**5. Diagnosis**

In non-endemic areas where clinicians and pathologists are not aware of this pathology, the diagnostic of histoplasmosis in HIV-infected patients is difficult due to the unspecific symptoms in progressive disseminated form. For clinicians, it is important to remember that even short exposure in endemic area should be a reason to consider histoplasmosis in HIV-infected patients, as early and rapid diagnosis followed by initiation of optimal treatment is able to improve survival.

In April 2020, WHO released a set of recommendations for the management of histoplasmosis among PLWHIV [1], which contain guidelines for the diagnosis and treatment with the aim to provide the same approach for the entire health system, not only for the countries that face the highest burden as North America, Central America, South America, and some countries from Asia and Africa.

According these guidelines, "test and treat" concept for detecting and treating all HIV-infected persons is the most important strategy as this reduce the number of opportunistic infections, including histoplasmosis. Further, among people living with HIV, "disseminated histoplasmosis should be diagnosed by detecting circulating Histoplasma antigen" on the basis that:


not able to differentiate the active from past infection; also, they cross-react with other antigens from Coccidioides, Paracoccidioides, or Blastomyces;


Urine antigen detection test is more sensitive than the serum antigen test for AIDS patients with disseminated histoplasmosis. Different publications showed that 92–100% of patients have antigenuria compared to almost 50–92.3% who present antigenemia [64, 84] depending on the type of assay. False-positive results in testing urinary antigen assay could appear in other mycoses as Blastomyces dermatitidis, Talaromyces marneffey, and Paracoccidioides brasiliensis because they have the same class of cell wall galactomannan, but not in aspergillosis [84]. In transplant recipients who received thymoglobulin or in cases associated with the presence of rheumatoid factor, the Histoplasma serum antigen could be false positive, and thus, urinary Ag is required [64].

Antigen detection is an important tool for monitoring the therapeutic response. In case of persistent antigenuria with failure to decrease after 1 month of treatment an ongoing infection is present [85]; meanwhile, increased titers should advise about the possibility of relapse [86]. For CNS histoplasmosis, antigen detection is a reliable to orientate the diagnosis as this becomes positive in less than one week combined with detection of antibodies from CSF and serum, as culture requires more than 2 weeks for growth [87].

However, the investigation of an HIV-infected person must be comprehensive, in order to evaluate the immune status of the patient and the extension of the disease. Also, other co-infection must be ruled out. Some unspecific biological abnormalities could indicate PDH as adjunct laboratory markers: very high level of serum lactate dehydrogenase (>600 UI/ml) [88], increased level of ferritin (>1000 ng/ml) [45, 89], increased AST level associated with increased alkaline phosphate and thrombocytopenia [88, 90], and hematuria and proteinuria [90].
