Dierenfaculteit_nr03_2009:dierenfaculteit

Vlaams Diergeneeskundig Tijdschrift, 2009, 78 Case report 183
Disseminated Penicillium radicum infection in a dog, clinically resembling
multicentric malignant lymphoma
Gedissemineerde Penicillium radicum infectie bij een hond klinisch gelijkend op een multicentrisch maligne lymfoom 1J.P. de Vos, 2E. van Garderen, 3H. Hensen, 4I. Tange, 5I. Curfs-Breuker, 1B. Vandevelde, 5J. F.
1De Ottenhorst, Clinic for Companion Animal Medicine and Veterinary Oncology Referral Centre, van Diemenstraat 83, 4535 AR Terneuzen, The Netherlands 2Laboratory for Pathology and Histology, Animal Health Service, Postbus 9, 7400 AA Deventer, 3Veterinary Clinic IJzendijke, Minnepoortstraat 14, 4515 BC, IJzendijke, The Netherlands 4Zorgsaam Foundation Zeeuws-Vlaanderen, Laboratory of Medical Microbiology, Wielingenlaan 2, 4535 PA Terneuzen, The Netherlands 5Department of Medical Microbiology and Infectious Diseases C70, Mycologie, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands After detecting fungal organisms in smears of enlarged peripheral lymph nodes in a dog, determination was
performed through culturing and genetic typing. The fungus was identified as Penicillium radicum by amplifi-
cation of fungal DNA encoding of the ribosomal internal transcribed spacer region and comparison with DNA
databases. In vitro susceptibility testing revealed multiresistance. In the literature, P. radicum is mentioned as a
phosphate solubilizing agent used in agriculture for promoting plant growth. This is the first publication of a dis-
seminated P. radicum infection in a dog. The generalized lymphadenopathy and hypercalcemia strongly resem-
bled a multicentric lymphoma.
Hypercalcemia in granulomatous diseases, including disseminated fungal infections, is caused by activated
macrophages possessing 1α-hydroxylase, which is able to convert 25-hydroxyvitamin-D into calcitriol. Although
disseminated fungal infections are extremely rare in The Netherlands and Belgium, they should be included in
the differential diagnosis of dogs with multicentric lymphadenopathy and hypercalcemia.
In uitstrijkjes van vergrote perifere lymfeknopen van een hond werden schimmelstructuren aangetoond. De deter- minatie vond plaats via kweekmedia en een genetische typering. Het DNA dat codeert voor de "ribosomal internaltranscribed spacer region" werd vermenigvuldigd, vergeleken met openbare DNA-databases en geïdentificeerd alsovereenstemmend met dat van Penicillium radicum. In vitro gevoeligheidstesten toonden een multiresistente schim-mel aan. Het gebruik van P. radicum in de landbouw wordt beschreven om plantengroei te stimuleren.
Door de gegeneraliseerde lymfeknoopzwelling en hypercalcemie vertoonde het ziektebeeld een sterke gelijkenis met een multicentrisch lymfoom. Hypercalcemie in granulomateuze ziektebeelden, inclusief gedissemineerde schim-melinfecties, wordt veroorzaakt door de omzetting van 25-hydroxyvitamine-D in calcitriol door geactiveerde macro-fagen die 1α-hydroxylase bevatten. In Nederland en België komen systemische schimmelinfecties sporadisch voormaar ze dienen toch te worden opgenomen in de differentiaaldiagnose van honden met gegeneraliseerde lymfeknoop-zwelling en hypercalcemie. Dit is de eerste publicatie van een gedissemineerde P. radicum infectie bij een hond.
bined microbiological and histopathological/cytologi-cal examination, if the infection is to be correctly tre- The diagnosis in animals of disseminated fungal in- ated and resolved. The principal route of infection for fections, which are extremely rare in The Netherlands fungal diseases in dogs is inhalation, from which dis- and Belgium, can be complicated. Most mycoses are semination can occur. Occasionally, direct wound con- easily confused with other disease entities, since the tamination and ingestion also play an important role clinical picture of an animal with systemic mycosis is in the pathogenesis of the disease, especially in histo - very unspecific. The causative agent needs to be plasmosis (Krohne, 2000).
