Bacterial and Mycotic Infections in Immunocompromised Hosts: Clinical and Microbiological Aspects Edited by Maria Teresa Mascellino www.esciencecentral.org/ebooks Brucellosis: A Global Re-emerging Zoonosis Clinical Aspects, Associations and Brucellosis in SpecificConditions Al-Anazi KA1* and Al-Jasser AM2 Department of Adult Hematology and Hematopoietic, Stem Cell Transplant, Oncology Centre, King Fahad Specialist Hospital, KSA 1 2 Central Laboratory, Ministry of Health, KSA *Corresponding author: Khalid Ahmed Al-Anazi, Consultant HematoOncologist, Department of Adult Hematology and Hematopoietic Stem Cell Transplant, Oncology Centre, King Fahad Specialist Hospital, P.O. Box: 15215, Dammam 31444, Saudi Arabia, Tel: 966–03–8431111; Fax: 966–03–8427420; E-mail: [email protected] Abbreviations: B.: Brucella; FUO: Fever of Unknown Origin; ESR: Erythrocyte Sedimentation Rate; CRP: C-Reactive Protein; CAT scan: Computerized Axial Tomography; MRI: Magnetic Resonance Imaging; CSF: Cerebrospinal Fluid; BBB: Blood Brain Barrier; CNS: Central Nervous System; IV: Intravenous; HIV: Human Immunodeficiency Virus; HSCT: Hematopoietic Stem Cell Transplantation; ESRD: End Stage Renal Disease; CFS: Chronic Fatigue Syndrome; ME: Myalgic Encephalopathy Introduction Brucellosis, the commonest zoonosis worldwide, is caused by Gram-negative, intracellular coccobacilli that affect various body organs [1-3]. Infection can be acquired by several means and has recently been increasingly recognized in patients with comorbid medical conditions and in immunocompromised individuals . Not only duration of the incubation period, but also presentation and clinical manifestations of Brucellosis are very variable. Brucella infections can be localized or disseminated and are very variable in severity. Complications, chronic infections and relapses are prone to occur [1,2]. Human Brucellosis has protean clinical manifestations and the onset may be acute or insidious. The infection is usually underdiagnosed due to the misleading clinical picture. Hence, treatment may be delayed and complications may evolve . Sustaining a high index of suspicion is essential particularly in risk individuals and in patients living in endemic areas as early diagnosis and prompt therapy improve the outcome and prevent complications [1-3]. Clinical Manifestations of Brucellosis The infective dose is relatively low as 10 to 100 organisms are sufficient to cause infection/disease . Duration of the incubation period is variable. Usually it ranges between 1 week and 2 months but it can be as short as 5 days and as long as several months. During the incubation period, the clinical features are protean and non-specific [1,2]. Presentation of Brucellosis is also very variable. It may present as an acute febrile illness or as a chronic infection. It can cause both localized infection as well as systemic and generalized disease. Severity of the infection is also very variable as it may be totally asymptomatic or can cause severe and potentially fatal illness. Relapses and complicated infections may also be encountered [1,2]. Complications of Brucellosis Osteoarticular complications Osteoarticular disease is the most common complication of Brucellosis as it has been described in 10 to 85% of patients [13,14]. The spectrum of bone and joint involvement by Brucellosis includes: arthritis, bursitis, tenosynovitis, osteomyelitis, spondylitis and sacroiliitis [13-16]. Spondylitis is the most common and most important form of osteoarticular involvement by Brucellosis in adults as it has been reported in 6-58% of cases . Spondylitis may be difficult to diagnose and can be complicated by potentially devastating neurological OMICS Group eBooks Fever is the commonest clinical feature. Insidious onset of fever, high grade and irregular, with chills lasting for days to weeks is the most usual presentation [1-3,5]. As the infection may be atypical in presentation, some cases present with fever of unknown origin (FUO) [2,5]. Other symptoms of Brucellosis include: night sweats, rigors, myalgia, arthralgia, low backache, anorexia, malaise, fatigue, weakness, weight loss, headache, dizziness, depressed mood, dyspepsia, nausea, vomiting, abdominal pain, cough, dyspnea, hemoptesis, testicular pain and burning micturition. Physical examination may reveal: swelling of joints, tenderness over joints and the lower back, splenomegaly, hepatomegaly, external lymphadenopathy, jaundice, mouth ulcerations, scrotal swelling and a variety of cutaneous eruptions [1-12]. The clinical manifestations and complications of Brucellosis included in 2 major retrospective studies and 1 meta-analysis are summarized in Table 1 [5,9,12]. 002 Clinical feature Buzgan et al [RS, 1028 patients] Mantur et al [RS,792 patients ] Dean et al [MA, 57 studies] Fever 72.2 78.9 78 Arthralgia 73.7 23.1 65 Fatigue 71.2 1.7 39 Sweating 64.8 3.9 54 Weight loss 42.4 1 26 Myalgia 36.1 NA 47 Back pain 21.2 14.8 45 Chills 33.9 NA 45 Nausea & vomiting 24.9 NA 26 Abdominal pain 6.7 3.2 19 Headache 14.4 2.5 35 Cough 2 3.5 NA Scrotal pain 3.4 2 NA Splenomegaly 14.5 18.5 26 Hepatomegaly 20.6 11.3 23 Lymphadenopathy 2.4 2.9 NA Spondylitis 3.1 NA 12 Sacroiliitis 6.2 NA 15 Endocarditis 0.7 NA 2 Skin lesions 2.4 NA 6 Scrotal swelling 3.4 NA 10 RS: Retrospective study; MA: Meta-analysis; NA: not available Table 1: Percentages of clinical manifestations of brucellosis. and vascular conditions. Back pain, fever and constitutional symptoms are the most common manifestations . Spondylitis typically affects men over the age of 40 years. Areas of the spine that are involved include: lumber (60%), thoracic (19%) and cervical (12%). Tuberculosis of the spine should be included in the differential diagnosis . Laboratory abnormalities in Brucella spondylitis include: elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), leucopenia or leucocytosis (at times with pus formation), anemia, thrombocytopenia and moderate elevation of liver enzymes (Table 2). Blood