Background Zygomycosis is an increasingly emerging life-threatening infection. There is no single comprehensive literature review that describes the epidemiology and outcome of this disease. Methods We reviewed reports of zygomycosis in the English-language literature since 1885 and analyzed 929 eligible cases. We included in the database only those cases for which the underlying condition, the pattern of infection, the surgical and antifungal treatments, and survival were described. Results The mean age of patients was 38.8 years; 65% were male. The prevalence and overall mortality were 36% and 44%, respectively, for diabetes; 19% and 35%, respectively, for no underlying condition; and 17% and 66%, respectively, for malignancy. The most common types of infection were sinus (39%), pulmonary (24%), and cutaneous (19%). Dissemination developed in 23% of cases. Mortality varied with the site of infection: 96% of patients with disseminated disease died, 85% with gastrointestinal infection died, and 76% with pulmonary infection died. The majority of patients with malignancy (92 [60%] of 154) had pulmonary disease, whereas the majority of patients with diabetes (222 [66%] of 337) had sinus disease. Rhinocerebral disease was seen more frequently in patients with diabetes (145 [33%] of 337), compared with patients with malignancy (6 [4%] of 154). Hematogenous dissemination to skin was rare; however, 78 (44%) of 176 cutaneous infections were complicated by deep extension or dissemination. Survival was 3% (8 of 241 patients) for cases that were not treated, 61% (324 of 532) for cases treated with amphotericin B deoxycholate, 57% (51 of 90) for cases treated with surgery alone, and 70% (328 of 470) for cases treated with antifungal therapy and surgery. By multivariate analysis, infection due to Cunninghamella species and disseminated disease were independently associated with increased rates of death (odds ratios, 2.78 and 11.2, respectively). Conclusions Outcome from zygomycosis varies as a function of the underlying condition, site of infection, and use of antifungal therapy.

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Epidemiology and Outcome of Zygomycosis: A Review of 929 Reported Cases

Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans

Tick-borne rickettsioses are caused by obligate intracellular bacteria belonging to the spotted fever group of the genus Rickettsia. These zoonoses are among the oldest known vector-borne diseases. However, in the past 25 years, the scope and importance of the recognized tick-associated rickettsial pathogens have increased dramatically, making this complex of diseases an ideal paradigm for the understanding of emerging and reemerging infections. Several species of tick-borne rickettsiae that were considered nonpathogenic for decades are now associated with human infections, and novel Rickettsia species of undetermined pathogenicity continue to be detected in or isolated from ticks around the world. This remarkable expansion of information has been driven largely by the use of molecular techniques that have facilitated the identification of novel and previously recognized rickettsiae in ticks. New approaches, such as swabbing of eschars to obtain material to be tested by PCR, have emerged in recent years and have played a role in describing emerging tick-borne rickettsioses. Here, we present the current knowledge on tick-borne rickettsiae and rickettsioses using a geographic approach toward the epidemiology of these diseases.

Update on Tick-Borne Rickettsioses around the World: a Geographic Approach

During most of the 20th century, the epidemiology of tick-borne rickettsioses could be summarized as the occurrence of a single pathogenic rickettsia on each continent. An element of this paradigm suggested that the many other characterized and noncharacterized rickettsiae isolated from ticks were not pathogenic to humans. In this context, it was considered that relatively few tick-borne rickettsiae caused human disease. This concept was modified extensively from 1984 through 2005 by the identification of at least 11 additional rickettsial species or subspecies that cause tick-borne rickettsioses around the world. Of these agents, seven were initially isolated from ticks, often years or decades before a definitive association with human disease was established. We present here the tick-borne rickettsioses described through 2005 and focus on the epidemiological circumstances that have played a role in the emergence of the newly recognized diseases.

Tick-Borne Rickettsioses around the World: Emerging Diseases Challenging Old Concepts

Rickettsioses are caused by species of Rickettsia, a genus comprising organisms characterized by their strictly intracellular location and their association with arthropods. Rickettsia species are difficult to cultivate in vitro and exhibit strong serological cross-reactions with each other. These technical difficulties long prohibited a detailed study of the rickettsiae, and it is only following the recent introduction of novel laboratory methods that progress in this field has been possible. In this review, we discuss the impact that these practical innovations have had on the study of rickettsiae. Prior to 1986, only eight rickettsioses were clinically recognized; however, in the last 10 years, an additional six have been discovered. We describe the different steps that resulted in the description of each new rickettsiosis and discuss the influence of factors as diverse as physicians' curiosity and the adoption of molecular biology-based identification in helping to recognize these new infections. We also assess the pathogenic potential of rickettsial strains that to date have been associated only with arthropods, and we discuss diseases of unknown etiology that may be rickettsioses.

