Hello everybody, my name is James McMurrough. I work as an advanced practitioner in Small Animal medicine and Veterinary cardiology, and I'm here to talk to you about managing pyrexia in Primary Care practise. What we'll do today in this 45 minute, 1 hour session is hopefully go through, all the fundamentals really of what you need to be able to, decide that a patient has.
A pyrexia, why they might have a pyrexia, how are you going to investigate that, and ultimately how are you're going to treat it as well. The lecture will be aimed at, practitioners in primary care practise, and some of the things that we'll talk about in this lecture are things that you may have access to in primary Care practise, or be familiar with performing such as arthrocentesis, but some of the things we discuss as well. We'll highlight sort of techniques and procedures that are available at a more specialist level, in, in referral practise and the things I think it's worth being aware of to help people sort of understand, when you might be coming towards the limits, of what you can do with that individual patient and when it might be time in fact for a referral.
So first things first, we'll just kind of define what a fever is really and I'm gonna use the term fever and pyrexia interchangeably, mostly using p pyrexia. So this is an increase in the thermoregulatory set point of the body. And this occurs, in the anterior hypothalamus, secondary to the release of pyrogens, so these are substances most commonly released from neutrophils and monocytes, associated with inflammation that cause an increase in the patient's, bodily temperature by increasing that thermoregulatory set point, within the brain.
The most common, factors, that are associated with this are interleukin 1 and 6, and tumour necrosis factor alpha. This is different from hyperthermia, and it's important to be aware of this from the get-go, really, because the causes of these are very different and also the whether or not we treat and how we treat them as well is really quite different. So hypothermia, unlike P pyrexia, is just an increase in the bodily temperature without there being an increase in the thermoregulatory set set point.
So this can be due to multiple external or pathophysiological causes, so some examples we have may be due to, say, hypothermia associated with exercise, particularly overweight dogs, and perhaps those who have respiratory impairment, such as brachycephalic Airway syndrome and aren't able to pant effectively to cool. We may see hypothermia in patients with seizures, we may see it in patients with hypermetabolic disorders such as hypothermia, sorry, hyperthyroidism in cats. We can see it secondary to certain drugs, certain intoxications, and of course even simply stress associated with visiting the veterinary clinic.
So as I say, two different lists of causes, and we'll sort of highlight, how that affects our diagnostic pathway in the next few slides. OK. So just moving on from P pyrexia to Pyrexia of unknown origin, PUO Pyrexia can be associated with some obvious clinical signs in some patients.
And in some of these individuals, a diagnosis might easily be achieved, an example being, say, a puppy who presents with profound gastroenteritis, they're unvaccinated, they have diarrhoea, vomiting, and they undergo Parvaviral testing and test positive. It's quite appropriate. For that pet to have a pyrexia associated with its viral enteritis, and a diagnosis can be reached really quite quickly.
However, there are some patients that don't achieve the diagnosis quite so quickly, and these fall under a category of PUO. So there's a few different definitions that have been proposed in both human and veterinary medicine. But a good one to use is a patient who's got a temperature of over 39.2 °C that's gone on for at least 3 weeks, OK?
So quite important to remember that, at least 3 weeks' duration, and they must have had 3 or more visits to a veterinarian for, for basic assessment, basic evaluation, and or. During that time, had 3 days of hospitalisation at a clinic in which no obvious cause of the pyrexia has been identified. Some people as well would consider, a pyrexia of unknown origin is a patient who shows a lack of response to broad spectrum antibiotics for a period of 5 to 10 days.
This is something that, you know, is quite common in primary care practise, for there to be, an initial assessment, some initial evaluation, you know, perhaps consider. A course of antibiotics, assuming that if it's a bacterial infection, it'll likely be sensitive to that antibiotic and the patient will get better. When we start antibiotics in a lot of our patients, we should start seeing improvements within a couple of days and really most infections we know these days probably respond to just a 5 day course of antibiotics.
So if you have a patient that's been on anti-viruses for 5, 10 days and their pyrexia has not resolved, those are the kind of patients as well that that would fall under the category of a PUO. So pyrexia, you know, can be good, can be bad for our patients and for our owners, and essentially it can be positive because pyrexia is protective, in patients and is kind of part of a pathophysiological response to various disease states, and this is at least until a temperature of 41.1 °C is reached, at which point it can be really, you know, quite significantly deleterious.
But what we do know is that pyrexia, In some studies in humans, in particular. Have shown that there is improved survival, associated with pyrexia, and we also know that when you have a fever, there is a shorter, duration of illness, even though Pyrexia itself does induce clinical signs. The actual Period, in which a patient will be symptomatic is reduced when, when it's associated with a pyrexia.
Pyrexia also improves, immune system function. Helping with, neutrophil mobility, and phagocytic, abilities as well. As well as macrophage function and lymphocyte function.
And also, in the production of, acute phase proteins, so these are increased, in a patient that is febrile, so all these things. You know, go together to help be protective in a patient that has a fever to help them sort of improve in response to whatever is causing the problem. Sorry about the the child in the background yelling dad there.
So just moving on to the deleterious effects of pyrexia. So firstly we have the clinical signs that it causes to the animal, making them feel unwell and that itself of course is a welfare problem and of course it's something that the owners pick up on and is the reason why they're presenting to the clinic. You know, generally these clinical signs are relatively mild, the clinical signs that have secondary to pyrexia, and they are normally transient, as, you know, the patient does tend to get over the pyrexia at a point, but obviously it's not nice for the pet and, and not nice for the owner.
