犬埃立克体病诊断、治疗的实验研究
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摘要
目的：通过人工接种埃立克体的方法使比格犬感染埃立克体病原，记录并分析实验犬的临床表现、血液涂片中的病原学特征、血液、脾的PCR检测和测序结果、血液生化和血液生理变化、病理学变化以及盐酸多西环素治疗后的各项指标变化，为我国犬埃立克体病临床和实验室诊断以及治疗提供参考。
方法：
①将感染我国犬埃立克体病原的病犬血通过静脉注射的方法接种健康的比格犬；
②记录接种后比格犬的体温、精神状况、便、尿、咳嗽、呕吐、体表出血斑点等临床症状；
③采取发热后的病犬血做血液涂片，进行姬姆萨染色，并在光镜下对血细胞中的埃立克体病原包涵体进行观察；采取发热后病犬血液做电镜标本，并在透射电镜下对包涵体内的病原进行观察；
④采用PCR的方法对发病后比格犬血液进行了检测并对PCR产物进行了提纯和测序；
⑤采用全自动生化仪和血球计数仪，测定并统计分析发病前后比格犬血液生理生化指标的变化；
⑥采取发病后未经治疗而死亡的2条病犬脏器的样本，常规方法制作组织病理切片，H．E．染色，并进行显微镜拍照观察；
⑦采用盐酸多西环素口服治疗的方法治疗4条发病犬，对治疗前后比格犬各项生理生化指标进行比较，并对治疗效果进行评估。
结果：
①临床症状：比格犬感染埃立克体病的潜伏期为5—19天，临床症状主要表现为急性发热、精神沉郁、食欲时好时坏直至废绝、体重急剧减轻、眼结膜逐渐苍白、出血、个别病犬出现程度不同的腹泻带鲜红血丝和暗红色血液、血尿、咳嗽和呕吐症状。未经治疗的病犬濒死期十分消瘦，全身多处继发感染，并分别于发病后第27和35天出现衰竭表现；
②病原观察：发病后的比格犬的血液涂片的光镜观察可见到埃立克体包涵体，单核细胞的细胞质和血小板中的埃立克体包涵体被染成紫色；血液标本的电镜观察发现单核细胞和血小板包涵体内有多个病原体；
③PCR检测和测序：六条比格犬在发病后用埃立克体属特异性引物做PCR检测结果都为阳性，两条未经治疗而死亡的病犬的脾脏组织PCR检测结果也为阳性；测序结果表明，一份目的DNA与犬埃立克体Gzh982株16SrRNA基因序列的相似性为98％，另一份目的DNA与犬埃立克体Gzh981株16SrRNA基因序列的相似性为99％；
④血液生理生化变化：血液生理生化：血常规检测发现感染后RBC、WBC、HGB、HCT、PLT、MPV、LYM、MONO和RDW显著降低(P＜0.05)，其余指标均无显著性差异。血生化检测发现感染后ALT和AST显著升高(P＜0.05)，ALB极显著降低(P＜0.05)，其余指标变化不显著。
⑤病理组织学观察：剖检见主要器官和皮下出血、淤血，脾、肝极度肿胀，肺出血明显；病理组织学变化的主要特征是淋巴结的严重水肿，脾、肝、肺和肾的血管内及血管周围存在浆细胞和淋巴细胞灶性增生和膀胱固有层炎性细胞小灶状浸润等；
⑥治疗试验：4条投服盐酸强力霉素的实验犬于治疗后第2天，体温开始下降，临床症状有所缓解；第4天，体温降至正常，食欲、精神明显好转；治疗结束后15天，姬姆撒染色的血液涂片的单核细胞和血小板内不再有犬埃立克体包涵体，血液常规和生化检测发现白细胞、血红蛋白、酶等指标基本恢复正常。2条未经治疗的对照犬的症状逐渐恶化，分别于发病后第27、35天死亡。
结论：
六条实验比格犬成功的感染了埃立克体病原；首次对我国犬埃立克体病的血液生理生化的变化、病理组织学变化和治疗进行了系统的研究，为临床上诊断犬埃立克体病提供了多方位的参照；再次证实了我国犬埃立克体病的致病病原体是犬埃立克体Gzh982和犬埃立克体Gzh981。
Objective: Infect beagle dogs with ehrlichiosis through inculation, make records and analysis the clinical features, inclusion body of blood cell, results and sequences of blood and spleen extract by PCR, biochemistry and routine indexes changes of blood, pathological changes and changes of all these items above after treatment with Doxycycline Hyclate. It is supposed to prompt the research on canine ehrlichiosis diagnosis and treatment in China, also contribute to human ehrlichiosis research.
