A 77-year-old man treated with prednisolone for pemphigus developed severe sepsis
	by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Several
	antibiotics were administered. A peripheral blood smear showed growth of a large
	number of yeast extending pseudohyphae which could be seen both inside and outside
	of leucocytes. Antifungal agents were added immediately, however, he did not recover.
	Several days later, blood culture showed Candida albicans septicemia. The autopsy
	revealed microabscesses in the lung, heart, liver and kidney. A large amount of
	neutrophil invasion and yeast with peudohypae were also detected

Hiromichi, Iwasaki

Ikegaya, Satoshi

Okada, Toshiharu

Shigemi, Hiroko

Tai, Katsunori

Ueda, Takanori

Community Repository of Fukui

 1 
Fulminant candidemia diagnosed by prompt detection of pseudohyphae in a 
peripheral blood smear 
 
Satoshi Ikegaya MD, PhD
1
, Katsunori Tai MD
1
, Hiroko Shigemi MD
1
, Hiromichi 
Iwasaki MD, PhD
1
, Toshiharu Okada
2
, Takanori Ueda MD, PhD
1 
 
1
 Division of Hematology and Cardiology and 
2
Department of Clinical Laboratory, 
Faculty of Medical Science, University of Fukui, Fukui 910-1193, Japan 
 
Short title: Candidemia in a peripheral blood smear 
Category: case report 
Corresponding author: Satoshi Ikegaya 
Address: 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan 
Phone / Fax: +81-776-61-3111 / +81-776-61-8109 
E-mail: sikegaya@u-fukui.ac.jp 
 
Key words  candidemia diagnosis; blood smear; autopsy 
 
*Manuscript (All MS Text Pages, Title Page, Abstract, References and Figure Legends)
 2 
Abstract 
  A 77-year-old man treated with prednisolone for pemphigus developed severe sepsis 
by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Several 
antibiotics were administered. A peripheral blood smear showed growth of a large 
number of yeast extending pseudohyphae which could be seen both inside and outside 
of leucocytes. Antifungal agents were added immediately, however, he did not recover.  
Several days later, blood culture showed Candida albicans septicemia. The autopsy 
revealed microabscesses in the lung, heart, liver and kidney. A large amount of 
neutrophil invasion and yeast with peudohypae were also detected.
 3 
Background 
  The diagnosis of Candidemia is performed primarily by blood culture tests, it takes 
for several days to obtain the results. We report a rare case with candidemia in which 
the diagnosis was made rapidly by identification of numerous yeast with pseudohyphae 
and phagocytosis in the blood smear samples collected for the purpose of complete 
blood count. 
 
