Leptospirosis, Brecellosis, Meningococcemia

Leptospirosis • Leptospirosis is an emerging infectious disease of global importance • clinical manifestations varying • from inapparent infection to fulminant, fatal disease. • In its mild form, present as an influenza-like illness • In severe leptospirosis, Weil's syndrome.

• In most countries, leptospirosis in humans is an underestimated problem.

Etiological Agent • the genus Leptospira comprised two species: the pathogenic L. interrogans and the free-living L. biflexa • The pathogenic leptospires are divided into serovars according to their antigenic composition. More than 250 serovars make up the 26 serogroups.

Epidemiology • is an important zoonosis • worldwide distribution • affecting at least 160 mammalian species. – Rodents, especially rats, are the most important reservoir – e.g. Icterohaemorrhagiae and Copenhageni with rats, Grippotyphosa with voles, Hardjo with cattle, Canicola with dogs, and Pomona with pigs

Transmission • direct contact with urine, blood, or tissue from an infected animal • or exposure to a contaminated environment; • human-to-human transmission is rare. • Since leptospires are excreted in the urine and can survive in water for many months, water is an important vehicle in their transmission.

• In 1999, more than 500,000 cases were reported from China, (Mortality 0.9 to 7.9%). • In Brazil, more than 28,000 cases were reported in the same year. • In the United States, the 40–120 cases reported annually to CDC •

• Certain occupational groups are at especially high risk; – – – – –

veterinarians, agricultural workers, sewage workers, slaughterhouse employees, workers in the fishing industry.

• Such individuals may acquire leptospirosis through direct exposure to or contact with contaminated water and soil. • Recreational water activities, such as canoeing, windsurfing, swimming, and waterskiing, place persons at risk.

Pathogenesis • Leptospires enter the host through abrasions in the skin or through intact mucous membranes, especially the conjunctiva and the lining of the oro- and nasopharynx. • Drinking of contaminated water may introduce leptospires through the mouth, throat, or esophagus. • After entry of the organisms, leptospiremia develops, with subsequent spread to all organs • All forms of leptospires can damage the wall of small blood vessels; this damage leads to vasculitis with leakage and extravasation of cells, including hemorrhages.

Clinical Manifestations • The incubation period is usually 1–2 weeks but ranges from 2 to 20 days • Many Leptospira-infected persons remain asymptomatic. • In symptomatic cases, clinical manifestations vary from mild to serious or even fatal. – Anicteric form: seen in >90% of symptomatic persons – Severe leptospirosis with profound jaundice (Weil's syndrome): seen in 5–10% of individuals.

Anicteric Leptospirosis • present as an acute influenza-like illness, • fever, chills, severe headache, nausea, vomiting, and myalgias. • Muscle pain, which especially affects the calves, back, and abdomen, is an important feature of leptospiral infection. • Less common features include sore throat and rash. • The patient usually has an intense headache (frontal or retroorbital) • sometimes develops photophobia, mental confusion. • Pulmonary involvement, manifested in most cases by cough and chest pain and in a few cases by hemoptysis.

• The most common finding on physical examination – fever with conjunctival suffusion. – muscle tenderness, lymphadenopathy, pharyngeal injection, rash, hepatomegaly, and splenomegaly. – The rash may be macular, maculopapular, erythematous, urticarial, or hemorrhagic. Mild jaundice may be present.

• Most patients become asymptomatic within 1 week. • After an interval of 1–3 days, the illness recurs in a number of cases. • The start of this second (immune) phase coincides with the development of antibodies. • Often the fever and myalgias is less pronounced. • aseptic meningitis ~15%

Severe Leptospirosis (Weil's Syndrome) • is characterized by jaundice, renal dysfunction, and hemorrhagic diathesis; by pulmonary involvement in many cases; and by mortality rates of 5–15%. • this syndrome is frequently seen with infection due to serovar Icterohaemorrhagiae/Copenhageni. • Rhabdomyolysis, hemolysis, myocarditis, pericarditis, congestive heart failure, cardiogenic shock, adult respiratory distress syndrome, necrotizing pancreatitis, and multiorgan failure have all been described during severe leptospirosis.

• Leptospirosis should be differentiated from other febrile illnesses associated with headache and muscle pain, such as dengue, malaria, enteric fever, viral hepatitis, Hantavirus infections, and rickettsial diseases.