cultures may be positive in up to 85% of cases. Coomb’s test is invariably positive and agglutination tests may be positive in up to 90% of cases [13,16]. Plain X-rays, computerized axial tomography (CAT) scans, bone scans and magnetic resonance imaging (MRI) are useful in the diagnosis of spinal Brucellosis. Although bone scans are very useful, MRI is the method of choice for diagnosis and follow-up in spondylitis caused by Brucellosis [13,16-19]. The radiological features appear 3 to 5 weeks after the onset of the clinical manifestations . The radiological abnormalities are variable and they include: focal spondylitis, epiphysitis, diskitis with disc collapse, paravertebral abscesses and osteomyelitis (bone destruction) that may involve more than one bone or vertebral level and that may occur in 6-50% of patients (Figure 1) [13-16,18,20,21]. Treatment of spondylitis includes a combination of antimicrobials in addition to other measures such as analgesia, immobilization to reduce pain and drainage of abscesses if present. The best combination therapy includes doxycycline and aminoglycoside and response rate using this regimen ranges between 60 and 90% of treated patients. Doxycycline and rifampicin combination can be given alternatively while the combination of co-trimoxazole and ciprofloxacin is not recommended as it has been reported to yield a poor outcome. Longer duration of treatment is usually required. While some studies have shown that 6 to 12 weeks may be the optimal duration, other studies have shown that treatment for 12 to 18 weeks is associated with more optimal outcome. However, aminoglycosides are usually recommended during the first 3 weeks of chemotherapy [13,16,22,23]. In the management of osteoarticular complications of Brucellosis, early diagnosis and correct management are important to prevent harmful effects of Brucellosis [24,25]. The treatment of choice in most cases of spinal Brucellosis is antibiotic therapy primarily [13,24]. Brucella infection of prosthetic joints has been reported in patients requiring total joint arthroplasty. This serious complication may be introduced during surgery or through hematogenous spread or seeding. However, most infections are caused by Gram positive cocci. Negative cultures do not rule out the presence of osteoarticular Brucellosis. Combined medical (doxycycline and rifampicin therapy) and surgical (re-implantation) treatment is usually recommended . Arthritis develops in about 26% of patients having acute, subacute or chronic Brucellosis. Patients usually experience: fever, joint pain, sweating and fatigue. The joints involved arranged in an order of decreasing frequency are: sacroiliac, knees, hips and spine. Treatment is usually in the form of drug combination, either streptomycin and tetracycline or streptomycin and rifampicin. Antimicrobial therapy is usually associated with excellent cure rates as arthritis usually resolves without sequelae. Brucellosis should be considered in the differential diagnosis of arthritis in areas that are endemic for the infection [19,22]. Vertebral osteomyelitis is another serious complication of Brucellosis. It is associated with high rates of treatment failure and functional sequelae. The duration of treatment for vertebral osteomyelitis caused by Brucellosis is usually 3 months. Although MRI is considered the method of choice for the diagnosis of osteoarticular and spinal involvement by Brucellosis, bone scan is another valuable method to detect spinal and osteoarticular involvement by Brucellosis. It is useful at diagnosis and during follow up in chronic and relapsing cases of Brucellosis . Percentage Elevated ESR 69.4 Elevated CRP 57.5 Anemia 26.4 Positive rheumatoid factor Leucopenia Leucocytosis 12.7 10.7 8.4 Thrombocytopenia 7.03 Thrombocytosis 1.1 ESR: erythrocyte sedimentation rate;CRP: C-reactive protein Table 2: Laboratory abnormalities in 1239 patients with brucellosis. OMICS Group eBooks Laboratory abnormality 003 (a) (b) (c) Figure 1: (A): MRI of lumbar spine in a patient with brucellosis showing evidence of paravertebral and epidural abscess; (B): MRI of thoracic spine in a patient with brucellosis showing evidence of multifocal spondylodiskitis; (C): MRI of tibia in a patient with brucellosis showing evidence of osteomyelitis. Neuro Brucellosis Neurological complications develop in 2-7% of patients with Brucellosis [26-28]. The clinical manifestations of neuroBrucellosis are very heterogeneous and can be categorized into: central, peripheral, focal or diffuse. The onset can be acute or chronic [26,29,30]. The clinical manifestations of neuroBrucellosis include: (1) meningitis that can be acute or chronic with acute Brucella meningitis being the commonest presentation of neuroBrucellosis, (2) meningoencephalitis, (3) signs of meningeal irritation such as neck stiffness, (3) headache and isolated intracranial hypertension, (4) polyradiculoneuritis: peripheral and cranial nerve palsies, sensory and motor abnormalities in addition to paraplegia and quadriplegia, (5) brain and epidural abscesses, (6) subdural hematomas, intracerebral hemorrhages, subarachnoidal hemorrhages, transient ischemic attacks and hemiplegia, (7) convulsions, coma and stupor, (8) cerebellar dysfunction, gait abnormalities and spastic paraplegia, (9) myelitis and chorea, (10) depression, psychosis and dementia, (11) backache, areflexia and hearing loss, (12) mycotic aneurysms and (13) Guillain-Barre syndrome [26-30]. Cerebrospinal fluid (CSF) analysis usually shows: leucocytosis with predominant lymphocytosis, elevated CSF protein and low CSF glucose [26,27,29]. CSF cultures for Brucella may be positive. Brucella serology and blood cultures are usually positive. Pus cultures from brain abscess may be positive for Brucella species and brain biopsy usually reveals granuloma formation with central necrosis . MRI may show: brain parenchymal swelling causing decreased lateral ventricular volume, hydrocephalus with periventricular edema, meningeal