And the other thing as well that we have to bear in mind is that, with the increased metabolic rate that pyrexia causes, the patient needs to take on more energy, otherwise they're gonna be, at an energy, sort of deficit really, and, and be. Malnourished, so, pyrexia can increase, the metabolic requirement by up to about 30%. And this can be a problem in patients that already don't want to eat because they feel unwell because of their pyrexia.
Now of course as well, we need to bear in mind that, you know, when our temperature becomes really very elevated, so particularly above 41.1, degrees C, this is where actually, yes, the pyrexia itself can be actually really very harmful. Now it's very uncommon to see this with P pyrexia, and it's something that's more associated with hyperthermia.
Again, think of the status epilepticus patient, but when our temperature does get above that sort of cut off. We start to have, the breakdown of proteins in the body, we get activation of DIC, so body-wide, coagulation, abnormalities. We can get metabolic abnormalities, neurological damage, you know, and ultimately, .
Multiple organ dysfunction, so again, uncommon for our pyorexic patients to get that profoundly P pyrexic and generally we're gonna be monitoring the pyrexia, but how aggressively we need to sort of treat the pyrexia itself rather than the underlying cause, you know, is, is sort of debatable. So what do we consider the normal reference interval for temperature? Well, perhaps 38 to 39.2 °C.
Would be a good range, although some studies have shown that, anxious patients in the veterinary clinic have had temperatures up to 37.9 degrees, yeah, 39.7 degrees, sorry, in, in those circumstances.
Bear in mind as well that the magnitude of the pyrexia does not correlate with the causes, and that's been identified again, in retrospective studies, so I've always thought, well, you know. An elevated temperature can be caused by neoplasia, it can be caused by bacterial infection, I've always assumed that a bacterial infection, you know, is inherently more inflammatory and would be associated with a higher temperature, but it's just not the case really. So when we get on to talking about our differential diagnoses, we can't use the absolute temperature in degrees to help us unfortunately differentiate the causes.
And bear in mind as well that some inflammatory diseases, you know, may be identified in a patient that doesn't even have an elevated temperature, so certainly Myocarditis patients, so those who have infection of the heart muscle itself, endocarditis patients, those that have bacterial infection, most commonly the mitral and aortic valves of the heart. And patients with disco spondylitis, so, infection of the vertebral bodies, these can all have, you know, very profoundly inflammatory diseases, secondary to bacterial infection and may not be febrile at all. So moving on to our list of differential diagnoses, and it's awfully long for patients who have pyrexia of unknown origin, and rather than present an exhaustive list here, I thought I'd just sort of go through the different groupings that we have for the differentials and just sort of talk you through the, the more common diseases that we want to be thinking about and which species are sort of more commonly affected by which.
So we've got immune-mediated, infectious, neoplastic, inflammatory and miscellaneous causes. Now at referral level, immune-mediated disease has been identified as the most common cause of pyrexia of unknown origin. In dogs, and second to that is infectious disease in dogs, followed by neoplastic and, and inflammatory.
Now in cats, infectious disease is at least as common, if not slightly more common at referral level. So anyway, within, immune mediated diseases, what we can think about are, some of the immune-mediated problems, that don't have the most obvious outward clinical signs, and probably the most important example to be aware of is immune-mediated polyarthritis IMPA. So this is an inflammatory disease of multiple joints, often most commonly affecting the peripheral joints, so carpi, tarsi, in dogs.
And. Can be secondary or primary, but ultimately leads to pyrexia and and in some patients, they don't have really apparent lameness, if they do, it can be sort of a shifting lameness, it's not consistently identifiable and a lot of these patients as well can have joints that don't, do not feel effused. So they can be quite tricky to diagnose really, or at least have an index of suspicion that they could have an IMPA, based on a history taken and clinical examination alone.
But nonetheless, IMPA is, well, at least in one study was identified as being the most common immune mediated disease that was diagnosed at referral level in dogs. We then have steroid responsive meningitis arthritis, so again, a disease of dogs, and this typically, is an immune-mediated inflammation of the meninges, which leads to, neck pain. Now, the neck pain isn't the most apparent thing either in some patients, as they may present simply with a history of just being off colour.
And being lethargic, and it's only when you observe those patients in the clinic, going to eat or drink from the bone that the bowl, sorry, that they look like they just seem uncomfortable doing so and may have a bit of a sort of stilted, gait as well. These patients, ultimately, you know, need, CSF sampling to achieve a diagnosis, and that's always something that's, you know, not, not going to be generally, readily accessible in primary care practise, but nonetheless an important cause to be aware of. We then have immune mediated polymyositis, again, a disease of dogs that may present with quite profound weakness and have really elevated creatine kinase levels in a standard profile in the primary care clinic.
And then, systemic, lupus erythematosus. So this is one of those polysystemic immune mediated diseases where we may have several different immune mediated problems sort of all rolled into one. So again, these are all more common in in dogs than cats.
Now of course IMHA and ITP can also can cause pyrexia and immune-mediated diseases, but they're normally, Readily identifiable on basic sort of blood work testing, you know, a hemogram and biochemical testing. And can be diagnosed quite quickly, so don't really sort of commonly fall in to the sort of pyrexia of unknown origin group. Then moving on to infectious diseases, we can break these down into bacterial, viral, fungal, or protozoal.
So starting with the bacterial, they can either be systemic or localised. So within systemic infections, it could be a bacteremia, sepsis, if you will, which is blood within the, I'm sorry, bacteria within the bloodstream that can get there from any source in the body. And, but we also have some specific, systemic infectious diseases as well.