Methods:
①Healthy beagle dogs were infected by blood samples from natural infected ehrlichosis dogs in China through vein injection.
②Recorded clinical symptoms such as temperature, consciousness, stool, urine, cough, vomiting, blood speckle on skin, etc.
③Made blood smears of postfebrile beagle dogs, then dyed them by Gimesa, the ehrlichia pathogen inclusion bodies were observed through light microscope; Blood were collected to make electron samples, then the samples were observed through electron microscopy.
④Detected the blood samples of postfebrile beagle dogs by PCR, then the PCR products are purified and sequenced.
⑤Blood samples were obtained from 6 Beagle dogs before and after infection, then detected biochemistry indexes and routine indexes of blood by automatic biochemistry apparatus and automatic globulimeter respectively, the dataes were analyzed by statistic method.
⑥Pathological sections of Organ samples from the two untreated beagle dogs were made by routine method, dyed by H.E, then observed and photographed under microscope.
⑦4 sick dogs were treated by Doxycycline hydrochloride through oral medication, compared these indexes before and after treatment by statistic method, then evaluated the therapeutic efficiecy.
Results:
①Clinical symptoms: the incubation period is 5 to 19 days after beagle dogs were injected with ehrlichia, dogs presented acute fever, depression, appetite declining, serious weight loss, conjunctiva pale gradually, subcutaneous hemorrhage. A few dogs presented diarrhea with blood stools, blood urine, cough and vomit. The untreated dogs were extraordinary emaciated, with severe secondary infection, and got exhaustion in 27 and 35 days after innoculation respectively.
②Pathogen observation: Blood smears of all 6 postfebrile beagle dogs were detected with ehrlichia pathogen inclusion bodies with purple dyeing; more than one pathogens were in cytoplasmic vacuoles of mononuclear cells and platelets with electron microscope observation.
③PCR detection and sequencing: All 6 beagles dogs were PCR positive after fever, the spleen samples from two untreated dogs were PCR positive too; the sequencing results showed that one of the PCR products had a 98% similarity with ehrlichia Gzh982, while the other was 99% similar to ehrlichia Gzh981;
④Blood biochemistry and routine: RBC, WBC, HGB, HCT, PLT, RDW, MPV, LYM, MONO and RDW significantly decreased (P＜0.05) after fever in blood routine detection; ALT and AST significantly increase (P＜0.05), while ALB decreased significantly (P＜0.05). The other indexes didn't have any significant changes.
⑤Histopathology examination: Obvious subcutaneous hemorrhage and stagnation of blood were found in the major tissues and organs, and severe swollen enlargement in spleens and livers by macroscopic way; The histological-pathological changes were characterized by severe dropsy in lymph node, accumulation of lymphocytes and plasma cells in blood vessels in livers, spleens, lungs and kidneys, and accumulation of lymphocytes and plasma cells in Lamina propria of urinary bladder;
⑥Therapeutic test: The body temperature of 4 beagle dogs dropped at the second day after treated with Doxycycline Hyclate, and the clinical symptom of the four dogs got better; 4 days after treatment, the body temperature dropped to normal level, appetite and consciousness got better obviously; 15 days after final treatment, there was no ehrlichia inclusion body in cytoplasmic vacuoles of mononuclear cells and platelets of blood smears with purple dyeing, the indexes of blood biochemistry and blood routine restored to normal level in all 4 treated dogs; the clinical symptoms of the 2 untreated beagle dogs served as control group deteriorated gradually, died at the 27th and the 35th day post fever respectively.