enhancement in posterior fossa, multiple hypodense periventricular lesions that may be ischemic or demyelinating in nature and spinal epidural abscesses [26,28,29]. Presence of neurological dysfunction in the absence of other neurological manifestations strongly supports the diagnosis and response to anti-Brucella treatment confirms the diagnosis of neuroBrucellosis [26-29]. Differential diagnosis of neuroBrucellosis includes: neurosyphilis, neurotuberculosis and other neurological and psychiatric disorders [26,27,29]. Clinicians serving in endemic areas should consider the likelihood of neuroBrucellosis in patients presenting with unexplained neuropsychiatric manifestations [26,27,30]. Appropriate therapy for neuroBrucellosis requires: the use of 2 or 3 antimicrobials that cross blood brain barrier (BBB), supportive care and symptomatic treatment in addition to treatment of specific complications such as convulsions. The antimicrobials that are commonly used in the treatment of neuroBrucellosis include: ceftriaxone: 2 grams intravenously (IV) twice daily, rifampicin: 600 mg per day, doxycycline 100mg twice daily, trimethoprim-sulfamethoxazole 960 mg twice daily in addition to ciprofloxacin and streptomycin. Treatment of neuroBrucellosis can range from 1to19 months, although it is advisable to give antimicrobials for at least 4 to 6 months [26,29]. Cardiovascular complications Cardiac involvement in Brucellosis is relatively rare [31,32]. The cardiovascular complications of Brucellosis include: (2) Pericarditis that may be acute, pericardial effusions and cardiac tamponade [32,33]. (3) Myocarditis . (4) Infection of cardiac devices causing devise dysfunction . (5) Endarteritis, polyserositis and thrombophlebitis [2,33]. Management of endocarditis involves combined medical and surgical therapy [34,36]. Antibiotic therapy for Brucella endocarditis includes combination therapies for prolonged periods of time. The first line is usually composed of: rifampicin: 900 mg orally twice daily, OMICS Group eBooks (1) Endocarditis which is the main cardiovascular complication of Brucellosis. It accounts for most of the 5% deaths encountered in Brucellosis. Endocarditis can affect native as well as prosthetic valves, but mainly involves predisposed ones e.g. prosthetic valves and those affected by congenital or rheumatic heart disease. It predominantly involves aortic valve then mitral valve. Although rare, Brucella endocarditis is a potentially fatal complication. Subclinical onset is associated with poor prognosis. Massive aortic root endocarditis and pseudoaneurysms have been reported. Endocarditis may also be encountered during relapse of Brucellosis [31-34]. 004 streptomycin 12-16mg/kg daily intramuscularly and doxycycline 200 mg twice daily. Alternatively: rifampicin (900mg orally, twice daily) combined with tetracycline 8mg / kg orally, thrice daily and cotrimoxazole 15mg/kg twice daily can be given. Antibiotic treatment should be continued for at least 6 months post-operatively as surgery may be needed for defective valves [31,35,36]. Pulmonary complications Pulmonary abnormalities, although rather rare, should be considered a focal form of Brucellosis . Presentation of respiratory tract involvement is usually with fever, paroxysmal dry cough or cough productive of mucopurulent sputum, pleuritic chest pain in addition to sweating and fatigue. In most patients, physical examination reveals signs consistent with consolidation or pleural effusion [38,39]. The clinical and radiological manifestations of Brucellosis involving the respiratory tract include: pneumonic patches and consolidation consistent with labor or bronchopneumonia, pleural effusions with predominance of monocytic or lymphocytic infiltration, interstitial pneumonitis, pulmonary granulomas or solitary nodules, bilateral glass round opacities and military mottling, empyema, pneumothorax, hilar and paratracheal lymphadenopathy, perivascular and peribronchial thickening, centri-acinar emphysematous changes and atelectasis [37-39]. Brucella species can be cultured from pleural fluid, but the yield from sputum or bronchoalveolar lavage is usually poor. Treatment is usually in the form of combination therapy that includes two of the following agents: doxycycline, rifampicin, streptomycin and cotrimoxazole. Pulmonary involvement by Brucellosis has good prognosis provided combined antimicrobial therapy is administered early in the course of the infection [37-39]. Chest wall involvement is a rare manifestation of Brucellosis. Presentation is usually with parasternal masses and nodular lesions over the chest wall that may be misdiagnosed as tuberculosis or malignancy . Cutaneous involvement Cutaneous lesions are usually considered non-specific findings in patients with Brucellosis. Cutaneous involvement has been reported in 1 to 14% of patients with Brucellosis. Skin lesions may appear at presentation, during the course of the illness or at relapse [41-45]. A variety of skin manifestations have been reported including: disseminated erythema, diffuse maculopapular eruption, papulonodular lesions, erythema nodosum-like eruption, psoriasiform eruption, malar eruption, palmar erythema and eczema, ecchymoses, purpura, leucocytoclastic vasulitis, panniculitis and multiple skin abscesses [41-46]. Hematogenous spread of the organisms can be the most important pathogenic mechanism [41,42]. Serological tests for Brucellosis may be positive and blood cultures may be positive in up to 77% of patients, with B.mellitensis being the commonest species cultured [42,43,46]. Skin biopsy is usually positive and may facilitate the diagnosis of Brucellosis. A variety of histopathological features have been described including: dermal inflammatory infiltrates with dominance of lymphocytes and histiocytes, perivascular and periadnexal arrangement of infiltrates and focal granulomatous changes. Cultures of skin lesions, particularly in case of abscess formation, may be positive for Brucella