promptly diagnosed and identified, usually by a com- The purpose of this report is to describe a case of Vlaams Diergeneeskundig Tijdschrift, 2009, 78 disseminated canine fungal infection. To the best of genic nodules with a diameter of 5 – 10 mm. To in- our knowledge, this is the first report of a dissemina- vestigate the presence of lymphoma, ultrasound gui- ted P. radicum infection in a dog. Furthermore, infec- ded, fine needle aspiration biopsies were performed of tion in humans with this species is not mentioned in peripheral lymph nodes, the spleen, and the mediasti- an extensive review of invasive disease due to Peni- nal and medial iliac lymph nodes, and submitted for cillium species other than P. marneffii (Lyratzopoulos cytological examination. et al., 2002). In this series, P. purpurogenum, P. brevi- At the pathology laboratory, the air-dried smears compactum and P. piceum were among the most iden- were stained according to May-Grünwald Giemsa.
tified species. In humans, systemic infections with Some smears from each location were not stained, but Penicillium species other than P. marneffei are rare, were rather stored temporarily to allow immunocyto- due to the inability of most non-marneffei species to logical analysis of the presumed lymphoma, thus esta- grow at 37oC (Santos et al., 2006; Horré et al., 2001). blishing its T-cell or B-cell origin. However, cyto-logically the smears of the lymph nodes and the spleen were not consistent with lymphoma, since the lym-phoid cells demonstrated a heterogeneous morpho- A 4-year-old male Dutch Braque with a body logy, which is indicative of lymphoid cells in various weight of 13.8 kg was presented in November 2007 stages of differentiation. This finding is consistent with with a mass, 3.5 cm in diameter, located in the left- reactive hyperplasia of the lymphoid cells and not with ventral subcutaneous tissues of the neck. A complete neoplastic proliferation. In addition, moderate num- physical examination showed no other abnormalities.
bers of neutrophils and macrophages were present in A fine needle aspiration biopsy of the mass was per- the smears. The macrophages had frequently fused into formed and cytological examination revealed small multinucleated giant cells. Remarkably, the presence lymphocytes, a moderate number of neutrophils, some of ill-defined cytoplasmic structures was noted in a plasma cells, and intracellular fungal hyphae in ma- significant number of macrophages and giant cells.
crophages. A blood examination consisting of a com- Although these structures were not very well stained in plete blood count (CBC) and routine serum bio- the May-Grünwald Giemsa stain, their branching mor- chemistry profile showed no abnormalities, although phology was highly suggestive of phagocytized fungi no blood calcium concentration was determined at that (Figure 1). As a consequence, a presumptive diagnosis time. The dog was treated with a total dose of 100 mg of a systemic mycosis was made on the basis of the ketoconazolea once daily per os for 3 weeks. cytological findings. In order to study the microscopic One week after end of therapy, the dog was sub- aspects of these fungi in more detail, the smears of the mitted again with fever, anorexia and a stiff gait. The lymph nodes and spleen that were temporarily stored mass in the neck had doubled in size. Treatment was were fixed overnight in 10% buffered formalin (pH started with 5 mg/kg enrofloxacinb once daily per os 7.2) and stained with periodic acid Schiff reagent and 10 mg/kg amoxicillinc twice daily per os. The (PAS). The fungal hyphae that were ill-defined in the mass was surgically removed, and post-operative in- May-Grünwald Giemsa stain demonstrated affinity for cision showed the aspect of an abscess. Histopatholo- the PAS stain, and their presence in macrophages and gical examination was not performed at that time.
multinucleated giant cells was clearly outlined (Figure Wound healing was uneventful and antibiotic therapy was stopped 10 days after surgery.
