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Febbre Q P. Urbano Frank Macfarlane Burnet

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1 Febbre Q P. Urbano Frank Macfarlane Burnet 1899-1985
Capitolo da USAMRIID Frank Macfarlane Burnet Attribuì a una rickettsia la causa della febbre Q

2 In natura Malattia zoonotica Patologia in circa la metà degli infetti
Serbatoi varii Bovini, ovini, caprini …altri, anche animali da compagnia Agente: Coxiella burnetii Penetrazione per inalazione di aria contaminata Patologia in circa la metà degli infetti Per lo più, quadro clinico acuto, complesso ‘la Febbre Q’, dominato dalla polmonite atipica Possibili forme croniche, dominate dall’endocardite Overview Q fever is a zoonotic disease caused by Coxiella burnetii, a species of bacteria that is distributed globally.  In 1999, Q fever became a notifiable disease in the United States but reporting is not required in many other countries. Because the disease is underreported, scientists cannot reliably assess how many cases of Q fever have actually occurred worldwide.  Many human infections are inapparent. Cattle, sheep, and goats are the primary reservoirs of C. burnetii.  Infection has been noted in a wide variety of other animals, including other species of livestock and in domesticated pets.  Coxiella burnetii does not usually cause clinical disease in these animals, although abortion in goats and sheep has been linked to C. burnetii infection.  Organisms are excreted in milk, urine, and feces of infected animals. Most importantly, during birthing the organisms are shed in high numbers within the amniotic fluids and the placenta.  The organisms are resistant to heat, drying, and many common disinfectants.  These features enable the bacteria to survive for long periods in the environment.  Infection of humans usually occurs by inhalation of these organisms from air that contains airborne barnyard dust contaminated by dried placental material, birth fluids, and excreta of infected herd animals.  Humans are often very susceptible to the disease, and very few organisms may be required to cause infection. Ingestion of contaminated milk, followed by regurgitation and inspiration of the contaminated food, is a less common mode of transmission.  Other modes of transmission to humans, including tick bites and human to human transmission, are rare. Signs and Symptoms in Humans Only about one-half of all people infected with C. burnetii show signs of clinical illness. Most acute cases of Q fever begin with sudden onset of one or more of the following: high fevers (up to ° F), severe headache, general malaise, myalgia, confusion, sore throat, chills, sweats, non-productive cough, nausea, vomiting, diarrhea, abdominal pain, and chest pain. Fever usually lasts for 1 to 2 weeks. Weight loss can occur and persist for some time. Thirty to fifty percent of patients with a symptomatic infection will develop pneumonia. Additionally, a majority of patients have abnormal results on liver function tests and some will develop hepatitis. In general, most patients will recover to good health within several months without any treatment. Only 1%-2% of people with acute Q fever die of the disease. Chronic Q fever, characterized by infection that persists for more than 6 months is uncommon but is a much more serious disease. Patients who have had acute Q fever may develop the chronic form as soon as 1 year or as long as 20 years after initial infection. A serious complication of chronic Q fever is endocarditis, generally involving the aortic heart valves, less commonly the mitral valve. Most patients who develop chronic Q fever have pre-existing valvular heart disease or have a history of vascular graft. Transplant recipients, patients with cancer, and those with chronic kidney disease are also at risk of developing chronic Q fever. As many as 65% of persons with chronic Q fever may die of the disease.   The incubation period for Q fever varies depending on the number of organisms that initially infect the patient. Infection with greater numbers of organisms will result in shorter incubation periods.  Most patients become ill within 2-3 weeks after exposure. Those who recover fully from infection may possess lifelong immunity against re-infection. Diagnosis Because the signs and symptoms of Q fever are not specific to this disease, it is difficult to make an accurate diagnosis without appropriate laboratory testing. Results from some types of routine laboratory tests in the appropriate clinical and epidemiologic settings may suggest a diagnosis of Q fever.  For example, a platelet count may be suggestive because persons with Q fever may show a transient thrombocytopenia.  Confirming a diagnosis of Q fever requires serologic testing to detect the presence of antibodies to Coxiella burnetii antigens. In most laboratories, the indirect immunofluorescence assay (IFA) is the most dependable and widely used method. Coxiella burnetii may also be identified in infected tissues by using immunohistochemical staining and DNA detection methods. Coxiella burnetii exists in two antigenic phases called phase I and phase II. This antigenic difference is important in diagnosis. In acute cases of Q fever, the antibody level to phase II is usually higher than that to phase I, often by several orders of magnitude, and generally is first detected during the second week of illness.  