Evaluation of doramectin for the treatment of experimental canine spirocercosis

The nematode Spirocerca lupi is primarily a parasite of dogs, which causes typical lesions of esophageal nodular granulomas, aortic aneurysms and spondylitis. In order to evaluate the therapeutic effect of doramectin on experimental canine spirocercosis, seven beagle dogs experimentally infected with 40 infectious S. lupi larvae (L(3)) were treated with doramectin. Treatment was commenced following endoscopic visualization of esophageal granulomas, and typical S. lupi eggs were detected in the feces. The treatment protocol included six treatments of doramectin (400 microg/kg subcutaneously) at 2 weeks intervals, followed by monthly injections until the disappearance of the esophageal granulomas or the end of the study (768 days post-inoculation).Eggs could not be found on fecal examinations 3-10 days after the first or second doramectin treatment. In addition, a gradual decrease in size of granulomas was noticed in all seven dogs during the course of the study. Esophageal granulomas had completely resolved in six of the seven dogs between day 35 and day 544 post-initial doramectin treatment, by day 35 in one dog (after three treatments), by day 43 in two dogs (after four treatments), by day 98 in one dog (after seven treatments), by day 460 in one dog (after 18 treatments) and by day 544 in another dog (after 21 treatments). In one dog, remnants of S. lupi granulomas could still be seen 544 days post-initiation of treatment with doramectin. Multiple subcutaneous injections of doramectin (400 microg/kg) were shown to be effective and safe in the treatment of canine spirocercosis.     

The sensitivity of direct faecal examination, direct faecal flotation, modified centrifugal faecal flotation and centrifugal sedimentation/flotation in the diagnosis of canine spirocercosis

Several faecal examination techniques have shown variable sensitivity in demonstrating Spirocerca lupi (S. lupi) eggs. The objective of this study was to determine which faecal examination technique, including a novel modified centrifugal flotation technique, was most sensitive to diagnose spirocercosis. Ten coproscopic examinations were performed on faeces collected from 33 dogs confirmed endoscopically to have spirocercosis. The tests included a direct faecal examination, a faecal sedimentation/flotation test, 4 direct faecal flotations and 4 modified faecal centrifugal flotations. These latter 2 flotation tests utilised 4 different faecal flotation solutions: NaNO3 (SG 1.22), MgSO4 (SG 1.29), ZnSO4 (SG 1.30) and sugar (SG 1.27). The sensitivity of the tests ranged between 42% and 67%, with the NaNO3 solution showing the highest sensitivity in both the direct and modified-centrifugal flotations. The modified NaNO3 centrifugal method ranked 1st with the highest mean egg count (45.24 +/- 83), and was superior (i.e. higher egg count) and significantly different (P < 0.05) compared with the routine saturated sugar, ZnSO4 and MgSO4 flotation methods. The routine NaNO3 flotation method was also superior and significantly different (P < 0.05) compared with the routine ZnSO4 and MgSO4 flotation methods. Fifteen per cent (n = 5) of dogs had neoplastic oesophageal nodules and a further 18% (n = 6) had both neoplastic and non-neoplastic nodules. S. lupi eggs were demonstrated in 40% of dogs with neoplastic nodules only and 72.9% of the dogs with non-neoplastic nodules. The mean egg count in the non-neoplastic group (61) was statistically greater (P = 0.02) than that of the neoplastic group (1). The results show that faecal examination using a NaNO3 solution is the most sensitive in the diagnosis of spirocercosis. The modified centrifugal flotation faecal method using this solution has the highest egg count. The study also found that dogs with neoplastic nodules shed significantly fewer eggs than dogs with non-neoplastic nodules.     

Spirocercosis-associated esophageal sarcomas in dogs. A retrospective study of 17 cases (1997-2003)