Several fine needle aspirates were performed again Two months after surgery the dog developed signs aseptically from the prescapular lymph nodes and sub- of general fatigue, polydipsia and polyuria. On physi- mitted for fungal culture. The aspirated material re- cal examination there was generalized lymphadeno- mained in the syringes and was inoculated in a laminar pathy and splenomegaly. Abnormalities noted on the flow safety cabinet in Sabouraud agar and Malt extract serum biochemistry profile were a moderate hypercal- agar within 30 minutes and incubated at 24°C and 37 cemia (3.32 mmol/l; reference range 1.98–3.00 °C. After 5 days of incubation, fungal cultures were mmol/l), slightly elevated creatinin (98 μmol/l; refe- clearly visible (Figures 3 and 4). rence 70 μmol/l), and an increased ALAT (257 U/l; re- Microscopic characteristics of Penicillium spp. ference range 0–113 U/l). No abnormalities were were seen after 14 days of incubation, which observed on a CBC. A cranial mediastinal mass was prompted a molecular approach, because classical detected on thoracic X-rays. In addition, enlarged morphological identification is inherently difficult.
lymph nodes were visible in the hilus of the lungs.
DNA was isolated from a 15-day-old pure colony The findings were considered not to be related to using a standard protocol (Boom et al., 1990). The the initial fungal abscess, and as a result the dog was genomic DNA encoding the ribosomal internal referred to De Ottenhorst Clinic in Terneuzen, the Ne- transcribed spacer (ITS) region was amplified by therlands, with strong suspicion of multicentric T-cell using 5'-TCCGTAGGTGAACCTGCGG-3' and 5'- lymphoma. On physical examination, all peripheral TCCTCCGCTTATTGATATGC-3' primers.d All am- lymph nodes were moderately enlarged. Body tempe- plicons were purified by using High Pure chemistry,e rature was normal. Abdominal palpation revealed sple- and sequenced by using a MegaBACE DYEnamic ET nomegaly and severely enlarged medial iliac lymph Dye terminator kit,f as suggested by the manufacturer.
nodes. On ultrasound, the spleen showed hypo-echo- Reaction products were purified by ethanol pre-

Vlaams Diergeneeskundig Tijdschrift, 2009, 78 Figure 1. Smear of a fine needle aspirate of a prescapu-
Figure 2. An air-dried smear of a prescapular lymph node
lar lymph node, stained according to May Grünwald-
was fixed overnight in 10% buffered formalin and stained
Giemsa. In the center a giant cell is present that
with PAS showing fungi, macrophages and multi-
demonstrates cytoplasmic impressions of ill-defined fun-
nucleated giant cells. The bar represents 10 µm.
gal structures (arrow). The bar represents 10 µm.
Figure 3. A colony of 14-day-old P. radicum on Sabou-
Figure 4. Reverse side of colony of P. radicum, with
raud agar.
cipitation, dissolved in distilled water, and analyzed One hundred microliters of the suspension were added on a MegaBACE 500 capillary DNA analysis to each well of a 96-well flat-bottom microtitration platformg under standard electrophoretic conditions.
plate and incubated at 35oC for 48 hours. MIC was de- The ITS sequence obtained for the isolate was termined visually and spectrophotometrically as a ≥ compared to the public DNA databases by using the 50% reduction of growth compared to that of the drug- BLAST interface at http://www.ncbi.nlm.nih.gov/ free growth control for fluconazole. Also the lowest BLAST/ (Altschul et al., 1997), and proved to be concentration of drug showing absence of growth was 100% identical to previously reported P. radicum compared to that of the growth control for amphoteri- sequences. Molecular determination was confirmed by cin B and the azoles. For caspofungin and anidulafun- the CBS Fungal Biodiversity Center - KNAW, Utrecht, gin, the MEC (minimum effective concentration) was The Netherlands (http://www.cbs.knaw.nl), and the P. determined microscopically as the lowest concentra- radicum isolate was deposited in the culture collection tion in which abnormal, short and branched hyphal as CBS 122887.