species [41-43,46]. Hematological abnormalities Leucopenia is more frequently encountered in acute Brucellosis. Lymphopenia significantly correlates with the severity of clinical manifestations e.g. bleeding and hepatic involvement. Relative lymphocytosis may occasionally be encountered. Pancytopenia is commonly seen, often at presentation. Anemia is also a common consequence of Brucella infection and may be severe. Thrombocytopenia is occasionally encountered and may be severe (Table 2). Bleeding diathesis and even disseminated intravascular coagulation may occur. Hemolytic anemia that may be acute and Coomb’s positive can also be seen. Elevation of ESR and CRP may also be seen (Table 2) [3,4754]. Bone marrow examination in patients with Brucellosis usually shows: hypercellular or normocellular marrow, epitheliod giant cell granulomas that are usually small with indistinct borders mimicking granulomas of tuberculosis and sarcoidosis. Histiocytic phagocytosis may be seen with or without peripheral pancytopenia [47,48,54,55]. Microangiopathic hemolytic anemias, e.g. thrombotic thrombocytopenic purpura, have been reported in patients with acute Brucellosis. Despite the severity of this rare complication, complete recovery has been encountered with early and prompt therapy using plasma exchange, antimicrobial therapy for Brucellosis and corticosteroids [56-59]. Thrombocytopenic purpura has also been reported in patients with Brucellosis. Early recognition of this complication is essential as central nervous system (CNS) hemorrhage is associated with high mortality rates. Nevertheless, treatment of Brucellosis in addition to corticosteroid therapy can control both disorders [60,61]. Capillary leak syndrome has been reported in patients with Brucellosis and pancytopenia. Patients may present with: fever, sweats, weakness, hepatosplenomegaly, peripheral edema, hypoalbuminemia and elevation of liver enzymes. With anti-Brucella therapy, both clinical and laboratory manifestations usually resolve . In patients living in areas that are endemic for Brucellosis, presentation with FUO and pancytopenia should alert treating physicians to the possibility of having an underlying or an associated primary hematological disorder such as myelofibrosis or myelodysplastic syndrome [63,64]. In patients having Brucellosis and hematologic malignancy, simultaneous treatment of infection and hematologic malignancy can be considered to decrease morbidity and mortality . Hepatic complications (1) Chronic suppurative hepatosplenic Brucellosis: this is a rather severe complication of Brucellosis that mainly represents a local reactivation of previous Brucellosis. The diagnosis is often difficult and successful management requires mainly medical therapy with antimicrobials against Brucellosis. However, surgical intervention may be required in case of complications e.g. drainage of pus. Abdominal CAT scan usually shows calcium deposits surrounded by hypodense areas. Agglutination antibodies are usually positive but in low titers. Pus cultures may be positive for Brucella species, while blood cultures for Brucella are often negative. Polymerase chain reaction (PCR) may detect Brucella antigen in pus cultures. The differential diagnosis includes infective endocartitis and splenic infarctions with abscess formation [66-68]. (2) Hepatic granulomas and Brucella hepatitis: hepatic granulomas are commonly reported in patients with Brucellosis. The majority of these cases were due to B.melitensis and they were reported in Spain and France. Approximately 70% of the granulomas in the Spanish series were reported in patients with liver disease caused by Brucellosis. B.abortus is known to cause of hepatic granulomas that are indistinguishable from sarcoidosis and tuberculosis [69-72]. (3) Hepatic brucellomas that may induce cholestasis have also been reported [73-75]. OMICS Group eBooks Clinical hepatitis develops in 3-20% of Brucellosis patients. Acute and chronic liver dysfunction as well as disease can occur in patients infected with Brucellae [2,65]. 005 Genitourinary complications The genitourinary system is affected in 2-20% of cases having Brucellosis . Epidedymoorchitis is the most common form of genito-urinary system involvement. Orchitis usually presents with a testicular mass that is indistinguishable from a malignant process [76,77]. The first reports of Brucella species causing granulomatous orchitis were in the years 1928 and 1929 . Epidedymoorchitis is usually encountered in young patients and most of the cases are unilateral . The most common laboratory findings are: leucocytosis and elevated CRP. Patients usually respond very well to medical treatment which is usually in the form of a combination of antimicrobials [77,78]. Relatively less common genitourinary complications of Brucellosis include: pyelonephritis, male infertility with reduced score counts for spermatogenesis in addition to red blood cells and pus in semen, prostatitis, testicular as well as tubo-ovarian abscess formation, cystitis, interstitial nephritis, glomerulonephritis and renal abscesses [2,79,80]. Disseminated Brucella infection Rare but potentially fatal complications of Brucellosis include: (1) disseminated infection with abscesses and nodules in liver, lung, pleura and spine, (2) pancytopenia combined with endocarditis and meningitis, (3) pancytopenia with disseminated abscesses in liver and gall bladder and (4) Brucella bacteremia complicated by septic shock. Such cases require prompt diagnosis and early institution of appropriate therapy that includes surgical drainage, artificial ventilation, transfusion of blood products and antimicrobial chemotherapy [81-84]. Other rare complications of Brucellosis 1. Gastrointestinal involvement: Brucellosis may be complicated by: acute cholecystitis, spontaneous bacterial peritonitis, ileitis, colitis and diverticulitis presenting with acute abdomen [85-88]. 