How Many Have Died from Undiagnosed Human Immunodeficiency Virus–Associated Histoplasmosis,A Treatable Disease? Time to Act

Human immunodeficiency virus (HIV)–associated disseminated Histoplasma capsulatum capsulatum infection often mimics tuberculosis. This disease is well know in the United States but is dramatically underdiagnosed in Central and South America. In the Amazon region, given the available incidence data and the regional HIV prevalence, it is expected that, every year, 1,500 cases of histoplasmosis affect HIV patients in that region alone. Given the mortality in undiagnosed patients, at least 600 patients would be expected to die from an undiagnosed but treatable disease. The lack of a simple diagnostic tool and the lack of awareness by clinicians spiral in a vicious cycle and made a major problem invisible for 30 years. The HIV/acquired immunodeficiency syndrome community should tackle this problem now to prevent numerous avoidable deaths from HIV-associated histoplasmosis in the region and elsewhere.In the Guianas and the Amazon Basin, the prevalence of human immunodeficiency virus (HIV) is approximately 1%. There have been some decreases in incidence in some states in this region, but recent increases in incidence in northern states of Brazil have been reported.^1–3 The population of the Amazon basin is estimated to be approximately 10 million persons,⁴ which would imply that approximately 100,000 persons are HIV positive in the Amazon Basin.The Amazonian environment is suitable for the growth of Histoplasma capsulatum.⁵ For immunocompetent patients, this organism causes mostly benign infections, but in severely immunodepressed HIV-infected patients, infection with this organism leads to a fatal disease in the absence of diagnosis and treatment. There lies the problem. Clinical symptoms are unspecific and often mimic those of tuberculosis.^6,7 Diagnosis is difficult and requires invasive procedures (biopsies, bone marrow smears), and trained staff to detect H. capsulatum, often after weeks of culture.⁸ Severe infections are often fatal within days.⁹ However, death often occurs after long delays in which patients are unsuccessfully treated for unconfirmed tuberculosis. Patients die because they are not treated for a treatable disease and because there is no diagnosis test. With no diagnosis, this possibility is not included in the diagnostic and treatment algorithms of clinicians who, despite unknowingly encountering this disease on a regular basis, have never seen a case because it was never diagnosed. In this context, then why give presumptive treatment of a disease that is not present?It is tragic but it makes total sense. It is even frighteningly tragic when one crunches the numbers to estimate what it means that after 30 years of the HIV epidemic, one of the leading causes of acquired immunodeficiency syndrome (AIDS) in the Amazon¹⁰ still goes largely unrecognized and evolves under the radar of national plans and international funding efforts.The only incidence data available for this region suggests that the incidence of histoplasmosis during the highly active antiretroviral therapy era was 1.5 cases/100 person-years.¹⁰ The historical mortality rate of disseminated histoplasmosis was > 30% despite mycology expertise.^7,8 This finding indicates that for 100,000 HIV patients, there would be 1,500 cases of histoplasmosis/year and 600 deaths/year, and probably more if undiagnosed. This finding also indicates that for more than 30 years the cumulated death rate in the region must have been huge, in the tens of thousands.A rational sceptic could rightly doubt this claim from the generalization of data from the smallest South American territory to the entire Amazon and elsewhere. However, when one reviews the literature, it becomes evident that histoplasmosis is present throughout the region, this fact has been known for decades, and that we should have been paying more attention.⁵ The high prevalence of histoplasmin test reactivity in the region was known even before AIDS was identified in 1981.¹¹ Histoplasmosis has been an AIDS-defining illness since 1993. We should have connected the dots earlier.How could something so huge escape the attention of the HIV/AIDS community in the region? One explanation for this dramatic blind spot is that in the region, the diagnostic capacity for mycology has been insufficient. It has been long argued that medical mycology is a neglected area of biology, and that the often low incidence of mycoses is caused by a lack of medical mycologists rather than the absence of the mycoses.¹² Another explanation is that the standard conceptualization of HIV/AIDS, the usual indicators, and the Joint United Nations Programme on HIV/AIDS terminology and framework did not explicitly entail disseminated histoplasmosis or the regional AIDS-defining illnesses. The anesthetic effect of the familiarity of vertical concepts and vertical programs can make it difficult to reframe the problem and see what was always there.For better diagnostic and treatment, we should know what AIDS is to direct diagnostic hypotheses when caring for individual patients. Misdiagnosing histoplasmosis as tuberculosis, not only delays a life-saving treatment of the individual patient, but it can confound tuberculosis statistics (incidence, resistance, mortality) and make it difficult to evaluate tuberculosis program results.The current financial difficulties should not stand in the way of building the diagnostic capacity for detection of histoplasmosis. It does not necessarily cost much to do the diagnosis. Treatment relies on amphotericin B for severe forms and itraconazole for non-severe forms and prophylaxis.⁷ Both drugs are generic drugs that are perfectly affordable. The toxicity of amphotericin B leads industrialized countries to use the costly liposomal version of the drug. However, The Drugs for Neglected Disease Initiative is releasing a cheap alternative that was developed for treatment of cryptococcosis.¹³ This is an opportunity for resource-limited countries in disease-endemic areas for treatment of histoplasmosis. We should not wait any longer. Every year wasted to build capacity for diagnosis and treatment of histoplasmosis in the Amazon Basin and elsewhere leads to hundreds of deaths that could have been avoided. This is not acceptable.     

Variable temporoinsular cortex neuroanatomy in primates suggests a bottleneck effect in eastern gorillas

We describe an atypical neuroanatomical feature present in several primate species that involves a fusion between the temporal lobe (often including Heschl's gyrus in great apes) and the posterior dorsal insula, such that a portion of insular cortex forms an isolated pocket medial to the Sylvian fissure. We assessed the frequency of this fusion in 56 primate species (including apes, Old World monkeys, New World monkeys, and strepsirrhines) by using either magnetic resonance images or histological sections. A fusion between temporal cortex and posterior insula was present in 22 species (seven apes, two Old World monkeys, four New World monkeys, and nine strepsirrhines). The temporoinsular fusion was observed in most eastern gorilla (Gorilla beringei beringei and G. b. graueri) specimens (62% and 100% of cases, respectively) but was seen less frequently in other great apes and was never found in humans. We further explored the histology of this fusion in eastern gorillas by examining the cyto‐ and myeloarchitecture within this region and observed that the degree to which deep cortical layers and white matter are incorporated into the fusion varies among individuals within a species. We suggest that fusion between temporal and insular cortex is an example of a relatively rare neuroanatomical feature that has become more common in eastern gorillas, possibly as the result of a population bottleneck effect. Characterizing the phylogenetic distribution of this morphology highlights a derived feature of these great apes. J. Comp. Neurol. 522:844–860, 2014. © 2013 Wiley Periodicals, Inc.     

Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey

Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.     

Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going?

Metronomic (low-dose, long-term and frequently administered) chemotherapy has attracted renewed interest for the past few years, in particular because of possible positive association with molecular targeted agents. Cyclophosphamide is the most widely-explored agent in such an approach. The main possible mechanisms of actions identified in preclinical models, whatever the histology of tumor, are the stimulation of the immune system and anti-angiogenic action. Retrospective studies and numerous phase II clinical trials have been published in diverse clinical settings, mainly in patients with highly pretreated advanced tumors. The tolerance seems to be acceptable; some objective responses have been reported. Nevertheless, the regimens were very heterogeneous, and most of these studies are not randomized. This makes it difficult to objectively evaluate the additional value of the metronomic administration of cyclophosphamide. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach.