Mediterranean spotted fever in child and adult patients: investigation from an endemic region in Bulgaria.

OBJECTIVES: Mediterranean spotted fever (MSF) is a tick-borne endemic disease caused by Rickettsia conorii conorii and transmitted to humans by the brown dog tick Rhipicephalus sanguineus. It is characterized by fever, maculopapular rash and a tick bite skin lesion "tache noire". The disease affects all age groups and usually has mild to moderate course. It has long been considered a benign infection. However, very severe "malignant" forms with fatal outcome strongly influenced by the patients' age were also observed. We aimed to reveal the features of MSF in children by comparing them with some of the disease patterns in adults. METHODS: Our prospective study data are based on the monitoring of all inpatients of the Clinic of Infectious Diseases in Plovdiv City and environs, the largest MSF endemic region in Bulgaria. The total number of patients admitted and treated for MSF over a study period of 10 years is 549, the incidence reaching 9.44/100,000. MSF is confirmed by antibody response to a specific antigen measured by indirect immunofluorescence assay (IFA). IgG ≥ 128 and/or IgM > 64 were considered to be indicative of acute infection. RESULTS: Eighty-five (15.48%) patients were children up to 14 years of age and 464 (84.52%) were aged 15-85 years. The skin lesion "tache noire" was present in 73.68% of children, and in 76.93% of the older age groups; symptoms as anorexia, nausea, vomiting, abdominal pain, and diarrhoea were more frequent in children, till general weakness and malaise was prevalent in adults. Children accounted approximately for 70% of the disease mild forms. No lethality was registered in this age group. Even though there were isolated cases of severe and malignant forms, children did not undergo the fatal complications seen in adults. CONCLUSION: Knowledge of the peculiarities of MSF in children will contribute to children's health protection, timely diagnose and disease prevention.

Unusual Maculopapular Rash on the Scalp of a Patient with Mediterranean Spotted Fever.

OBJECTIVE: To report a rare case of maculopapular rash on the scalp in a patient with Mediterranean spotted fever (MSF). CLINICAL PRESENTATION AND INTERVENTION: A 58-year-old woman with breast cancer and chemotherapy-induced alopecia contracted MSF. Her clinical features were typical, except for a maculopapular rash covering the scalp. The diagnosis of MSF was confirmed by immunofluorescent assay. The disease had a favorable course and the patient was discharged in good condition. CONCLUSION: The rash on the scalp described in this report enriches our knowledge on the clinical characteristics of MSF.

Mediterranean spotted fever--classification by disease course and criteria for determining the disease severity.

INTRODUCTION: Mediterranean spotted fever (MSF) in Bulgaria is caused by Ricketsia conorii conorii with a major vector the dog tick, Rhipicephalus sanguineus. The first cases of re-emerging MSF were reported in this country in the early 1990s after some 20 years of absence and then registered an annual increase until 2001-2003 after which the disease prevalence declined. MSF still poses a serious health problem in the country as severe, complicated cases with lethal outcome occur. The aim of this paper was to classify the forms of MSF according to the course of the disease process and to devise criteria for the disease severity in order to enable comparison of clinical manifestations of the disease at different stages of spreading, in different age groups, and between endemic and non-endemic regions in this country and abroad. PATIENTS AND METHODS: The study was carried out in a comparative aspect during the first phase of increase (1993-2003) with incidence of 11.88 per 100000 population and during the second phase of decline (2004-2011) with incidence of 9.56 per 100000 population. The disease was etiologically confirmed in 883 hospitalized patients by the positive antibody response to the specific antigen--Ricketsia conorii conorii by means of the immunofluorescence assay (IFA). The criteria we used for the classification of the forms of MSF included: 1. Typicality: forms having the most characteristic features of the MSF - eschar, fever, papular/maculopapular rash on the trunk and extremities, including hands and feet. 2. Manifestation: forms represented by all or some of the typical symptoms, giving sufficient grounds for preliminary diagnosis. 3. DURATION: fulminant, acute and protracted forms. The criteria for severity differentiate between mild, moderate, severe or malignant forms, and include clinical and laboratory parameters as shown in the present study. RESULTS: Classification of the forms according to MSF course defines them in order of severity, typicality, manifestation, duration of symptoms, complications and age characteristics. According to the accepted criteria for severity and with respect to the studied I and II phase of the disease the mild forms are 41.16%-35.62% (p > 0.05), moderate forms are 32.79%-43.11% (p < 0.01), severe forms are 16.03%-11.37% (p = 0.05), malignant forms are 6.56%-8.68% (p > 0.05), and mortality is 3.46%-1.19% (p < 0.05). The mean age was significantly higher for patients with severe forms of MSF (58.59 +/- 4.32 yrs) compared with those with moderate (46.10 +/- 3.71 yrs, p < 0.05) and mild forms (42.05 +/- 3.50 yrs, p < 0.01). For children up to 14 years old mild forms are more common than in adults over 65 (p < 0.0001). Among children up to 14 years old there were no lethal outcomes, while mortality rate in the patients older than 65 was as much as 10%. All this indicates that MSF runs a milder course in children and a severe, complicated course in the elderly. CONCLUSION: The criteria for MSF severity we have selected are based on our own experience and the experience of other authors. They are based on the reaction of human organism to the pathogenic agent and can be used during the different phases of emergence and development of rikettsial diseases, regardless of their geographic distribution. Unified use of these criteria would eliminate the differences in the data reported by different researchers regarding the disease development and severity.

Dynamics in serum cytokine responses during acute and convalescent stages of Mediterranean spotted fever.

UNLABELLED: Mediterranean spotted fever (MSF) is a re-emerging rickettsiosis in Bulgaria after 20 years of absence (1972-1992), and it has since been affecting many people annually in the endemic regions of the country. The role of cytokines in MSF is still in the focus of research due to their complex participation in the immune pathogenesis of the disease. AIM: To study the changes in the serum cytokine concentrations in MSF patients. PATIENDS AND METHODS: Eighty patients with MSF and 20 healthy controls were enrolled in the study. The pro-inflammatory and immunoregulatory cytokines IL-1beta, TNF-a, IL-6, IL-8, IL-12, IFN-gamma, IL-2, and IL-10 were studied in the burst of disease, at clinical recovery stage, and two weeks later. The disease etiology was verified by indirect IFA in the Referral Rickettsiosis Laboratory. The cytokine levels were determined by ELISA (BioSource Europe S.A). RESULTS: In the disease flare up patients showed a manifold increase in the activity of IL-1beta (p < 0.01), TNF-alpha (p < 0.001), IL-6 (p < 0.001), and IL-8 (p < 0.001) compared with the controls. Significant elevation in IFN-gamma and IL-12 values (p < 0.001) was also found. The increase in the immunoregulatory IL-10 also reached statistical significance (p < 0.001), while the rise in IL-2 did not (p > 0.05). Followed in dynamics, only IL-1beta and IL-6 measured up the control levels at the time of clinical recovery. Two weeks later, in the early convalescence IL-12 and TNF-alpha further diminished but did not normalize their values. CONCLUSION: Our findings show that MSF is characterized by a Th1 cytokine profile. The patient's immune system responds by proinflammatory and immunoregulatory cytokine production that accompanies the rickettsial vasculitis and contributes to the healing process. The latter is probably not fully achieved in the early convalescent period, according to our data concerning some pro-inflammatory cytokines' elevation at this period.

HIV/AIDS-associated Kaposi's sarcoma with multiple skin-mucosal disseminations following ultraviolet (puva) photochemotherapy.

UNLABELLED: HIV/AIDS infection in Bulgaria has spread over about 1200 registered patients and it is supposed that the number of the undetected cases is four times higher. Kaposi's sarcoma is rarely observed in our country and no cutaneous-mucosal dissemination is reported for the time being. AIM: The aim of the study is to present a case of disseminated Kaposi's sarcoma in a HIV/ AIDS patient who underwent Psoralen--UVA radiation treatment (PUVA) for total alopecia. METHODS: HIV was proved through ELISA and Western blot (InnoLia HIV I/II Score). PCR method (COBAS-Amplicor HIV-1 MT, 1,5) was used to determine viral load (VL). Monitoring was realized by flow-cytometric phenotype analysis of the immune cells. Biopsy of a skin lesion was performed for histomorphological analysis. Computed axial tomography (CAT) of the visceral organs was also applied. RESULTS: The patient's face, chest, back and upper extremities are covered by more than 50 typical for Kaposi's sarcoma skin tumors and several isolated lesions are found in the oral cavity mucosa. The histological results show dilated vascular spaces with large endothelial cells and spindle-like tumor cells in irregularly formed fascicles. Monitoring of the immune cells and the viral load before and after the application of highly active antiretroviral therapy (HAART) showed CD4+ T cell number = 0.147 x 10(9)/l and VL = 216 000 copies HIV-RNA/ml plasma when the disorder was first detected. A very good effect appeared 4 months after the HAART start: the mucous membrane lesions disappeared and the skin tumors decreased by number and dimensions. In the same time the CD4+ T cell number increased up to 0.255 x 10(9)/l and VL values decreased < 400 c/ml. CONCLUSION: Disseminated form of Kaposi's sarcoma can be provoked by additional immunosuppressive factors like the implementation of PUVA therapy. Early initiation of HAART improves the process and prevents visceral dissemination.

HIV-1 genetic diversity and demographic characteristics in Bulgaria.

HIV-1 strain diversity in Bulgaria is extensive and includes contributions from nearly all major subtypes and the Circulating Recombinant Forms (CRF): 01_AE, 02_AG, and 05_DF. Prior to this study, HIV-1 sequence information from Bulgaria has been based solely on the pro-RT gene, which represent less than 15% of the viral genome. To further characterize HIV-1 in Bulgaria, assess participant risk behaviors, and strengthen knowledge of circulating strains in the region, the study "Genetic Subtypes of HIV-1 in Bulgaria (RV240)" was conducted. This study employed the real time-PCR based Multi-region Hybridization Assay (MHA) B/non-B and HIV-1 sequencing to survey 215 of the approximately 1100 known HIV-1 infected Bulgarian adults (2008-2009) and determine if they were infected with subtype B HIV-1. The results indicated a subtype B prevalence of 40% and demonstrate the application of the MHA B/non-B in an area containing broad HIV-1 strain diversity. Within the assessed risk behaviors, the proportion of subtype B infection was greatest in men who have sex with men and lowest among those with drug use risk factors. During this study, 15 near full-length genomes and 22 envelope sequences were isolated from study participants. Phylogenetic analysis shows the presence of subtypes A1, B, C, F1, and G, CRF01_AE, CRF02_AG, CRF05_DF, and one unique recombinant form (URF). These sequences also show the presence of two strain groups containing participants with similar risk factors. Previous studies in African and Asian cohorts have shown that co-circulation of multiple subtypes can lead to viral recombination within super-infected individuals and the emergence of new URFs. The low prevalence of URFs in the presence of high subtype diversity in this study, may be the result of successful infection prevention and control programs. Continued epidemiological monitoring and support of infection prevention programs will help maintain control of the HIV-1 epidemic in Bulgaria.

Guillain-Barré syndrome in a Child with Ongoing Viral Hepatitis A.

Guillain-Barré syndrome (GBS) belongs to the group of peripheral immune-mediated neuropathies often preceded by an inflammatory episode. GBS is rarely associated with hepatitis A virus (HAV) infection, the latter as a rule antecedent of the neurological disorders. This association is quite rare in childhood, and so far, only isolated cases have been described. We report an unusual case of pediatric GBS which development coincided with the development of HAV IgM (+) viral hepatitis A. From the second to the 14th day after admission to the hospital for mild jaundice of the skin and sclera in a 12-yr-old boy, the following neurological disorders have developed: absent Achilles and knee-jerk reflexes, diminished brachioradialis reflex, moderately decreased muscle power in the upper extremities and more pronounced power loss in the lower extremities. Facial palsy developed bilaterally, more expressed to the right. There was albuminocytologic dissociation of the cerebrospinal fluid and electrodiagnostic study showed findings compatible with the GBS subdivision - Acute inflammatory demyelinating polyneuropathy (AIDP). HAV could trigger GBS in the very beginning of liver inflammation in children. This insight may help wide range of medical professionals to early recognize and treat the peripheral neuropathy.