Laboratory and Radiologic Findings • • • • •

WBC count 3000 to 26,000/ L, with a left shift; in Weil's syndrome, leukocytosis is often marked. Mild thrombocytopenia in up to 50% of patients ESR elevated. LFT – elevated serum levels of bilirubin – alkaline phosphatase – mild increases (up to 200 U/L) in serum levels of aminotransferases. – Prolonged PT

• CXR • CSF

• A definite diagnosis of leptospirosis – isolation of the organism from the patient – or on seroconversion – or a rise in antibody titer in the microscopic agglutination test (MAT). – ELISA – These rapid tests, latex agglutination test, or ELISA methodology – Cultures: Ellinghausen-McCullough-Johnson-Harris (EMJH) medium

Treatment • Treatment should be initiated as early as possible. • In milder cases, oral treatment with tetracycline, doxycycline, ampicillin, or amoxicillin should be considered. • For severe cases of, intravenous administration of penicillin G, amoxicillin, ampicillin, ceftriaxone, cefotaxime or erythromycin is recommended . • In rare cases, a Jarisch-Herxheimer reaction develops within hours after the start of antimicrobial therapy

Meningococcenia • Neisseria meningitidis is the etiologic agent of two life-threatening diseases: – meningococcal meningitis – fulminant meningococcemia.

• Meningococci are gram-negative aerobic diplococci and have a polysaccharide capsule. • transmitted among via respiratory secretions. • Colonization of the nasopharynx or pharynx is much more common than invasive disease.

• Meningococci are classified into serogroups according to the antigenicity of their capsular polysaccharides. • Five serogroups (A, B, C, Y, and W-135) are responsible for >90% of cases of meningococcal disease worldwide.

• Epidemiology • Meningococcal disease occurs worldwide as isolated (sporadic) cases, institution- or communitybased outbreaks, and large epidemics. • N. meningitidis is still a leading global cause of meningitis and rapidly fatal sepsis, often in otherwise-healthy individuals. • Serogroup A strains, which caused most of the large epidemics of meningococcal disease

Pathogenesis • Meningococci that colonize the upper respiratory tract are internalized by nonciliated mucosal cells and may traverse them to enter the submucosa, from which they can make their way into the bloodstream. – Fulminant Meningococcemia: 15% – Meningitis + Meningococcemia: 30% – Meningitis: 55%

Clinical Manifestations • • • •

Upper Respiratory Tract Infections Meningococcemia Meningitis Other Manifestations

Meningococcemia • fever, chills, nausea, vomiting, and myalgias. • Prostration is common. • The most distinctive feature is rash. – Erythematous macules rapidly become petechial and, in severe cases, purpuric. – the lesions are typically found on the trunk and lower extremities, they may also occur on the face, arms, and mucous membranes. – The petechiae may coalesce into hemorrhagic bullae or may undergo necrosis and ulcerate. – Patients with severe coagulopathy may develop ischemic extremities or digits, often with a sharp line of demarcation between normal and ischemic tissue.

• The Waterhouse-Friderichsen syndrome is a dramatic example of DIC-induced microthrombosis, hemorrhage, and tissue injury.

• Meningitis • Other Manifestations – Arthritis occurs in ~10% of patients with meningococcal disease. – Meningococcal pneumonia – meningococcal pericarditis – Primary meningococcal conjunctivitis – meningococcal urethritis

Diagnosis • The definitive diagnosis is established by recovering N. meningitidis, its antigens, or its DNA from normally sterile body fluids (e.g., blood, CSF, or synovial fluid) or from skin lesions. • Meningococci grow best on Mueller-Hinton or chocolate blood agar • A Gram's stain of CSF reveals intra- or extracellular organisms in ~85% of patients with meningococcal meningitis. • The latex agglutination test • PCR amplification of DNA in buffy coat or CSF samples

Treatment – 1. Ceftriaxone 2 g IV q12h (100 mg/kg per day) or cefotaxime 2 g IV q4h – 2. For penicillin-sensitive N. meningitidis: Penicillin G 18–24 million units per day in divided doses q4h (250,000 units/kg per day) – 3. Chloramphenicol 75–100 mg/kg per day in divided doses q6h – 4. Meropenem 1.0 g (children, 40 mg) IV q8h – 5. In an outbreak setting in developing countries: Long-acting chloramphenicol in oil suspension (Tifomycin), single dose • Adults: 3.0 g (6 mL) • Children 1–15 years old: 100 mg/kg • Children <1 year old: 50 mg/kg

Chemoprophylaxis – Rifampin (oral) • Adults: 600 mg bid for 2 days • Children 1 month old: 10 mg/kg bid for 2 days • Children <1 month old: 5 mg/kg bid for 2 days

– Ciprofloxacin (oral) • Adults: 500 mg, 1 dose

– Ofloxacin (oral) • Adults: 400 mg, 1 dose

– Ceftriaxone (IM) • Adults: 250 mg, 1 dose • Children <15 years old: 125 mg, 1 dose

– Azithromycin (oral) • 500 mg, 1 dose

Vaccination • Vaccinationc A, C, Y, W-135 vaccine (Memomune, Aventis Pasteur) • or • A, C vaccine Single 0.5-mL subcutaneous injection • New C; A, C; and A, C, Y, W-135 meningococcal conjugate vaccines

Brucellosis • Brucellosis is a bacterial zoonosis • brucellae are small, gram-negative, unencapsulated, nonsporulating rods or coccobacilli • The nomen system recognizes – B. melitensis, which is the commonest cause of symptomatic disease in humans and for which the main sources are sheep, goats, and camels – B. abortus, which is usually acquired from cattle or buffalo – B. suis, which generally is acquired from swine – B. canis, which is acquired most often from dogs. – B. ovis, which causes reproductive disease in sheep, and – B. neotomae, which is specific for desert rodents, have not been clearly implicated in human disease..

• Human brucellosis is usually associated with occupational or domestic exposure to infected animals or their products. – Farmers, shepherds, goatherds, veterinarians, and employees in slaughterhouses and meat-processing plants. – Dairy products, especially soft cheeses, unpasteurized milk, and ice cream, are the most frequently implicated sources of infection; raw meat and bone marrow may be sources under exceptional circumstances

• Brucellosis may be acquired by ingestion, inhalation, or mucosal or percutaneous exposure.

Clinical Features •

fever, which may be associated with profuse sweats, especially at night. (1) Left untreated, the fever of brucellosis shows an undulating pattern that persists for weeks before the commencement of an afebrile period that may be followed by relapse. (2) The fever of brucellosis is associated with musculoskeletal symptoms and signs in about one-half of all patients.

• lose appetite and weight; nonspecific myalgia, headache, and chills. • the presentation of brucellosis often fits one of three patterns: – febrile illness that resembles typhoid but is less severe – fever and acute monoarthritis, typically of the hip or knee, in a young child – and long-lasting fever, misery, and low-back or hip pain in an older man.

• Osteomyelitis more commonly involves – the lumbar and low thoracic vertebrae than the cervical and high thoracic spine.

• Individual joints that are most commonly affected – are the knee, hip, sacroiliac, shoulder, and sternoclavicular joints – the pattern may be one of monoarthritis or polyarthritis.

• dry cough • chest x-ray, although pneumonia, empyema, intrathoracic adenopathy, or lung abscess can occur. • One-quarter of patients have hepatosplenomegaly, and 10–20% have significant lymphadenopathy • Neurologic involvement is common • Endocarditis occurs in ~1% of cases

Diagnosis • clinical picture of brucellosis is not distinctive, the diagnosis must be based on a history of potential exposure, a presentation consistent with the disease, and supporting laboratory findings. • Blood inv • standard agglutination test (SAT) is still the mainstay of serologic diagnosis • Isolation of bacteria: Isolation of brucellae from blood, CSF, bone marrow, or joint fluid or from a tissue aspirate or biopsy sample is definitive, and attempts at isolation are usually successful in 50–70% of cases. • Biopsied samples of tissues such as lymph node or liver may show noncaseating granulomas

Treatment

• streptomycin monotherapy showed that relapse was common; thus dual therapy with tetracyclines became the norm • "gold standard" for the treatment of brucellosis in adults is IM streptomycin (0.75–1 g daily for 14–21 days) together with doxycycline (100 mg twice daily for 6 weeks). • rifampin (600–900 mg/d) plus doxycycline (100 mg twice daily) for 6 weeks. • ofloxacin (400 mg twice daily) or ciprofloxacin (500 mg twice daily), given together with rifampin for 6 weeks, may become accepted as an alternative to the other 6week regimens for adults • For adults with acute nonfocal brucellosis (duration, <1 month), – a 6-week course of therapy incorporating at least two antimicrobial agents is required.

• Complex or focal disease necessitates 3 months of therapy.