Journal of Advances in Medicine and Medical Research

33(3): 115-144, 2021; Article no.JAMMR.65200 ISSN: 2456-8899 (Past name: British Journal of Medicine and Medical Research, Past ISSN: 2231-0614, NLM ID: 101570965)

Disseminated ; A Threat in Advanced HIV Disease Population in Sub-Saharan ?

Christine E. Mandengue1*, Bassey Ewa Ekeng2 and Rita O. Oladele3

1Department of Internal Medicine, Dermatology Unit, Cliniques Universitaires des Montagnes, Université des Montagnes, Bangangté, Cameroon. 2Department of Medical Microbiology and Parasitology, Teaching Hospital, University of Calabar, Calabar, . 3Department of Medical Microbiology and Parasitology, College of Medicine, University of Lagos, Lagos, Nigeria.

Authors’ contributions

This work was carried out in collaboration among all authors. Author CEM conceived the article and drafted the initial outline and finalized the manuscript. Author BEE added articles and revised editing English. Author ROO reviewed the manuscript and corrected editing English. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/JAMMR/2021/v33i330825 Editor(s): (1) Dr. Muhammad Torequl Islam, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Bangladesh and Ton Duc Thang University, Viet Nam. Reviewers: (1) Berhanu Bekele Abuwa, Hawassa University, Ethiopia. (2) D Nagaraju, Govt. Degree College Eturngaram, India. (3) Sachin Rohane, Dr. Babasaheb Ambedkar Technological University, India. Complete Peer review History: http://www.sdiarticle4.com/review-history/65200

Received 10 December 2020 Review Article Accepted 13 February 2021 Published 02 March 2021

ABSTRACT

Background: Histoplasmosis is a neglected acquired immune deficiency syndrome (AIDS)- defining disease in sub-Saharan African countries, which is commonly misdiagnosed as tuberculosis (TB) due to similar imagery and clinical features; patients usually receive presumptive anti-TB treatment that is considered as anti-TB treatment failure. Patients with advanced human immunodeficiency virus (HIV) disease (AHD), CD4<200/mm3 or World Health Organisation clinical stage 3 or 4, develop disseminated histoplasmosis (DH) diagnosed at a late stage or at post- mortem, owing to poor clinical suspicion, lack of rapid diagnosis tools to offer rapid and accurate results, and non-availability and accessibility of appropriate antifungal medications. We report 31 cases of DH amongst patients with AHD in sub-Saharan African population from the literature, highlighting the challenging care issue in sub-Saharan Africa. ______

*Corresponding author: E-mail: [email protected], [email protected];

Mandengue et al.; JAMMR, 33(3): 115-144, 2021; Article no.JAMMR.65200

Results: Out of 31 reported cases 64.51% (20/31) were caused by var capsulatum, 48.38% (15/31) being immigrants in Europe, Canada and Japan, with 41.93% (13/31) mortality, and 6 cases having no reported outcome. The poor index of suspicion on the part of clinicians; the lack of skilled laboratory personnel and rapid and accurate diagnosis tools of histoplasmosis for a proper detection of either classical or African histoplasmosis coexisting in many sub-Saharan African countries; and the non-availability and accessibility of appropriate antifungal medications were the most challenges in caring DH in advanced HIV disease population in sub-Saharan Africa. Conclusion: there is a need for prompt and routine screening of advanced HIV disease patients in sub-Saharan Africa for histoplasmosis as an AIDS-defining illness.

Keywords: Advanced HIV disease; AIDS; antifungal medications; disseminated histoplasmosis; histoplasma diagnosis tools; sub-Saharan Africa.

ABBREVIATIONS PDH :progressive disseminated histoplasmosis ≈ : consistent with PTH :parathyroid hormone IRS: immune ADP : adenopathy reconstruction syndrome AFB : acid fast bacilli RF : renal failure AH : African histoplasmosis TMP/SMX :trimethoprim-sulfamethoxazole AHT : arterial hypertension VL : viral load ALT : alanine aminotransferase NR : Non-revealed ATB : antibiotic ATF: antifungal treatment ART : antiretroviral treatment 1. INTRODUCTION AST : aspartate aminotransferase ARDS : acute respiratory distress Human histoplasmosis is an invasive cART :conventional caused by a , Histoplasma ART CMV : cytomegalovirus capsulatum (Hc), occurring at an increasing rate CT : computed tomography with the human immunodeficiency virus (HIV) CXR : chest x-rays epidemics with a high death rate in patients. In a GC : general condition study by Adenis et al (2014), the death rates DE : direct examination observed in HIV-associated histoplasmosis were DAH : disseminated African histoplasmosis 45.3% with 16.8% of early death in French DIC :disseminated intravascular Guiana [1]. coagulation EBV : Epstein Barr virus Classically, two types are encountered in F/U : follow-up humans: histoplasmosis due to Histoplasma GFR : glomerular filtration rate capsulatum var. capsulatum (Hcc), known as HAART : highly active classical histoplasmosis, which is endemic in ART Hb : hemoglobin North and Latin America and can also occur HMG : hepatomegaly worldwide, and African histoplasmosis due to HSM : hepatosplenomegaly Histoplasma capsulatum var. duboisii (Hcd) HVB : hepatitis B virus which is found mainly in Africa. Both types of HT : hypertension histoplasmosis coexist in parts of west and IRS : immune reconstitution syndrome central African countries [2]. LDP : lymphadenopathy LN : Patients with advanced HIV disease (PAHD), NR : non revealed CD4 <200/mm3 or World Health Organization PLTS : platelets (WHO) clinical stage 3 or 4, develop TSP : total serum protein disseminated histoplasmosis (DH), commonly SM : splenomegaly associated with a poor prognosis [3,4]. Despite TB : tuberculosis being classified as an AIDS-defining illness in US : ultrasonography 1987, and a major cause of death in PAHD, PBN : bronchopneumopathy histoplasmosis remains a neglected infection in PBS : peripheral blood smear most African countries, owing to lack of clinical PCR : polymerase chain reaction suspicion on the part of practitionners, lack of

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skilled laboratory personnel and infrastructure to the 46 African countries designated by UN as make diagnosis, and poor availability of sub-Saharan Africa), and HIV/AIDS combined antifungal medications [5,6]. Moreover, owing to with terms relevant to DH including broad terms similarities between histoplasmosis and such as `diagnosis' and `management'. The tuberculosis (TB), most advanced AIDS patients Boolean operator `AND' and `OR' were used to with presumptive TB receive anti-TB treatment combine and narrow the searches. The even when sputum acid fat bacilli (AFB) and/or references in all relevant papers were reviewed GeneXpert is negative; DH is then diagnosed in for additional publications that may not have late stage or at post-mortem. A report by Oladele been cited elsewhere (`snow balling'). et al (2017) [7] revealed an 8.7% prevalence of chronic pulmonary in a cohort of 3. RESULTS AND DISCUSSION patients being managed as smear negative/TB treatment failure. How many of these patients Table 1 which is a non-exhaustive case-patients could have had histoplasmosis? A number of reported in SSA and from Sub-Saharan Africans PAHD who are lost to follow-up might have died living in the West [10-31], gives a caricature of of DH without being diagnosed. histoplasmosis in PAHD.