2. Eye complications: Uveitis is the most frequent ocular presentation of Brucellosis and posterior uveitis is the most frequent uveal syndrome. Other ophthalomological complications include: keratoconjunctivitis, endophthalmitis, choroiditis, iridocyclitis, corneal ulcers, nummular keratitis, papilledema, cataract, glaucoma, diplopia, ophthalmoplegia, optic neuritis and atrophy in addition to phthisis bulbi [2,89]. It is important to rule out uveitis through an ophthalmic examination in every suspicious case of Brucellosis, as uveitis is a potentially blinding complication [89,90]. 3. Brucellosis does not appear to be associated with hearing loss, while mastitis is a very rare presentation of Brucellosis in female patients [91,92]. 4. Acute renal failure and spontaneous splenic rupture have also been reported [93,94]. Relapse of Brucellosis Relapses occur in 4.7 to 29% of patients with Brucellosis [2,6,9,95]. Relapses usually occur within 3 to 12 months of discontinuation of the antimicrobial therapy [1,2,6]. The risk factors for relapse include: male sex, old age, lymphopenia, deficient immunologic response such as in associated human immunodeficiency virus (HIV) infection, presence of an aggressive disease or a chronic infection, positive blood cultures during initial infection, an inadequate choice of antibiotics, monotherapy rather than combination treatment, shortened duration of therapy, localized foci of infection, positive family history, living in endemic area and rarely resistance to antimicrobial therapy [1,2,6,95-98]. Relapse is not usually associated with: the initial or subsequent antibiotic susceptibility, the specific antimicrobial regimen used to control the initial infection or having a high risk occupation [1,2,6,98.99]. Clinical differentiation between relapse and reinfection in areas of ongoing exposure can be difficult . The highest relapse rates have been encountered in patients with complications such as osteoarticular involvement [9,95]. Independent predictors of relapse include: positive blood cultures at baseline, temperature of ≥ 38 0C and duration of symptoms less than 10 days . During relapse: blood cultures may be positive, ESR and CRP are usually elevated [1,96,97]. A repeat, but a longer course of a standard therapeutic regimen such as the combination of doxycycline, streptomycin and/or rifampicin and surgical intervention in case of localized foci of infection are usually successful in most relapses [1,2,6,9]. Chronic Brucellosis Although no uniform definition has been agreed upon, chronic Brucellosis traditionally refers to the persistence of clinical manifestations for at least one year after establishment of the diagnosis of Brucellosis [1,2]. Chronic Brucellosis is characterized by: (1) localized infection such as spondylitis, osteomyelitis, tissue abscess or uveitis producing recurrent bouts of fever and other clinical manifestations, (2) relapse in patients with an objective evidence of infection such as high 1gG antibody titers and/or recovery of Brucellae from blood or tissues and (3) manifestations such as chronic fatigue syndrome and psychoneurosis [1,2,6]. The diagnosis of chronic Brucellosis should be established on history and clinical grounds. The following laboratory tests confirm the clinical suspicion of chronic infection: positive blood cultures, positive Brucella serology and positive quantitative real-time PCR [2,100,102-106]. In some patients with chronic infection, symptoms are attributed to chronic Brucellosis in the absence of objective evidence of infection ie low antibody titers and sterile cultures. Such patients typically have a cyclic course with intermittent backache, arthralgia, sweating and signs of psychoneurosis [1,2]. Chronic infections are usually rare and the cause of chronic Brucellosis is usually a focus of infection in tissues that may require prolonged antimicrobial therapy and surgical intervention such as drainage of an abscess [1,2,6]. Associations and Brucellosis in Specific Conditions Brucellosis in pregnancy In endemic areas, the cumulative incidence of Brucellosis in pregnant women may reach 1.3 per 1000 obstetric deliveries and up to OMICS Group eBooks The clinical manifestations of chronic Brucellosis include: sweating, fatigue, malaise, tiredness, weakness, anorexia, depression, arthralgia, myalgia, headache, lower backache, pain in temporomandibular joints, irritability, insomnia, abdominal pain, diarrhea, constipation, arthritis, and lymphadenopathy [2,100-102]. There are 2 types of chronic Brucellosis: (1) chronic Brucellosis with clear history of acute infection, where Brucella symptomatology continues after the acute attack. (2) chronic Brucellosis without clear history of acute infection, where Brucella symptomatology becomes more pronounced in the chronic phase [1,2,100]. 006 92.3% of infected pregnant ladies give history of unpasteurized milk consumption [107,109]. Brucellosis in pregnancy can present in an acute, subacute or a chronic manner . The clinical manifestations of Brucellosis in pregnancy include: fever, chills, sweating, anorexia, fatigue, weight loss, abdominal or chest pain, gastrointestinal upset, arthralgia, urticaria, lymphadenopathy and hepatosplenomegaly . Occasionally, it may be complicated by: Brucella bacteremia, septic shock, neuroBrucellosis and even disseminated intravascular coagulation [110,111]. Brucellosis in pregnancy is associated with: spontaneous abortion, intrauterine fetal death, premature rupture of membranes, preterm delivery, low birth weight and postpartum endometritis but not with congenital malformations [107,108,112-118]. Preterm delivery and intrauterine fetal death may possibly be related to the acute illness rather than transplacental infection . Vaginal bleeding at presentation is usually associated with spontaneous abortion . Delivery of pregnant women with Brucellosis may cause infection of the delivery team . Presence of carbohydrate erythritol in animal placenta appears to be a preferential medium and a growth factor for Brucellae in