Laura Galimberti

Histoplasmosis among human immunodeficiency virus-infected people in Europe : Report of 4 cases and review of the literature

Abstract: We reviewed the clinical, microbiologic, and outcome characteristics of 72 patients with human immunodeficiency virus (HIV)-associated histoplasmosis (4 newly described) reported in Europe over 20 years (1984-2004). Seven cases (9.7%) were acquired in Europe (autochthonous), whereas the majority involved a history of travel or arrival from endemic areas. The diagnosis of progressive disseminated histoplasmosis (PDH) was made during life in 63 patients (87.5%) and was the acquired immunodeficiency syndrome (AIDS)-presenting illness in 44 (61.1%). Disease was widespread in 66 patients (91.7%) and localized in 6 (8.3%), with the skin being the most frequent site of localized infection. Overall skin involvement was reported in 47.2% of the patients regardless of whether histoplasmosis was acquired in Africa or South America. Reticulonodular or diffuse interstial infiltrates occurred in 52.8%. The diagnosis was made during life by histopathology plus culture in 44 patients (69.8%), histopathology alone in 18 (28.5%), and culture alone in 1 (1.5%). During the induction phase amphotericin B and itraconazole (74.6%) were the single most frequently used drugs. Both drugs were also used either in combination (10.2%) or in sequential therapy (11.8%). Cumulative mortality rate during the induction phase of treatment was 15.2%. Overall, 37 patients died (57.8%); death occurred early in the course in 18 (28.1%). Seven of 40 patients (17.5%) who responded to therapy subsequently relapsed. Autopsy data in 13 patients confirmed the widespread disseminated nature of histoplasmosis (85%) among AIDS patients with a median of 4.5 organs involved. The results of the present report highlight the need to consider the diagnosis of PDH among patients with AIDS in Europe presenting with a febrile illness who have traveled to or who originated from an endemic area. Abbreviations: AIDS = acquired immunodeficiency syndrome; CMV = cytomegalovirus, Hcc = H. capsulatum var. capsulatum; Hcd = H. capsulatum var. duboisii; HIV = human immunodeficiency virus; PCP = Pneumocystis pneumonia; PCR = polymerase chain reaction; PDH = progressive disseminated histoplasmosis; PR = present report.

The Role of Cryptococcal Antigen Assay in Diagnosis and Monitoring of Cryptococcal Meningitis

In a recent paper evaluating the significance of cryptococcal antigen test results for 29 Chinese human immunodeficiency virus (HIV)-negative patients affected by cryptococcal meningitis, Lu and colleagues (8) showed in all patients a decrease of antigen titer from the baseline following antifungal therapy and suggested that a decrease can be used to monitor antifungal therapy efficacy but cannot be used as an index of cure. We have reviewed our experience with 66 HIV-positive patients out of 118 with cryptococcal meningitis for whom at least three serial determinations (at baseline, day 7, and day 14) of cryptococcal antigen tests on cerebrospinal fluid (CSF) were available (1). A total of 440 determinations (range, 3 to 28 antigen determinations; median, 5 antigen determinations) were available, and for 55 patients the last determination was considered (median, 13 weeks; range, 2 to 84 weeks). In Fig. ​Fig.11 is depicted the kinetics of CSF cryptococcal antigen together with the results of CSF culture. Overall, 53 patients (80%) showed a decrease of CSF antigen titer from the baseline (7 of whom had negative results), as follows: 27 cases of 1 to 3 dilutions, 16 cases of 4 to 6 dilutions, and 10 cases of 7 or more dilutions. However, 13 out of 15 of these patients for whom postmortem examination was available, despite evidence of several intravitam negative CSF cultures, still had cryptococcal meningitis or disseminated disease at autopsy (demonstrated by histopathology). Eight patients had an increase in the CSF antigen titer (four of 1 to 3 dilutions and four of 4 to 8 dilutions), and five showed stable (i.e., the same value) results throughout the follow-up. All the patients but two with an increase of CSF antigen titer had persistent positive CSF culture and died; four underwent autopsy showing disseminated cryptococcosis. FIG. 1. Change over time of CSF cryptococcal antigen titers and correlation with CSF cryptococcal cultures in 66 HIV-positive patients. Data of CSF antigen are median values. Data regarding CSF cultures refers to the total number of patients (n = 66), ... Our experience regarding the role of cryptococcal antigen to monitor antifungal therapy in AIDS patients is in keeping with that previously reported by Powderly et al. (11), who showed the lack of any correlation of changes of CSF or serum cryptococcal antigen and the outcome of cryptococcal meningitis. However, a high CSF antigen level has been identified as a sign of poor prognosis in patients with AIDS (1, 7); interestingly, more recently Thay cohorts of HIV-positive patients with cryptococcal meningitis showed a significant positive correlation between CSF cryptococcal colony-forming units (CFU) and CSF cryptococcal antigen titers at baseline (P < 0.0001), but the rapid rate of decline in CSF CFU was not correlated with that in CSF cryptococcal antigen titers (2). As shown in Table ​Table1,1, regardless of the different hosts in whom cryptococcal meningitis is diagnosed, among all methods employed the cryptococcal CSF antigen had the best overall sensitivity (94.1%) followed by the serum antigen (93.6%). However, some differences were observed in the different categories of hosts, with lower sensitivity in AIDS and immunocompetent patients (92%) and higher sensitivity among the other immunocompromised hosts without HIV infection. Persistently elevated CSF cryptococcal antigen in HIV-infected patients carries a poor prognosis and indicates ongoing production of viable Cryptococcus neoformans in tissue. In conclusion, CSF cryptococcal antigen seems to be the best test for diagnosis of cryptococcal meningitis in terms of sensitivity, but it is an unreliable tool, at least among HIV-positive patients, to drive therapeutic monitoring, particularly in assessing the point of discontinuation of antifungal therapy in HIV-infected patients. TABLE 1. Efficiency of different techniques in the diagnosis of cryptococcal meningitis in different hostsa

