. The CNS involvement in PDH is rare and the most common form is basal meningitis, even meningeal syndrome is described in less than 10% of these patients. Four classical forms of CNS histoplasmosis have been described, three of them in subacute form: isolated subacute or chronic meningitis, subacute or chronic form that associates other localizations (liver, lymphatic nodes, mucocutaneous, etc.), and focal lesions in the brain or histoplasmoma [71]. CNS symptoms during PDH have a slow progression starting with headache, confusion, and altered sensorium followed in weeks by seizures, ataxia, and focal deficits. Similar to tuberculosis, basilar meninges are affected, thus oculomotor nerves II, IV and VI are involved with cranial nerve palsy. In evolution, hydrocephalus could appear that requests neurosurgical evaluation for insertion of a shunt after few weeks of antifungal treatment [70]. The cerebrospinal fluid (CSF) is clear with pleocytosis (between 10 and 100 cells and the predominance of lymphocytes), elevated protein level, and hypoglycorrhachia in up to 80% of the patients. Direct examination of CSF is frequently negative, but culture could confirm histoplasmosis if the quantity and the time of growth are sufficient (several weeks are needed with the delay of the diagnosis). In subacute form of PDH in HIV-infected patients, due to the lack of antibodies in CSF correlated with the immunosuppression grade; this test is positive in less than 70% of the cases but Ag detection could provide a positive result in more than 90% of the cases [71]. Still, no technique is validated for detection of Histoplasma capsulatum antigen in CSF, this test being available only for urine samples. Histoplasmoma determines mass effect and the computer tomography scan detects ring enhancement with the administration of contrast, like in abscesses (toxoplasmosis) or malignancies [62]. The stereotactic brain biopsy is needed, and the result confirms the diagnosis as yeasts are detected in the caseous center of the granulomas [72].

Autopsy series have described others lesions as every single organ can be affected in subacute form of PDF. The involvement of adrenal glands has been reported in up to 80% of the cases although symptoms are rarely present and most of the time

## *HIV-Associated Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.111389*

as unique manifestation [73]. At the gross examination, both adrenals are enlarged, which corresponded with the previously CT images performed. Focal areas containing parasitized macrophages can be found in both medulla and cortex. In severe infection, diffuse infiltration in parenchyma led to the destruction of both adrenal glands. Four categories of histopathological lesions have been described that are correlated with the host reaction against Histoplasma capsulatum: tuberculoid, anergic, mixed, and sequelae [74]. Adisson's disease with fever, malaise, nausea, vomiting, orthostatic hypotension, hyponatremia, and hyperkalemia occur in less than 10% of patients when extensive lesions have destroyed both adrenal glands.

Chronic progressive disseminated histoplasmosis is the third syndrome with the mildest RES involvement but also with the mildest macrophages parasitization [63], and is characterized by mildest and prolonged manifestation during years, occasionally intermittent and it is described only in adult people. Constitutional symptoms such as fatigue, weakness, gradual weight loss, malaise, lethargy, and low-grade fever are intermittently present. The pathognomonic sign is oropharyngeal ulcerations that are well delimited, deep, and painless. All the mucosal areas could be involved: oral cavity, lips, tongue, pharynx, nasal septum, larynx, labia, or penis. Biopsies performed for single lesions to exclude oral squamous carcinoma indicate granulomas with macrophages containing yeasts, but simple MGG-stained smears (May-Grunwald-Giemsa) or periodic acid-Schiff stains are useful to visualize Histoplasma capsulatum. Hepatosplenomegaly is present in almost a third of the patients, and in few cases, chronic granulomatous hepatitis has been described [75]. Chronic meningitis appears as single manifestation of the disease [45], in contrast to the subacute form where multiple organs are involved. Endocarditis, bone infection (septic arthritis and osteomyelitis), Addison disease, and pancytopenia caused by bone marrow suppression have been cited in literature as uncommon. Not recognized and treated, chronic PDH progresses to death.

Another distinct form is immune reconstitution inflammatory syndrome (IRIS) as a complication of starting cART in HIV-infected patients when a decay greater than 1 log in viral load associates inflammatory and atypical clinical features with signs and symptoms unexplained by a newly acquired infection or treatment failure [75, 76]. Both forms have been described as the immune system begins to recover following treatment: "unmasking" IRIS (flare-up of an underlying and previously undiagnosed histoplasmosis) and "paradoxical" IRIS (flare-up of a previously treated histoplasmosis). Compared to other pathogens, the incidence of histoplasmosis-associated IRIS is low (0.74 cases at 1000 HIV-infected person-years) and remain stable during the last 20 years in French Guyana where histoplasmosis is the most frequent opportunistic infection in HIV [76]. The clinical findings are polymorphic as in disseminated form with fever, lymph node enlargement, digestive, hematologic, respiratory, mucocutaneous manifestations and less frequent neurological, rheumatological, or ocular involvement [76].

Some clinical differences have been noted between the two variants, especially in Africa where H. capsulatum var. capsulatum coexists with H. capsulatum var. duboisii and HIV-epidemic remain the main health problem in the last decades. Due to the tropism of the variety duboisii for lymph nodes, skin, and bones, in HIV-infected patients, the dissemination of this yeast associates with classical PDH ulcers, nodules, psoriasis plaque, subcutaneous nodules, osteolytic lesions in the skull, ribs, vertebrae and enlarged lymph nodes [4].

Co-infections with other opportunistic infections have been described, due to the immunocompromised status of HIV-infected patients. In countries from Latin-America, the percentage of triple infections is very high: Columbia (51%), Brazil (43%), Argentina (42%), French Guyana (37–42%), and Panama (25%) [77].

The most reported is association with tuberculosis as this is the leading opportunistic infection related to HIV [77–80]. Both are able to spread and determine miliary forms and granuloma formation. The overlapping symptoms can delay the final and complete diagnosis. In this context, constitutional signs are frequently present with respiratory symptoms in only half of the patients despite that chest X-rays reveal infiltrates of the lungs [78]. Other common clinical findings associated with fever are: lymphadenopathy, hepatomegaly, splenomegaly, gastrointestinal pain, abnormal liver function tests, anemia, leukopenia, and thrombocytopenia [79]. If tuberculosis diagnosis is rapid by direct microscopic observation of acid-fast-bacilli (AFB), the histoplasmosis diagnosis confirmation is more difficult, primarily by histopathology if the patient is not living in an endemic area. Blood and bone marrow culture are useful to diagnose both disseminated diseases [79]. Co-occurrence of TB/histoplasmosis disseminated infections must be suspected by the persistence of the symptoms after completion of anti-Koch's regimen in patients with confirmed TB; thus, H. capsulatum must be tested from different specimens [80].

Other opportunistic infections (OI's) associated with histoplasmosis-HIV coinfection have been described: pneumocystosis [81], cryptococcal infection [82], cytomegalovirus infection, Salmonella infection, candidiasis, and toxoplasmosis [75]. Sometimes, more co-infections could be hosted by the same HIV-infected person [83]. As all of them are associated with severe immunodepression and have non-specific clinical signs and symptoms, clinicians must by aware of these possibilities and investigate in order to confirm the diagnostic and to provide appropriate treatment.