Conclusions:
The results showed all six beagle dogs infected ehrlichia successfully. It was the first time that the blood biochemistry and blood routine changes, histopathology changes and treatment of canine ehrlichosis in China were studied systematically. It proved once again the pathogen was ehrlichia Gzh982 and ehrlichia Gzh981 in ehrlichosis dogs in China.
方法：
①将感染我国犬埃立克体病原的病犬血通过静脉注射的方法接种健康的比格犬；
②记录接种后比格犬的体温、精神状况、便、尿、咳嗽、呕吐、体表出血斑点等临床症状；
③采取发热后的病犬血做血液涂片，进行姬姆萨染色，并在光镜下对血细胞中的埃立克体病原包涵体进行观察；采取发热后病犬血液做电镜标本，并在透射电镜下对包涵体内的病原进行观察；
④采用PCR的方法对发病后比格犬血液进行了检测并对PCR产物进行了提纯和测序；
⑤采用全自动生化仪和血球计数仪，测定并统计分析发病前后比格犬血液生理生化指标的变化；
⑥采取发病后未经治疗而死亡的2条病犬脏器的样本，常规方法制作组织病理切片，H．E．染色，并进行显微镜拍照观察；
⑦采用盐酸多西环素口服治疗的方法治疗4条发病犬，对治疗前后比格犬各项生理生化指标进行比较，并对治疗效果进行评估。
结果：
①临床症状：比格犬感染埃立克体病的潜伏期为5—19天，临床症状主要表现为急性发热、精神沉郁、食欲时好时坏直至废绝、体重急剧减轻、眼结膜逐渐苍白、出血、个别病犬出现程度不同的腹泻带鲜红血丝和暗红色血液、血尿、咳嗽和呕吐症状。未经治疗的病犬濒死期十分消瘦，全身多处继发感染，并分别于发病后第27和35天出现衰竭表现；
②病原观察：发病后的比格犬的血液涂片的光镜观察可见到埃立克体包涵体，单核细胞的细胞质和血小板中的埃立克体包涵体被染成紫色；血液标本的电镜观察发现单核细胞和血小板包涵体内有多个病原体；
③PCR检测和测序：六条比格犬在发病后用埃立克体属特异性引物做PCR检测结果都为阳性，两条未经治疗而死亡的病犬的脾脏组织PCR检测结果也为阳性；测序结果表明，一份目的DNA与犬埃立克体Gzh982株16SrRNA基因序列的相似性为98％，另一份目的DNA与犬埃立克体Gzh981株16SrRNA基因序列的相似性为99％；
④血液生理生化变化：血液生理生化：血常规检测发现感染后RBC、WBC、HGB、HCT、PLT、MPV、LYM、MONO和RDW显著降低(P＜0.05)，其余指标均无显著性差异。血生化检测发现感染后ALT和AST显著升高(P＜0.05)，ALB极显著降低(P＜0.05)，其余指标变化不显著。
⑤病理组织学观察：剖检见主要器官和皮下出血、淤血，脾、肝极度肿胀，肺出血明显；病理组织学变化的主要特征是淋巴结的严重水肿，脾、肝、肺和肾的血管内及血管周围存在浆细胞和淋巴细胞灶性增生和膀胱固有层炎性细胞小灶状浸润等；
⑥治疗试验：4条投服盐酸强力霉素的实验犬于治疗后第2天，体温开始下降，临床症状有所缓解；第4天，体温降至正常，食欲、精神明显好转；治疗结束后15天，姬姆撒染色的血液涂片的单核细胞和血小板内不再有犬埃立克体包涵体，血液常规和生化检测发现白细胞、血红蛋白、酶等指标基本恢复正常。2条未经治疗的对照犬的症状逐渐恶化，分别于发病后第27、35天死亡。
结论：
六条实验比格犬成功的感染了埃立克体病原；首次对我国犬埃立克体病的血液生理生化的变化、病理组织学变化和治疗进行了系统的研究，为临床上诊断犬埃立克体病提供了多方位的参照；再次证实了我国犬埃立克体病的致病病原体是犬埃立克体Gzh982和犬埃立克体Gzh981。
Objective: Infect beagle dogs with ehrlichiosis through inculation, make records and analysis the clinical features, inclusion body of blood cell, results and sequences of blood and spleen extract by PCR, biochemistry and routine indexes changes of blood, pathological changes and changes of all these items above after treatment with Doxycycline Hyclate. It is supposed to prompt the research on canine ehrlichiosis diagnosis and treatment in China, also contribute to human ehrlichiosis research.
