Focus on Upper and Lower Respiratory Diseases

Transcription

1 Proceedings of the American Association of Equine Practitioners - Focus Meeting Focus on Upper and Lower Respiratory Diseases Salt Lake City, UT, USA 2010 Next Focus Meetings: July 24-26, Focus on Colic Indianapolis, IN, USA September 18-20, 2011 Focus on Dentistry Location TBD Reprinted in the IVIS website with the permission of the AAEP

2 Rhodococcal Pneumonia Steeve Giguère, DVM, PhD, Diplomate ACVIM Author s address: College of Veterinary Medicine, University of Georgia, Athens, GA, 30602; e- mail: gigueres@uga.edu. Take Home Message Rhodococcus equi is a common cause of pneumonia in foals but extrapulmonary manifestations are common. Bacteriologic culture and/or polymerase chain reaction (PCR) amplification of the vapa gene combined with cytological examination of a tracheobronchial aspirate (TBA) are necessary to make a definitive diagnosis of pneumonia caused by R. equi. The combination of a macrolide (erythromycin, azithromycin, or clarithromycin) with rifampin remains the mainstay of therapy. Introduction Rhodococcus equi, a Gram-positive facultative intracellular pathogen replicating in macrophages, is one of the most important causes of disease in foals between 3 weeks and 6 months of age, with most foals showing clinical signs before the age of 4 months. R. equi has also been increasingly recognized as an important cause of pneumonia in immunosuppressed people, especially those infected with HIV. R. equi is considered to be a saprophytic inhabitant of the soil. Although all horse farms are likely to be infected to various degrees with R. equi and antibody is widespread in the horse population, the clinical disease is enzootic and devastating on some farms, is sporadic on others, and is unrecognized on most. This probably reflects differences in environmental (temperature, dust, soil ph, soil type) and management conditions as well as differences in virulence of isolates. On enzootic farms the disease leads to significant financial loss because of the cost of therapy and occasional death of foals. Although the virulence of R. equi likely depends on many determinants, isolates from pneumonic foals characteristically contain a large plasmid which encodes a gene responsible for the expression of a virulence associated protein (VapA) on the surface of the bacteria at temperatures > 34 C. Foals experimentally infected with virulent (plasmid containing) R. equi develop severe pneumonia whereas plasmid cured derivatives are rapidly cleared and fail to induce lesions. 1 Inhalation of dust particles laden with virulent R. equi is the most important route of pneumonic infection in foals. Ingestion of the organism is a significant route of exposure but does not lead to hematogenously acquired pneumonia unless the foal has multiple exposure to very large numbers of bacteria Clinical Manifestations The most common manifestation of R. equi infections in foals is a chronic suppurative bronchopneumonia with extensive abscessation. The slow spread of the lung infection combined with the remarkable ability of foals to compensate for the progressive loss of functional lung, 80