animals . Brucellosis causes fewer spontaneous abortions in humans than in animals due to the absence of erythritol in human placenta and fetus . The absence of erythritol in human placenta and the presence of anti-Brucella activity in the amniotic fluid have been thought to protect against abortion. Nevertheless, positive Brucella cultures have been obtained from human placenta, aborted fetuses and other products of conception [116,119]. In pregnant ladies with Brucellosis living in endemic areas, the incidence of spontaneous abortion ranges between 24.4% and 53% and positive Brucella serology may be encountered in 2.89% of pregnant women [107,108,113]. Brucella seropositivity is not more common in women with spontaneous abortion or miscarriage than in women with normal pregnancy outcome [120,121]. Some studies have shown that there is no relationship between the magnitude of Brucella agglutination titre and the occurrence of spontaneous abortion while others have shown that Brucella titres above 1:160 are associated with higher incidence of spontaneous abortion [107,108,115,122]. Brucellosis in pregnancy should be treated as soon as the diagnosis is made in order to prevent complications such as maternal morbidity, abortion and transmission of disease to fetus [108,112,116]. There are no randomized trials for the treatment of Brucellosis in pregnancy, but the most commonly used regimen is the combination of rifampicin and cotrimoxazole [108,113,116]. However, Brucellosis in pregnancy has been successfully treated with single agents such as rifampicin or cotrimoxazole and with other combinations such as rifampicin and ceftriaxone [107,112,117,120,123]. Monotherapy with either rifampicin or cotrimoxazole is inadequate and is associated with high relapse rates . The treatment of choice should be effective and should have minimal adverse effects . In pregnant women presenting with febrile illness, the beneficial effects of treatment are usually encountered . The optimal duration of antimicrobial therapy is 6 weeks and the success rate of antibiotic treatment for Brucellosis in pregnant women may reach 90% [109,117,120]. Health education of the target population is advisable to prevent the disease and its complications. Screening programs for Brucellosis in pregnant women living in endemic areas is recommended [108,124]. Brucellosis should also be kept in the differential diagnosis of fever in pregnant females living in endemic areas as early diagnosis and prompt therapy have been shown to improve the outcome considerably [108,124]. Congenital and neonatal Brucellosis Congenital Brucellosis is very rare and its diagnosis indicates a substantial local endemic activity . Congenital and neonatal Brucellosis are usually associated with the presence of untreated maternal Brucellosis or Brucella bacteremia in the pregnant mother [125,126]. Neonates become congenitally infected with Brucellosis by the following means: transplacental transmission from an infected mother, exposure to blood, urine or genital secretions during delivery, breast feeding and blood or exchange transfusion in the early neonatal period [117,125-128]. The clinical manifestation include: fever, anemic symptoms or features of bone marrow failure, jaundice, respiratory distress, vomiting, irritability, convulsions, hepatosplenomegaly, septic shock, multiorgan involvement, meningitis and endocarditis [125,127-129]. The diagnosis is made in the presence of: a compatible clinical picture, positive Brucella serology or positive cultures for Brucella obtained from blood or breast milk [125,127-129]. The choice of drug therapy is very limited due to side effects such as fluoroquinolone induced cartilage damage, teeth staining and fatty necrosis of liver caused by tetracyclines and cotrimoxazole induced kernicterus [125,127-129]. However, the teratogenic potential of rifampicin, fluoroquinolones and cotrimoxazole is simply unknown . In individual cases, cotrimoxazole has been used successfully and there have been no reports of gentamicin toxicity . The combination of an aminoglycoside e.g. gentamicin or amikacin plus rifampicin or cotrimoxazole is usually successful and may prevent complications [125,127-129]. Brucellosis in children Involvement of the nervous system is rare in childhood Brucellosis [131,147]. Childhooh neurobrucllosis may present with meningitis, meningoencephalitis, meningomyelitis, cerebellar ataxia, acute facial palsy, peripheral neuritis and chorea [131,134,147]. CSF examination shows lymphocytic pleocytosis, high protein and low glucose concentrations. Serum and CSF Brucella agglutination titres are usually positive . Treatment usually comprises combination of 3 of the following drugs: rifampicin, cotrimoxazole, doxycycline and streptomycin [131,147]. An additional therapy with dexamethasone may be beneficial. NeuroBrucellosis should be suspected in children living in endemic areas presenting with unexplained neurological manifestations . Brucella bacteremia is not uncommon in children living in endemic areas . It occurs more frequently in males than in females . The most common presenting symptoms are fever and arthralgia. At least 95% of affected children have Brucella agglutination titres of ≥ 1:320 [148,149]. Treatment comprises the use of the following agents in various combinations: rifampicin, cotrimoxazole, streptomycin, gentamicin and tetracycline for 6 weeks [148,149]. Resistance to cotrimoxazole ranges between 22 and 29% and relapses can be encountered in 5 to 13% of cases [148,149]. OMICS Group eBooks The incidence of childhood Brucellosis varies according to the geographic location and the strain of Brucella species. Where B. abortus is endemic, childhood Brucellosis is relatively uncommon while in areas that are endemic for B. melitensis, children represent 20-25% of all cases of Brucellosis [131,132]. Childhood Brucellosis is more frequently encountered in males than in females [132-134]. The main sources of Brucella infection