clusters were observed compared with the long, un- The broth microdilution method was performed in branched hyphal clusters that were seen in the growth duplo according to CLSI M38-A2 (Clinical and Labo- control (Clinical and Laboratory Standards Insitute, ratory Standards Insitute, 2008). Briefly, a spore sus - 2008). The MIC or MEC for amphotericin Bi, itraco- pension of the isolate was made in 0.9% sterile saline nazolej, fluconazolek, voriconazolek, anidulafungink, with 0.05% Tween 40. The optical density was adjus- posaconazolel, isavuconazolem, and caspofunginn were ted to 80 to 82% T with a spectrophotometer at 530 8, >16, >64, >16, 0.016, >16, 2, and >16 mg/L, res- nm, and then the isolate was diluted 1000 times in pectively. The P. radicum isolate displayed resistance RPMI medium (final concentration 1-5 x 103 CFU/ml).
to the majority of the antifungals tested. Isavuconazole Vlaams Diergeneeskundig Tijdschrift, 2009, 78 had the lowest MIC (2 mg/L) compared with the other abscess. Moreover, the time between the locally azoles and the MEC (0.016 mg/L) of anidulafungin curative surgery and the development of the suggested the isolate to be susceptible.
generalized lymphadenopathy justified putting Meanwhile, the dog had difficulties in eating and lymphoma high on the list of differential diagnoses.
was manually fed by the owner, but vomited almost The genus Penicillium is among the most common after each meal. In expectation of the results of the an- fungi in the environment. Approximately 15 species tifungal susceptibility testing, therapy was started with are known to cause opportunistic human mycoses in 1 mg/kg maropitantg once daily as a subcutaneous in- immunocompromised patients (Lyratzopoulos et al., jection and 5 mg/kg itraconazoleh once daily per os.
2002). In dogs, several cases of disseminated Penicil- Vomiting stopped and three days after the beginning lium infection have been described in recent years.
of therapy a moderate hypercalcemia (3.39 mmol/l; re- Among them are P. purpurogenum (Zanatta et al., ference range 1.98–3.00 mmol/l) still remained. 2006), P. commune (Kano et al., 2006) and P. brevi- Fourteen days after the beginning of itraconazole compactum (Caro-Vadillo et al., 2007). A review of therapy, the condition of the dog still had not improved opportunistic fungal infections in 10 dogs noted one and the size of the lymph nodes had not decreased. The case of non-specified penicilliosis (Watt et al., 1995). dog also developed uncontrolled muscular spasms in P. radicum is mentioned in the literature as a phos- the head, an uncoordinated gait and an uncoordinated phate solubilizing fungus used in agriculture for plant motoric activity when reaching out for food. Serum growth promotion (Wakelin et al., 2007). The dog des- biochemistry profile abnormalities noted at that time cribed in this article was living in an agrarian area, but included an increase in ureum concentration (14.8 no attempt was made to isolate the fungus from the mmol/l; reference range 2.3–9.1 mmol/l), a creatinin dog's environment, or to investigate the use of P. ra- concentration of 133 μmol/l, a total serum calcium dicum in locally applied fertilizers. concentration of 3.71 mmol/l, alkaline phosphatase A common theme in the clinical outcome of a fun- (151 E/l; reference range 0–130 U/L), alanine gal infection is the response of the immune system. If aminotransferase (214 U/l: reference range 0–133 the inoculum is small and the animal is immunocom- U/L), and a normal albumin concentration (27g/l; petent, the infection is usually limited to the port of reference range 22-35 g/l). CBC showed a normal entrance and resolves with few or no clinical signs. As leukocyte count (6.7 x 109/l; reference range 6.0-17.0 in human patients, we can hypothesize that canine pa- x 109/l), a normal lymphocyte count (2.6 x 109/l; tients with systemic mycotic infections lack a proper reference range 0.7-5.0 x 109/l), neutropenia (2.5 x immune response to the fungus. Although not convin- 109/l; reference range 3.6-13.0 x 109/l), and a normal cingly proved, there are indications that immunosup- number of monocytes (1.6 x 109/l; reference range 0.1- pression – for example, through the neutropenia – in 1.7 x 109/l). Considerable polydipsia and polyuria were the dog described in this case report was the main still present, and forced diuresis through fluid therapy cause of the fungus becoming invasive. Clinical signs and furosemide treatment to attempt to normalize the in canine patients with disseminated fungal infections hypercalcaemia was not yet started. Corticosteroid are primarily determined by the loss of function of the therapy was considered to be contra-indicated because infected and inflamed organ systems, which causes it could possibly promote further deterioration through non-specific clinical symptoms. However, draining the suspected immunosuppression in this dog.