3 make early clinical diagnosis difficult. Early clinical signs often only consist of a mild fever or a slight increase in respiratory rate that may not be apparent unless foals are exercised or stressed by handling. As the disease progresses, clinical signs may include decreased appetite, lethargy, fever, tachypnea, and labored breathing. Cough and bilateral nasal discharge are inconsistent findings. Extrapulmonary manifestations of rhodococcal infections are common. In a retrospective study of 150 foals with R. equi infections, 111 (74%) had at least 1 of 39 extrapulmonary disorders. 2 Survival was significantly higher among foals without extrapulmonary disorders (32/39 [82%]) than among foals with extrapulmonary disorders (48/111 [43%]), but many such disorders were only recognized after death. 2 Intestinal lesions are present in approximately 50% of foals with R. equi pneumonia presented for necropsy. 3 However, the majority of foals with R. equi pneumonia do not show clinical signs of intestinal disease. Abdominal lesions may include ulcerative enterocolitis and typhlitis over the area of the Peyer's patches, granulomatous or suppurative inflammation of the mesenteric and/or colonic lymph nodes, or in some cases a single large abdominal abscess may be the only lesion. 3 Polysynovitis is present in approximately 25-30% of cases with R. equi infections. 2,4 The degree of joint effusion is variable and, in most cases, lameness is mild or absent. Cytological examination of the synovial fluid usually reveals a nonseptic mononuclear pleocytosis and bacteriologic culture of the synovial fluid is negative. 4 Histologic examination of the synovial membrane of a few affected foals revealed lymphoplasmacytic synovitis suggesting an immune-mediated process. 5,6 Immune-mediated processes may also contribute to the development of uveitis, anemia, and thrombocytopenia in some foals infected with R. equi. 2 Bacteremic spread of the organism from the lungs or gastrointestinal tract may occasionally result in septic arthritis and, more commonly, osteomyelitis. However, foals can occasionally develop R. equi septic arthritis or osteomyelitis without apparent lung involvement or other source of infection. R. equi vertebral osteomyelitis or diskospondylitis resulting in spinal cord compression has also been reported. 7-9 Other rare extrapulmonary manifestations of R. equi infections in foals include panophthalmitis, guttural pouch empyema, sinusitis, pericarditis, nephritis, and hepatic, renal, and intracranial abscessation. 2 Diagnosis The distinction between lower respiratory tract infections caused by R. equi and that caused by other pathogens is problematic especially on farms with no previous history of R. equi infections. Many diagnostic tests including a complete blood count (CBC), fibrinogen level, radiographs or ultrasound of the chest, and serology may help distinguish R. equi pneumonia from that caused by other pathogens. However, bacteriologic culture or PCR amplification of the vapa gene, combined with cytological examination of tracheobronchial exudate, is the only way to make a definitive diagnosis. The presence of large Gram-positive pleomorphic coccobacillus in tracheobronchial fluid is highly suggestive of R. equi infections. Cytologically, intracellular Gram-positive pleomorphic rods can be identified in approximately 60% of foals in which R. equi was cultured from a TBA. There may be other bacteria present as well. Blood cultures are rarely positive. 81

4 A CBC including plasma protein and fibrinogen concentration should be performed in all cases suspected of having R. equi pneumonia. Hyperfibrinogenemia is the most consistent laboratory finding, although rare cases may have normal fibrinogen concentrations. Neutrophilic leukocytosis with or without monocytosis is also common. Foals with R. equi pneumonia tend to have higher fibrinogen concentrations and leukocytes counts than foals from which other pathogens are isolated. 10,11 However, individual variation precludes the use of fibrinogen concentrations and WBC as diagnostic tests or prognostic indicators for an individual animal. Thoracic radiography and ultrasonography are useful in evaluating the severity of pneumonia and in assessing response to therapy. A prominent alveolar pattern characterized by ill defined regional consolidation is the most common radiographic abnormality. The consolidated lesions are often seen as more discrete nodular and cavitary lesions compatible with pulmonary abscessation. Ultrasonographic evaluation often reveals extensive consolidation with welldefined abscesses. Serological approaches to diagnose R. equi infections in foals divide into 3 major types: agar gel immunodiffusion, synergistic hemolysis inhibition, and enzyme-linked immunosorbent assay. The serologic diagnosis of R. equi infections is problematic because the widespread exposure of foals to this organism at a young age leads to antibody production without necessarily producing clinical disease. In addition, maternally-derived antibody may cause positive reactions in some serological assays which further confound the interpretation of the test. Currently available serological assays, whether conducted on single samples or multiple samples to assess seroconversion, do not differentiate between diseased and healthy foals raised on enzootic farms Treatment A wide variety of antimicrobial agents are active against R. equi in vitro. However, because R. equi is a facultative intracellular pathogen surviving and replicating in macrophages and therefore causes granulomatous lesions with thick caseous material, many of these drugs are ineffective in vivo. For example, in one study all 17 foals with R. equi pneumonia treated with the combination of penicillin and gentamicin died despite the fact that all isolates were sensitive to gentamicin. 4 The combination of rifampin and erythromycin became the treatment of choice in the 1980s and has dramatically reduced foal mortality since its introduction. In recent years, clarithromycin or azithromycin, 2 newer generation macrolides, often replace erythromycin in the combination with rifampin. Macrolides and rifampin are highly active against R. equi in vitro but only exert bacteriostatic activity. Of the 3 macrolides listed above clarithromycin is the most active against R. equi in vitro. 15 The combination of a macrolide and rifampin is synergistic both in vitro and in vivo and the use of the two classes of drugs in combination reduces the likelihood of R. equi resistance to either drug. Rifampin and macrolides are lipid soluble, allowing them to penetrate cell membranes and caseous material. Advantages of azithromycin and clarithromycin over erythromycin in foals include enhanced oral bioavailability, prolonged half-lives, and much higher concentrations in bronchoalveolar cells and pulmonary epithelial lining fluid. 16 These properties of the newer generation macrolides contribute to their lower dosages and longer dosing intervals. Concentrations of clarithromycin in pulmonary epithelial lining fluid and bronchoalveolar cells of foals at steady state are 82