So these are organisms that often affect more than one organ at a time. So within dogs. We could think about sort of Lyme's disease, ehrlichiosis, leptospirosis, for instance, and then in cats, perhaps, we may be thinking about Bartonellosis, Mycobacterial infections, OK, so.
Each sort of species is at risk of different polysystemic diseases, and some of these can sometimes be tricky to identify, you know, as they can cause clinical signs within lots of different organ systems, so don't always consistently present in the same sort of way. We then have localised bacterial infections, so for instance, an abscess that's in any part of the body, so, a liver lobe abscess, a lung lobe abscess, OK? Which are normally identified with the use of diagnostic imaging that we'll get onto later on.
But we may have other localised infections as well, so septic arthritis in dogs, for instance, you know, is an important one. Now most dogs with septic arthritis. Will present with one very small and painful joint with a high temperature, and that's different for an IMPA, the immune-mediated Disease, where multiple joints are affected.
And also I said earlier that with IMPA we typically get peripheral joints affected, whereas with septic infections, it's more commonly the larger joints, particularly, elbow joints in dogs, and often those that have a history of, degenerative joint disease as well. Bacterial endocarditis, really important one to be aware of because it can carry quite a poor prognosis and we often pick these patients quite late up in the disease course, at which point a lot of the damage can already be done, but ultimately this is, infection of the valves of the heart in dogs, so it most commonly affects the mitral and aortic valves in, younger, larger, male dogs. And will cause pyrexia in association with a murmur, and that murmur might be a new murmur in that individual or a murmur that has got louder.
And that can help push us towards echocardiography, and, blood culture in these patients at an early stage. It's also seen in dogs that have had a history of, congenital heart disease as well, as well as that puts them at increased risk of secondary bacterial infection. Disco spondylitis, infection of the vertebral bodies is something.
That as well we see in dogs and that can be secondary to urinary tract infections, so that's important to sort of be aware of and again it's something that we identify primarily on imaging. Myocarditis, can really be quite difficult to, to diagnose in dogs, although there are, published, set of criteria for the diagnosis of this, that's been published in the Journal of Veterinary Cardiology. But these patients can present with very sort of subtle clinical signs and you know, ultimately it's a very hard disease to diagnose definitively without myocardial biopsy.
And we also may get things like localised pneumonias, we may get Pyotthorax, which of course we see in dogs as well as cats and pyometra as well, as urinary tract infections as cause of these, you know, more localised bacterial diseases. And then moving on to the viral infections, a lot of these are more, feline problems. Quite honestly, a lot of canine viruses.
Can cause an elevated temperature, but often they're again causing quite specific clinical signs and quite readily diagnosable, such as my example earlier of canine Parva virus. But within viral infections of cats that can cause the elevated temperature, probably the, the three most important ones to be thinking about are feline Infectious peritonitis, feline Infectious, sorry, Feline immunodeficiency virus, FIV and feline leukaemia virus as well. Then we've got fungal infections, so much less common in the UK but perhaps easily overlooked as well.
But, the most common one that we might think about in the UK is aspergillosis. Now, not nasal or yonnaal aspergillosis in dogs, also cats, but less commonly, but those patients obviously present primarily with nasal signs quite often aren't febrile, but actually aspergillosis that is, more atypical, disseminated and invasive, so for instance, you know, aspergillosis can cause. Disco spondylitis in dogs if you're particularly unlucky, and these can be really quite tricky to diagnose, you often use a combination of techniques, imaging findings and sampling of these areas as well, for cytology, combined, you know, with fungal culture.
Now. It's worth noting I suppose at this point that fungal infections are particularly difficult to treat as well in our small animals and the prognosis can be really quite poor, particularly in, disseminated fungal disease in dogs, and, more localised disease that we've often sort of see in cats, you know, can be more responsive to treatment, but also I think it's worth noting at this point the importance in our history, of, travel and, and being aware of what diseases in the region you're in and and in any regions that the animals travel to, what diseases are endemic there and what they're at increased risk of. And we've then got protozoal infections, so Babesiosis in dogs would be a good example, and of course toxoplasmosis, an important one in cats.
So lots of infectious diseases out there to be aware of and and consider testing for. And then we've got our neoplastic diseases. It can in theory be any neoplastic disease, but some of the more common, ones that have been associated with fever in in various studies, you know, those are lymph proliferative diseases, so leukemias, lymphomas, we may also see in histiocytic round cell disease, multiple myeloma as well, of dogs, .
But ultimately any tumour, you know, can, can be inflamed and cause a high temperature and sometimes it's, you know, secondary to er infection of the tumour or areas of necrosis er within the tumour itself. And then within our inflammatory diseases, so this is quite a short sort of list of causes, but we might be thinking about, steatitis, pansteatitis in cats more so than dogs, hypereaxenophilic syndrome, which we see in cats and, and less commonly certain breeds of dogs like Rottweilers, . And also er myositis, er you know, and maybe sort of chronic pancreatitis as well.
And then finally are miscellaneous diseases as well, so panosteitis, metaphysio osteopathy, idiosyncratic drug reactions and myelodysplasia. So as you can see, it's really quite an exhaustive list of differentials, and I think the important thing to sort of be aware of is not having all of those, you know, in the back of your head at all times, but actually being able to look at an exhaustive list of differentials and really refine them in the patient that's in front of you based on how they are presenting and the information you already have on them regarding history, physical examination. Age, breed, you know, sex, and some basic testing really.