in childhood are: consumption of raw milk and dairy products, close animal contact and recent history of travel to endemic areas [131,132,134-142]. The clinical manifestations of Brucellosis in children include: fever, sweating, lethargy, clinical evidence of bleeding e.g. epistaxis or hematuria, nasopharyngitis, arthralgia, myalgia, hepatosplenomegaly and weight loss [131,133-145]. Fever, which may be prolonged, is the commonest clinical feature as it is encountered in 75-100% of cases while arthritis is usually seen in 5075% of patients [135,137-140,142]. Arthritis is usually oligoarticular with predominant involvement of lower limb joints. Unlike in adults, axial skeletal involvement is rarely encountered . Childhood Brucellosis may be complicated by: neuroBrucellosis, endomyocarditis, osteomyelitis, skin lesions, bacteremia and relapse [131,132,135,136,146-149]. Various skin eruptions have been reported and lesions include: maculopapular eruptions, petechiae, purpura, impetiginous and psoriasiform lesions, papules and Pityriasis alba [131,135,146]. 007 Hematological abnormalities are variable and include: anemia that may be hemolytic in nature, leucopenia, lymphopenia or relative lymphocytosis, monocytosis, thrombocytopenia, pancytopenia with hypersplenism, disseminated intravascular coagulation and hemophagocytosis [132,134-140,143,144,146,150]. Bone marrow examination usually shows hypercellular or normocellular marrow with non-caseating granulomatous lesions. Bone marrow may be infiltrated with histiocytes, eosinophils or plasma cells [144,146,150]. Hematological abnormalities are common and they correlate well with disease severity . Other laboratory abnormalities include elevation of ESR, liver enzymes and immunoglobulin levels [136,143,150]. In acute brucllosis, serum levels of IgG and IgM are increased while in inactive chronic disease, serum levels of IgM and IgA levels are usually elevated . Brucella serology is positive in almost 100% of cases with Brucella agglutination titres ≥ 1:320 or even ≥ 1:160 [138,139,148-150]. Positive blood and bone marrow cultures for Brucella species are encountered in 30-60% of cases [132,136,139,144,148]. The differential diagnosis of Brucellosis in children includes: enteric fever, malaria, rheumatoid arthritis and FUO . There is no consensus on the treatment of childhood Brucellosis as single agents as well combinations of 2 or even 3 drugs have been used [131,132,134,139-143,145,147-149,151-153]. Most of the drug combinations comprise cotrimoxazole in addition to rifampicin, streptomycin, gentamicin or tetracycline [131,132,134,139-143,145,147-149,151-153]. In children less than 7 to 8 years of age: cotrimoxazole, rifampicin and gentamicin can be given, while in children more than 7 to 8 years of age: tetracycline, rifampicin and gentamicin are usually prescribed for 3 to 6 weeks [145-153]. Although drug combinations have been found to improve outcome and prevent relapse, some complicated cases have been successfully treated with a single agent e.g. cotrimoxazole [131,137,141]. Uncomplicated cases can be treated for 3 to 6 weeks, while in complicated cases e.g. those with arthritis, endocarditis and meningitis, prolonged treatment for 3 months is usually recommended [137,141,143,147,153]. Skin lesions may disappear 8-10 days after starting antibiotic therapy . In contrast to Brucellosis in adults, childhood Brucella endocarditis can be cured with antimicrobial therapy alone . Brucellosis in childhood may cause serious complications. Early recognition of infection, prolonged antibiotic therapy as well as careful and long-term follow up improves the outcome [133,134]. Prolonged combination therapy improves outcome and prevents relapses. The overall relapse rate is usually about 9% . Combined drug regimens incorporating cotrimoxazole in addition to rifampicin or gentamicin can prevent disease relapse [141,142]. Brucellosis in acute leukemia and in stem cell transplant In patients with acute leukemia living in endemic areas, Brucellosis can cause systemic infections, complicated bacteremia and serious morbidity. Brucellosis may develop at presentation of acute leukemia or even if leukemia is under control. Early diagnosis of Brucellosis and prompt administration of appropriate antimicrobial therapy usually improve the outcome in such immunocompromised individuals. Presentation is usually with fever and pancytopenia. Antimicrobial therapy can be administered simultaneously with cytotoxic chemotherapy to control both Brucellosis and leukemia but in case of bacteremia, prompt antimicrobial therapy may become essential [154-156]. Brucellosis and even Brucella bacteremia can develop in recipients of hematopoietic stem cell transplantation (HSCT) living in endemic areas at any stage of their illness. Like in patients with acute leukemia, presentation is usually with fever and cytopenias. Prompt therapy with appropriate antimicrobials such as streptomycin, doxycycline and ciprofloxacin will control the infection and prevent further complications . Brucellosis and renal disease Brucellosis has been reported in patients with end stage renal disease (ESRD) living in endemic areas. Such cases usually present with FUO but if left untreated, the infection may be complicated by serious complications such as neuroBrucellosis, paravertebral and epidural abscesses and peripheral arthritis [158,159]. On the other hand, Brucellosis has been reported to cause ESRD. Renal biopsies in patients having Brucellosis as a cause of ESRD have shown: mesangial and diffuse proliferative glomerulonephritis, rapidly progressive and focal segmental glomerulonephritis as well as exudative glomerulonephritis. Other renal complications of Brucellosis include: pyelonephritis, interstitial nephritis, mixed cryoglobulinemia and IgA nephropathy. Antimicrobial therapy given for Brucellosis usually improves the renal involvement . Brucellosis coexisting with other infections and medical illnesses Brucellosis