Increased Risk of Bartonella Infections in Humans

Bartonellosis has emerging zoonoses of the Vector Borne Diseases (VBD) complex. Progress in evolution and changes of causer, enabled the expansion, and increased number of clinically manifest forms of disease appearance of severe disseminated forms of infections and co-infections in humans, difficult for diagnosis, therapy and prognosis. The Bartonellosis may have a benign and self-limiting evolution in a host, or potentially fatal infections. Etiological agents can provoke a granulomatous or an angioproliferative histology damages. In severely immunodeficient cases (pulmonary tuberculosis, carcinomatosis, HIV infection, patients who underwent organ transplantation etc.), Bartonella infections can be difficult and often with unpredictable course of the fatal prognosis. Present the large specter of clinical manifestations: prolonged fever, erythema nodosum like syndrome, and the other skin manifestations, sub-acute bacterial endocarditis, difficult pulmonary disturbances, bacillary angiomatosis (BA) and hepatic peliosis (HP), bacteriemia or a combination of these. In period 2007-2015 on Clinic for Infectious Diseases in Podgorica, 25 cases with Bartonella infection were diagnosed. In total sample, the most frequent were diagnosed CSD in 19 cases. During 2015 in two cases with HIV/AIDS infection, BA was diagnosed, and in four cases PH was diagnosed.

Open Journal of Clinical Diagnostics plex [1] [2] [3] [4].Progress in evolution and changes of infectious agents enabled the expansion, increased number of clinically manifest forms of disease, appearance of severe disseminated forms of infections and co-infections in humans, difficult for diagnosis, therapy and prognosis [5] [6] [7] [8].
Bartonellosis are diseases known even from ancient period on basis the clinical picture and the assumed relationship with animals-natural reservoirs of pathogens [25] [26].Newel epidemiological data present as Bartonellosis has wide spread in the World, including wild and domestic mammals, especially in areas with hot and humid climate [27] [28].
Often the transmission of Bartonella spp. in humans occurs by traumatic contact with infected animals (cat scratch, cat bite, likely), by vectors-cat fleas (Ctenocephalides felids) or other blood-sucking arthropods (e.g.Sand fly, Phlebotomies, Human louse).For some Bartonella species, the vectors are known [28]- [33].In 3.6% of cases method of transmission has not been known.
Bartonella agents have detected in several tick species, including Ixodes (Ix) ricinus, Ix. scapularis, Ix.Persulcatus, Dermacentor reticulatus, Rhipicephalus sanguineus [34] [35] [36] [37], but their competence in disease transmission is unclear.Data of the many epidemiological studies present co-infective participation of Bartonella species in 28% of cases with chronic Lyme borreliosis (LB) [38].The controversial diagnosis of chronic Lyme disease is often giving to patients with prolonged, medically unexplained physical symptoms.Many such patients are also treating for chronic co-infections with Babesia, Anaplasma, or Bartonella in the absence of typical presentations, objective clinical findings, or laboratory confirmation of active infection [39] [40].From a number isolates of borrelia burgdorferi (bb), has found two main fractions of heat shock proteins (HSP60 and HSP70), which cross-react with antigens of other microorganisms, pointed the possibilities of transmission of Bartonella agents through bb.The fact of exist co-infective forms of disease and knowledge's that Bartonella in Types of potential more participants in co-infections, determines geographical distribution of infective agents in natural foci [38] [39] [40] [41].
Experimentally is demonstrated that Ix. ricinus can transmit B. henselae during a blood meal.However, the replication of bacteria has rarely reported in the ticks, we do not support the hypothesis that ticks are natural competent vectors of Bartonella spp.[32] [34] [35] [36].
In the study of the 386 tick specimens collected in spring 2009 from migratory birds on the Mediterranean area was positive for RNA of Bartonella in 98.9% of the ticks [38].There present evidence that Bartonella can replicate within ticks and no definitive evidence of transmission by a tick to a vertebrate host.
The pathogenesis of Bartonrlla infection has not fully known.The Bartonellosis may have a benign self-limiting evolution in a host, or potentially fatal infection.The causers can provoke a granulomatous or an angioproliferative histopathology damages.There are two conceptually distinct Bartonella-associated syndromes: bacteriemia (in the absence of focal tissue vascular proliferative response) and the tissue infection bacillary angiomatosis (BA) or hepatic peliosis (HP) associated with angiogenic response [42] [43] [44].
Today Oroya fever and Verruga peruana has called Carrion's disease and the others [26].