The evidence is quite limited. It's been published regarding pyrexia of unknown origin in dogs and cats and is, is limited to a few retrospective case series, the five of which I've, I've put on the screen here for you, that really sort of describe. At a referral level, the causes of clinical findings in and outcomes of patients with fever of unknown oxygen in series is ranging from 50 to 140 different cases.
So again, I'll be referencing these intermittently throughout the rest of the talk. The initial approach to the investigation of Pyrexia should start by differentiating P pyrexia from hypothermia. We've already described how we can do that a little bit earlier on with the use of Physical examination and History.
So what are we going to look for on the physical examination then? Well, fever itself causes very non-specific clinical signs, such as lethargy, anorexia, depression, we can see hypopnia and stiffness as well associated with it, the. Are very non-specific findings and of course could be seen with many different diseases, and so it can't, it's not that useful in a lot of patients, but we need to be very thorough.
With our physical examination to try and identify any other abnormalities that can help point us in the right direction with these patients, so we want a comprehensive nose to tail based approach, it must include an ophthalmic exam. So full examination of the retina, to look for any evidence of, of lesions of the retina, that would help push us towards, systemic, particularly infectious diseases, as well as a full neurological examination. Which will help allow us to sort of rule in and out neurological disease within our febrile patient.
We need to pay close attention, of course, to palpation. Can we feel any evidence of any swellings anywhere that could represent neoplastic change, abscessation, . Could we feel any lymphadenomegaly, which may represent reactive change, to immunogenic stimulation, or it might be representative of the primary disease process itself, such as lymphadenitis er or neoplasia.
We want to have a good auscultation of the patient's chest, as I say, paying particular attention to lung sounds and auscultation of the heart. Do we hear any evidence of adventitious lung sounds that might push us towards a respiratory cause? Do we have any muffling of the heart or lung sounds that might push us towards pleural space disease?
Is the heart regular in its rhythm, if it's not, that might indicate a primary myocardial problem or the myocardium is being affected secondarily to another problem, and of course, is there any evidence of a heart murmur, which would really increase the index of suspicion that there could be endocarditis causing the high temperature. Bear in mind that patients who are febrile may have elevated, resting heart rates. Otherwise, we can then, move on to abdominal palpation, again, paying particular attention to any evidence of space occupying lesions.
We want to be, assessing the patient's bodily condition score as well as, their muscle condition score to get a better idea about severity, and chronicity. We know that for a PUO the temperature generally is elevated for 3 weeks or more, but the more severe the disease process, and particularly if it's associated with hyperexia or anorexia, we may get quite profound loss of lean muscle mass, and we know that loss of lean muscle mass, in several studies has been associated with more severe disease and poorer outcomes, in individuals. And by getting a baseline on their muscle condition score and bodily condition score as well as weight, that's going to help us also monitor this patient's response to appropriate treatment.
Once we've completed the physical examination and an in-depth history, we should already have, a sort of revised differential list, . For that individual patient, although it's quite hard at this point to categorically sort of rule out many of those differentials, but certainly you may have an increased index of suspicion of, say, bacterial endocarditis in, in the dog with the heart murmur, for instance, than if you hadn't heard the murmur. But nonetheless, the next step in investigation is, is the same for all patients.
We're then gonna move on to a minimum database of biochemistry, haematology, and urinalysis. So on our biochemistry. We're going to assess major, major organ function, how are the kidneys looking, how are the liver enzymes, are they elevated or not?
We're going to have a look at the proteins, so paying particular attention to the globulins, as globulins can be raised in quite a lot of our patients with pyrexia of unknown origin, and that can indicate evidence of inflammation or neoplasia. The magnitude of hypoglobulinemia can be useful in that a marked hyperglobulinemia could push us a little bit more towards, neoplastic causes, although it isn't, you know, there's no defined cutoffs, but certainly, we may consider the use of serum protein electrophoresis, as well if we have a decent hypoglobulinemia. And that would be to look at those globulins and determine whether or not it's more consistent with a monoclonal or polyclonal gammopathy.
Monoclonal gammopathy has of course been more suggestive of neoplasia and plasma cell neoplasia and lymphoma, whereas polyclonal gammopathy has been more suggestive of inflammation, er, and infection. Otherwise we'll have a look at the, electrolytes as well. We may have a look at the cholesterol, we know that cholesterol can be an independent, indicator of poorer outcomes in ICU based patients.
Our cholesterol may be low with . Hepatic disease, it may be low in patients with malabsorption from the gastrointestinal tract, but may also be increased in patients who have, you know, post hepatic disease, for instance. So we'll look at the haematology and I think this is always preferred to be submitted externally, to a pathologist's lab for.
Complete blood count with smear evaluation, OK, so remember whenever we are looking at a haematology, the numbers that we get out of our machines should always be interpreted in light of a smear. And that smear should be a fresh smear of EDTA blood taken, straight away at the time, a venal puncture. And essentially what we're going to be interested in looking at there is well, is there any evidence of anaemia?
OK. We know that, a mild non-regenerative anaemia is really common in patients with chronic inflammatory or neoplastic, or immune-mediated disease, but we can rule out immune-mediated anemias, with the use of, smear analysis to sort of exclude the presence of spherocytosis, agglutinates and potentially combine that with the Coombs test as well, . We, may also see, abnormalities of the platelet count, so we know that, of course, there are different, disease types that can cause, particularly, thrombocytopenia, so splenic sequestration, consumption, if it's, particularly immune-mediated, or, if the patient is, is suffering from DIC.