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Rickettsioses as paradigms of new or emerging infectious diseases.

To the Editor: The number of new rickettsial species that cause diseases in humans is rapidly increasing (1). Moreover, many of the species first described in ticks have been recently shown to be pathogenic. Of the 10 species or subspecies found to be pathogens after 1984, a total of 7 were first isolated from ticks (2). We report the first isolation of Rickettsia massiliae from a patient. The bacterium was isolated in Sicily in 1985 and identified in 2005.

A 45-year-old man was hospitalized in Palermo, Italy, on June 6, 1985, for fever and a rash. He had been febrile since May 25 and did not respond to antimicrobial drug treatment using cefamezin, a first-generation cephalosporin. On examination, he had a necrotic eschar on his right ankle, a maculopapular rash on his palms and soles (Figure A1), and slight hepatomegaly. Leukocyte count was normal; he received tetracyclines for 13 days and fully recovered. He seroconverted (from 0 to 1:80 between day 11 and day 24) by indirect immunofluorescence to Rickettsia conorii (R. conorii spot, bioMerieux, Marcy l'Etoile, France).

Four milliliters of heparinized blood sampled before treatment were inoculated in a 25-cm2 flask containing Vero cells and incubated at 33°C in a CO2 incubator (1). Direct immunofluorescence test on a sample of the patient's serum was positive 7 days later. The strain was stored for 20 years and tested in 2005 at the Unite des Rickettsies for identification, and R. massiliae was identified. DNA was extracted from the cell culture supernatant and used as template in 2 previously described polymerase chain reaction (PCR) assays that targeted a portion of the rickettsial ompA gene as well as a portion of the rickettsial gltA gene (3,4). Amplification products of the expected size were obtained from this extract but from no concurrently processed control materials, including 3 negative controls. DNA sequencing of the positive PCR products gave 100% identity with R. massiliae for ompA (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"RBU43792","term_id":"1174112","term_text":"gb||RBU43792"}}RBU43792) and 99.9% homology for gltA (GenBank accession no. RSU 59720).

R. massiliae was first isolated from Rhipicephalus ticks in Marseilles (5). It is transmitted transovarially in Rhipicephalus turanicus (2). R. massiliae is commonly found in Rhipicephalus sanguineus or R. turanicus in France, Greece, Spain (identified as Bar 29) (6), Portugal, Switzerland, Sicily (D. Raoult, unpub. data), Central Africa, and Mali (2). R. massiliae may be commonly associated with these ticks, which are distributed worldwide.

R. massiliae is grouped phylogenically with Rickettsia rhipicephali and Rickettsia aeschlimannii (Figure A2). Bacteria from this group have a natural resistance to rifampin that is associated with an rpoB sequence that is different from that of other rickettsiae. This isolate was not tested for antimicrobial drug susceptibly (7). Rifampin resistance leads us to believe that this isolate may cause a Mediterranean spotted fever–like disease that was described in children in Spain (7,8). Serologic findings were recently reported that showed some patients in Barcelona, Spain, with reactions that indicate R. massiliae (B29 strain) rather than R. conorii (6). However, serologic reactions are only presumptive; isolation from a patient is the required to initially describe a new disease (9).

This Sicilian index case shows that R. massiliae is a human pathogen. It contraindicates using rifampin to treat Mediterranean spotted fever in areas where R. massiliae is endemic, as it cannot as yet be differentiated from R. conorii infection. R. massiliae is a new example of a strain identified in ticks for several years before its first isolation from a human patient (10). The longest delay was observed for Rickettsia parkeri, which was isolated from ticks in 1939 but not from a patient until 2004. Many authors labeled R. parkeri a nonpathogenic rickettsia during this time (1). In the present case, the human isolate was obtained before the tick isolate but was not further identified. When this strain was isolated, R. conorii was the sole Rickettsia sp. found in ticks in southern Europe. Moreover, only 1 tickborne pathogenic Rickettsia sp. was believed to circulate in a single area. Since that time, several tickborne rickettsial diseases have been shown to exist in the same area, which prompted us to retrospectively identify this strain. The patient was reexamined in May 2005, after this identification. He is healthy and has no remaining antibodies against Rickettsia spp.

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Rickettsia massiliae Human Isolation

Background: Most studies of anti-transglutaminase (anti-tTG) assays have considered preselected groups of patients. This study compared the sensitivity, specificity, and predictive value of an immunofluorescence method for anti-endomysial antibodies (EmAs) and two anti-tTG ELISAs, one using guinea pig tTG (gp-tTG) and the other human tTG (h-tTG) as antigen, in consecutive patients investigated for suspected celiac disease (CD).

Methods: We studied 207 consecutive patients (99 men, 108 women; age range, 17–84 years) who underwent intestinal biopsy for suspected CD. Patients presented with one or more of the following: weight loss, anemia, chronic diarrhea, abdominal pain, dyspepsia, alternating bowel habits, constipation, pain in the joints, and dermatitis. At entry to the study, an intestinal biopsy was performed and a serum sample was taken for IgA EmAs, anti-gp-tTG, and anti-h-tTG.

Results: Intestinal histology showed that 24 patients had partial or total villous atrophy; in these patients the diagnosis of CD was confirmed by follow-up. The remaining 183 patients had villous/crypt ratios that were within our laboratory’s reference values and were considered controls. Serum EmAs, anti-gp-tTG, and anti-h-tTG were positive in all 24 CD patients; in the control group, none were positive for serum EmAs, but 15 of 183 (8.2%) were positive for anti-gp-tTG, and 6 of 183 (3.3%) were positive for anti-h-tTG. Sensitivity was 100% for all assays, whereas specificity was 100% for the EmA, 92% for the anti-gp-tTG, and 97% for the anti-h-tTG assay. The negative predictive value was 100% for all assays; the positive predictive value was 100% for the EmA, 80% [95% confidence interval (CI), 65–95%] for the anti-h-tTG ( P = 0.03 vs EmA) and 60% (95% CI, 44–76%) for the anti-gp-tTG assay ( P = 0.0002 vs EmA). Areas (95% CIs) under the ROC curves were 0.987 (0.97–1.0) for anti-h-tTG and 0.965 (0.94–0.99) for anti-gp-tTG. Most of the patients testing false positive for anti-tTG had Crohn disease or chronic liver disease.

Conclusions: Although both anti-tTG ELISAs showed optimum sensitivity, their lack of specificity yielded positive predictive values significantly lower than those for the EmA assay.

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Comparison of Anti-Transglutaminase ELISAs and an Anti-Endomysial Antibody Assay in the Diagnosis of Celiac Disease: A Prospective Study

In vivo and in vitro cytokine profiles and mononuclear cell subsets in sicilian patients with active visceral leishmaniasis

Pathogenesis of rickettsial eschars: The tache noire of boutonneuse fever

Leishmaniasis represents a severe, increasing, public health problem. The perspective of its control is highly dependent on research progress, on therapeutic manipulations of the immune system, and on vaccine development. There is a correlation between the clinical outcome of Leishmania infection and the cytokine response profile. While a protective immune response against Leishmania has been clearly identified to be related to the influence of a type-1 response and IFN-gamma production, the precise role of T helper (TH) 2 cytokines in non-healing infections requires further exploration. IL-4 and IL-13 (TH2 cytokines) can promote disease progression in cutaneous leishmaniasis, whereas IL-4 would appear to enhance protective type-1 responses in visceral leishmaniasis. Thus, the TH1/TH2 paradigm of resistance/susceptibility to intracellular parasites is probably an oversimplification of a more complicated network of regulatory/counter regulatory interactions. Moreover, the presence of antigen specific regulatory T cell subsets may provide an environment that contributes to the balance between TH1 and TH2 cells. Finally, the involvement of CD8 positive T cells has been described, but the modality of their function in this kind of infection has not been so far elucidated.

https://journals.sagepub.com/doi/pdf/10.1177/039463200702000302

Serafino Mansueto

Papers

Rickettsia massiliae Human Isolation

Comparison of Anti-Transglutaminase ELISAs and an Anti-Endomysial Antibody Assay in the Diagnosis of Celiac Disease: A Prospective Study

In vivo and in vitro cytokine profiles and mononuclear cell subsets in sicilian patients with active visceral leishmaniasis

Pathogenesis of rickettsial eschars: The tache noire of boutonneuse fever

Immunopathology of leishmaniasis: an update.