Methodology
In In four cases there were extirpated affected lymph glands and performed microbiological and hystopathological analysis.Skin lesions, as if to Kaposi sarcoma was also analyzing histological.If is necessary, where used the other diagnostic methods as komputerising tomography (CT), X-Rey diagnostics and others.

Results
In our study the largest group of Bartonellosis was represented CSD in 19 cases.
The 40% patients have cities inhabitants, 40% live in suburban and 20% in rural locations.Age distribution of patients presents 11 (%) cases of children population, and adult's population in 8 (%) cases.The most CSD cases present a be-Open Journal of Clinical Diagnostics nign, self-limiting disease, but in vulnerable and immune deficient cases, infection present difficult disease.In the clinical specter of CSD, common infective syndromes (fever, malaise, chills, and fatigue) have 78% of cases.The transitory liver disturbances have registered in 67% cases.Perinaud oculoglandular syndrome is not registered, but 50% of patients had conjunctivitis.In total examined group, 19 (100%) cases with CSD had previous contact with a cat.Primo affect has registered in 75% cases (Figure 1).
In addition to the general symptoms in our patients dominant clinical manifestations of CSD has regional enlarged lymph nodes presented in all patients, persisted for several weeks or months then may be it s spontaneous regression and complete resolution in 75% cases.In 25% of cases inflammatory changes in the lymph nodes, manifested hyperplasia, granulomatous inflammation with suppuration and exulcerating glands (Figure 3).Results of microbiological and histological analysis emphasized the following characteristics (Figure 5).Microbiological preparates stained by Woirting Sttar were negative.At the physical examination in both patients has registered: distended abdomen with painful, enlarged liver and spleen, and mild as cites.He also had moderate lower limbs edema.Laboratory analyses present leucopenia and anemia, mild elevated levels of serum transaminases.AST (asparat aminotransferase) and ALT (alanin aminotransferase), Lactate dehydrogenase (LDH), total bilirubin, Gamma glutamate transferasis and alkaline phosphates were also elevated.
On the Chas X-ray, he had infiltrations of the lung.The CD4 count was 5/mm 3 on addmition, and viral load (VL), >600.000cop/ml.On ultrasound and CT abdominal examinations is founded the changes in the liver, spleen, pancreas.Mild ascites and bilateral pleural effusion has found.The myelogram displayed dysmyelopoiesis.
Despite therapy with ceftriaxone, ciprofloxacine, trimethoprim-sulfamethoxazole the patient's condition worsened.When an elderly patient fever persisted in irregular spikes, the skin lesions increased in number and size consisting of edematous and livid nodules on the right face and nose and some of the lesions progressed to ulceration.Laboratory analyses get worsted, elevation of the hepatic enzymes, total bilirubin, alkaline phosphates and gamma glutamat transferases.
In third week, there has been a deterioration of disease.Further increase has noted in the liver size, and in the number of erythematous papules with spontaneous bleeding in a few, and worsens in laboratory analyses.
The following abdominal ultrasound showed enlarged liver associated to signs of diffused parenchyma disease.Histology reveals vascular proliferation with the presence of neutrophils adjacent to the blood vessels.Bacteria, is not can be demonstrate by modified silver staining (within-starry silver stain).Detection of Bartonella DNA in tissue managed using Polymerase Chain Reaction (PCR).
Lymph nodes were enlarging in the peripancreatic, perihilar, and retroperitoneal regions, as well as ascites and slight enlargement of the spleen.Despite all given therapy he died to the end of the third week of hospitalization.
A few months later the same year Peliosis hepatis (PH) has detected in four cases.In relation to age, it was three children cases, aged of 5, 7 and 9 years, and one case aged of 18 years.Common to all cases were data on close and prolonged contact with cats, in three younger cases with data on reusable scratch and bite of cats, and the absence of symptoms of CSD.The older patient did information that constantly sleeping with their pets (cats) in the same bed.In one case with diagnosed and treated pulmonary tuberculosis, confirmed diagnosis of bartonellosis, at the first moments, present many differential diagnostic problem.
In 2 (13.33%) cases with CSD, in acute phases, with common infective syndromes the symptoms of erythema nodosum are present (Figure 8).

Discusion
Montenegro is an endemic area for a considerable number of VBD.Natural conditions and geographical position (Mediterranean area), changes in environmental characteristics of vectors and infectious agents are main predisposing factors for the expansion and increasing importance of these infections.Resistance to antibiotics additionally complicates disease prognosis [44] [45].
Bartonellosis is zoo-noses in which progress in evolution and changes of infectious agents enabled expansion and appearance of severe disseminated forms of infection and co-infections as demonstrated by investigations in the world and in our study [4]  In Central Nervous System (CNS), encephalopathy is an infrequent, but important signs of disease.Persistent intellectual impairment was been reported.
Ocular manifestations of bartonellosis present Perinaud oculoglandular syndrome develop in 2% -3% of patients, manifested with the characteristic granulomatous lesion on the conjunctiva and the periocular adenopathy, papillitis.
Posterior segment findings include optic neuropathy, neuroretinitis, vitreitis, and others.In our patients, except transitory conjunctivitis, is not registered serious disruption of ocular disturbances.
Bacillary angiomatosis (BA) and bacillary peliosis (PH) are vascular proliferative manifestations of Bartonella infection that occur predominantly in immune deficient patient, rare in immune-competent cases.
BA typically involved the skin and was believe to resemble Kaposi sarcoma, but can affect other organs such as the respiratory tract, bone marrow, lymph Investigates are covered: Bartonella henselae, B. burgdorferi, Coxiella burneti, Leishmania donovani, Babesia spp.and others.
Peliosis hepatis (PH) is a rare vascular disease.The epidemiology and pathohistology of disease is still unclear [4] [15].In 80% of patients passes asymptomatically, and accidentally discovered during ultrasound diagnostics or during the autopsy.It is most often found in the liver, but can also occur in the spleen, bone marrow, the lungs, lymph nodes, kidneys, adrenal glands, and other parts of the gastrointestinal tract.
PH is an uncommon condition of the sinusoidal system of the liver with enlargement and dilatation resulting in blood-filled cavities with a diameter up to several centimeters.The rare cases, it may be complicated by rupture with resultant bleeding.
It was first report in the early 1950s in patients with tuberculosis, but his also founded in many other pathological conditions such has also been reported in related to drugs and chemicals, bacterial infections, hematological and other malignancies, organ transplanting, and other.
Several publications have appeared leading to a more precise classification of the structural abnormalities in PH, which can be subdivide into a parenchyma form, with enlarged sinusoidal cavities, and a phlebectatic form, which characterized by regular sinusoidal cavities with per sinusoidal fibrosis [16]. In

Conclusions
Montenegro is a Mediterranean country, with a significant and broad spectrum It is necessary to diagnose CSD in patients with adenopathy, to differentiate CSD to a number a neoplastic diseases, examples lymphoma, leukemia, and the other neoplasm's [11] and large specter of emerging infectious diseases, example fungal infection, toxoplasmosis, tularemia, tuberculosis, plaque, lymphogranuloma venerum (LGV), AIDS, Syphilis and other.However, this can be difficult because of limitations to the currently available confirmatory diagnostic tests [12].
Immune deficient patients with the same organism lead to a very different disease.BA -PH is increase.Angioproliferative lesions resembling those of Kaposi sarcoma in the skin, liver, spleen, bone marrow and other organs characterizes this disease [45].
period, 2007-2015 on Clinic for Infectious Diseases in Podgorica, Montenegro, were diagnostics in total 25 cases with Bartonella infection.The frequency of diagnosed cases increased significantly in the last two years, when they has registered with the CSD and the first cases of BA and PH as well as significantly more severe forms of diseases.In the total sample, the most frequent were diagnosed CSD in 19 cases.During 2015 in two cases with HIV/AIDS infection, was diagnosed bacillary angiomatosis (BA), like Kaposi sarcoma, and in four cases peliosis hepatis (PH) was diagnosed.The investigation used epidemiological, clinical, serological Indirect Immune Fluorescent (IIF), Enzyme Liked Immunosorben Assay (ELISA) methods, Polymerase Chain Reaction (PCR).The ultrasound diagnosis has used for making diagnosis of enlarged lymph nodes, liver and spleen and for monitoring the development of the disease.