A total of 31 cases-patients in AHD with CD4 < Estimating the true burden of histoplasmosis in 3 sub-Saharan Africa (SSA) is difficult owing to the 50/mm .were captured, with 48.38% (15/31) paucity of data. However, few publications and reported in African immigrants in Europe, non-published papers reported its existence in Canada and Japan, with a mean age of 34.32 Africa in both HIV negative and positive persons, and 41.93% (13/31) mortality. It appears in Table and in PAHD. Oladele et al (2018) reported a 1 that 67.7% (21/31) of classical histoplasmosis total of 470 documented cases of histoplasmosis (Hcc) were recorded while 32.25% (10/31) of in Africa based on literature research, in both HIV patients were infected with African positive and negative persons, and a total of histoplasmosis (Hcd). It is known that despite 32/735 (4.4%) positive histoplasmine skin test in HIV epidemic in SSA, Hcd is not commonly a similar population study in Nigeria [5,8]. Two described as acquired immunodeficiency studies from Cameroon (2015 and 2019) syndrome (AIDS) defining illness, most cases reported respectively 13% [9] and 26%1 of DH in being reported from African immigrants. It is also PAHD. The endemicity of HIV and TB and the pointed out from Table 1 that in most patients DH existence of histoplasmosis in SSA, necessitates revealed a background of advanced AIDS, in late our concern for prompt diagnosis and stage with fatal course or at post mortem. These appropriate management of histoplasmosis. challenges are directly linked to: 1) DH Currently, to the best of our knowledge, most commonly misdiagnosed as TB; 2) DH countries in SSA have not included diagnosis presenting as a persistent fever of unknown and treatment of DH in their HIV package of care etiology in patients with unknown HIV status, and for PAHD. revealing AHD; 3) DH associated with coinfections; 4) The laboratory tools of diagnosis In this study we highlight the challenging care and lastly; 5) The difficulties of DH care and issue of histoplasmosis in PAHD in SSA. treatment.

2. METHODOLOGY 3.1 DH Misdiagnosed as TB

A search of literature on DH in HIV-infected TB is one of the commonest opportunistic Africans preceding 30 September 2020 were infection in SSA, where both TB and HIV performed using African Journals Online (AJOL), infections are highly endemic, and are both Google Scholar, PubMed, Cochrane Library, considered a cause of death among people living Africa-Wide: NiPAD, CINAHL (accessed via with HIV (PLHIV) [4,32]. Moreover, clinical and EBSCO Host) databases, and grey literature to imagery similarities between TB and identify all published papers regarding the topic. histoplasmosis lead to mistakes in advanced Articles published in other languages (e.g., AIDS population, histoplasmosis being French and Italian) were considered if they were misdiagnosed as TB. Consequently, patients cited in any of the databases searched. The main experience automatic presumptive anti-TB search comprised individual searches using treatment based only on clinical diagnosis of TB detailed medical subject heading (MeSH) terms despite being negative for sputum GeneXpert for DH, Sub-Saharan Africa (also the names of test, and resulting in “anti-TB treatment failure”.

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Nine reported case-patients with histoplasmosis discriminating between both infections in a were clinically diagnosed and initially and context on AHD [36-38]. unsuccessfully treated for TB. DH (Classical or African types) was finally detected in late stage Only one documented case-patient has been and revealed advanced AIDS (case-patients 1, 2, reported in Table 1 (case-patient 16) presenting 3, 5,7,14, 26, 27 and 28), with a fatal course of with a 1-year history of prolonged fever of the patient (case-patients 1, 2, 7, and 27), or at unknown origin, weight loss and wasting, and postmortem (case-patients 5 and 14). This tested positive for HIV; DH and TB revealed situation is mainly linked to the ignorance of advanced AIDS. Unfortunately, the outcome of histoplasmosis by clinician practitionners, the the patient was not precised. focus of African governments on TB or lack of government engagement that prevents any The co-infection might be under-reported in SSA significant developments with respect to the owing to misdiagnosis, endemicity of TB infection other major causes of death in AIDS patients, and similarities between both infections. namely histoplasmosis. It is noteworthy that two However, Oladele reported in 2018 TB case-patients late diagnosed for DH were cured associated histoplasmosis in Africa with (case-patients 26 and 28). frequencies from 8% to 15% [5]. Thus, a high index of suspicion is mandatory in SSA 3.2 DH Presenting as a Persistent Fever countries, along with availability of accurate tools of Unknown Etiology in Patients with of diagnosis to disclose the co-infection for Unknown HIV Status accurate treatment.

Symptoms of DH are nonspecific and are often 3.4 DH and Other Co-infections indistinguishable from those of other febrile illnesses like malaria, bacterial pneumonia, or Other infections and parasites associated with other undiagnosed infections in African countries. DH are reported on Table 1: cerebral toxoplasmosis, Fusarium verticillicoïdes, Due to low financial conditions and lack of health Mycobacterium avium, intestinal Strongiloides insurance schemes in most SSA countries, stercoralis, and disseminated cytomegalovirus patients pay from pocket for care that is not infection (Case-patients 8, 11, 12, and 15). They covered in the antiretroviral therapy (ART) appear as minor condition though death was programs. They are thus exposed to self- recorded in patient 8 with cerebral toxoplasmosis medication in cases of fever, without any and disseminated African histoplasmosis co- detection of the disease. This leads to a delay in infection, due to acute respiratory syndrome and the diagnosis and treatment of histoplasmosis. disseminated intravascular coagulation. As previously reported in French Guiana and in

India [33,34], and as shown in Table 1 are 10 case-patients (4, 11, 13, 15, 16, 17, 21, 23, 29 3.5 The Laboratory Tools of Diagnosis and 30) with unknown HIV status presenting with fever ≥ 1 week that were later discovered to have Laboratory tests used for the diagnosis of developed DH revealing a background of DH in PAHD include mycology culture, advanced AIDS (CD4 < 50/mm3) at late stage histopathology of affected organs, cytology of with fatal course. Diagnosis of DH was mainly body fluid or aspirates, and molecular techniques performed by biopsies of skin lesions, [39-43]. “accidently” by routine peripheral blood film, and at post-mortem. DH should therefore be Culture in Sabouraud medium is the gold screened in advanced AIDS patients with standard, but takes up to 8 weeks to yield growth prolonged fever [35]. of colonies; the method is risky (inhalation of spores) for laboratory personnel and requires a 3.3 DH and Co-infections in AHD laboratory with biosafety level 3 safety equipment and facilities [39-43]. 3.3.1 DH and TB co-infection Histopathology demonstrates the presence of DH and TB co-infection seems more frequent in cells in tissue biopsies, but with a risk of advanced AIDS patients in Latin American misidentification with other pathogens, namely countries with frequencies from 2% to 38% and , Penicillium marneffei, the same symptoms although several studies , , tried unsuccessfully to identify clinical patterns Toxoplasma gondii, Leishmania donovani, and