Or it may be, loss if the patient is bleeding, it may also be, a lack of production from the marrow itself. And when we typically see, bone marrow diseases causing a lack of production of cell types, unless there's a primary immune mediated cause, we often see by or pancytopenia, so more than one cell line being reduced. So if you do see a bye or a pancytopenia, multiple cell lines reduced, that certainly could push you towards a bone marrow disease, with a sort of non-immunological basis and, and, and push us towards our bone marrow sampling.
And we may see an elevated platelet count, so often reactive thrombocytosis is quite common in chronic inflammatory diseases. It may also be seen in splenectomized patients out of interest. And then very importantly, we're going to look at our white cells as well.
So a lot of patients, who have inflammatory infectious disease, may have an inflammatory leukogram, so a neutrophilia with a monocytosis, with, an eosinopenia and a lymphopenia, and the smear analysis may indicate whether or not there's evidence of sort of left shift. And that's going to be something we're going to see sort of quite commonly in our patients with inflammatory, and immune mediated disease. We can also use the smear analysis to rule out the presence of atypical cells, so to look for, for instance, evidence of stage 5, lymphoma, OK?
The urinalysis also should be performed at this stage, firstly because it's always good practise to run a urinalysis, anytime that you're doing a biochemistry. It really helps you interpret some of those biochemical, parameters, but also we're gonna want to culture that urine to help, rule out as early as we can, lower urinary tract infection. So this urinalysis therefore must be taken by a cystocentesis.
OK, we don't want to be, culturing free-catch urine samples or even catheterized, urine samples because of the probability, of bacteria in the external genitalia, contaminating the sample. On the urinalysis, as I say, we're gonna want to culture it with sensitivity, we're also gonna want to look at the protein level in the urine, so of course we can do that with the use of protein dipstick, but it's quite a crude estimate, so we're also gonna want to run a urine protein creatinine ratio. Now this is something that is quite commonly elevated in our pyrexic patients because.
There are a lot of disease processes that cause a secondary secondary immune complex, glomerulonephritis, so lots of the infectious, immune mediated and neoplastic diseases can cause a degree of proteinuria, and we can identify that at this stage. Determine the magnitude of the proteinuria and decide whether or not that means anti-proteinuric therapy itself or whether we're simply going to in the first instance, treat the underlying cause, you know, the patient's fever and then monitor for resolution of that proteinuria. We're also gonna have a look at and make sure, you know, that there's no other, evidence of, urinary tract inflammation or disease by looking at a sediment, examination as well.
So at this stage we often have abnormalities on our test work in the fever of unknown origin patient but often aren't at a definitive diagnosis and really we then combine this ClinPath testing . With whole body imaging. Using either thoracic radiographs and abdominal ultrasound scan or perhaps whole body CT, and appropriate sampling as well.
Now when we're looking at the whole body imaging, what we're doing there is saying, OK, let's screen this patient as appropriately as we can. Looking at those internal organs within the thoracic and abdominal cavities for any evidence of infectious disease, any evidence of inflammatory disease, and neoplastic disease as well. So if we see any abnormalities, lymphadenomegaly, an abscess within any of these regions, we're also going to want to be doing sampling at that point as well.
Now, depending on what the abnormality is and what organ it's in, will determine how we're going to sample, but I think you have to be prepared for all eventualities really. Many of our enlarged lymph nodes or mass lesions that are identified, certainly within the abdominal cavity or within the lung tissue, as long as it is against the thoracic wall, can be aspirated with very little risk. And we typically recommend submitting that for a minimum, of a cytological evaluation, but I would certainly also pay, reasonable sort of consideration to whether or not you, for instance, might want to culture that, as well.
So if we're going to take an aspirate, we can spray our aspirate through the needle onto a glass slide for cytology, but what we can also do is take an aspirate and then instead of spraying it onto a glass slide for cytology, just put some sterile saline through that needle and into a charcoal swab. For bacterial and fungal cultures, and there is also potentially the utility in performing PCR testing on aspirates, for certain infectious diseases as well, if you want to potentially increase our sensitivity, particularly with certain organisms that that don't culture, you know, very well. If we're not performing aspirates, we may consider, true cut biopsy.
So generally, these may be reserved for patients who've already had aspirates, and those aspirates have not yield, you know, a definitive diagnosis, and we can perform Tru-Cut biopsy with the use of ultrasound guidance within the thorax. Or the abdomen, and then of course these tissue samples can be submitted for histopathology again, making sure you're putting the appropriate samples in the appropriate tubes so that we could also, always have a biopsy sample in plain tubes so that we can do, culture on that and any, molecular testing such as PCRs as well. And this can really sometimes make a big difference getting a biopsy versus just an aspirate.
If you do have a patient, you know, that has a fever of unknown origin, you identify a mass and based on the patient's presentation, the appearance of the mass on imaging, you're very suspicious of neoplasia and you aspirate it and just get inflammation. You know, that could be suggestive of perhaps a misrepresentative sample, because there is an area of inflammation, necrosis within the mass that has been sampled and perhaps doesn't represent the fact that there is a neoplastic disease. So if you aspirate results don't fit with the rest of your clinical picture, you know, don't forget the importance of them following that up with a biopsy, whether it's the surgical one or taken with the use of, ultrasound guidance.