skin tracts and lymphadenopathy have regularly been The day the results of the antifungal susceptibility reported in several systemic fungal infections (Krohe, testing became available, the creatinin level had in- creased to 171 μmol/l, with a total serum calcium con- Hypercalcemia has been well described in a variety centration of 4.17 mmol/l. The peripheral and medial of neoplastic and granulomatous diseases. Serum cal- iliac lymph nodes, as well as the spleen, were severely cium concentration is tightly regulated by a complex enlarged and the total condition of the dog rapidly de- system of calcitropic hormones. Parathyroid hormone clined. Euthanasia was performed on the owner's re- (PTH) and the biologically active form of vitamin D, quest and no permission was obtained for necropsy.
calcitriol or 1,25-dihydroxyvitamin D (1,25-(OH)2D3),are the most physiologically relevant calcitropic sub- stances, with actions at the levels of bone, kidney andgut. Neoplasms such as lymphoma can alter the cal- Disseminated fungal infections in companion cium homeostasis indirectly through the production of animals are extremely rare in The Netherlands and endocrine factors that result in hypercalcemia of ma- Belgium. In patients where such an infection clinically lignancy. This paraneoplastic condition is most often leads to generalized lymphadenopathy, splenomegaly due to the synthesis and release of parathyroid hor- and hypercalcemia, lymphoma should be included in mone-related peptide by neoplastic cells and the en- the differential diagnostic work-up. This was suing increase of osteoclastic bone resorption. Another especially true for the dog described in this case report, mechanism for this hypercalcemia operates through where there was no positive proof that the fungal the excess production of 1,25-dihydroxyvitamin D organism detected on cytology specimens obtained from extra-renal sources (Clines et al., 2005; Sharma, from the mass in the neck was either the primary cause of or secondarily involved in the development of the Human patients with hypercalcemia during a dis- Vlaams Diergeneeskundig Tijdschrift, 2009, 78 seminated fungal infection are known to have their vi- j Janssen Research Foundation, Beerse, Belgium tamin D metabolite levels increased (Spindel et al., k Pfizer Central Research, Sandwich, United Kingdom 1995). Calcitriol is a major biologically active meta- l Schering-Plough, Kenilworth, USA bolite of the vitamin D sterol family. Vitamin D pre- m Basilea Pharmaceutica, Basel, Switserland cursors are either ingested in the diet or synthesized in n Merck Sharp & Dohme BV, Haarlem, The Nether- the skin from 7-dehydrocholesterol through exposure to sunlight. Hydroxylation occurs in the liver to form25-hydroxyvitamin D (25-(OH)D3). 25-(OH)D3 is hy- droxylated in the kidney to form 1,25-(OH)2D3. Therenal 1α-hydroxylation of 25-(OH)D Altschul S.F., Madden T.L., Schäffer A.A., Zhang J., Zhang 3 is the major re- cognized control point of vitamin D metabolism, res- Z., Miller W., Lipman D.J. (1997). Gapped BLAST and ponding to phosphate, PTH and calcitriol PSI-BLAST: a new generation of protein database search concentrations. Vitamin D receptors within renal proxi- programs. Nucleic Acids Research 25, 3389-3402.
mal convoluted tubule cells are involved in an auto- Boom R., Sol C.J., Salimans M.M., Jansen C.L., Wertheim- van Dillen P.M., van der Noordaa J. (1990). Rapid and crine negative feedback loop whereby increased levels simple method for purification of nucleic acids. Journal of of 1,25-(OH)2D3 will down-regulate 1,25-(OH)2D3 Clinical Microbiology 28, 495-503.