has been reported in patients having other infections such as leishmaniasis, hepatitis C infection, HIV and viral hemorrhagic fevers e.g. dengue fever. In such patients, cytopenias are major complications. Treatment of both infections and supportive care will prevent further complications [161-166]. Brucellosis has also been reported in patients having chronic medical illnesses such as polycythemia rubra vera, chronic osteoarthritis, liver cirrhosis, pulmonary fibrosis and rheumatoid arthritis receiving infliximab therapy. Early institution of appropriate antimicrobial therapy is essential to control Brucella infection and to prevent evolution of complications [167,168]. Approximately 40% of patients with infections caused by Brucella species develop systemic and chronic manifestations indistinguishable from chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME). Approximately 10% of patients with CFS/ME have been found to have presence of Brucella species infections as shown by PCR . Patients infected with Brucellosis may present with neurological manifestations compatible with multiple sclerosis. However, old and new literature provides conflicting data on the association between Brucellosis and multiple sclerosis [170-172]. Brucellosis and solid tumors It has been postulated that chronic Brucellosis may be associated with tumor formation. Brucella species DNA, not Brucella species organism, has been identified in CNS tumors such as medulloblastomas. Further studies are needed to explore the true association between Brucella species DNA positivity and CNS tumor formation . Brucellosis may also simultaneously present with other solid tumors e.g. ovarian cancer. In such cases, treatments for both Brucellosis and the primary cancer should be administered to control both disorders . OMICS Group eBooks Brucellosis and chronic neurological disorders 008 Brucellosis and FUO Infections account for 25 to 47% of all cases of FUO. Brucellosis has ranked number 2 to number 5 amongst infectious causes of FUO. In geographical locations that are endemic for Brucellosis, higher proportions of patients presenting with FUO are ultimately diagnosed to have Brucellosis [175-178]. Differential Diagnosis of Brucellosis The differential diagnosis of Brucellosis includes: tuberculosis, sarcoidosis, syphilis, typhoid fever, malaria, mycoplasma infections tularemia in addition to other infections, rheumatic disorders and causes of FUO [4, 179,180]. Brucellosis Case Definition Brucellosis clinical illness is characterized by an acute or an insidious onset of fever, night sweats, undue fatigue, anorexia, weight loss, headache and arthralgia . A confirmed case of Brucellosis is defined as a clinically compatible illness with a laboratory confirmation of the infection using one of the following: (1) isolation of Brucella species from an appropriate clinical specimen, or (2) 4 fold or greater rise in Brucella agglutination titer using standard tube agglutination or equivalent ( >1/180 ), or (3) a single significantly high titer against Brucella ( >1/160 ) or demonstration by immunofluorescence of Brucella species in an appropriate clinical specimen [181,182]. A probable case of Brucellosis is defined as a clinical illness in a person who is epidemiologically linked to a confirmed case or a clinical illness with supportive serology (Brucella agglutination titer ≥ 1/160) in one or more specimens obtained after the onset of symptoms . Course and Prognosis of Brucella Infections Human disease may last for 3 months as the organism is slowly growing and as the organism can survive for up to few months in both hot and cold environments particularly moist conditions . Unfavourable outcome is associated with complications and treatment failure. Mortality due to Brucellosis is generally low ie below 5% of untreated cases. Most deaths are due to complications such as endocarditis and meningitis [2,4]. Conclusions Brucellosis is a global, re-emerging zoonosis that constitutes a major health and economic problem in many parts of the world. 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Akdeniz H, Irmak H, Seckinli T, Buzgan T, Demiröz AP (1998) Hematological manifestations in Brucellosis cases in Turkey. Acta Med Okayama 52: 63-65. 50. Dilek I, Durmus A, Karahocagil MK, Akdeniz H, Karsen H, et al. (2008) Hematological complications in 787 cases of acute Brucellosis in Eastern Turkey. Turk J Med Sci 38: 421-424. 51. Abdi-Liae Z, Soudbakhsh S, Jafari S, Emadi H, Tomaj K (2007) Haematological manifestations of Brucellosis. Acta Med Iranica 45: 145-148. 52. Crosby E, Liosa L, Miro Quesada M, Carrillo C, Gotuzzo E (1984) Hematological changes in Brucellosis. J Infect Dis 150: 419-424. 53. Sari I, Kocyigit I, Altuntas F, Kaynar L, Eser B (2008) An unusual case of acute Brucellosis presenting with Coombs-positive autoimmune hemolytic anemia. Inter Med 47: 1043-1045. 55. 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Martin-Moreno S, Soto-Guzman O, Bernaldo-de-Quirös J, Reverte-Cejudo D, Bascones-Casas C (1983) Pancytopenia due to hemophagocytosis in patients with Brucellosis: a report of four cases. J Infect Dis 147: 445-449. 010 59. Di Mario A, Sica S, Zini G, Salutari P, Leone G (1995) Microagiopathic hemolytic anemia and severe thrombocytopenia in Brucella infection. Ann Hematol 70: 59-60. 60. Young EJ, Tarry A, Genta RM, Ayden A, Gutuzoo E (2000) Thrombocytopenic purpura associated with Brucellosis: report of 2 cases and literature review. Clin Infect Dis 31: 904-909. 61. Sevinc A, Buyukberber N, Camci C, Buyukberber S, Karsligil T (2005) Thrombocytopenia in Brucellosis: case report and literature review. J Natl Med Assoc 97: 290-293. 62. Erkurt MA, Sari I, Gul HC, Coskun O, Eyigun CP, et al. (2008) The first documented case of Brucellosis manifested with pancytopenia and capillary leak syndrome. Inter Med 47: 863-865. 63. Bakri FG, Al-Bsoul NM, Magableh AY, Shehabi A, Tarawneh M, et al. 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