Prospective observational study of fever in hospitalized returning travelers and migrants from tropical areas, 1997-2001.

BACKGROUND An estimated 50 million people each year from industrialized countries visit tropical areas: 3% to 11% of these travelers report a febrile illness on their return. We conducted a 5-year prospective observational study on the causes of fever in patients admitted to a university teaching hospital after returning from the tropics. METHODS We enrolled in this study all consecutive patients admitted to the Division of Infectious Diseases of the University of Milan, Italy, between January 1997 and December 2001 presenting with fever (oral temperature > or =37.5 degrees C) and a history of travel to a tropical country in the previous 6 months. RESULTS Seven percent (147/2,074) of all hospital admissions in the study period were due to fever in travelers and migrants returning from the tropics. Malaria accounted for 47.6 % of all admissions (70/147), followed by presumed self-limiting viral infections (12%). Pretravel screening and vaccination strategies could have prevented a considerable number of hospitalizations (e.g., hepatitis A and typhoid fever). The most useful investigations were blood examination and PCR for malaria, which gave positive results in 65% of cases in which they were performed. CONCLUSIONS During a 5-year period, the number of patients returning from tropical areas who were admitted with fever to a university hospital in northern Italy remained stable; malaria was the most frequent diagnosis, and should be considered in any febrile patient returning from the tropics. With the exception of hepatitis A and dengue fever infections, in a real-world setting serology is of modest utility and is probably overused.

Plasmodium knowlesi: the emerging zoonotic malaria parasite.

Plasmodium knowlesi was initially identified in the 30s as a natural Plasmodium of Macaca fascicularis monkey also capable of experimentally infecting humans. It gained a relative notoriety in the mid-30s as an alternative to Plasmodium vivax in the treatment of the general paralysis of the insane (neurosyphilis). In 1965 the first natural human infection was described in a US military surveyor coming back from the Pahang jungle of the Malaysian peninsula. P. knowlesi was again brought to the attention of the medical community when in 2004, Balbir Singh and his co-workers reported that about 58% of malaria cases observed in the Kapit district of the Malaysian Borneo were actually caused by P. knowlesi. In the following years several reports showed that P. knowlesi is much more widespread than initially thought with cases reported across Southeast Asia. This infection should also be considered in the differential diagnosis of any febrile travellers coming back from a recent travel to forested areas of Southeast Asia. P. knowlesi can cause severe malaria with a rate of 6-9% and with a case fatality rate of 3%. Respiratory distress, acute renal failure, shock and hyperbilirubinemia are the most frequently observed complications of severe P. knowlesi malaria. Chloroquine is considered the treatment of choice of uncomplicated malaria caused by P. knowlesi.

AIDS‐associated cryptococcosis: a comparison of epidemiology, clinical features and outcome in the pre‐ and post‐HAART eras. Experience of a single centre in Italy

To assess the prevalence, clinical and immunological characteristics, risk factors and survival of patients with AIDS‐related cryptococcosis in the era of highly active antiretroviral therapy (HAART).