In chronic Q fever, the reverse situation is true.  Antibodies to phase I antigens of C. burnetii generally require longer to appear and indicate continued exposure to the bacteria.  Thus, high levels of antibody to phase I in later specimens in combination with constant or falling levels of phase II antibodies and other signs of inflammatory disease suggest chronic Q fever. Antibodies to phase I and II antigens have been known to persist for months or years after initial infection. Recent studies have shown that greater accuracy in the diagnosis of Q fever can be achieved by looking at specific levels of classes of antibodies other than IgG, namely IgA and IgM.  Combined detection of IgM and IgA in addition to IgG improves the specificity of the assays and provides better accuracy in diagnosis.  IgM levels are helpful in the determination of a recent infection.  In acute Q fever, patients will have IgG antibodies to phase II and IgM antibodies to phases I and II.  Increased IgG and IgA antibodies to phase I are often indicative of Q fever endocarditis.   Treatment Doxycycline is the treatment of choice for acute Q fever. Antibiotic treatment is most effective when initiated within the first 3 days of illness. A dose of 100 mg of doxycycline taken orally twice daily for days is a frequently prescribed therapy.  Quinolone antibiotics have demonstrated good in vitro activity against C. burnetii and may be considered by the physician. Therapy should be started again if the disease relapses. Chronic Q fever endocarditis is much more difficult to treat effectively and often requires the use of multiple drugs. Two different treatment protocols have been evaluated: 1) doxycycline in combination with quinolones for at least 4 years and 2) doxycycline in combination with hydroxychloroquine for 1.5 to 3 years. The second therapy leads to fewer relapses, but requires routine eye exams to detect accumulation of chloroquine. Surgery to remove damaged valves may be required for some cases of C. burnetii endocarditis. Prevention In the United States, Q fever outbreaks have resulted mainly from occupational exposure involving veterinarians, meat processing plant workers, sheep and dairy workers, livestock farmers, and researchers at facilities housing sheep. Prevention and control efforts should be directed primarily toward these groups and environments. The following measures should be used in the prevention and control of Q fever: Educate the public on sources of infection. Appropriately dispose of placenta, birth products, fetal membranes, and aborted fetuses at facilities housing sheep and goats. Restrict access to barns and laboratories used in housing potentially infected animals. Use only pasteurized milk and milk products. Use appropriate procedures for bagging, autoclaving, and washing of laboratory clothing. Vaccinate (where possible) individuals engaged in research with pregnant sheep or live C. burnetii. Quarantine imported animals. Ensure that holding facilities for sheep should be located away from populated areas.  Animals should be routinely tested for antibodies to C. burnetii, and measures should be implemented to prevent airflow to other occupied areas. Counsel persons at highest risk for developing chronic Q fever, especially persons with pre-existing cardiac valvular disease or individuals with vascular grafts. A vaccine for Q fever has been developed and has successfully protected humans in occupational settings in Australia. However, this vaccine is not commercially available in the United States. Persons wishing to be vaccinated should first have a skin test to determine a history of previous exposure. Individuals who have previously been exposed to C. burnetii should not receive the vaccine because severe reactions, localized to the area of the injected vaccine, may occur. A vaccine for use in animals has also been developed, but it is not available in the United States. Significance for Bioterrorism Coxiella burnetii is a highly infectious agent that is rather resistant to heat and drying. It can become airborne and inhaled by humans. A single C. burnetii organism may cause disease in a susceptible person.  This agent could be developed for use in biological warfare and is considered a potential terrorist threat. Q Fever Disease in Humans http://www.haps.nsw.gov.au/edrsrch/edinfo/qfever.html Q fever has an incubation period of 2-5 weeks. The illness is often asymptomatic or may manifest with acute onset of high fever with muscle pain and severe headache. The acute illness usually lasts 1-2 weeks, however, recovery may be significantly delayed in those with Q fever hepatitis or pneumonia. Complete recovery with immunity is the rule. A small number of patients may relapse years later with chronic endocarditis or granulomatous hepatitis. These complications are usually diagnosed serologically. Between 5-15% of patients develop a post-Q fever chronic fatigue syndrome that may last many months and is not associated with serological activation, in contrast to chronic Q fever. Antibiotic therapy is indicated for acute and chronic disease due to Q fever. Unfortunately, most patients with post-Q fever chronic fatigue do not respond to such therapy.