There are significant advantages to performing advanced imaging like CT over radiography and ultrasound, but it is generally more expensive, it is not widely available, and of course there are some, you know, considerations, you know, the use of ionising radiation, and the fact that the contrast enhancement that we use in CT scan. Can affect renal function in patients with compromised kidney function. But nonetheless, I, I, I think in general at referral level, advanced imaging does take preference to, thoracic radiographs and abdominal ultrasound, but, but in primary care practise they are absolutely, you know, appropriate at this stage, and we just have to be make sure that we're doing a really, good series of radiographs, including the thorax and actually the abdomen as well, so you can have a look at the bony structures, for instance, we wouldn't want to.
And you not radiograph the abdomen and miss radiographic changes of a lumbar disco spondylitis, for instance, in a dog. We want to make sure that those radiographs are performed under general anaesthesia, they are 3 viewed, they are inflated, you know, to increase our diagnostic potential, of those films. And then the abdominal ultrasound scan, you know, again, the, the quality of that study is, is honestly very operator dependent.
So based on the experience of the sonographer and the facilities available, and, you know, bear in mind that you, you may be limited in that respect in what you can do with that individual, what diseases you could definitively, you know, rule out, . You know, based on your sort of level of experience and facilities, and also bear in mind, patient size as well. We do know that once patients get over 25 kilogrammes in size, there is some evidence base that CT is just always preferred to abdominal ultrasonography, simply because of the amount of depth penetration and resolution we're able to achieve with ultrasound, in those larger patients.
So we're also going to at this point consider testing for infectious diseases, and we're gonna base which diseases we're going to test for on everything that we know about the patient up until this point, you know, including what diseases are endemic in that area, what diseases they're at risk of, i.e., vaccination status, worming status, .
And, you know, base our infectious disease testing on our sampling that we've performed, are we doing serology and PCRs on blood, or are we doing cultures, and PCRs, for instance, on aspirate samples. So once this stage, has been completed, you know, if you still don't have a definitive diagnosis, these cases, you know, are problematic, quite honestly. To work up further from here, particularly, in the sort of setting of a primary care practise, and this is where we start to sort of think, OK, well, at this point, would it be beneficial for the patient to consider onward referral for re-evaluation and further investigations that, that may, you know, involve sort of, techniques, or equipment that's not currently available to you, or based on, you know, your level of experience.
Your capabilities, or you're happy to proceed to this sort of second tier, of further investigations, in clinic. Just quickly on the screen here, I've, I've got an example of a case that we saw sort of not long ago at our practise, and this really, documented, how useful, advanced imaging can be in some of these cases. It was a dog that had a history of pyrexia, a young I believe it was a German Shepherd dog, and very few of the clinical signs, referring vets investigations were largely unremarkable, including, blood work, urinalysis, and thoracic radiographs.
We then performed a CT scan. And essentially noted a couple of things. Firstly, there was a small pneumothorax which wasn't present on the referral radiographs that had been done several days prior, so likely had developed during that time, but there were very subtle changes.
In the left caudal lung lobe here, suggestive of inflammation and possibly a tract consistent with a migrating foreign body. So even though we didn't see clearly, the foreign body within this lung tissue, we had a lot of imaging findings that suggested there was a foreign body in there, the pneumothorax, the. The, migrating tract, and some of these patients even end up, with sublumbar abscessation in these skeletal muscles here, as the migrating foreign bodies make their way out of the lung tissue through the diaphragm and up out into the, the, the musculature in this region.
So, you know, the use of advanced imaging in this patient allowed us to increase our index of suspicion that there was an inhaled foreign body, scope the patient, unfortunately not identify said foreign body, but proceed nonetheless to lung lobectomy and identify a migrating grass horn that made its way just through this lung lobe and into the pleural space. So at this point, we may consider some initial treatment. We've ruled out, hopefully, quite a lot of disease processes, particularly a lot of the neoplastic ones, based on our imaging and sampling at this point.
And before further investigation, dependent on client expectations and, and the, the presenting signs of the animal, we may elect for initial treatment course, prior to the further investigations. And this can be considered with a five-day course, of a broad-spectrum antibiotic with appropriate, tissue penetration, such as Amoxiclavulanic acid. Or we may consider perhaps doxycycline, that also is good broad spectrum, but also allows, coverage for some organisms, particularly the vector-borne organisms and Mycoplasma species, that sinulox, I'm sorry, amoxicclavulanic acid, I shouldn't say that, doesn't cover for.
If the patient of course responds to this course of antibiotics, then we can determine it may well be an infectious cause and then simply monitor the patient from there rather than investigate further. If they don't respond, then it really does indicate the need for that next level of further investigations. Antipyretics could be considered at this point as well, mainly to limit the clinical signs, associated with the pyrexia.
However, we do have to be cautious, that we don't, mask a fever. In a patient and consider them, you know, well again, and miss the fact that there is still an underlying problem that, that, that will be progressively getting worse and we're just not detecting that temperature. Because of the use of our antipyretics.
So that next tier of investigations, what are we looking at here? Well, based on our index of suspicion of what's going on with that patient, we can sort of tailor these to the individual. And base them on specific sort of body systems or some of the patients presenting signs.
We may, in other cases, really not have, a very high index of suspicion about any one disease process and might end up, you know, performing multiple of these different tests all at the same time, primarily because a lot of them involve the patient being under general anaesthetic, and it's probably more straightforward for an individual to undergo one procedure. It was probably cheaper to do all the sampling at one time than stage it over multiple different. Examinations.
Now we should also as well, before we launch into this second level of testing, consider, where we are with the case and see if anything has changed, because that does sometimes happen with these patients, and we may want to actually repeat some of our earlier tests, you know, I've certainly seen patients with infectious problems affecting their kidneys that are not azotemic at presentation. But a week into investigations, you know, suddenly are. I've had patients who do not have elevated CRP at first presentation.