Cryptococcus neoformans Infection in a Cohort of Italian AIDS Patients: Natural History, Early Prognostic Parameters, and Autopsy Findings

Abstract. This observational cohort study of 4,160 AIDS patients hospitalised in a single institution in northern Italy between January 1985 and December 1999 was carried out in order to assess the natural history of cryptococcosis, the epidemiological trend of this opportunistic infection, the risk factors predictive of death at 10 weeks, the response to therapy, and autopsy findings. Cryptococcosis was diagnosed in 177 (4.2%) patients and was the AIDS-defining disease in 2.8% of cases. Its prevalence decreased significantly over time (from 6.4% in the period 1985–1989 to 5.7% in 1990–1993, 3.1% in 1994–1996, and 1.9% in 1997–1999, P<0.0001). Although neurologic disease was the most frequent clinical picture, a significant proportion of the patients (24.2%) presented with extraneural cryptococcosis. In a Cox multivariate analysis, high titres of cerebrospinal fluid antigen (>5000) and drug addiction were predictive of death at 10 weeks. A complete clinical and mycological response was achieved in 60.8% of the treated patients, with the highest response rate being observed in those treated with amphotericin plus flucytosine (66.6%). Cryptococcosis relapsed in 12.8% of patients on secondary prophylaxis. Autopsy findings demonstrated that cryptococcosis is a disseminated disease, but long-term antifungal treatment may be able to eradicate it in a subgroup of patients.

Tuberculosis cutis miliaris disseminata due to multidrug-resistant Mycobacterium tuberculosis in AIDS patients.

Two patients with AIDS and disseminated tuberculosis characterized by cutaneous involvement are reported. They developed a maculopapular skin eruption, from which a multidrug-resistantMycobacterium tuberculosis strain was isolated. In both cases the clinical course was rapidly fatal. Tuberculosis cutis miliaris disseminata should be differentiated from the skin lesions frequently seen in HIV-infected patients, especially from folliculitis. In patients with tuberculosis, the appearance of cutaneous lesions may be due to the haematogenous dissemination of mycobacteria. Therefore, early identification of the causative organism by use of optimal microbiological methods is fundamental.

Chagas disease in Europe: A review for the internist in the globalized world

Chagas disease (CD) or American trypanosomiasis identified in 1909 by Carlos Chagas, has become over the last 40years a global health concern due to the huge migration flows from Latin America to Europe, United States, Canada and Japan. In Europe, most migrants from CD-endemic areas are concentrated in Spain, Italy, France, United Kingdom and Switzerland. Pooled seroprevalence studies conducted in Europe show an overall 4.2% prevalence, with the highest infection rates observed among individuals from Bolivia (18.1%). However, in most European countries the disease is neglected with absence of screening programmes and low access to diagnosis and treatment. Physicians working in Europe should also be aware of the risk of autochthonous transmission of Trypanosoma cruzi to newborns by their infected mothers and to recipients of blood or transplanted organs from infected donors. Finally, physicians should be able to recognize and treat the most frequent and serious complications of chronic Chagas disease, namely cardiomyopathy, megacolon and megaesophagus. This review aims to highlights the problem of CD in Europe by reviewing papers published by European researchers on this argument, in order to raise the awareness of internists who are bound to increasingly encounter patients with the disease in their routine daily activities.

High frequency of adverse reactions and discontinuation with benznidazole treatment for chronic Chagas disease in Milan, Italy.