3 Coxiella burnetii Piccolo batterio pleomorfo, parassita intracellulare obbligato Estrema virulenza Bastano 1-10 particelle per avviare l’infezione; alta concentrazione nei tessuti infetti (annessi fetali!), nei secreti (latte!) e negli escreti Forte resistenza agli agenti naturali di disinfezione [non sono spore, ma si comportano come tali] SUSCEPTIBILITY TO DISINFECTANTS: Resistance to disinfectants documented; reported susceptibility to sodium hypochlorite, formalin, phenols varies; susceptible to ethanol, glutaraldehyde and gaseous formaldehyde (humidity control is essential) PHYSICAL INACTIVATION: Resists elevated temperatures, dessication, osmotic shock, UV; inactivated by ether, chloroform, gamma irradiation, 130°C for 60 min. SURVIVAL OUTSIDE HOST: Extremely resistant to drying and is stable under a variety of environmental conditions; survives for months and even years in the environment; dried sputum - 30 days; dust - up to 120 days; dried urine of guinea pig - 49 days; feces of tick 586 days; milk - 42 months at 4-6°C; wool months at 4-6°C SOURCES/SPECIMENS: A wide range of domestic and wild mammals are natural hosts and may serve as potential source of infection to laboratory and animal care personnel; infected arthropods; blood, urine, feces, milk, and tissues of infected animal or human hosts; placenta of infected sheep may contain millions of organisms/gram tissue; milk may contain 100,000 organisms/gram

4 C. burnetii come aggressivo biologico
Rientra nella Categoria B Abbastanza facile da procurarsi, coltivare, disseminare Provoca morbosità moderata e bassa letalità Gli USA lo svilupparono come arma ‘per ragioni umanitarie’ Richiede misure specifiche per migliorare le possibilità diagnostiche e il sistema di sorveglianza e controllo

5 Patogenicità Fino a metà delle infezioni è asintomatica, autolimitante
Malattia febbrile acuta, a esordio improvviso [incubazione dose-dipendente: 2-3 settimane] brividi, cefalea, astenia, ipersudorazione; vomito, diarrea, … polmonite, pericardite, epatite, sepsi… Letalità < l% Malattia cronica: Endocardite Letalità ca. 65% Only about one-half of all people infected with C. burnetii show signs of clinical illness. Most acute cases of Q fever begin with sudden onset of one or more of the following: high fevers (up to ° F), severe headache, general malaise, myalgia, confusion, sore throat, chills, sweats, non-productive cough, nausea, vomiting, diarrhea, abdominal pain, and chest pain. Fever usually lasts for 1 to 2 weeks. Weight loss can occur and persist for some time. Thirty to fifty percent of patients with a symptomatic infection will develop pneumonia. Additionally, a majority of patients have abnormal results on liver function tests and some will develop hepatitis. In general, most patients will recover to good health within several months without any treatment. Only 1%-2% of people with acute Q fever die of the disease. Chronic Q fever, characterized by infection that persists for more than 6 months is uncommon but is a much more serious disease. Patients who have had acute Q fever may develop the chronic form as soon as 1 year or as long as 20 years after initial infection. A serious complication of chronic Q fever is endocarditis, generally involving the aortic heart valves, less commonly the mitral valve. Most patients who develop chronic Q fever have pre-existing valvular heart disease or have a history of vascular graft. Transplant recipients, patients with cancer, and those with chronic kidney disease are also at risk of developing chronic Q fever. As many as 65% of persons with chronic Q fever may die of the disease.  