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Cryptococcus neoformans; the use of special Histoplasma antigen detection tools is not yet histochemical stains like Periodic Acid Schiff available in most SSA countries. It was used only (PAS) and Gomori methenamine silver (GMS) in Tanzanian specimens (serum and urine), facilitates differentiation between these testing being performed in the USA (Miravista pathogens by highlighting Hc yeast wall [39-43]. Diagnostics, Indianapolis) [48]. Making this tool Hc stains poorly with Gram stain and is rarely widely available and accessible in SSA countries detected by this modality; Calcofluor white, a would reduce the burden of histoplasmosis fluorescent stain that binds chitin in the cell wall mortality in advanced AIDS patients. of all fungi is more useful [41]. Meanwhile Hcc are ovoid, 2-4µ in size, with thin Diagnosing DH and TB co-infection is a nonrefractile cell walls and a narrow-base challenge in AHP in SSA countries without rapid budding, predominantly phagocytosed within diagnostic tools. Only one documented case- macrophages and histiocytes, seen in clusters in patient (case 16) has been reported on Table 1. many organisms but sometimes in extracellular TB testing was performed by culture of sputum spaces; although Hcd is larger, 6-12µm and while skin biopsy detected Histoplasma sp. easily distinguishable from the more common Direct microscopy is still widely used and variety [39-42].]. provides quick results with strong performance for TB and histoplasmosis, but it seems not Cytology of tissue aspirates or fine-needle appropriated for the diagnosis of histoplasmosis aspiration and fluids stained with GMS or PAS [38,46]. Making Histoplasma antigen and TB often show narrow-based budding yeast cells LAM Ag readily available in SSA countries, will mainly within macrophages [41]. aid quick detection in PLHIV at risk of developing both infections, or presenting with signs and PCR techniques have a sensitivity and specificity symptoms of TB in advanced AIDS situation. for DH, but not yet used routinely [39-43]. 3.6 DH Care and Treatment Histoplasma antigen detection validated in 2019 and included in the WHO essential diagnostic list Amphotericin B and itraconazole are both the has become a leading tool to diagnose most effective antifungal fungicidal medications histoplasmosis in AHP [43-46] with rapidity and indicated for the first-line treatment of overall sensitivity and specificity of 95%-97%, histoplasmosis, and recommended by the being more sensitive in urine than in serum, and Infectious Diseases Society of America (IDSA) no need of laboratories with higher levels of for treatment induction while waiting for biocontainment [6,38,41,42,46]. laboratory confirmation in a patient with a strong suspicion of histoplasmosis [38,40,49,50]. Table 1 reports that DH has been diagnosed mostly by direct examination using staining with For moderately severe to severe disease, PAS, GMS, H&E, Mucicarmin, or Giemsa stains, liposomal amphotericin B (3.0 mg/kg daily, 1–2 on tissue biopsies or aspirates, or by culture on weeks) is used, then switched to oral Sabouraud medium, or medium sometimes not itraconazole (200 mg 3 times daily for 3 days and often specified. PCR was performed in only four then 200 mg twice daily for a total of at least 12 case-patients (6, 8, 19 living in the West; and 29 months); deoxycholate amphotericin B (0.7–1.0 at Senegal). Apart from Cameroon where mg/kg daily) may be an alternative in patients cultures were performed at the Pasteur Institute who are at a low risk for nephrotoxicity in a biosafety level 3 safety laboratory, only direct [38,49,50]. examination were used in other SSA countries. Routine peripheral blood smear also detected Itraconazole is indicated for mild to moderate DH “accidently” in four cases (12, 21, 23 and 29), disease (200 mg 3 times daily for 3 days, then the fourth being confirmed by PCR. Stained twice daily for at least 12 months) treatment blood film may detect DH in about 40%, but monitoring being recommended for 12 months should not be used in early stages or with low after the end of the therapy to detect early signs fungal burdens, owing to its low sensitivity [47]. of relapse, by checking blood levels of Cultures of buffy coat confirmed DH in one case- itraconazole and monitoring of Histoplasma patient (case 11). This method commonly used in antigen concentrations on sera or urine [49,50]. Latin America could be an alternative in SSA in case a biosafety level 3 safety laboratory is Most case-patients treated with these available [6]. medications in this study were living in the West.

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Only case-patients 1 and 2 from Congo with 4 deaths and 1 healing, outcome not being were treated with deoxycholate amphotericin B revealed in 3 patients; ≥ 2 risk factors were found and/or itraconazole, without treatment in 19 patients, with 7 deaths and 9 healings, monitoring, with fatal outcome in patients. These outcome not being indicated in 1 patient, and 2 medications are costly and still unavailable in patients being lost to follow-up who could have most SSA countries despite itraconazole was died. It is noteworthy that patients are commonly added to the WHO list in 2017. Fluconazole lost to follow-up in SSA countries, owing to the which is available in generic is commonly used in low financial income of patients and/or their high doses as in case-patient 24, from relatives that support the treatment cost, and the Cameroon. lack of health insurance schemes; they usually die at a supposed cost-effective native treatment Treatment of DH and TB co-infection is center. challenging. Table 1 shows that the treatment- protocol of case-patient 16 was not clearly Complications during the treatment course as described and he was finally lost to follow-up; he fever, ascites, peritonitis, immune reconstitution may have died as did all case-patients treated syndrome, renal failure, acute respiratory concomitantly with antifungal treatment and anti- distress syndrome associated to disseminated TB treatment. intravascular coagulation, and invasive treatment e.g. laparotomy and splenectomy were recorded The WHO released guidelines 2017 (screening, on Table 1. They are additional challenges in DH diagnosis and treatment of the most common cure and treatment, along with clinical opportunistic diseases in HIV-infected people) [4] presentation mimicking public health infectious had not indicated the treatment of histoplasmosis disease such as lepra. and TB co-infection in AIDS persons, thus making it more difficult as the treatment DH is a serious infection in patients with AHD, monitoring for both DH and TB is unavailable in with heterogenic presentation, single algorithms SSA. It is known that histoplasmosis still being difficult to extract. Thus clinical medications, amphotericin B and itraconazole, expertise still remains important. Authors from are respectively nephrotoxic and hepatotoxic; French Guiana recently tried to point out four itraconazole is also associated with anti-TB major “typical’’ proteiform expressions of DH, treatment drug interactions; rifampicin and covering the most frequent situations rifabutin may decrease itraconazole blood levels encountered in this population, each of which leading to treatment and clinical failure [49-52]. leading to search for distinct differential Replacing rifampicin with a fluoroquinolone diagnoses [55]. especially moxifloxacin used in the treatment of multidrug resistant and extensively drug-resistant - first situation: patients with a digestive TB, might obviate the drug-drug interaction presentation (differential diagnose: although extending the treatment for as long as intestinal pathogens, endoscopy) 12-18 months [38,52]. Thus repurposing another - second situation: patients with fever, fluoroquinolone could be an alternative in general condition impairment but no focal SSA countries in case moxifloxacin is not signs (differential diagnose: typical available. mycobacterial infections) - third situation: patients with enlarged Clinical or biological risk factors for poor lymph nodes (differential diagnose: prognosis or death in PAHD are well-defined tuberculosis and lymphoma) [50,53,54]. They are recorded on Table 2 in 27 - fourth situation: patients with a pulmonary case-patients, although not commonly quantified. presentation (differential diagnose:

tuberculosis, and bacterial According to the Centers for Disease Control and pneumonia) Prevention, the presence of only one risk-factor predicts a poor prognosis or death in patients with advanced AIDS [53]. Screening these situations and risk factors for death in patients could additionally help Table 3 shows outcome of the case-patients. preventing fatal outcome in DH in AHD Only 1 risk-factor was found in 8 case-patients, population in SSA.

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Table 1. A caricature of histoplasmosis in PAHD in sub-Saharan Africans illustrating the challenge care issue: misdiagnosis of histoplasmosis as tuberculosis, lack of accurate diagnosis tools for definite diagnosis of histoplasmosis, lack of effective antifungal medications and treatment monitoring, poor clinical course with complications leading to death

Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART Chandenier et al, 1995 [16] 1 Congo, 26 F Unknown HIV Presumptive TB (skin abscesses AH Amphotericin B (4, 4 g in 6 Death status, 04 and large cervical ADP) revealing AIDS at months), Itraconazole 300 mg/j months HIV test positive late stage (duration NR), Pregnancy Yeast ≈ Hcd (pus and biopsy misdiagnosed as Poor clinical course: abscesses, stains NR) TB - Remissions and relapse of skin Others: Pseudomonas from lesions and abscesses. abscess of the lobula of the ear - Febrile ascitis: anti TB and ATF treatment stopped after 1.5 months, AGC, bloody vomiting. 2 Congo, 44 M Unknown HIV Skin lesions: ulcerative, and DAH Ketoconazole 600 mg/dx 2 ½ Death status. crusty lesions, and molluscum- revealing AIDS at months presumptive TB like growths. HIV test positive. late stage Poor clinical course: political (skin lesions, Numerous yeasts ≈ Hcd on skin misdiagnosed as crisis, financial distress, closure massive weight biopsies (stains NR) TB of the hospital, several lost to lost and LDP), follow-up and complications: unsuccessful anti - Peritonitis, skin involvement; TB treatment numerous Hcd on pus; Amphotericin B (total dose 3,5g x 11 months Itraconazole 3tablets/d x 3weeks, - Severe abdominal pain, and hematemesis 3 Congo Unknown HIV PGC, SM. Skin lesions: scars of DAH Amphotericin B 1 mg/ kg within NR 41 M status. ophthalmic zona; nodules; MC- revealing AIDS 10 days (progressive dose), Presumptive TB like lesions; cervical, submental, misdiagnosed as duration of treatment depending

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART (fever, 13 kg axillar and inguinal ADP. TB to clinical condition of the patient weight loss in 2- CT scan: consolidation and months), cavitation right pulmonary upper unsuccessful anti lobe TB treatment ( HIV test positive, no AFB on 1month) sputum Hb: 5.9 g/dl), PLTS: 64 × 10 9/l TSP: 6.3 g/dl with albumin: 2.5 g/dl and globulins: 3.8 g/dl. AST /ALT 134 IU/137 IU; yeast forms ≈f Hc. (trephine and bone marrow biopsy, bone marrow aspirate) Pillay et al, 1997 [11] 4 South Africa unknown HIV Fever, LDP, ulcer (left lower leg, DH Patient died on 2nd day of Death prior 8, F status, tip of the tongue and angle of the revealing hospitalization. Postmortem to definite general malaise, mouth). advanced AIDS specimens from liver, lungs, diagnosis fever, respiratory HMG, presumptive pneumonia at late stage lower limbs, skin lesions and LN distress (3 (Pneumocystis carinii ) (postmortem demonstrated histoplasmosis weeks) CT scan: consolidation and diagnosis) cavitation of right upper lobe of the lung HIV test positive, TB skin test (-) and no AFB on sputum Hb 5.9 g/dl), PLTS: 64 × 10 9/l, AST /ALT 134 IU/137 IU yeast forms of Hc on Trephine bone marrow biopsy and bone marrow aspirate (stains NR):

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART Ouattara et al, 1998 5 Ivory Coast AIDS, CD4: Pallor, T 38°C, HMG, SM, CXR: DH :/ Death prior 32, M 7/mm3, ART. diffuse and slight infiltrates on in advanced to definite Presumptive both lungs, and massive LDP on AIDS patient diagnosis disseminated TB: left hilum. misdiagnosed as fever, gradual US of abdomen: HSM, LDP; TB (postmortem massive weight No AFB on sputum samples; TB diagnosis) loss, and night skin test (-) sweets (1year) yeast cells ≈ Hcc on tissues from autopsy (mediastinal LN, lung, gut, liver and ) Rivasi et al, 2001 [13] 6 Ghana living AIDS, CD4: Fever, significant weight loss DH Returned to Ghana prior to NR in Italy for 7 352/µl Herpes skin lesions: wildfire papules, in advanced definitive results and ATF years, Zoster, malaria, umbilicated and ulcerative AIDS patient treatment 36, M Candida lesions, face and upper esophagitis extremities CXR: nodules infiltrates on right upper lobe. Yeast cells of Hcc (nodule biopsy, H&E, PAS and GMS, and mucicarmin stains), confirmed by PCR testing Mosam et al, 2006 [14] 7 South Africa Unknown HIV Emaciation, pallor, fever, general DH Poor clinical course under Death 11, M status, 1 year of LDP, HMG, and acute BPN, revealing AIDS at treatment repeated hyperpigmented cutaneous late stage (2 weeks conventional antibiotic treatment (NR) plaques and nodules misdiagnosed as treatment, for chest HIV test positive, CD4 not TB Presumptive anti TB therapy, IV infections and available routinely, Hb: 91 g/L, amphotericin B (1 mg/kg per day)

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART diarrhoea, 1- PLTS 94×10⁹ / L. month loss of CXR: bronchiectasis and acute weight, cough, pneumonia. No AFB on 3 and skin lesions sputum specimens Yeast cells of Hcc on skin biopsy (PAS and Fontana-Masson stainings) Murata et al, 2007 [15] 8 Ghana, living AIDS, Left facial nerve palsy and DAH Poor clinical course under Death in Japan for Weight loss (10 atactic gait, Glasgow Coma in advanced treatment (itraconazole, 400 many years, kg), herpes- Scale:15. Isochoric and round AIDS patient mg/d, conventional amphotericin from many zoster, and pupils. Prompt light reflex and B, 1 mg/kg/d switched to European headache. intact ocular movement; right liposomal amphotericin B, 3 countries 45, ptosis. Left hemiplegia and mg/kg/d: severe RF) M pyramidal tract signs. Oral . SM. CT: brain mass; MRI contrast- enhancing mass lesion with peripheral edema; Brain biopsy suggestive of cerebral toxoplasmosis. Toxoplasmosis tests positive Hb 13.5 g/dl; PLTS: 27.2 × 104/µl; LDH: 370IU/l; CD4 24/µl and VL10 copies /ml. Yeast-like cells ≈ Hcd on routine PBS confirmed by PCR test Loulergue et al, 2007 [16 9 DR Congo, HIV-1, fever of Fever, left axillary tumefaction 2 AH Poor clinical course under Death living in unknown origin, inches diameter in advanced treatment (Itraconazole, 400

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART France left axillary CD4 100/mm3. AIDS patient mg/d x 3 weeks, then 1 year 37, M tumefaction Histology of adenopathy: amphotericin B (total dose 1,200 negative for necrosis and large yeasts, mg), then itraconazole 400 mg/d, fungus, and TB culture ≈ Histoplasma sp. lowered to 200 mg/d for 3 years) (Ziehl, PAS, and – HIV-related encephalitis 3 GMS) years after despite ART (5 months): 10 DR Congo, AIDS, CD4 < Skin nodules, right cervical ADP AH Itraconazole (400 mg/d, no Recovery living in 50/mm3, HAART and a right Bell's palsy in advanced response > 1 month treatment) France Pneumocystis numerous yeast cells of Hcd on AIDS patient then conventional amphotericin B 41, M jiroveci direct examination of the lymph (1 mg/kg/d switched to liposomal pneumonia node (stains NR) amphotericin B, 3 mg/kg/d) Culture ≈ Histoplasma sp Severe RF > 8 days treatment switched to itraconazole after 1 month, 400mg/d (long term therapy). Stable condition 11 years later 11 DR Congo, unknown HIV Frontal swelling and generalized DAH Liposomal amphotericin B, Recovery living in status, weakness revealing switched after 1 month to France since Fever of unknown HIV test positive, CD4 45/mm3 advanced AIDS, Itraconazole (dose NR), then age of 18 origin (duration yeasts of Hcd (skin biopsy, and Fusarium Fluconazole x2 years and 3 months NR) stains NR) Culture ≈ verticilioïdes months (dose NR) 2, F Histoplasma sp coinfection E. coli (pyelonephritis) Radiography: diffuse bone lytic lesions Bone biopsy: large yeasts of Hcd Culture of the buffy coat positive for Fusarium verticilioïdes. Débat-Zoguereh et al, 2008 [17]

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART 12 Ghana, living AIDS, ART Massive cachexia, fever, profuse DH Liposomal amphotericin B x 14 Recovery in France >18 (irregular bloody diarrhea (15 times daily), in advanced days (doses adapted to renal years observance) profuse skin papulonodules, and AIDS patient and clearance), switched to 38, M Presumptive ulcerations of the gums M. avium Itraconazole 600 mg/d (doses CMV colitis CT scan: pulmonary interstitial coinfection adapted to plasmatic monitoring) (nonspecific syndrome, HSM Healing of all signs of DH, ulcerations on CD4: 6 /mm3, VL17 700 although Histoplasma sp still colon biopsy, and copies/ml (4,25log); Hb 8.3 g/dl, detected in bone marrow highly positive PLTS 18 G/l); LDH 17 962 g/l, macrophages pp65 ASAT /ALAT: 16 ×N/1.5 ×N, antigenaemia), uremia 32 mmol/l and successful creatininemia 337 mmol/l. treatment with PBS. + bone marrow aspirate ganciclovir and stools: yeast cells ≈ Hcc. Culture of same specimens and Hemoculture (standard and Sabouraud medium): Histoplasma sp Hemoculture and stool culture: Mycobacterium avium complex (MAC). Ndiaye et al, 2011 [18] 13 Senegal Unknown HIV Fever (NR), poor GC, papulo- DAH NR NR 50, M status, Fever of nodules, umbilicated and revealing unknown origin necrotic skin lesions, and oral advanced AIDS (duration NR), involvement (NR) deterioration of HIV test (+), CD4 4/mm3 GC, and Yeast-bodies of Hcd on biopsy of disseminated skin ulcerative skin lesions (stains eruption with oral NR) Culture: Histoplasma sp

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART involvement (01 month) Mandengue et al, 2011 14 Cameroon 34, HIV-1 +, ART T 38.8°C, poor GC, weakness, DH revealing / Death prior F (irregular jaundice, skin eruption (papulo- advanced AIDS to definite observance) nodules, pustules, umbilicated, misdiagnosed as diagnosis Presumptive TB and hemorrhagic crusty lesions), TB (postmortem (cough, fever, fetid nasal discharge, and vulva diagnosis) weight loss, and ulceration, HSM miliary on x-rays CD4: 1/mm3; Hb: 5.4g/dl; PLTS: of the lungs, but 7000/mm3. ASAT/ALAT: 410 no AFB on /146 IU/L sputum) and 6- abdominal US: coelio-mesenteric months LDP and HSM unsuccessful anti skin biopsy: Hcc (PAS and GMS TB treatment stains), culture (Sabouraud medium): Histoplasma sp Inojosa et al, 2011 [20] 15 Ghana, living Unknown HIV Fever, mild HSM, diffuse small PDH Liposomal amphotericin B (3 NR in Italy status sized LDP, and seborrhoeic like revealing mg/kg/day, for 9 days), switched Lost to 30, M Fever, weakness, dermatitis with scratching lesions advanced AIDS, to Itraconazole (200 mg bid) follow up malaise, and HIV test positive, CD4 17/mm3, associated AHT Ivermectine (S. stercoralis) weight loss, HT VL 218,000/µl; Creatinine 2.58 and intestinal A month later: no recovery of (Amlopidine 10) mg/dl, urea 69 mg/dl; Hb: 9.1 Strongyloides renal function, HT not under g/dl, PLTS: 93,000/µl, AST / ALT stercoralis control, CD4 248/mm3 and 299/140 U/L, LDH: 2,782 U/L. undetectable viral load Yeast cells of Hcc on bone marrow biopsy (H&E, GMS and PAS) Strongyloides stercoralis on

