# Fatal Invasive Cryptococcal Infection in an HIV-Negative Elderly Patient with Decompensated Hepatic Cirrhosis

Authors: Shigeru Koba; Kazuki Ueda; Masahiro Mori; Kenji Miki; Shinsaku Imashuku
Journal: Case Reports in Hepatology
 (2018)

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## Abstract

Diagnosis of invasive cryptococcal infection in apparently nonimmunocompromised patients is difficult and often delayed. Human immunodeficiency virus- (HIV-) negative patients with decompensated hepatic cirrhosis might be at high risk of cryptococcal infection. We report here an 82-year-old Japanese female with end-stage hepatic failure and undergoing renal dialysis, hospitalized with septic shock-like symptoms. The patient had had hepatitis B virus (HBV) infection in the past. She survived only 4 days following admission. During hospitalization, she was found to have pleural effusion and ascites.Cryptococcus neoformans was obtained from blood culture but not from pleural effusion culture. Consequently, the patient was diagnosed as having invasive cryptococcosis in association with HBV-related hepatic cirrhosis. Unfortunately, the patient died prior to receiving antifungal agents. Twelve Japanese cases of hepatic cirrhosis-related invasive cryptococcal infection, consisting of previously described and this case, were summarized for discussion of the clinical features and outcomes.


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## Body

## 1. Introduction

Invasive cryptococcal infection, or cryptococcosis, usually develops in immunocompromised hosts, e.g., in human immunodeficiency virus- (HIV-) positive patients. However, it also occurs in HIV-negative subjects. Cryptococcosis-related mortality is high and does not differ between HIV-positive and HIV-negative patients [1]. Although cryptococcal infection of the lungs and nervous system is common, gastrointestinal cryptococcosis can occur in the absence of infection of above organs [2], as innate and adaptive immune dysfunction is noted in patients with end-stage liver disease [3]. Thus, cryptococcal peritonitis has been reported, with some cases progressing to fungemia and/or meningitis in instances of alcoholic [4], hepatitis B virus (HBV) [5, 6], or hepatitis C virus (HCV) [7] related decompensated hepatic cirrhosis. We report here a fatal Japanese case ofCryptococcus neoformans fungemia related to HBV cirrhosis in an elderly patient with pleural effusion and ascites. We also reviewed previously reported similar cases in Japan.


## 2. Case Presentation

An 82-year-old female was transferred to the emergency department of our hospital with general malaise followed by septic shock-like symptoms. She had been undergoing renal dialysis over the past 2 years. The patient’s test was negative for HIV, HCV, and human T-cell leukemia virus 1, and she did not have any type of cancer, was not undergoing chemo- or corticosteroid therapy, and showed no evidence of autoimmune diseases, but she had a history of HBV infection. She was not a drinker. Prior to admission, she had been in another hospital where she was diagnosed with end-stage hepatic failure (Child-Pugh stage C) and treated for anorexia, hypotension, and hypoglycemia. On admission, the patient complained of malaise, followed by a state of Japan Coma Scale I-3 (Glasgow Coma Scale E3V1M5), with severe hypotension (blood pressure unmeasurable). She was afebrile, severely anemic, and icteric, with liver dysfunction and hemorrhagic tendency but without peritoneal signs, such as localized guarding. Laboratory tests indicated high serum C-reactive protein levels, increased direct bilirubin, and extremely high hyaluronic acid and type IV collagen levels, in association with reduced total protein and albumin levels, as well as reduced prothrombin time and markedly low choline esterase activity. All these were compatible with decompensated liver dysfunction. For the complement system, reduced 50% hemolytic complement (CH50) and C3 levels, with normal C4 levels, were noted (Table1). Abdominal computed tomography revealed pleural effusion and small ascites (Figure 1). Pleural effusion was aspirated; cell counts therein were determined to be 272/μL, and the culture was negative. Abdominal paracentesis and spinal tap were not performed. During her admission, she was cared for by intubation in the intensive care unit because of persistent hypotension and low blood oxygen saturation (SpO2). Blood culture on admission yieldedCryptococcus (Figure 2) on day 4 of admission when she died. Also, positive serum cryptococcal antigen (titer; 1:128) was confirmed postmortem. Consequently, the patient was diagnosed as having invasive cryptococcal infection linked to HBV-related hepatic cirrhosis and died prior to receiving antifungal agents. Later, the presence ofC. neoformans was confirmed.Table 1
Laboratory data on admission.
CBC  Hepatic WBC (3000-8500) /µL 9200 CRP (0-0.29) mg/dL 9.68  Hb (11-16) g/dL 7.2 AST (13-37) U/L 58  MCV (83-100) fL 119 ALT (8-45) U/L 32  PLTs (150K-360K)/µL 57K LDH (122-228) U/L 362  Hemostatic  ChE (206-477) U/L 25  PT (80-100)% 26.2 g-GTP (8-33) U/L 23  PT-INR (0.9-1.1) 2.24 T. bil (0.3-1.3) mg/dL 6.68  APTT sec 60.2 D. bil (0.1-0.3) mg/dL 4.70  APTT-control sec 28.1 Total protein (6.7-8.3) g/dL 4.4  Fibg (200-400) mg/dL 88 Albumin (4.1-5.2) g/dL 1.9  FDP (0.0-2.5)µg/mL 16.8 Ammonia (20-70)µg/dL 173  D-dimer (0.0-1.0)µg/mL 10.2 Hyaluronic acid (0-50) ng/mL 41,112  Type IV collagen (0-140) ng/mL 872  Renal & Electrolytes  Ceruloplasmin (21-37) mg/dL 14.1  BUN (7.8-18.9) mg/dL 48.7 Viral studies  Cre (0.45-0.82) mg/dL 3.97 HBs-Ag/HBs-Ab neg/pos  eGFR 9 HBc-Ab pos (59.6)  UA (2.5-5.8) mg/dL 4.1 HCV-Ab neg  Na/ K/ Cl mmolL/L 141/ 5.2/ 105 HCV-core protein <3  Immunological  HIV neg  IgG (820-1740) mg/dL 851 HTLV-1 neg  IgA (90-400) mg/dL 424 Pleural fluid  IgM (52-270) mg/dL 21 Cell counts; /µL 272  C3 (80-140) mg/dL 44 Differential; mono %/ poly % 57.7/42.3  C4 (11-34) mg/dL 11.6 Protein; g/dL 2.4  CH50 (30-45) U/mL 15 ADA (40-50) U/L 17.1 Abbreviations for Table1. WBC=white blood cell count, Hb=hemoglobin, MCV=mean corpuscular volume, PLTs=platelet counts, PT=prothrombin time, APTT=activated partial thromboplastin time, Fibg=fibrinogen, FDP=fibrin degradation product, BUN=blood urea nitrogen, Cre=creatinine, eGFR= estimated glomerular filtration rate, UA=uric acid, Ig=immunoglobulin, CH50=50% hemolytic unit of complement, C3=complement 3, C4=complement 4, CRP=C-reactive protein, AST=aspartate aminotransferase, ALT=alanine aminotransferase, LDH=lactate dehydrogenase, ChE=choline esterase, g-GTP=gamma-glutamyl transpeptidase, T. bil=total bilirubin, D. bil=direct bilirubin, HB=hepatitis B virus, Ag=antigen, Ab=antibody, HCV=hepatitis C virus, HIV=human immunodeficiency virus, HTLV-1= Human T-cell leukemia virus type 1, ADA=adenosine deaminase.Figure 1
Computed tomography of the abdomen. Pleural effusion (a) and ascites (b) are seen. Within the liver, no abscess lesions were noted.Figure 2
Cryptococci obtained from the blood culture. (a, b) Gram stain, (c) India ink stain, and (d) Grocott stain. The stains revealed characteristic budding-like features (a, d) and encapsulation (b, c) (original magnification, ×1000).
(a) (b) (c) (d)Survey of Reports of Japanese Cases.We used the Igaku Chuo Zassi (ICHUSHI; the Japan Medical Abstract Society, www.jamas.or.jp) to survey data for patients in Japan who suffered from invasive cryptococcal infection related to liver cirrhosis and/or failure during the years 1990–2016. The keywords used were “liver cirrhosis”, “peritonitis”, “meningitis”, and “systemic cryptococcal infection”. Cases concurring with cancer were excluded. We identified 11 cases, mostly short abstracts and not full papers [8–18] (Table 2). Including the case described in the current report, a total 12 cases were analyzed. Of these cases, nine patients were over 50 years old and the male/female ratio was 9/3. The following causes of liver cirrhosis were reported: HBV (n=2), HCV (n=2), alcohol (n=2), primary biliary cirrhosis (n=2), and unknown (n=4). Treatment was known for eleven cases except for one. Seven cases received antifungal agents, of which four were alive and three had died at the time of reporting. All four cases not given antifungal agents died. Although detailed information was limited in the retrieved reports, it appears that the outcome may have been better in certain cases who were diagnosed early and had the antifungal treatment been provided in a timely manner.Table 2
Cirrhosis-related cryptococcosis; Japanese experiences.
Reference Age/Gender Causes of liver cirrhosis Symptoms Cryptococcalinfection Treatment Outcome(survival) 1 Nakamura 2016 68/F PBC fever peritonitisfungemia MCFG Died(32 days) 2 Haga 2015 59/M HCV dyspneaPE pulmonary,MRSA surgery Died(8 days) 3 Hokari 2010 58/F PBC diarrhea systemic VCM Died(16 days) 4 Akiyama 2010 64/M Alcohol seizure meningitis AMPH-BF-FLCZ Died(23 days) 5 Mitomi 2004 43/M Alcohol headachefever, general malaise meningitis FLCZAMPH-B Died(57 days) 6 Touge 1999 60/M HBV headachenausea meningitis FLCZ Alive 7 Arata 1996 58/M NA fevercavernous lung mass pulmonary/meningitis FLCZ Alive(22 days+) 8 Miyazaki 1993 70/M HCV disturbed consciousness meningitis FCLZ Alive 9 Yoshizawa 1992 58/M NA feverdyspnea fungemiasystemic antibiotics Died 10 Okazaki 1990 43/M NA disturbed consciousness systemic NA Died 11 Yamamoto 1990 32/M NA feverheadache hematemesis meningitis 5-FCMCZ Alive 12 Present case 82/F HBV general malaisehypotension coma fungemia none Died(4 days) Abbreviations. PBC=primary biliary cirrhosis, HBV=hepatitis B virus, HCV=hepatitis C virus, NA=not available, PE=pleural effusion, MRSA= Methicillin-resistant Staphylococcus aureus, MCFG=Micafungin, VCM=Vancomycin, AMPH-B=Amphotericin-B, F-FLCZ= fosfluconazole, FLCZ= fluconazole, 5-FC= flucytosine, MCZ= miconazole.