production (Clines et al., 2005). Other known impor- Caro-Vadillo A., Payá-Vicens M.J., Martínez-Merlo E., Gar- tant extra-renal sites of calcitriol production are the cía-Real I., Martín-Espada C. (2007). Fungal pneumonia placenta and granulomatous tissue (Clines et al., caused by Penicillium brevicompactum in a young Staf- fordshire bull terrier. The Veterinary Record 160, 595-596. However, hypercalcemia associated with granulo- Clines G.A., Guise T.A. (2005). Hypercalcaemia of malig- matous disease arises from an alteration of endogenous nancy and basic research on mechanisms responsible for vitamin D metabolism. Macrophages activated in res- osteolytic and osteoblastic metastasis to bone. Endocrine- ponse to granulomatous inflammation are able to con- Related Cancer 12, 549-583. Clinical and Laboratory Standards Institute. (2008). Refe- vert 25-hydroxyvitamin D, produced by the liver into rence method for broth dilution antifungal susceptibility calcitriol in an unregulated manner by possessing the testing of filamentous fungi. Approved standard M38-A2.
1α-hydroxylase enzyme (Sharma, 2000; Dusso et al., In: Clinical and Laboratory Standards Institute. 2nd ed., 1991; Mellanby et al., 2006; Monkawa et al. 2007). Wayne, PA, USA.
In companion animals, hypercalcemia related to Dial S. (2007). Fungal diagnostics: current techniques and granulomatous disease has been reported in dissemi- future trends. Veterinary Clinics of North America Small
nated histoplasmosis, blastomycosis, coccidiomyco- Animal Practice 37, 373-392. sis, tuberculosis and schistosomiasis (Mellanby et al., Dow S.W., Legendre A.M., Stiff M., Greene C. (1986). Hy- 2006; Dial, 2007; Dow et al., 1986). Animals with hy- percalcemia associated with blastomycosis in dogs. Jour- percalcemia related to granulomatous disease are ex- nal of the American Veterinary Medical Association 188, pected to have high serum concentrations of calcitriol Dusso A.S., Finch J., Brown A., Ritter C., Delmez J., Schrei- and of total and ionized calcium. However, their PTH ner G., Slatopolsky E. (1991). Extrarenal production of values will be low. Serum calcium concentrations re- calcitriol in normal and uremic humans. Journal of Clini- turn to normal with successful treatment.
cal Endocrinology & Metabolism 72, 157-164.
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samples is to be supplemented by newer identification Kano R., Ito K., Imagi M., Watari T., Tokuriki M., Hase- techniques such as PCR, to obtain a proper determi- gawa A. (2006). Isolation of Penicillium commune from nation of the causative organism. In vitro susceptibility a pulmonary infection in a dog. The Veterinary Record testing is of value to make targeted treatment possible.
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Uit het verleden
Op het eten van een kalfskop
Maakt je klaar, maak je klaar, De kallefskop is gaar, Ei, hoor hem lekker koken! Mijn maagje danst op dat geluid, De kop die wil de ketel uit, Ik heb hem al geroken.
Wie zou niet, wie zou niet, Als hij 't verhemelt ziet, Een stukje daarvan wensen? Wat zijn de harsens hagelwit, Zie of er ook een kei in zit, Dit zijn drie van acht strofen die de lof van kalfskop Als in de meeste mensen.
bezongen lang voordat er sprake was van BSE. De kopverscheen op zijn geheel op tafel: met tong, kaak- spiertjes en hersenen! De kei in de hersenen is een al-lusie op het ‘keisnijden' dat toen nog toegepast werd Gans en kip, gans en kip, bij sommige geesteszieken. Het werkje werd neerge- Kapoen en watersnip, pend door Jan de Regt, een van die vrolijke poëten die Wie zou er naar je talen? Hollands' Gouden Eeuw afsloten. Hij stierf in 1715.
Geen pluimgedierte, wild of tam, Geen verwarring mogelijk dus met zijn naamgenoot, Geen ossetong, geen hanekam, de eerste anatomieprof aan de Gentse veeartsenijs- Mag bij de koppen halen chool, geboren te Rotterdam in 1899.
Jan de Regt Uit: "Geheime gedichten" gekozen door Wim Zaal, De Arbeiderspers, Amsterdam, 1974, p. 36-37 die bij de
Regt aantekende: door zijn gebrek aan keurigheid raakte hij al in de achttiende eeuw vergeten.

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