Figure 1 .
Figure 1.Skin primo affect after cat scratch.On basis their appearances and localization, present indicator of the Bartonella way in CSD infection (Photo documentation of Professor Bogdanka Andric).

Figure 4 .
Figure 4. Ultrasound diagnosis: In the central zones of enlarged lymph nodes there are hot spots colliqation (Appendix).

Figure 7 .
Figure 7. Ultrasound diagnosis of PH in our patient: More focal changes in liver parenchyma.Enlarged lymph nodes in the hillary liver region and para-pancreatic region (Appendix).

B.
Andric et al.DOI: 10.4236/ojcd.2018.8300435 Open Journal of Clinical Diagnostics nodes, adrenal glands, gastrointestinal tract, liver and spleen.The causer's of BA/HP are B. henselae and B. quintana.Some studies have described the prevalence of BA in patients with immunodeficiency [1] [2] [4]-[10].In period of 2012 to 2015, we are studied 50 HIV-infected persons, for the detection of co-infective forms of diseases.The spectrum of infective agents, potentially participants in these common basis of HIV infected persons, included intracellular agents, whose reactivation and participation in co-infections with HIV based on declining immunity and potentially reactivation of the spectrum causers such tuberculosis, coxiellosis, brucellosis, micoplasmae pneumonia, Chlamydia, listeriosis, EBV, CMV.Participation of infectious agent's of VBD complex, in common infective forms of diseases, based on the epidemiological and immunological environment characteristics and evolutionary changes of infectious agents of VBD complex.The geographical area dictates the potential participants in the co-infections.
which is due to unrecognized disease treated long time with tuberculostatics, and immune deficiently patients, who was treated with dual antibiotic therapy, in addition to regular antiretroviral therapy.Untreated Bartonella infection can be fatal in HIV-infected patients as demonstrated in our study.Our patients with co-infection B. hensellae and HIV, among numerous multisystem changes, developed tumor lesions on the face, like Kaposi sarcoma, and in the purple dermal nodes sites of the thoracic and abdominal region, the histological verified as vasculitis.Vasculitis has a heterogeneous presentation, and often are accompanying by large specter of opportunistic agents.These have mediated by immunological factors or by direct vascular injured.Along with many other systemic complications, and progression, contributed to the fatal outcome of the diseased[20].
of vector borne diseases (VBD) representation, including bartonellosis.Our first experiences with this disease were focused on the detection of the most frequent manifestation of disease, cat scrach disease (CSD).But in the period from 2007 to 2015, based on our research, we were surprised by the diversity of clinical manifestations in patients which confirmed the etiological diagnosis of bartellellosis, also found in the numerous references of other investigators in the world, and created big diagnostic, therapeutic difficulties.
in natural hosts and vectors can be shared their DNA with the different agents of the VBD complex (e.g.B. burgdorferi, Babesia spp., Rickettsiae and Bartonella spp.), opened a new chapter in the study of Bartonellosis.
B. Andric et al.DOI: 10.4236/ojcd.2018.8300427 Open Journal of Clinical Diagnostics natural condition, [31]four cases with PH, clinical diagnosis based on ultrasound diagnosis, Rarely Bartonellosis spreads and causes granulomatous hepatitis[20][30]or Open Journal of Clinical Diagnostics granulomas in the spleen or bone marrow.In our study in 60% of patients are registered increase activity of liver enzymes (AST, ALT, LDH), and enlarged liver and the spleen.co-infectiveforms of disease, in which participating B. helsellae and B. burgdorferi, Rickettsial agents, Coxiella burneti and other[10][13][31].Endocarditis due to B. quintana was been reported in both immune compromised and immune competent cases.The presenting symptoms are usually those of sub acute bacterial endocarditis, with malaise, weight loss, and fever.Valvule vegetations are been often demonstrated on echocardiography, as was reported for one HIV-infected patient with B. quintana endocarditis who developed both aortic and mitral valvule vegetations.Because Bartonella organisms are not isolated from routine blood cultures, Bartonella appears to be a cause of culture-negative endocarditis.In our study, endocarditis is not registered.
In our study, the therapeutic treatment has done in all patients.generally are administered in combination with tetracycline and trimetoprim, except one case, Open Journal of Clinical Diagnostics