6 Schema patogenetico

7 EPIDEMIOLOGIA Cosmopolita
Incidenza sottostimata, per difficoltà di diagnosi Endemica in molte aree Focolai epidemici descritti in ambienti particolari Macelli, allevamenti ovini, laboratori medici o veterinari, …; latte non pastorizzato, …

8

9 L’epidemia di Grottaglie (1945)
Da American Journal of Epidemiology Approfondimento

10 Bibliografia italiana
Epidemiology and infection. 2005;133(2): An outbreak of Q fever in a prison in Italy. Starnini G, Caccamo F, Farchi F, Babudieri S, Brunetti B, Rezza G. Ann Ig Sep-Oct;1(5): [Prevalence of antibodies against Coxiella burnetii in 2 geographical zones of Tuscany] Tiscione E, Ademollo B, Donato R, Roller S, Signorini LF. Eur J Epidemiol Aug;12(4): Investigation of a Q-fever outbreak in northern Italy. Manfredi Selvaggi T, Rezza G, Scagnelli M, Rigoli R, Rassu M, De Lalla F, Pellizzer GP, Tramarin A, Bettini C, Zampieri L, Belloni M, Pozza ED, Marangon S, Marchioretto N, Togni G, Giacobbo M, Todescato A, Binkin N.

11 L’epidemia carceraria leggi

12 Clin Infect Dis. 1999 Apr;28(4):866-72.
Consecutive epidemics of Q fever in a residential facility for drug abusers: impact on persons with human immunodeficiency virus infection. Boschini A, Di Perri G, Legnani D, Fabbri P, Ballarini P, Zucconi R, Boros S, Rezza G. San Patrignano Medical Center, Rimini, Italy. Abstract Two large outbreaks of Q fever occurred in 1987 and 1988 in an agricultural community for the rehabilitation of drug users. Approximately 40% of the residents were human immunodeficiency virus (HIV)-positive. Two hundred thirty-five residents presented with clinical evidence of a flulike syndrome that was confirmed to be Q fever; moreover, a large proportion of residents developed an asymptomatic infection. Clinical signs and symptoms were rather nonspecific: fever, malaise, and muscle pain that were often associated with pulmonary symptoms. Single or multiple opacities were detected, with mild interstitial inflammation evident on chest roentgenograms. The source of infection was the sheepfold, which is part of the stock-farming activity of the community. Both outbreaks occurred just after lambing had begun. Residents who were exposed during the first epidemic were protected in the second one. The attack rate among HIV-positive residents was significantly higher than that among HIV-negative residents in the first outbreak, whereas only a slight, marginally significant difference was observed in the second outbreak. The clinical features of Q fever did not differ between HIV-positive and HIV-negative individuals. No cases of relapse or chronic disease were observed.

13 Attualità [2010] È in corso in Olanda una pesante epizoozia
Impennata dei casi umani Notifications of Q fever in the Netherlands ­- that in earlier years averaged 17 human cases annually [1] ­- increased to 168 cases in 2007, 1000 in 2008, and over in 2009. Vedi nota Preoccupazione in Europa Most Dutch goat breeders are infected by Q fever The majority of the Dutch goat holders and their family members are infected by Q fever. This information emerged during the international congress on Q fever in Breda. Tests, carried out by RIVM, involving 120 goat holders and their family members, showed that 83 per cent of them were infected by the _Coxiella burnetii_ bacterium. Veterinarians were found to be infected as well: 80.5 per cent of the 133 tested vets were found to have had contact with _Coxiella burnetii_. An investigation covering 5600 blood samples showed that some 2.4 per cent of the Dutch population has already been infected. For people in close contact with animals, the percentage is 6.9 per cent [this relates, most probably, mainly to contact with pets; details would help. - Mod.AS]