Five days later, they do have an elevated CRP, and, and double-check your Physical examination as well, because not only could you have missed something on the first pass, but also some of these problems will have progressed and will now be showing detectable signs, on a Physical examination. So we did mention, CRP briefly, C-reactive protein, a little bit earlier. This can be performed in dogs.
It's an acute phase protein, that's elevated, secondary to inflammation and infection and, and, that can be used at this stage. For a couple of reasons really, one, it can help suggest that that patient does have a primary inflammatory or autoimmune disease, although bear in mind that there are several infectious and autoimmune diseases that don't cause such significant elevation. In CRP, IMPA, for instance, doesn't consistently increase CRP in all patients.
And when we look at infectious diseases, we know that, for instance, bacterial, aspiration pneumonia very commonly increases CRP. However, Borella bronchi septica as a cause of pneumonia in dogs does not consistently increase our CRP. So it's not the be-all and end-all, and I certainly wouldn't categorically exclude differentials based on the CRP.
But it can be useful to help reinforce your idea that a patient has significant inflammatory disease, but also can allow you to help monitor that patient if you have their CRP at baseline, you can serially repeat that during treatment to document improvements. We've mentioned as well, that we may consider referral at this stage, depending on the individual case, or at a minimum even discussing it, with, somebody at referral level just to sort of say, look, this is where I'm at with this case, these are my thoughts thus far, these are the test results. Can you see any glaring mistakes, Is there anything you'd be doing that I've not done, you know, what do you think?
So otherwise we may look at starting with some blood culture. So blood culture can be used to identify bacteremia, which can tell us about whether or not the patient has a sepsis, but also is one of the really important criteria for making a diagnosis of bacterial endocarditis. So to perform a blood culture, we need to take 3 blood samples at 30 to 90 minutes apart from 3 different sites on the patient, all with very strict aseptic technique, and each sample needs to go into its own.
Blood culture bottle as well to be sent to the lab and what we're hoping for is culture at more than one site and with the same organism and it's not a common bacterial commensal and that would be a positive culture. Now do bear in mind as well that there are a lot of patients who have sepsis, who have bacterial endocarditis, who do culture negative, unfortunately, and that the prior use of antibiotics will reduce the likelihood of a positive blood culture. So arthrocentesis, this is something that's very commonly performed in the PUO workup, as I mentioned earlier, there are a lot of IMPA patients who do not have obvious joint effusions, who do not have reproducible joint pain or manipulation.
And we do know that of course IMPA can be a secondary process, you know, it can occur secondary to other neoplastic diseases, to other infectious diseases, to GI diseases, to distant infectious diseases. So even if you don't think the patient has a primary IMPA, they may well have a secondary one. And still warrant arthrocentesis, so we want to do this, from 3 or more joints, and we definitely want to sample some peripheral joints, so carpi and tarsi as well.
This needs to be done with strict aseptic technique. I'm not gonna go into it in huge amounts of detail cos a lot of good resources out there that you can use for sort of approaches to each of these joints, but we want to take joint fluid sample, at a minimum for cytological analysis. So if you get enough fluid, fill an EDTA tube or if not, an impression smear on a glass slide, and that's to look, like I say, for evidence of, of neutrophilic, infiltrates, and a lack of infectious organisms, hopefully.
Within that fluid, and we also want to pop some joint fluid in plane tubes as well to allow us to perform, particularly PCRs and cultures. To look for infectious organisms if we are in fact, suspecting an infectious disease process. And these can be looked at quite readily in-house, you know, an IMPA, really causes this quite profound, neutrophilic pleomorphism on the cytology, you know, and if you're having a patient, you're really suspecting IMPA, but you're not going to get back your external cytology for, 3 to 5 days because of the post, you can look there and then in house at that smear and honestly start glucocorticoid therapy at that stage and that patient will markedly improve in the 1st 48 hours and before you even get your external results back, which is quite good.
CSF sampling, so this would allow us to basically screen for, types of meningitis, whether that's bacterial, protozoal, or viral. This will be performed generally via a cisternum magna approach, although we could use a lumbar, approach. Do bear in mind, however, the importance of excluding brain stem herniation with the use of advanced imaging before.
CSF sampling as not to cause, you know, significant injury to the patient, and also be very aware of aseptic technique, be very aware of, the risks of any potential coagulopathies, they may have, and. Sort of also your own level of confidence with this this procedure. And what we tend to do is, is take these, CSF samples, and again, submit them for external cytological analysis in EDTA, and, smears, but also, plain tubes as well for, serological, and, and molecular testing, the PCRs.
Also, it's worth contacting your lab to just ask exactly how do you want these samples sending over. As there are different ways that we can sort of process these in-house, with like the hanging drop technique, popping in EDTA with a single drop of formalin, just to help cellular preservation cos these cell samples are very, very fragile, from CSF, you know, and, and it can be significantly degraded, during storage and transit. So do contact your lab if you are considering CSF taming, just to see exactly what their sort of sample requirements are before you go ahead and take, these samples.
Aspiration of lymph nodes, we spoke about this, already and what we might do with those samples. Echocardiography, again, in the patient that we're suspecting could have, endocarditis, or myocarditis. So this image we have on the right here, was a male neutered rag doll cat that presented with p pyrexia.