5 considerably higher than concentrations reported following daily administration of azithromycin to foals. However, clarithromycin concentrations at these sites decrease rapidly, whereas the release of azithromycin from cells is much slower, resulting in sustained concentrations of azithromycin in tissues for days following discontinuation of therapy. In a retrospective study, the combination clarithromycin-rifampin was significantly more effective than erythromycinrifampin or azithromycin-rifampin, especially in foals with severe radiographic lesions. 17 Because polymicrobial infections are common, a third antimicrobial agent may be necessary if another pathogen resistant to macrolides and rifampin is isolated in significant numbers along with R. equi. The combination of gentamicin or amikacin with erythromycin or rifampin in vitro gives significant antagonistic activity against R. equi compared with either drug alone. 18 However, the clinical significance of this in vitro finding has not been established. Resolution of clinical signs, normalization of plasma fibrinogen concentrations and radiographic or ultrasonographic resolution of lung lesions are commonly used to guide the duration of therapy which generally ranges between 2 and 12 weeks depending on the severity of the initial lesions. Although well tolerated by most foals, macrolides commonly cause diarrhea. Most of the time the diarrhea is self-limiting and does not necessitate cessation of therapy but affected foals should be monitored carefully because some may develop severe diarrhea, leading to dehydration and electrolyte loss that necessitate intensive fluid therapy and cessation of oral macrolides. The incidence of diarrhea in foals treated with erythromycin-rifampin has ranged between 17 and 36%. 17,19 In most cases, diarrhea was mild and self-limiting. In the same study, the incidence of severe diarrhea necessitating administration of IV fluids was not significantly different between groups of foals treated with azithromycin-rifampin, clarithromycin-rifampin or erythromycin-rifampin. During surges of very hot weather an idiosyncratic reaction characterized by severe hyperthermia and tachypnea has been described in foals treated with erythromycin. Anecdotal reports suggest that these reactions may occasionally occur with newer macrolides as well. Administration of antipyretic drugs and placing the foal in a cool environment will treat this problem. Severe enterocolitis has also been reported in mares whose foals are being treated with erythromycin, presumably due to disruption of the mare's normal colonic microflora following ingestion of small amounts of active drug during coprophagia or from contamination of feeders or water buckets with drug present on the foal's muzzle. 20 Prognosis Prior to the introduction of the combination erythromycin-rifampin as the recommended treatment, the prognosis of R. equi pneumonia was poor with reported mortality rate as high as 80%. Using erythromycin and rifampin a successful outcome (as assessed by survival) in 50 (88%) of 57 foals with confirmed R. equi pneumonia has been reported. However, until recently there was no information on the impact of R. equi infections on future athletic performance. Recently, a large collaborative study involving several major veterinary hospitals was conducted in order to definitively assess the influence of prior R. equi pneumonia on racing performance. The records of 115 foals (49 Thoroughbreds [TB] and 66 Standardbreds [SB]) that had chest radiographs and were diagnosed with R. equi pneumonia based on culture of a TBA were reviewed. 21 All cases were treated with erythromycin and rifampin between 1984 and The survival rate was significantly higher in SB (80%) than in TB (61%). Death was more likely 83