TO THE EDITOR—We read with interest the experience by Miller et al regarding the tolerance to benznidazole treatment in a cohort of patients affected by chronic Chagas disease in Los Angeles, California [1]. In the last decade, physicians from Europe and the United States have been increasingly observing chronic Chagas disease in Latin American immigrants and have concomitantly been facing uncertainties about how to make a correct diagnosis and treat affected patients [2]. Both these issues have been dealt with in the Latin American literature due to the lack of previous direct experience by physicians from nonendemic areas [3]. In this context, 2 problems recently emerged regarding the treatment of the chronic indeterminate form and the mild cardiomyopathy of Chagas disease: (1) the shift from an attitude limited to counseling and follow-up to a position of actively offering treatment to all adult patients aged 19–50 years based on results indicating a reduced risk of progression of the disease and on new concepts of immunopathogenesis [3–5]; (2) the emergence of benznidazole as the best drug option available over nifurtimox (the other drug considered to be active against Trypanosoma cruzi) and posaconazole (an antifungal drug active in murine models) [6]. However, the use of a drug for which there is no direct (firsthand) experience requires the preliminary acquisition of complete information about its side effects and their relative rate of appearance. In this regard, in one of the major textbooks of internal medicine, it is reported that for benznidazole “adverse effects include rash, peripheral neuropathy, and rarely, agranulocytosis” [7]. A meta-analysis including studies published in the literature until October 2008 indicated that between 1% and 18% (median, 10%) of patients discontinued benznidazole treatment due to toxicity [4]. In the US guidelines, it is indicated that approximately “30% of patients experience both dermatologic adverse effects (usually mild to moderate) and a dose-dependent peripheral neuropathy. Bone marrow suppression is rare . . . additional reported adverse effects include anorexia and weight loss, nausea and/or vomiting, insomnia and dysgeusia” [8]. Moreover, other than the article by Miller et al, few reports have recently addressed the problem of the tolerance of benznidazole both in adults and children [9–15]; from the analysis of other studies (mainly conducted to evaluate drug efficacy) [3, 16–19], a higher than expected prevalence of dermatologic side effects, as well as higher rates of permanent drug discontinuation, emerge (Table 1). However, Miller et al underline in their work the high frequency of neuropathy (an expected adverse event) and angioedema (an unexpected adverse event). In this regard, we report our recent experience in Milan, Italy. Starting from July 2013 we began, with the collaboration of Médecins Sans Frontières, a screening program for Chagas disease directed to Latin American immigrants living in the nothern Italian city of Milan. Diagnosis of Chagas disease was performed through 2 positive serological tests according to World Health Organization recommendations: a chemiluminescent immunoassay with recombinant antigens (Abbott Architect Chagas, Abbott PRISM, Abbott Diagnostics) and an enzyme-linked immunosorbent assay with crude antigen (BioELISA Chagas III, BiosChile). Up to July 2014, 497 subjects (98% born in Central or South America) were enrolled in the study. Forty-four (8.8%) were found to be seropositive for T. cruzi: 39 (88.6%) from Bolivia, 4 (9.3%) from El Salvador, and 1 (2.3%) from Argentina. At present, 23 have completed assessments for cardiac involvement (eg, 12-lead electrocardiogram, chest radiograph, and echocardiogram) and gastrointestinal involvement (eg, esophagogram following the Rezende classification and barium enema). Eighteen patients have started treatment with benznidazole (Abarax, ELEA, Industria Argentina, 100 mg) at a dosage of 5 mg/kg/day in 2 divided doses (maximum dose 300 mg/day) for 60 days. As reported in Table 1, rash was observed in 6 (55%) patients and was the principal reason of drug discontinuation in 5 of them. Two patients (11%) presented

Diagnosis and Therapy for Hospitalized Imported Malaria in Adults in Italy

BACKGROUND The diagnosis and treatment of malaria in non-endemic countries presents a continuing challenge. METHODS Medical records were reviewed for 291 patients hospitalized with microscopically confirmed malaria diagnosed consecutively in two infectious diseases wards in Milano, Italy, between 1998 and 2007. RESULTS One hundred eighty-six (64%) were male; median age was 35 y (range 16-72 y). Of the 291 patients, 204 (70.1%) were non-immune travelers and 87 (29.9%) were considered semi-immune. In 228 patients (78.3%), Plasmodium falciparum was identified as the only causative malarial parasite. In 48 (16.5%), 9 (3.1%), and 1 (0.3%) cases, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae were diagnosed, respectively. Five mixed infections were observed (1.7%). Of the 233 falciparum cases (including mixed infections), 222 (95.3%) were acquired in sub-Saharan Africa. Fifty-four percent of P vivax infection were acquired in the Indian subcontinent and Southeast Asia. Chemoprophylaxis was used by 23.6% (61/258) subjects with only 32 fully compliant with the recommended regimen. At admission, fever, chills, and headache were present in 95.5, 59.5, and 55.3% of cases, respectively. Elevated serum lactate dehydrogenase levels (95%) and thrombocytopenia (82%) were the most frequently detected laboratory abnormalities. Thirty-five patients (15%) with P falciparum malaria presented with severe malaria according to the WHO criteria; in 19 patients (54.3%) more than one criteria was present. All patients recovered uneventfully. Inappropriate anti-malarial treatment occurred in 25 patients (8.6%) and were recorded more frequently among patients with a diagnosis of P vivax malaria (29.1%) as opposed to those affected by P falciparum (3.9%). CONCLUSIONS In our study more than two thirds of imported malaria cases were due to P falciparum with an excess of cases diagnosed in immigrants starting from the year 2000. Despite many available guidelines inappropriate initial malaria treatment is relatively frequent even when patients are managed in an infectious diseases ward.