Seventeen client-owned dogs diagnosed with spirocercosis-associated esophageal sarcomas were retrospectively reviewed. The most common clinical signs noticed were vomiting and/or regurgitation (94%), lethargy and depression (59%), pyrexia and anorexia (41% each). Leukocytosis (82%) and microcytic hypochromic anemia (30%) were the most common hematological abnormalities. Caudal thoracic masses were demonstrated on survey radiographs of 13/15 of the dogs and thoracic spondylitis was detected in 12/15 dogs. Spirocerca lupi eggs were detected in 2/8 patients and worms were demonstrated on 1/11 at necropsy. Ten cases underwent surgical attempt to remove the tumors. In six of them partial esophagectomy (PE) was performed and all of them survived the immediate postoperative hospitalization. Five of the cases that underwent PE also received chemotherapy after surgery (doxorubicin (Adriamycin, Upjohn)) with an average survival time of 267 days. The histopathological results of the esophageal tumors were osteosarcoma (9), fibrosarcoma (5) and undifferentiated sarcoma (1). In areas endemic to spirocercosis, regurgitation or vomiting in dogs and microcytic hypochromic anemia and neutrophilia warrant ruling out esophageal sarcomas. Proper surgical treatment could prolong the dogs' lifespan for months, and improve their quality of life.     

THE EFFECT OF POSITIONING ON THE RADIOGRAPHIC APPEARANCE OF CAUDODORSAL MEDIASTINAL MASSES IN THE DOG

In this prospective study, the effect of thoracic positioning on the visibility and size of caudal esophageal masses caused by spirocercosis was investigated. Dorsoventral (DV), ventrodorsal (VD) as well as left lateral recumbent (LLR) and right lateral recumbent (RLR) thoracic radiographs of 28 dogs, diagnosed endoscopically with spirocercosis, were evaluated. The radiographic findings were compared with those of esophageal endoscopy. Masses were seen equally well in left vs. right recumbency as well as in DV vs. VD positions but in DV/VD views 86% of masses were detected whereas in lateral views only 50% of masses were identified. In spirocercosis-endemic areas DV and RLR views are advised as they also allow for better visualization of descending aorta aneurysms and to avoid interpreting the potentially normally visible esophagus in LLR in large dogs as a mass.     

Magnetic resonance imaging findings of spinal intramedullary spirocercosis

Spirocerca lupi is a nematode infecting dogs in tropical and subtropical areas. Aberrant S. lupi migration to different body organs, including the spinal cord, has been documented. To date, the diagnosis of aberrant spinal cord migration was made at post-mortem examination or as an incidental finding, during spinal surgery. We describe two dogs with acute asymmetric paraparesis that were subsequently diagnosed with spinal cord spirocercosis. In magnetic resonance (MR) images of the spine, T2 hyperintense lesions were seen in the spinal cord of both dogs. The lesions appeared isointense on T1-weighted images and focal enhancement was detected after gadolinium administration. The MR imaging findings were compatible with focal inflammation, presumably along the parasite migration tract. Gross and microscopic pathologic findings confirmed the diagnosis of aberrant spinal intramedullary migration of S. lupi in one dog, and in the other dog, the clinical and imaging findings were supportive of this diagnosis.     

Serum alkaline phosphatase activity is not a marker for neoplastic transformation of esophageal nodules in canine spirocercosis

Background: Spirocerca lupi is a nematode of Canidae that matures within the esophageal wall to form fibroblastic nodules with potential for malignant transformation. Diagnosis is based on histopathologic examination, but false‐negative results may be obtained from samples collected by endoscopy. Serum alkaline phosphatase (ALP) activity, frequently increased in hepatobiliary disease, is also increased in a variety of neoplastic conditions in dogs, including appendicular osteosarcoma, and has also been reported to be increased in dogs with spirocercosis. Objective: The aim of this study was to evaluate serum ALP activity as a marker for malignant transformation of esophageal nodules in S. lupi‐infected dogs. Methods: In this retrospective study, medical records of dogs diagnosed with spirocercosis from 1991 to 2008 were reviewed, and serum ALP activity determined at presentation was compared between dogs with nonneoplastic and neoplastic nodules. Owing to use of multiple analyzers, ratios of ALP activity to the upper reference interval for ALP were calculated and compared. Results: Median ALP activity ratios were 0.65 (0.07–4.00) and 0.86 (0.10–3.40) for dogs with nonneoplastic (n=88) and neoplastic (n=32) nodules, respectively, with no significant difference (P=.18) and substantial overlap between groups. Tumors included osteosarcoma (15 dogs), fibrosarcoma (15 dogs), and anaplastic sarcoma (2 dogs); there was no difference in ALP activity between the dogs with osteosarcoma and fibrosarcoma. Conclusion: ALP is a poor marker of malignant transformation in canine spirocercosis.     

Copromicroscopic and molecular assays for the detection of cancer-causing parasitic nematode Spirocerca lupi

Spirocerca lupi (Nematoda, Spirurida) is a life-threatening parasitic nematode of dogs that is presently emerging in several countries. Nonetheless, canine spirocercosis is neglected and underestimated, mainly due to diagnostic limitations inherent to clinico-pathologic, diagnostic imaging and laboratory methodologies. Given the significant benefit of improved diagnosis, the present work evaluated the reliability of a recently described copromicroscopic approach, the FLOTAC technique, as well as a PCR-based assay with that of traditional coproscopic techniques to diagnose S. lupi infection. Ninety-four faecal field samples were collected from two endemic areas (i.e. 29 and 65 from Kenya and Israel, respectively) and processed using different coproscopic examination techniques. In particular, set I (Kenyan samples) comprised the modified flotation with Sheather's sugar solution and merthiolate-iodine-formalin technique, while set II (Israeli samples) comprised a flotation technique with zinc sulphate solution, a modified sugar flotation procedure and the FLOTAC method. All samples were also subjected to a semi-nested PCR protocol specific for a region internal to the mitochondrial cytochrome c oxidase subunit 1 gene of S. lupi. The coproscopic examinations showed low sensitivity and high variability, demonstrating the unreliability of the conventional methods for detecting S. lupi eggs. Nonetheless, the FLOTAC technique scored the highest number of positives and significantly higher number of S. lupi eggs per microscopic field compared to the other coproscopic methods. Additionally, of the coproscopically negative samples, 9 (45%) Kenyan and 21 (38.2%) Israeli samples scored molecularly positive using the PCR-based approach. The potential implications and perspectives for canine spirocercosis of these coproscopic and molecular diagnostic methodologies evaluated herein are discussed.     

The efficacy of milbemycin oxime against pre-adult Spirocerca lupi in experimentally infected dogs

The aim of this investigation was to determine the efficacy of milbemycin oxime in preventing the oesophageal encapsulation of Spirocerca lupi, following the experimental infection of dogs. Two studies were conducted which involved a total of 21 purpose-bred Beagles. Each dog was infected with approximately 40, third stage infective S. lupi larvae. The larvae were dissected from scarabaeid beetles that had been collected from areas endemic for spirocercosis. In the first study, milbemycin oxime (minimum dose 0.5mg/kg body weight) was administered to seven dogs on day 30 post-infection. Seven other dogs served as untreated controls. In the second study, milbemycin oxime (also at a minimum dose of 0.5mg/kg body weight) was administered to four of seven infected dogs on day 28 post-infection. Treatment was repeated at 14- or 28-day intervals. All of the dogs, from both studies, were euthanized 168 or 169 days after infection. All S. lupi were recovered, and lesions in the thoracic aorta and oesophagus were described and quantified. A single treatment with milbemycin oxime was 79.8% effective in preventing the establishment of S. lupi in the oesophagus. This treatment significantly (p<0.05) reduced both the number of S. lupi within the oesophagus and the size of the oesophageal nodules. The efficacy of anthelmintic treatment was increased to 100% when repeat doses of milbemycin oxime were administered at 14- or 28-day intervals. These repeat treatments completely prevented the establishment of S. lupi within the oesophagus and thereby averted the development of oesophageal nodules. As expected, none of the treatment protocols reduced S. lupi related damage within the aorta because the administration of milbemycin oxime only began after the larvae had completed their first stage of migration.     

Radiography for the diagnosis of spirocercosis in apparently healthy dogs, St. Kitts, West Indies

Fifty apparently healthy island dogs presenting to the Ross University School of Veterinary Medicine (RUSVM), St. Kitts, West Indies for neutering were used in this prospective study. Twelve of the dogs (24%) were diagnosed with spirocercosis based on a positive fecal analysis and characteristic lesions seen during esophagoscopy. Routine thoracic survey radiographs revealed changes previously reported with spirocercosis in 10/12 (sensitivity = 83%) infected dogs, but in none of the uninfected dogs (38/38; specificity = 100%). The most common radiographic changes were an increased fluid density within the caudal dorsal thorax on the lateral view and a widening and/or bulging of the caudal mediastinum on the dorsoventral view. After oral administration of barium sulfate, barium retention or a tortuous esophagus was visible in all infected dogs (12/12; sensitivity 100%) and in one uninfected dog (1/38; specificity 97%). The results show spirocercosis is common on St. Kitts and that radiographs are as dependable as fecal analysis and/or endoscopy in diagnosing the condition.     

Survey of the incidence, diagnosis, clinical manifestations and treatment of Spirocerca lupi in South Africa

A questionnaire survey of 716 veterinary practices was undertaken to determine the incidence of Spirocerca lupi in dogs in South Africa. In total, 49% of the questionnaires were returned, indicating a possible incidence of 28%. Fewer than 4 cases per year were recorded by 82% of the respondents; 4-12 by 14%; 12-24 by 3%; and more than 48 by only 1%. No seasonal incidence was reported by 48% of the respondents. Large breeds were considered to be at greater risk by 43% of respondents. No specific age or sex was identified to be at higher risk. The most common complaints by owners and clinical findings were vomiting (46%), weight loss (27%), coughing (21%) or regurgitation (20%), although 14% of respondents reported no abnormal clinical findings. Diagnostic methods used were radiology (74%), endoscopy (27%), post mortem examination (34%) and faecal flotation (4%). Complications associated with S. lupi were reported by 76% of respondents, which included oesophageal neoplasia (41%), hypertrophic osteopathy (38%) and acute haemothorax (30%). Specific treatments were used by 58% of the respondents, whereas 42% of the respondents either used no treatment (72%) or recommended euthanasia (28%). Of the treatment group, 52% used ivermectin, 27% doramectin, 13% other deworming drugs (benzimidazoles, nitroscanate), and 8% used disophenol. Sixty-three percent of the respondents considered their treatment ineffective, whereas 31% considered it effective, and 6% were unsure. The overall mortality rate was high.     

Successful resolution of oesophageal spirocercosis in 20 dogs following daily treatment with oral doramectin

The purpose of this study was to evaluate the effect of a daily oral dose of doramectin in dogs with spirocercosis. Twenty naturally infected dogs were treated with 0.5 mg/kg doramectin administered orally once daily for 42 days. In 13 of the dogs there was resolution of the nodules after 42 days. Nodules were eliminated in five of the remaining seven dogs following treatment for an additional 42 days. In the remaining two dogs, treatment continued for a further 42 days (total 126 days), resulting in complete resolution. No adverse events associated with treatment were observed. This study concluded that doramectin at 0.5 mg/kg once a day is effective in the elimination of Spirocerca lupi nodules in dogs.     

Mitochondrial cytochrome c oxidase subunit 1 (cox1) gene sequence of Spirocerca lupi (Nematoda, Spirurida): avenues for potential implications

Canine spirocercosis is a life-threatening parasitosis caused by Spirocerca lupi (Nematoda, Spirurida) that is presently emerging in several countries. This study characterised an informative region within the mitochondrial (mtDNA) gene encoding for the cytochrome c oxidase subunit 1 (cox1) of S. lupi by Polymerase Chain Reaction (PCR)-coupled sequencing. Specimens from five different countries in Europe, Asia and Africa were examined and two different sequence variants of cox1 (i.e. haplotypes) were determined, displaying nucleotidic variation at 6 of 689 positions. All of these positions were invariable among all the parasite individuals from Europe (haplotype 1) and among the African and Asian individuals (haplotype 2), but differed between Europe and Asia/Africa. The S. lupi cox1 sequences were consistent with those of other common Spirurida previously reported at both nucleotidic and phylogenetic levels. This study provides molecular information essential for identification of the nematode, irrespective of its life cycle stage. Crucial implications for the specific molecular diagnosis of clinical spirocercosis and investigation of the evolution, population genetics, ecology and epidemiology of S. lupi are discussed.     

Spiroceca lupi infection in dogs in Kenya

The prevalence of Spirocerca lupi infection in 346 dogs in Kenya was 78% (85% in 294 native dogs and 38% in 52 pet dogs). S. lupi lesions were distributed as follows: aorta (269 dogs), esophagus (217), thoracic spondylosis (16), stomach (8), lung (6), mediastinum (5), diaphragm (4), and kidney and omentum (1 each). Only one dog with an esophageal granuloma lacked concomitant aortic lesions. Clinical laboratory findings in dogs with and without spirocercosis were not significantly different. Upon fecal examination for S. lupi, eggs were found in 56% (81) of 145 native dogs with esophageal granulomas having a patent opening. One native dog and two pet dogs had osteosarcoma of the esophagus. Metastases of this tumor were observed in all three dogs, two of them had hypertrophic osteoarthropathy, and two had thoracic spondylosis. Fifty-three percent of 241 native dogs had renal calculi. In areas of high S. lupi prevalence, cattle, chickens, dung beetles and dogs were in close association.     

Aberrant extradural spinal migration of Spirocerca lupi: four dogs

Spirocerca lupi is a nematode mainly affecting dogs but has been found in other animals, particularly carnivores. Anatomical areas of typical and aberrant migration vary. This report describes four cases of Spirocerca lupi causing neurological symptoms, similar to thoracolumbar disc syndrome, as a result of aberrant migration of the nematode into the spinal canal. In two of the cases, the nematode could be demonstrated intraoperatively. The third was discovered on post-mortem examination, while the fourth case displayed compelling evidence of Spirocerca lupi involvement. Surgical removal of the Spirocerca lupi nematode would be the treatment of choice in cases of spinal migration, with therapeutic and preventive treatment with doramectin instituted to treat remote sites and prevent re-infection. In areas endemic for spirocercosis, Spirocerca lupi should be considered as an important differential diagnosis in cases that are presented with clinical signs suggestive of a spinal cord lesion.     

Treatment of esophageal spirocercosis with milbemycin oxime

Six medium sized mixed breed dogs treated with milbemycin oxime (11.5mg on days 0, 7 and 28 and then monthly) stopped shedding Spirocerca lupi ova after 3-44 days. There was no evidence of subsequent shedding in repeated tests (about 5/dog) carried out from 31 to 133 days after initiation of treatment. Esophageal nodules disappeared in all dogs within 95-186 days and radiographic signs resolved within 85-127 days in the five dogs that were studied. This preliminary data shows milbemycin oxime deserves further evaluation for the treatment of spirocercosis.     

Epidemiologic analysis of oral and pharyngeal cancer in dogs, cats, horses, and cattle.

Four hundred sixty-nine oral-pharyngeal malignancies diagnosed in dogs, cats, horses, and cattle and submitted to the Viterinary Medical Data Program between March 1, 1964, and Dec 31, 1974, were analyzed. Of these cases, 84% were in dogs. The most frequent oral-pharyngeal cancer in dogs was melanoma; in cats and horses, it was squamous cell carcinoma. In dogs, the risk of developing melanoma increased more with age than did the risk of developing squamous cell carcinoma and fibrosarcoma. Male dogs had significantly greater risk of developing fibrosarcomas and melanomas than did female dogs. The German Shorthaired Pointer, Weimaraner, Golden Retriever, Boxer, and Cocker Spaniel breeds had significantly higher risk and Dachshunds and Beagles had significantly lower risk, as compared with all breeds combined. There was no significant difference between observed and expected numbers of tonsillar carcinomas diagnosed at veterinary colleges located in small urban areas (less than 50,000 persons) as compared with large urban populations (greater than 500,000).     

Clinical signs and clinicopathologic abnormalities in dogs with clinical spirocercosis: 39 cases (1996-2004)

OBJECTIVE: To determine clinical signs and clinicopathologic abnormalities in dogs with naturally occurring clinical spirocercosis. DESIGN: Retrospective case series. ANIMALS: 39 dogs with spirocercosis. PROCEDURES: Medical records were reviewed, and information on signalment, residence (rural vs urban), owner complaints, physical examination findings, clinicopathologic abnormalities, radiographic and endoscopic findings, and concurrent systemic diseases was recorded. RESULTS: Hellenic hounds and mixed-breed dogs were overrepresented, compared with a group of 117 control dogs without spirocercosis that were examined because of gastrointestinal tract disease, and mean body weight of dogs with spirocercosis was significantly higher than mean body weight of control dogs. Odynophagia (34 [87%]), regurgitation (24 [62%]), and excessive salivation (14 [36%]) were the most common clinical findings. The most common radiographic abnormalities were a mass in the caudodorsal aspect of the mediastinum (15/35 [43%]) and spondylitis of the caudal thoracic vertebrae (10 [29%]). Parasitic nodules were seen during esophagoscopy in all 39 dogs. Normocytic, normochromic, nonregenerative anemia; neutrophilic leukocytosis; hyperproteinemia; and high alkaline phosphatase activity were significantly more common in dogs with spirocercosis than in a control group of 56 healthy dogs. Concurrent systemic diseases, mainly leishmaniosis, dirofilariosis, and monocytic ehrlichiosis, were documented in 14 (36%) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that clinical spirocercosis occurs more often in young-adult, large-breed dogs. Nonregenerative anemia, neutrophilic leukocytosis, hyperproteinemia, and high alkaline phosphatase activity may be useful clinicopathologic indicators of this disease.     

Canine breeds at high risk of developing inflammatory bowel disease in the south-eastern UK

Genetics are an important factor in the development of human inflammatory bowel disease (IBD); however, there is very little information available regarding the role of genetics in canine IBD. The purpose of this study was to gather information about which canine breeds in the south-eastern UK are at a high risk for developing IBD. Determination of such breeds may help further genetic research in this complex disease. The computer medical records at the Queen Mother Hospital for Animals, Royal Veterinary College dating from August 1, 2003 to December 31, 2009 were retrospectively searched for cases diagnosed with IBD. Five hundred and forty-six dogs with IBD were identified, representing 86 different breeds. The comparison group consisted of all dogs from these same 86 breeds without IBD admitted to the hospital during the same period that amounted to 27,463 dogs. The breeds at significantly higher risk of developing IBD compared with mixed-breed dogs consisted of weimaraner (odds ratio [OR]=3.6797, 95 per cent confidence interval [CI]=2.0167 to 6.7141, P<0.0001), rottweiler (OR=2.9697, 95 per cent CI=1.7569 to 5.0196, P<0.0001), German shepherd dog (GSD) (OR=2.4101, 95 per cent CI=1.5826 to 3.36705, P<0.0001), border collie (OR=1.9936, 95 per cent CI=1.1655 to 3.4101, P=0.0118) and boxer (OR=1.6961, 95 per cent CI=1.0441 to 2.755, P=0.0328). This study demonstrates for the first time canine breeds in the south-eastern UK that are highly susceptible to developing IBD. Identification of such breeds may allow for a more focused investigation of genetic mutations associated with canine IBD.     

Heat stroke in dogs: A retrospective study of 54 cases (1999-2004) and analysis of risk factors for death

The medical records of 54 dogs presented to the Hebrew University Veterinary Teaching Hospital and diagnosed with heat stroke were retrospectively reviewed. Data abstracted included history, clinical and clinicopathological signs at admission, treatment, disease progression, and outcome. Exertional and environmental heat stroke were present in 63% (34 of 54) and 37% (20 of 54) of the dogs, respectively, and 78% (42 of 54) were examined between June and August. The mean temperature and heat discomfort index in the particular days of heat stroke were significantly increased (P < .001, P < .001, respectively) compared with their corresponding average daily values. In 27 dogs the body temperature was > or = 41 degrees C (105.8 degrees F). Belgian Malinois (15%, odds ratio [OR] = 24, 95% confidence interval [CI95%] 8.2-64.5), Golden and Labrador Retrievers (21%, OR = 2.08, CI95% 0.95-4.2), and brachycephalic breeds (25%, OR = 1.7, CI95%], 0.81-3.21) were overrepresented, whereas small breeds (<8 kg) were underrepresented (2%, OR = 0.08, CI95%, 0.002-0.48). Thrombocytopenia (45 of 54 dogs) and prolongation of the prothrombin (PT) and activated thromboplastin (aPTT) times (27 of 47 dogs) were recorded during hospitalization. Disseminated intravascular coagulation (P = .013) and acute renal failure (P = .008), diagnosed in 28 of 54 and 18 of 54 of the cases, respectively, were risk factors for death. The overall mortality rate was 50%. Hypoglycemia (<47 mg/dL, P = .003), prolonged PT (>18 seconds, P = .05), and aPTT (>30 sec, P < .001) at admission were associated with death. Serum creatinine >1.5 mg/dL (P = .003) after 24 hours, delayed admission (>90 minutes, P = .032), seizures (P = .02), and obesity (P = .04) were also risk factors for death. Heat stroke in dogs results in serious complications and high fatality rate despite appropriate treatment.