Methods:
①Healthy beagle dogs were infected by blood samples from natural infected ehrlichosis dogs in China through vein injection.
②Recorded clinical symptoms such as temperature, consciousness, stool, urine, cough, vomiting, blood speckle on skin, etc.
③Made blood smears of postfebrile beagle dogs, then dyed them by Gimesa, the ehrlichia pathogen inclusion bodies were observed through light microscope; Blood were collected to make electron samples, then the samples were observed through electron microscopy.
④Detected the blood samples of postfebrile beagle dogs by PCR, then the PCR products are purified and sequenced.
⑤Blood samples were obtained from 6 Beagle dogs before and after infection, then detected biochemistry indexes and routine indexes of blood by automatic biochemistry apparatus and automatic globulimeter respectively, the dataes were analyzed by statistic method.
⑥Pathological sections of Organ samples from the two untreated beagle dogs were made by routine method, dyed by H.E, then observed and photographed under microscope.
⑦4 sick dogs were treated by Doxycycline hydrochloride through oral medication, compared these indexes before and after treatment by statistic method, then evaluated the therapeutic efficiecy.
Results:
①Clinical symptoms: the incubation period is 5 to 19 days after beagle dogs were injected with ehrlichia, dogs presented acute fever, depression, appetite declining, serious weight loss, conjunctiva pale gradually, subcutaneous hemorrhage. A few dogs presented diarrhea with blood stools, blood urine, cough and vomit. The untreated dogs were extraordinary emaciated, with severe secondary infection, and got exhaustion in 27 and 35 days after innoculation respectively.
②Pathogen observation: Blood smears of all 6 postfebrile beagle dogs were detected with ehrlichia pathogen inclusion bodies with purple dyeing; more than one pathogens were in cytoplasmic vacuoles of mononuclear cells and platelets with electron microscope observation.
③PCR detection and sequencing: All 6 beagles dogs were PCR positive after fever, the spleen samples from two untreated dogs were PCR positive too; the sequencing results showed that one of the PCR products had a 98% similarity with ehrlichia Gzh982, while the other was 99% similar to ehrlichia Gzh981;
④Blood biochemistry and routine: RBC, WBC, HGB, HCT, PLT, RDW, MPV, LYM, MONO and RDW significantly decreased (P＜0.05) after fever in blood routine detection; ALT and AST significantly increase (P＜0.05), while ALB decreased significantly (P＜0.05). The other indexes didn't have any significant changes.
⑤Histopathology examination: Obvious subcutaneous hemorrhage and stagnation of blood were found in the major tissues and organs, and severe swollen enlargement in spleens and livers by macroscopic way; The histological-pathological changes were characterized by severe dropsy in lymph node, accumulation of lymphocytes and plasma cells in blood vessels in livers, spleens, lungs and kidneys, and accumulation of lymphocytes and plasma cells in Lamina propria of urinary bladder;
⑥Therapeutic test: The body temperature of 4 beagle dogs dropped at the second day after treated with Doxycycline Hyclate, and the clinical symptom of the four dogs got better; 4 days after treatment, the body temperature dropped to normal level, appetite and consciousness got better obviously; 15 days after final treatment, there was no ehrlichia inclusion body in cytoplasmic vacuoles of mononuclear cells and platelets of blood smears with purple dyeing, the indexes of blood biochemistry and blood routine restored to normal level in all 4 treated dogs; the clinical symptoms of the 2 untreated beagle dogs served as control group deteriorated gradually, died at the 27th and the 35th day post fever respectively.
Conclusions:
The results showed all six beagle dogs infected ehrlichia successfully. It was the first time that the blood biochemistry and blood routine changes, histopathology changes and treatment of canine ehrlichosis in China were studied systematically. It proved once again the pathogen was ehrlichia Gzh982 and ehrlichia Gzh981 in ehrlichosis dogs in China.
引文
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