## 3. Discussion

Alveolar macrophages are the first line of defense againstC. neoformans infection, followed by neutrophils and monocytes. As a third line of defense, T- and B-cell responses are critical and produce various cytokines, such as interferon gamma and specific antibodies [19]. When such defense mechanisms break down in immunocompromised patients,C. neoformans emerges as an important pathogen [20].Invasive cryptococcal infection such as fungemia and/or meningitis mostly occurs in association with immunocompromised conditions, such as acquired immunodeficiency syndrome, or with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis [21, 22]. On the other hand, in patients with decompensated hepatic cirrhosis,C. neoformans invades the host through the gastrointestinal tract and causes peritonitis even in HIV-negative patients [4–6, 20, 21]. Some of these patients have localized peritonitis, but others further develop fungemia and/or meningitis [4, 6]. Although precise mechanism remains unknown, recent reports on cirrhotic patients complicated with invasive cryptococcal infection are accumulating [8, 9, 21, 23–25].The patient described in the current study exhibited septic shock-like symptoms on admission, with pleural effusion and ascites. Although pleural effusion as an initial clinical presentation in cryptococcosis has been reported [9, 23], the pleural fluid culture was negative in our case. During 4 days of admission with rapid deteriorating, we were unable to diagnose the disease prior to the patient’s death. We missed the chance to detect cryptococcal antigen and beta-D-glucan in time [26] and failed to examine the ascites and cerebral spinal fluid, but eventually blood culture yieldedC. neoformans. In hindsight, we speculated that the patient had already developed peritonitis and fungemia prior to referral to the hospital. This was compatible with a report that delayed diagnosis of cryptococcal peritonitis often results in death [5]. A report on a patient by Jean et al. [20] illustrates the difficulty of diagnosis, in which ascites was examined four times during 2 weeks after admission; upon fourth examination, both the ascites and serum became positive for the cryptococcal antigen. A week later, the cerebrospinal fluid culture yieldedC. neoformans.Including the same eight cases cited from literature, Albert-Braun et al. [4] analyzed 17 cases and Park et al. [6] analyzed 16 cases of HIV-negative cryptococcal peritonitis linked to cirrhosis. Of the 11 patients treated with amphotericin B with or without fluconazole; two patients survived [4], while 7 of 16 (44%) patients who did not receive antifungal treatment died [6]. Spec et al. reported high mortality (20/25; 80%) including 7 cases died before administration of antifungal therapy [24]. On the other hand, among the Japanese cases analyzed in the current study, antifungal agents were given to 7 of 12 (58%) patients, of which four were alive at the time of reporting. Unfortunately, the correlation of timing of antifungal agent administration and outcome could not be analyzed.Early diagnosis ofC. neoformans peritonitis is possible if India ink-positive encapsulated budding yeasts are visible upon microscopic examination of the ascites [5]. However, obtaining fungi from cultures of the ascites, blood, or cerebrospinal fluid takes 3–7 days. Although reports of cryptococcal peritonitis in cirrhotic patients are still limited, the incidence is likely underestimated when the physician does not recognize such a risk factor and the disease is not specifically looked for, as illustrated by the current report. When a patient presents with shock and coma, which are common clinical features of invasive cryptococcal disease [27], it appears to be already too late to offer life-saving treatment.In suspected cases of cryptococcal fungemia, depletion of the serum complement components should be evaluated. Complement C3 as well as CD11b are essential for neutrophil swarming aroundC. neoformans [28]. The ability of the serum to mediate C3 binding toC. neoformans is severely impaired in patients with invasive cryptococcal infection [29]. In fact, in the case reported in the current study, reduced CH50 and C3 levels, with normal C4 levels, matched the data presented in a previous report [29]. A more recent report on a patient who received eculizumab (a monoclonal antibody that blocks complement activation) and succumbed to disseminated cryptococcosis [30] may underscore the importance of the complement system in cryptococcal infection.In summary, to improve the outcome in patients with decompensated cirrhosis with ascites, awareness of the immune dysfunction-related risk of invasive cryptococcosis is indispensable. Early diagnosis of cryptococcal infection and prompt introduction of antifungal agents are required for life-saving. For any end-stage cirrhotic patients, beta-D-glucan and cryptococcal antigen assays as well as culture with India ink staining of blood, ascites, or spinal fluid are highly recommended.



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