6 in foals presented with respiratory distress and the non-survivors had a higher radiographic score on admission than survivors. Of the survivors 54% (for both SB and TB) had at least one racing start as opposed to 65% for the control population suggesting that horses contracting R. equi pneumonia as foals are slightly less likely to race. However, those foals that raced performed as well as expected. Prevention Decreasing the Size of Infective Challenge There is a progressive build up of infection on horse farms with prolonged use so that enzootic farms are likely to be those used for breeding horses for many years, those with heavy concentrations of mares and foals, and those located where summer temperatures are high, where the soil type is sandy, and where dust is extensive. Large numbers of foals kept on bare, dusty, manure-containing paddocks will result in heavy challenge, with clinical disease maintaining virulent bacteria. Although environmental conditions are major contributing factors, they are often impossible to alter. It is important to house foals in well ventilated, dust free areas, and avoid dirt paddocks and crowding. Pasture must be rotated to decrease dust formation and by consequent inhalation of R. equi. Any sandy or dirt areas should ideally be planted with grass and made "off limits" to foals or, alternatively, irrigation may be useful in decreasing dust formation. Manure should be removed from paddocks and composted. Because mares and foals tend to congregate around water sources and shade in hot summers, reduction in the size of mare-foal bands may help by reducing the destruction of grass and exposure to barren soil. Infected foals should be isolated as they are the major source of contamination of the environment with virulent bacteria. Earlier Recognition of the Disease Early recognition of R. equi cases with isolation and treatment of infected foals will reduce losses, prevent the spread of virulent organism and limit the cost of therapy on farms where the disease is devastating. For this reason a combination of careful daily observation as well as measurement of white blood cell counts on all the foals at 2-4 week intervals, although labor intensive, is a useful approach to early identification of R. equi infected foals on enzootic farms. 12 Periodic ultrasonographic examination of the chest of all the foals on enzootic farms (starting at 3-4 weeks of age) is the most useful method for early identification of pneumonic foals prior to development of clinical signs. 22 Ultrasonography also offers the advantage of evaluating the severity of lung involvement and assessing response to therapy. Passive Immunization Intravenous administration of hyperimmune (HI) plasma obtained from horses vaccinated against R. equi using various antigens has consistently proved effective in significantly reducing the severity of R. equi pneumonia in foals following experimental challenge. 23,24 However, results of studies evaluating the efficacy of various HI plasma preparations under field conditions have given contradictory results. 25,26 Administration of HI plasma prior to infection with R. equi is essential. 27 However, early administration may result in the decline of passively transferred antibody to a non-protective level at a time when foals are still susceptible to R. equi and 84

7 environmental challenge is high. Therefore, intravenous administration of 1 L of HI plasma within 48h of birth followed by a second administration at approximately 25 days of age may be the best approach on farms with high morbidity rates. A single administration at the beginning of the warm season may be sufficient for foals born early during the year in geographic areas where cold winter temperatures reduce environmental challenge. These recommendations are only guidelines and the best time for administration of HI plasma may in fact vary depending on the geographic location of the farm, the size of infective challenge, and the age at which most foals on the farm develop clinical signs. HI plasma for the prevention of R. equi pneumonia is commercially available in North America. HI plasma is expected to slightly decrease the incidence of the disease (by 30-40%) but will not prevent infection in all foals and should not lull farm owners into a false sense of security and reduce the need for continued vigilance. Whether this strategy is cost effective will vary from farm to farm. If used for the control of R. equi infections on enzootically infected farms, administration of HI plasma should always be combined with other control strategies, such as attempts at decreasing the size of infective challenge and early identification and treatment of infected foals. References 1. Giguère S, Hondalus MK, Yager JA, et al. Role of the 85-kilobase plasmid and plasmidencoded virulence-associated protein A in intracellular survival and virulence of Rhodococcus equi. Infect Immun 1999;67: Reuss SM, Chaffin MK, Cohen ND. Extrapulmonary disorders associated with Rhodococcus equi infection in foals: A retrospective study of 150 cases ( ). J Am Vet Med Assoc 2009;235: Zink MC, Yager JA, Smart NL. Corynebacterium equi infections in horses, : a review of 131 cases, Can J Vet Res 1986;27: Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi pneumonia in 48 foals: response to antimicrobial therapy. Vet Microbiol 1987;14: Kenney DG, Robbins SC, Prescott JF, et al. Development of reactive arthritis and resistance to erythromycin and rifampin in a foal during treatment for Rhodococcus equi pneumonia, Equine Vet J 1994;26: Madison JB, Scarratt WK. Immune-mediated polysynovitis in four foals, J Am Vet Med Assoc 1988;192: Chaffin MK, Honnas CM, Crabill MR, et al. Cauda equina syndrome, diskospondylitis, and a paravertebral abscess caused by Rhodococcus equi in a foal. J Am Vet Med Assoc 1995;206: Giguère S, Lavoie JP. Rhodococcus equi vertebral osteomyelitis in 3 Quarter horse colts. Equine Vet J 1994;26: Olchowy TW. Vertebral body osteomyelitis due to Rhodococcus equi in two Arabian foals. Equine Vet J 1994;26: Lavoie JP, Fiset L, Laverty S. Review of 40 cases of lung abscesses in foals and adult horses, Equine Vet J 1994;26:

8 11. Leclere M, Magdesian KG, Kass PH, et al. Comparison of the clinical, microbiological, radiological and haematological features of foals with pneumonia caused by Rhodococcus equi and other bacteria, Vet J Giguère S, Hernandez J, Gaskin JM, et al. Evaluation of WBC concentration, plasma fibrinogen concentration, and an agar gel immunodiffusion test for early identification of foals with Rhodococcus equi pneumonia. J Am Vet Med Assoc 2003;222: Giguère S, Hernandez J, Gaskin J, et al. Performance of five serological assays for diagnosis of Rhodococcus equi pneumonia in foals. Clin Diagn Lab Immunol 2003;10: Martens RJ, Cohen ND, Chaffin MK, et al. Evaluation of 5 serologic assays to detect Rhodococcus equi pneumonia in foals. J Am Vet Med Assoc 2002;221: Jacks S, Giguère S, Nguyen A. In vitro susceptibilities of Rhodococcus equi and other common equine pathogens to azithromycin, clarithromycin and 20 other antimicrobials, Antimicrob Agents Chemother 2003;47: Suarez-Mier G, Giguère S, Lee EA. Pulmonary disposition of erythromycin, azithromycin, and clarithromycin in foals. J Vet Pharmacol Ther 2007;30: Giguère S, Jacks S, Roberts GD, et al. Retrospective comparison of azithromycin, clarithromycin, and erythromycin for the treatment of foals with Rhodococcus equi pneumonia, J Vet Intern Med 2004;18: Prescott JF, Nicholson VM. The effects of combinations of selected antibiotics on the growth of Corynebacterium equi. J Vet Pharmacol Ther 1984;7: Stratton-Phelps M, Wilson WD, Gardner IA. Risk of adverse effects in pneumonic foals treated with erythromycin versus other antibiotics: 143 cases ( ), J Am Vet Med Assoc 2000;217: Baverud V, Franklin A, Gunnarsson A, et al. Clostridium difficile associated with acute colitis in mares when their foals are treated with erythromycin and rifampicin for Rhodococcus equi pneumonia. Equine Vet J 1998;30: Ainsworth DM, Eicker SW, Yeagar AE, et al. Associations between physical examination, laboratory, and radiographic findings and outcome and subsequent racing performance of foals with Rhodococcus equi infection: 115 cases ( ). J Am Vet Med Assoc 1998;213: Slovis NM, McCracken JL, Mundy G. How to use thoracic ultrasound to screen foals for Rhodococcus equi at affected farms. In Proceedings. Am Assoc Equine Pract 2005;51: Martens RJ, Martens JG, Fiske RA, et al. Rhodococcus equi foal pneumonia: protective effects of immune plasma in experimentally infected foals. Equine Vet J 1989;21: Prescott JF, Nicholson VM, Patterson MC, et al. Use of Rhodococcus equi virulenceassociated protein for immunization of foals against R equi pneumonia, Am J Vet Res 1997;58: Hurley JR, Begg AP. Failure of hyperimmune plasma to prevent pneumonia caused by Rhodococcus equi in foals. Aust Vet J 1995;72: Giguère S, Gaskin JM, Miller C, et al. Evaluation of a commercially available hyperimmune plasma product for prevention of naturally acquired pneumonia caused by Rhodococcus equi in foals. J Am Vet Med Assoc 2002;220:

9 27. Chaffin MK, Martins R.J., Martens J.G. Therapeutic effects of immune plasma in foals with Rhodococcus equi pneumonia, Equine Vet J 1991;12 (suppl):