 4 
Case report 
A 77-year-old man was admitted to a nearby hospital for treatment of the bilateral leg 
skin blister. He was treated with 50 mg prednisolone per day for 4 months under a 
diagnosis of pemphigus, an autoimmune blistering disease. The eroded skin lesions 
were becoming ulcers with heavy exudates spreading to the whole body (Figure 1). Due 
to the damaged skin and mucous membrane barriers, the patient suffered from a severe 
bacterial infection, resulting in sepsis. Ceftazidime (CAZ) has been originally 
administered, but his systemic state did not improve. 
  Several months later, he was transferred to our hospital for treatment of an active and 
severe skin infection caused by multi-drug-resistant Pseudomonas aeruginosa (MDRP) 
and methicillin-resistant Staphylococcus aureus (MRSA). Physical examination on 
admission showed a fever of 38.0°C, loss of consciousness, sinus tachycardia (120 beats 
per min), tachypnoea (20 breaths per min), systemic edema, pleural effusion and ascites.  
Blood pressure was 120/60 mmHg. Laboratory data showed pancytopenia with a white 
cell count of 3.5×109 /L (neutrophils 88%, lymphocytes 8%, monocytes 2%, 
metamyelocytes 1%, myelocytes 1%), anemia (hemoglobin 10.4 g/dl), 
thrombocytopenia (platelet count, 50.2×109 /L), hypoproteinemia (total protein 4.4 g/dl, 
albumin 2.4 g/dl) and increased C-reactive protein (14.4 mg/dl). Conversely, the serum 
level of (1-3)-β-D-glucan was in the normal range (<5 pg/ml). The antibiotic 
administration was changed from CAZ to a combination of imipenem/cilastatin 
(IPM/CS), isepamicin (ISP) and teicoplanin (TEIC) due to the antibacterial sensitivity 
results. His general state improved temporarily, however, deteriorated after several days. 
Growth of a large number of yeast extending several pseudohyphae was detected on a 
blood smear collected in EDTA stained with May-Grünwald-Giemsa which could be 
seen both inside and outside of leucocytes (Figure 2a). Since it was suspected to be 
 5 
Candida species morphologically, 400mg/day of fosfluconazole (F-FLCZ) was added 
immediately. It was documented that blood culture revealed Candida albicans 
septicemia three days later. The serum concentration of (1-3)-β-D-glucan increased to 
91.6 pg/ml. Yeast with pseudohyphae was persistently detected on peripheral blood 
smear examination. Despite additional administration of othet kind of antifungal drug, 
150 mg/day of micafungin (MCFG), the patient died. The autopsy showed 
microabscesses of Candida species in the lung, heart, liver and kidney. A large amount 
of neutrophil invasion on a hematoxylin and eosin-stained sample and yeast with 
peudohypae on a Groccot-stained sample were also found in the tissues (Figure 2b). 
 6 
Discussion 
  Autoimmune blistering diseases are a group of disorders in which the body 
mistakenly attacks the tissue, causing blistering lesions that primarily affect the skin, 
mucous and membranes, systemic application of steroids is the first-line treatment. 
Previously, there is only one report of autoimmune blistering disease complicated with 
candidiasis [1]. Our case had many risk factors of candidemia existed such as serious 
extensive skin ulcer, with a long term glucocorticoid therapy and broad spectrum 
antibiotic agents therapy [2]. 
  Candida species are dimorphic fungi with yeast or mycelial form. In the host 
organism, C. albicans usually has pathogenically a mycelial form which propagated 
rapidly in the blood and multiple organs [3]. Although pseudohyphae and true mycelia 
are typical of the parasitic adaptation of yeast, it matters whether they were obtained in 
vivo or in vitro. It was reported that in vitro phagocytosis of yeasts might occur 
by1-hour pre-incubation at 37°C [4]. However, the blood smear samples are prepared 
immediately after taking the patient’s blood without incubation in our institute. Since 
the findings in autopsy of the patient validated the presence of pseudohyphae in infected 
tissues, we guessed that germination and the formation of pseudohyphae may have 
occurred in vivo.  
  Several reports have indicated that fungal elements may be detected in peripheral 
blood smears from patients suffering from severe intestinal disease or hematological 
malignancies or infant [5,6,7]. Because the pathogen is too small for visual detection, 
diagnosis of candidemia is rarely made by peripheral blood smears. In these reports, a 
large numbers of fungal elements existed. Detection of candidemia by blood smear 
requires at least 1 × 105 CFU/mL of yeast, which is clinically unusual; therefore, 
detection of candidemia by blood smear was supposed to be impossible in most cases 
 7 
[8]. Septicemia is usually diagnosed by blood culture examination, however, the mean 
time required to positive yeast detection and to identify C. albicans were 35.3 h and 
85.8 h, respectively [9]. 
  In conclusion, careful observation of the peripheral blood smear may be useful for 
prompt diagnosis of candidemia. It is important for clinician to cooperate with 
laboratory staff to observe daily blood smear. 
 
 8 
References 
1. Kaloudova Y, Votava M, Rihova H, et al. Unusual course of treatment of a patient 
diagnosed with Pemphigus Vulgaris (case report). Acta Chir Plast 2003;45(3):83-7. 
[PubMed: 14733251] 
2. Bassetti M, Trecarichi EM, Righi E, et al. Incidence, risk factors, and predictors of 
outcome of candidemia. Survey in 2 Italian university hospitals. Diagn Microbiol 
Infect Dis 2007 Jul;58(3):325-31. [PubMed: 17350205] 
3. Veses V, Gow NA. Pseudohypha budding patterns of Candida albicans. Med Mycol 
2009;47:268-75. [PubMed: 19347739] 
4. Berrouane Y, Bisiau H, Le Baron F, et al. Candida albicans blastoconidia in 
peripheral blood smears from non-neutropenic surgical patients. J Clin Pathol 
1998;51:537-8. [PubMed: 9797733] 
5. Girmenia C, Jaalouk G. Detection of Candida in blood smears of patients with 
hematologic malignancies. Eur J Haematol 1994;52(2):124-5. [PubMed: 8119384] 
6. Nadir E, Kaufshtein M. Images in clinical medicine. Candida albicans in a 
Peripheral-Blood Smear. N Engl J Med 2005 Sep;8;353(10):e9. [PubMed: 16148280] 
7. Naidoo YL, Potgieter JJ. Images in haematology. Candida albicans in a peripheral 
blood film. Br J Haematol 2008;143(4):453. [PubMed: 18950468] 
8. Branda JA, Ferraro MJ, Kratz A. Sensitivity of peripheral blood smear review for the 
diagnosis of Candida fungemia. Arch Pathol Lab Med 2007;131:97-101. [PubMed: 
17227130] 
9. Fernandez J, Erstad BL, Petty W, et al. Time to positive culture and identification for 
Candida blood stream infections. Diagn Microbiol Infect Dis 2009 Aug;64(4):402-7. 
[PubMed: 19446982] 
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Figure legend 
Figure 1. Skin lesions of pemphigus, an autoimmune blistering disease, with erosions 
and ulcers with heavy exudates spreading over the whole body. 
 
Figure 2. Yeast with pseudohyphae in Candida albicans (a) on a blood smear specimen 
stained with May-Grunwald-Giemsa and (b) on a Groccot-stained lung sample in 
autopsy. 
Figure 1
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Figure 2a
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Figure 2b
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Fulminant candidemia diagnosed by prompt detection of pseudohyphae in a peripheral blood smear

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