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART stools 16 Liberia, living Unknown HIV Hard palatal ulcer, HSM and PDH Liposomal Amphotericin B lipid NR in Italy for 8 status, Fever, generalized LDP revealing (5 mg/kg/d) for 3 ½ months, Lost to years weight loss (5 kg) HIV test positive, CD4 11/mm3, advanced AIDS switched to fluconazole 400 mg follow-up 32, M and wasting Hb 8.8 g/dl, PLTS 74,000/µl); and TB co- Initiation of healing (CD4 (1year) LDH 1,041 U/L infection 102/mm3 (12%) and CT scan: osteolytic hard palate, undetectable viral load interstitial micro nodules in both lung; right pleural thickening; SM, coarse casting retro- peritoneal ADP, multiple LNs at mesenteric root, and pelvic peritoneal effusion. Mycobacterium tuberculosis on sputum (culture) yeast cells of Hcc (biopsy of the bottom of the palatal ulcer, Grocott staining), culture : Histoplasma sp 17 Ivory Coast, Unknown HIV T: 39°C), Tachycardia (rate NR) PDH Hemodialysis treatment x several NR living in Italy status HIV test (+), CD4: 2/mm3, in advanced weeks, Erythropoietin, 40, F Nausea, vomit, VL:7.580.000/µL; Creatinine: AIDS patient Gancyclovir, HAART, Liposomal and fever of 18.7 mg/dL; urea: 125 mg/dl, associated Stage amphotericin B adjusted to renal unknown origin GFR: 3 ml/min/1.73 mq; 5 renal failure, failure and Itraconazole oral (1week) inorganic phosphorus 8.6 mg/dL, and disseminated solution PTH 226 pg/mL; uricaemia 13.2 CMV co-infection mg/dL, Hb: 5.6 g/dl, PLTS: 365,000/µL, LDH: 2,208 U/l. CMV disseminated infection

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART US : increased-sized kidneys with increased echogenicity Hcc on bone marrow biopsy (Grocott stain) 18 Senegal, HIV1, HAART ( Severe oro-pharyngeal DH Ivermectine (S. stercoralis) Recovery living in Italy poor observance) candidiasis, and diffuse pruritic in advanced Pneumocystis prophylaxis for 23 years Pneumocystis papulonodules skin eruption AIDS patient HAART 47, M pneumonia CD4 2/µl (1%); Hb 12.1 g/dL; associated Liposomal amphotericin B (5 (Cotrimoxazole), AST/ ALT: 610 /142IU/L; LDH intestinal mg/kg x 3 weeks) switched to fever, cough, 249 U/L, Strongyloides oral solution itraconazole (dose dyspnea, CT scan: interstitial micronodular stercoralis NR). Satisfactory clinical course : dysphagia, and lesions widespread in both lungs infection CD4 138/mm3 wasting Yeast cells ≈ Hcc on bone syndrome (2 marrow biopsy (PAS and GMS) weeks) Stool examination: rhabditiform larvae (Strongyloides stercoralis infection); Borges-Costa et al, 2011 [21] 19 Congo, living HIV-1 + Palpable LN and HSM PDH Amphotericin B (total dose NR) Death in Portugal Fever, weight CD4: 28 cells/mm3; anemia and in advanced 55, M loss, diarrhoea leukopenia (NR); high hepatic AIDS patient and disseminated enzymes rate (NR) non-pruritic Yeast cells of Hcc on skin biopsy maculopapular (PAS stain), confirmed by PCR rash (3 months) and DNA sequentiation Dawood H, 2011 [22] 20 South Africa HIV , Intermittent Fever (39.8° C) and rigors, left DH HAART, Amphotericin B (1 Recovery 32, M fever and rigors, flank pain, increase in abdominal in advanced HIV mg/kg per d) for 14 d switched to increased circumference, pallor and disease followed Itraconazole 200 mg abdominal generalized LDP, SM and HM complicated with 2x/d.

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART circumference (> CD4 20/mm3, viral load <400 IRS Severe clinical course: : 3 months) and copies/mL, Renal impairment, hypokalemia, gradual weight Hb 6.6 g/dL, PLTS173 x 109/L, and thrombophlebitis, IRS, loss (6, 10 kg) Abdominal US: LPD, HSM, splenic abscess (splenic rupture Characteristic of histoplasmosis on US); laparotomy, planectomy (NR) on bone marrow aspirate and a wedge liver biopsy (H&E and trephine, and liver biopsy staining) : yeast of Hcc, 10 d No AFB on bone marrow and amphotericin B, switched to trephine and liver biopsy itraconazole 200 mg twice daily Mandengue et al, 2012 21 Cameroon 25, unknown HIV Fever (38.5°C), fatigue, weight DH / Death prior F status, persistent loss, distended and tender revealing to definite fever, weight loss abdomen, HM; difficulties with advanced AIDS diagnosis >10 kg, fatigue attention without focal at terminal phase and weakness, neurological deficit. (postmortem unsuccessful HIV test positive, CD4 7/mm3 Hb diagnosis) antipyretic and 7.3 g/dL; AST/ALT: 352/59 IU/L. antimalarial Routine PBS: yeast of Hcc- medications (self- Culture (Sabouraud medium): medication, Histoplasma sp. 1month) Scarlata et al, 2012 [24] 22 Ghana, living AIDS, CD4 Fever, catarrhal cough, diffuse DH Liposomal amphotericin B, 5 Recovery in Italy for 2 17/mm3, VL27 skin lesions: erythematous in advanced mg/kg /d switched to years, no trip copies, ART umbilicated or ulcerated papulo- AIDS patient Itraconazole 200 mg /8h the first to his native nodules, and pustules, deep mimicking lepra 3 days, then 200mg/12h. country circle line of the fore head Satisfactory clinical course: CD4 36, M mimicking lepra; HSM, and 34/mm3, healing of skin lesions generalized LDP. of the face, sclerotic and atrophic Anemia and leucopenia (NR), scars

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART and slight increased liver enzymes (NR), Mantoux test negative. CXR and CT: nodules disseminated on both lungs, hyperplasia and nodular infiltrates of the hila. MRI of the brain: hyperactivity and evidence of enhancement Skin and nasal mucosa biopsies (stains NR): Yeast cells of Hc. de Hoog et al, 2014 [25] 23 Ghana, living Unknown HIV Multiple small sized LN DH Liposomal amphotericin B 5 Recovery in status Fever (submandibular and inguinal). revealing mg/kg x two weeks, switched to Netherlands (39.3 °C), HIV test positive, CD4 = 0, and advanced AIDS Itraconazole 200 mg twice/d, for 8 years persistent cough VL: 5 million copies/ml. and detected on HAART after two weeks 27, M and night sweats, Hb 4.7 mmol/l, LDH 2967 U/l peripheral blood Gradual improvement, bloody sputum Routine blood smear and LN smear Job and daily activities resumed and weight loss biopsy (GMS stain): yeast after two months (20 kg) (3 weeks) figures of H. capsulatum Mandengue et al, 2015 [9] 24 Cameroon 38, HIV1+, ART Weight 53 kg. Skin lesions (face DAH HAART, Fluconazole 1600 mg/d Recovery M (irregular and forearms): squamous in advanced (4 times) interrupted after 1 m observance) papulo-nodules, and papulo- AIDS patient (unaffordable for the patient); Cough, fever, pustules; nasal and genital Satisfactory clinical course: weight loss and ulcerations. healing of fever, cough and skin weakness, Hb: 5.7 g/dl, PLTS: 3/mm3, lesions, weight 59kg, Hb: 12 ineffective ATB CD4=3/mm3 ; Syphilis test g/dL, PLTS 435 000/mm3 and treatments negative; no AFB on sputum CD4 289/mm3 (>1month) Skin biopsy (PAS and GMS