14 Febbre Q - Diagnosi Problematica la diagnosi clinica
Importante l’anamnesi Una trombocitopenia è indicativa Per la diagnosi etiologica Indiretta: sierologia IFA; FC; … Diretta Immunoistochimica Biomolecolare Prova biologica: in cavia (Strauss)* Isolamento in uovo embrionato* * solo in ambienti ad alto isolamento, con le cautele del caso

15 Sierodiagnostica Coxiella burnetii si presenta in due distinte fasi antigeni, I e II, ambedue importanti per la sierodiagnostica Nelle forme acute predominano gli anticorpi verso la Fase II, che compaiono verso la seconda settimana di malattia Nelle forme croniche succede il contrario; predominano gli anticorpi verso la Fase I, che compaiono più tardi, e indicano una continua esposizione all’agente. Alti titoli di anticorpi per la Fase I, con declino di quelli per la Fase II, devono far sospettare un infezione cronica, per lo più un’endocardite Gli anticorpi anti Coxiella persistono per mesi o anni Possibili gli studi sieroepidemiologici

16 Affinamento Sierodiagnostica
La determinazione della classe Ig degli anticorpi migliora l’accuratezza diagnostica Anticorpi IgM indicano che l’infezione è recente Anticorpi IgG alla Fase II, con anticorpi IgM verso le Fasi I e II sono indicativi di infezione acuta Alti titoli di anticorpi IgG e IgA verso la Fase I sono indicativi di endocardite

17 Febbre Q - trattamento La Doxiciclina è il trattamento consigliato per le forme acute Massima efficacia se iniziato entro i primi tre giorni Posologia standard: 100 mg per os, ogni 12 ore, per giorni In alternativa: i Chinolonici, che dimostrano una buona attività “in vitro’” La terapia va ripresa in caso di ricadute

18 Febbre Q cronica - terapia
L’endocardite da C. burnetii è molto più difficile da trattare, e richiede associazioni di antimicrobici per lunghissimi periodi: in alternativa: 1) doxiciclina in associazione con chinolonici per >4 anni 2) doxiciclina in associazione con idrossiclorochina per 1,5-3 anni Minori ricadute Necessari esami oftalmologici per monitorare l’accumulo di clorochina Può essere necessaria la rimozione chirurgica delle valvole danneggiate

19 Profilassi Inefficace la profilassi antibiotica
Vaccini sperimentali per C. burnetii in Fase I (USAMRIID; altro, australiano) Indicato per che è esposto al rischio ricercatori che lavorano con l’agente vivo 2° più comune agente di infezioni di laboratorio Allevatori di pecore Controindicato nei soggetti ipersensibilizzati Dettaglio delle cautele da adottare in: Prevention In the United States, Q fever outbreaks have resulted mainly from occupational exposure involving veterinarians, meat processing plant workers, sheep and dairy workers, livestock farmers, and researchers at facilities housing sheep. Prevention and control efforts should be directed primarily toward these groups and environments. The following measures should be used in the prevention and control of Q fever: Educate the public on sources of infection. Appropriately dispose of placenta, birth products, fetal membranes, and aborted fetuses at facilities housing sheep and goats. Restrict access to barns and laboratories used in housing potentially infected animals. Use only pasteurized milk and milk products. Use appropriate procedures for bagging, autoclaving, and washing of laboratory clothing. Vaccinate (where possible) individuals engaged in research with pregnant sheep or live C. burnetii. Quarantine imported animals. Ensure that holding facilities for sheep should be located away from populated areas.  Animals should be routinely tested for antibodies to C. burnetii, and measures should be implemented to prevent airflow to other occupied areas. Counsel persons at highest risk for developing chronic Q fever, especially persons with pre-existing cardiac valvular disease or individuals with vascular grafts. LABORATORY-ACQUIRED INFECTIONS: Second most commonly reported laboratory infection with outbreaks involving 15 or more persons recorded in several institutions; 278 reported cases with 1death

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