Sounds consistent with congestive heart failure and a murmur, and we see a really large vegetative lesion here. On the septal mitral leaflet that was causing this cat to be very, very systemically unwell and have signs consistent with congestive heart failure. Bone marrow sampling, this is less frequently performed in the PUO investigation, but sometimes is one of the, the latter tests that we, we look at, particularly good for screening for, neoplastic disease within the marrow which might not be well represented, you know, elsewhere within the body, .
Some patients we may be suspecting a secondary immune mediated problem in the bone marrow, you know, and, and, and warrant bone marrow sampling. Some of these patients may have bi or pancytopenias that might push us towards, bone marrow sampling. And ultimately what we're gonna do with these patients, you know, is perform a bone marrow aspirate and a core biopsy.
The aspirate is submitted in EDTA as a fluid but also on on glass slides for cytological analysis and tells us a huge amount about what's going on in the marrow, but ultimately the core biopsy as well should be submitted in formalin for histopathological analysis as well. We may also consider, PCR testing on some of these marrow samples. So for instance, cats can have latent, FELV infection whereby that, feline leukaemia virus is only represented on PCR of the bone marrow and isn't, for instance, detectable on blood.
PCRs, and you know, generally, whilst we can go beyond this with other investigations, the vast majority of patients who undergo this many tests at referral level, you know, normally end up with a diagnosis. That being said, about 20% in some studies of patients at referral level are found to have, no definitive diagnosis. So it's at this point we're going to look at further treatment, whether we have a definitive diagnosis.
Or whether we think we have a hypothesis but aren't 100% sure, and we might want to do some sort of therapeutic trials. So we've already mentioned the potential use of antipyretics, as symptomatic therapy, and the use of an antibiotic trial as well. One thing to make very clear, and I probably should have said this a lot earlier on, if we suspect an infectious disease and we use an appropriate, Broad spectrum antibiotic with good penetration into tissues for an appropriate period of time, often no more than 5 days, and there is no improvement in that patient, it is highly improbable they do not have a bacterial infection as the cause of their problem and rather than escalating antibiotic therapy.
And reaching for 2nd or 3rd line antibiotics, what we should instead should do is say, OK, it is unlikely they have a bacterial infection. We probably don't want to just prolong our antibiotic courses and add additional antibiotics, we instead want to investigate further or we want to try a different therapeutic trial, because if you don't respond to a 5 day course of Comox, you probably don't have a bacterial infection, OK. NSAIDs can be used instead, of, you know, well, can be used as an anti-inflammatory and an antipyretic, in our patients.
Do bear in mind, of course, that they may be contraindicated in lots of different disease states, for instance, where you have increased risk, of ulceration of the gastrointestinal tract, where you have abnormal, renal function. So just do be cautious of their use and again bear in mind they're only symptomatic therapy. We then have, steroids, prednisolone, good old vitamin P.
So at this point, of course we may have a primary immune mediated disease and, and be wanting to reach a Prednisone as the drug of choice. We may, however, not have, A definitive diagnosis, but be highly suspicious of an immune mediated problem and want to start a therapeutic trial with prednisolone and assess response. Now if that's the case, what we have to do is, you know, select the drug and the appropriate dose.
So we really are looking at 2 migs per kg. For immune-mediated disease, in cats and dogs, and sticking with that dose for a good few days, to document, response. If we're looking at treatment of inflammatory disease, we can use lower doses, 0.5 to 1 mg per kg of Prednisolone, but just do make sure that you are using the right dose for that individual if you're gonna start a therapeutic trial.
And give them the appropriate amount of time to have a response. Do bear in mind that of course glucocorticoids have their own side effect profile as well, you know, short term we've got polyuria, polydipsia, changes in behaviour, polyphagia, and then long term, Loss of lean muscle mass, muscle weakness, gain of of fat, increased risk of diabetes mellitus, dermatological changes, etc. Etc.
So owner education is, is really important at this stage. So if we've seen a significant response to our treatment, that should support our suspicions or our definitive diagnosis, so we can give ourselves a good old pat on the back, . To help us be sure that that that we're we're showing the appropriate response, we're going to be monitoring clinical signs.
With telephone conversations or in-person discussions with the owners, physical examination findings, so resolution of the temperature, improvement in bodily condition score and weight, resolution of masses, for instance. And we can also combine that with our clin path testing. So, as I said, we mentioned CRP as a useful marker, we can, document decreases in that.
We may see, normalisation of our leukocyte counts, normalisation of hyperglobulinemia, etc. Etc. We may also for some infectious diseases, consider repeating serologies to document decreasing.
Antibody titers, we may reculture, we may repeat PCRs, probably less commonly, quite honestly, but yeah, consider some repeat testing for our infectious diseases as well to try and document that they have cleared, that organism. And that's pretty much it really, so these cases can be some of the most challenging and soul destroying, er, but also some of the most rewarding cases as well to investigate and treat. I think you have to be very systematic in your approach, to the investigation.
And very thorough with your problem list and differential lists and really from the get-go, be prepared, you know, for lots of investment financially for the client and with respect to their time as well in lots of different diagnostic testing. That might be staged over several trips to the clinic and that ultimately, you know, whilst there are a large number of patients who can have a good outcome, particularly those who have surgical or medically manageable inflammatory immune mediated or infectious disease, yes, there are the neoplastic patients, but ultimately a lot of patients can do well. However, even at the highest levels, You know, which there are no financial or technical limitations, up to 20% of patients don't achieve a definitive diagnosis, you know, so I think owner education is really, really paramount from the get-go just to sort of set their expectations.
All right, well thank you very much for listening, and I will see you next time.