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART stains): yeast like organisms of Hcd Murphy et al, 2015 [27] 25 South Africa AIDS, CD4: Fever (NR), skin lesions (chin PDH Rapid deterioration of GC within Death 36, M 14/mm3, ART. and chest): flesh-colored in advanced 24h of admission with nodules, erosions on forehead, AIDS patient hypotension and worsening of (fluconazole disorientation involving skin and mental status 200mg/d) US of Abdomen: LDP and HSM. CNS Presumptive CNS CSF: normal pressure, (postmortem toxoplasmosis chemistry, and cells count diagnosis) (high dose Skin biopsy (stains NR): yeast- cotrimoxazole) like of Hcc Skin lesions (4weeks), Altered mental status and vomiting (1 week) 26 South Africa Unknown HIV Skin lesions (face, legs, and AH HAART Recovery 35, M status, hands): ulcerated nodules, ulcer revealing Itraconazole (200 mg twice /d) x presumptive TB, of the tongue, and destruction of advanced AIDS 1 year, then switched to polyadenitis, anti the nasal septum and nostrils. misdiagnosed as fluconazole 200 mg twice/d TB treatment (4 Oral candidiasis, TB and Healing of cutaneous lesions months) HIV test positive, CD4 14/mm3 within 9 months Pruritic skin Skin biopsy (Gram stain): yeast ulcerations (2 of Hcd, Culture: H c. months) 27 South Africa AIDS, CD4: 29 Cervical LDP, HSM DH Empiric anti TB therapy and Death 45, M cells/mm3 US of Abdomen: LDP on left in advanced HAART, then Amphotericin B for Epigastric pain, para aortic and splenic hilar, AIDS patient 14 days (dose NR), then h oral vomit, and bloody multiple splenic hypo densities, misdiagnosed as Fuconazole 800 mg/d for 30

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART diarrhea; and a solid mass in the hepatic TB days (maintenance therapy) perforated flexure of the colon. Poor clinical course: sepsis, duodenum ulcer Colonoscopy: 1.5 cm deep ulcer, reportedly Acinetobacter on endoscopy; hypertrophic edges in the baumannii bacteremia histoplasmosis on hepatic flexure biopsy (5years Biopsies (ulcers of the colon, prior) cervical LN, stains NR): numerous yeast cells ≈ histoplasmosis Nalwanga & Henning, 2016 [28] 28 AIDS, CD4:34 Evening fevers, generalized DH misdiagnosed Anti TB treatment (04 months). Recovery 29, F /μl, VL: 199,994 weakness, abdominal pain, as TB, in ATF treatment: amphotericin B copies/ml, diarrhea, vomiting. Skin lesions advanced AIDS (0.7 mg/kg, 14 d), switched to second line ART (face): hyperpigmented non-itchy patient fluconazole (400 mg x 2 /d, then (irregular and dome-shaped nodules HM a maintenance therapy. 400 mg observance), Albumin level 35.5 g/L. once daily). TMP/SMX US of the abdomen: LDP. Resolution of skin lesions and (prophylaxis) Skin biopsy (stains NR) ≈ H LDP Presumptive capsulatum infection (NR) extra pulmonary TB (4 kg Weight loss (46 to 42 kg), abdominal pain, diarrhea, vomiting, and evening fevers) (1 months), unsuccessful anti TB therapy (good observance):

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART continuing weight loss (about 15%) Dieng et al, 2017 [29] 29 Senegal Unknown HIV Fever (40.3°C), pallor of DH Worsen of patient GC, with Death prior 25, M status, conjunctiva, petechiae on nasal revealing multiple organs failure to definite spontaneous cavities, multiple bilateral advanced HIV diagnosis epistaxis of cervical and axillar firm and disease at late limited painless LN. Typical signs of stage abundance, oropharyngeal candidiasis. (postmortem persistent fever, HIV test positive, CD4: 3/mm3, diagnosis) and a progressive Hb: 7.9 g/dL, ASAT/ ALAT: 17x poor GC (3 N /3.6 x N. weeks) Thin blood smear for malaria: yeast cells ≈ Hcc, confirmed by PCR (DNA amplification from the blood of the thin smear (rDNA) Zanotti et al, 2018 [30] 30 Ivory Coast, unknown HIV Fever (38.8°C), severe asthenia, PDH Liposomal Amphotericin B Recovery living in Italy status, chills, and tachycardia (110 revealing HIV switched to Itraconazole after 03 19, F persistent fever bpm), mono-lateral tonsillar advanced weeks of induction therapy, and hypertrophy and submandibular disease cART (tenofovir/emtricitabine + LDP. with CMV & HVB dolutegravir). HIV test positive, CD4 19 cell/µL co-infections Poor clinical course: poor and VL:1,787,000 cp/mL; Hb 8.7 observance of both ART and g/dL, PLTS 80,000/µL); LDH ATF therapy; pregnancy: internal 5,201 U/L, EBV-DNA 1,297 abortion complicated by sepsis cp/mL, CMV-DNA 266 cp/mL, choc (wide spectrum ATB and HBV-DNA >700,000,000 therapy, many blood transfusions UI/mL and mechanical ventilation, Stool test: blood fever, pancytopenia), and skin

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART Biopsies of bone marrow, gut, lesions suggestive to lateral-cervical lymph node and histoplasmosis reactivation. tonsils (H&E, GMS, and PAS): Progressive improvement of her yeast cells ≈ histoplasmosis condition after fully adherence (type NR), Culture of bone with cART and histoplasmosis marrow aspirate (medium NR) : prophylaxis Hc Zhang & Sander, 2019 [31] 31 Zimbabwe, HIV (30years), Skin lesions (face, trunk, and DH Liposomal amphotericin B (2 Recovery living in ART (7 years, extremities): diffuse infiltrated, in patient with weeks, dose NR), switched to Canada for 7 failure treatment), scaly, verrucous, advanced HIV Itraconazole 200 mg PO BID for years weight loss, hyperpigmented plaques on the disease a planned 12-months course. 58, F decline general face (leonine facie), non- mimicking lepra Response to antifungal treatment cognitive function blanching, violaceous-to-brown assessed by serial serum (1 year), skin papules and plaques of varying Histoplasma antigen titers rash (cephalo- size with bleachable halo, caudally), fever, erythematous patches. night sweats, CD4 1 cell/μL VL 5.28 log headaches, copies/ml cough and No AFB on sputum sample. dyspnea (3 CT scan of the trunk: calcified months) granulomata in upper lobes of both lungs, bulky mesenteric and retroperitoneal LDP MRI scan of the brain: a small lesion within the right parietal lobe. Skin lesions biopsy (H&E, PAS, GMS, and Giemsa stains): numerous yeast-like organisms ≈

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Case- country of Past history- Mains findings Definite Treatment and clinical course Outcome patients Origin, Age, Underlying (Clinical, Laboratory and/or Diagnosis of (n°) sex disease: Radiology) Histoplasmosis HIV/AIDS, CD4 count, VL, ART Hcc. Culture of skin, bone marrow and retroperitoneal LN biopsies, and blood: H. capsulatum.

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Table 2. Risk factors for death in advanced HIV disease population

Case- Clinical signs Laboratory abnormalities Outcome Patients Fever > Weight Systolic BP < Diarrhea Respiratory Neurology Renal PLTS < Hb < 8.0 Albumin<3, urea 2 Creat AST > LDH > 2 x (N°) 39°C loss > 5% 90mmHg insufficiency involvolm. failure 100000/mm3 g/dl 5g/dl x Nl > 1,5 2,5 x Nl normal upper mg/dl upper limit limit 2 weight Death loss 3 Fever Weight 64×109 /L 5.9 2.5 134 IU NR loss 4 Fever respiratory 64×109 /L 5.9 134 IU Death distress 5 Weight Death loss 6 Hyper weight NR pyrexia loss 7 Fever weight 94×10 / L Death loss 8 weight Neurology 27.2 × 104/µl 370 IU/l Death loss involv (10kg) 9 Fever Death 11 Fever Recovery 12 Fever massive profuse 18 G/l 8,3 g/dl, 32 337 16xNl 17 962 Recovery cachexia bloody mmol/l mol/l IU/l, diarrhea (15x daily) 13 Fever NR 14 Fever weight 7000/mm3 5,4 g/dl 410 IU/L Death loss

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15 Fever weight arterial 93,000/µl 9.1 g/dl 69 2.58 299 IU/L 2,782 U/L Lost to loss hypertension mg/dl mg/dl follow-up 16 Fever weight 74,000/µl 8.8 g/dl 1,041 U/L Lost to loss (5 follow-up kg) 17 Stage 365 000/µl 5,6 g/dl 2.1 g/dl 125 18.7 2,208 IU/L Recovery 5 renal mg/dl mg/d failure 18 Fever 610 IU/L 249 U/L Recovery 19 Fever weight diarrhoea Anaemia elevated Death loss hepatic enzymes 20 Fever Weight 173 x 109/L 6.6 g/dl Recovery (39.8° C) loss (10 kg /6 months) 21 Fever weight 80/50 mmHg 7.3 g/dL 352 IU/L Death (38,5°C) loss >10 kg 22 Fever Recovery 23 Fever weight 4.7 2967 U/l. Recovery 39.3°C loss (20 mmol/l kg) 24 Fever weight 3/mm3 5.7 g/dl Recovery loss 25 Fever Altered Death mental status 27 Bloody Death diarrhea 28 Fever weight Diarrhea 35.5g/L Recovery loss(15%)

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29 Fever 7.9 g/dL 17xN Death (40.3°C) 30 Fever 8.7 g/Dl 5,201 U/L Recovery (38.8°C)

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Table 3. Outcome of patients related to the presence of risk factors in advanced AIDS case- patients

Number of Risk-factors Number of patients Outcome /Patients Death Recovery Lost to follow-up NR 1 8 4 1 / 3 ≥ 2 19 7 9 2 1 Total 27 11 10 2 4

4. CONCLUSION REFERENCES

DH is a serious threat in AHD population in SSA 1. Adenis A, Nacher M, Hanf M, Vantilcke V, countries that urgently need to be addressed, Boukhari R, Blachet D, et al. HIV- based on a continued engagement of: associated histoplasmosis early mortality and incidence trends: From neglect to  The clinicians; their training would increase priority. PLoS Negl Trop Dis the high index of suspicion on 2014;8(8):3100. histoplasmosis and particularly in AIDS Available:https://doi.org/10.1371/journal. population, and help educating PLHIV on pntd.0003100 risk factors associated with histoplasmosis 2. Gugnani HC. Histoplasmosis in Africa: A  The Governments; they should make all review. Indian J Chest Dis Allied Sci the WHO recommended tools of diagnostic 2000;42:271-277 PMID: 15597674 and antifungal drugs available, along with 3. Ousley j, Niyibizi AA, Wanjala S, antifungal treatment monitoring. Vandenbulcke A, Kirubi B, Omwoyo W, et  The Pharmaceutical companies: they could al. High Proportions of patients with reduce the cost of rapid diagnostic tools for advanced HIV are antiretroviral therapy detection of histoplasmosis and make experienced: Hospitalization outcomes effective antifungal drugs available in from 2 sub-saharan African Sites. Clin generic form and at low cost. Infect Dis. 2018;66(S2):126–32  The National and Pan African Working DOI: https://doi.org/10.1093/cid/ciy103 Group : with epidemiological studies data 4. World Health Organization. Guidelines for will be generated to determine the burden managing advanced HIV disease and rapid of DH in SSA initiation of antiretroviral therapy. Geneva, Switzerland; 2017. Accessed 20 November 2020. Ongoing actions including continuing national Available:http://www.who.int/hiv/pub/toolkit and pan African seminaries, workshops and multicentric published studies, involving clinicians s/advanced-HIV-disease-policy/en/. and laboratory technicians, Governments and 5. Oladele RO, Ayanlowo OO, Richardson international organizations (WHO, NGO, MD, Denning DW. Histoplasmosis in Africa: An emerging or a neglected International Scientific societies) would raise disease? PLoS Negl Trop Dis. interest on histoplasmosis in sub-Saharan Africa. 2018 ;12(1):0006046. Available:https://doi.org/10.1371/journal.pn CONSENT td.0006046

6. Nacher M, Silva Leitao T, Gómez BL, It’s not applicable. Couppié P, Adenis A, Damasceno L, et al.

The fight against HIV-associated ETHICAL APPOVAL disseminated histoplasmosis in the Americas: Unfolding the different stories of It’s not applicable. four centers. J. Fungi 2019, 5, 51 https://doi:10.3390/jof 5020051 COMPETING INTERESTS 7. Oladele RO, Irurhe NK, Foden P, Akanmu AS, Gbaja-Biamila T, Nwosu A, et al. Authors have declared that no competing Chronic pulmonary aspergillosis as a interests exist. cause of smear-negative TB and/or TB

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APPENDIX

1 Kuate Ngouanom Marius. Master Degree study, 2019, University of Buea (South West Region of Cameroon) Title: Prevalence And Risk Factors For Histoplasma Capsulatum Infection Amongst Hiv Patients Attending The Buea Regional Hospital Using The Optimum Imaging Diagnostics (Oidx) Histoplasma Antigen EIA. ______© 2021 Mandengue et al.; This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Peer-review history: The peer review history for this paper can be accessed here: http://www.sdiarticle4.com/review-history/65200

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