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infectious diseases are the second - most common cause of death ( after cardiovascular disease ) in end - stage renal disease ( esrd ) patients . cardiovascular diseases and infections account for 50% and 20% , respectively , of all deaths in esrd patients ( 2 ) .
currently , the number of patients that require dialysis as a result of diabetes mellitus is increasing .
, cryptococcosis occurs among human immunodeficiency virus ( hiv)-infected patients , solid - organ transplant recipients , and patients who undergo exogenous immunosuppression .
exposure to cryptococcus does not usually lead to overt disease , but inhaled cryptococcus can survive in the alveolar macrophages or granulomas .
the activation of cryptococcus in these locations is associated with the host immune status ( 3 ) . however
, disseminated cryptococcosis has also been reported in a few dialysis patients ( 4 - 6 ) .
we herein report a rare case of disseminated cryptococcosis with rapidly growing lung nodules in an esrd patient who received dialysis following percutaneous coronary intervention ( pci ) .
this case suggests that dialysis can cause innate immune disorder and the reactivation of cryptococcosis .
a 73-year - old man who had been diagnosed with type 2 diabetes mellitus at 35 year of age , who had severe diabetic neuropathy and diabetic - esrd complained of respiratory distress and sudden chest pain . on the first day of treatment , he visited the emergency room .
a physical examination revealed that his body temperature was 35.4c , his heart rate was 90 beats / min with a regular rhythm ; and his blood pressure was 130/77 mmhg .
the laboratory data showed a wbc count of 8,800/l with a shift to the left ( neutrophils 82% ) , hb 10.2 g / dl , blood urea nitrogen ( bun ) 82.2 mg / dl , creatinine ( cre ) 6.50 mg / dl , hba1c 5.9% , creatine kinase ( ck ) 189 iu / l , c - reactive protein ( crp ) 8.51 mg / dl , brain - type natriuretic peptide ( bnp ) 127.4 pg / ml .
1 ) . an electrocardiogram revealed st - segment elevation and poor r - wave progression in leads v1-v3 , and echocardiography revealed apical and ventricular asynergy .
, the patient went into cardiorespiratory arrest and cardiopulmonary resuscitation was performed , followed by mechanical ventilation .
ventilator assistance was discontinued . however , the patient produced an increasing volume of sputum , which began to appear purulent .
pseudomonas aeruginosa was identified from a sputum culture , and tazobactam / piperacillin ( taz / pipc ) ( 4.5 g q12h ) was administered . despite this therapy ,
the patient 's respiratory condition worsened and a chest computed tomography ( ct ) scan on day 15 revealed bilateral perihilar opacities , pleural effusion , and atelectasis .
we suspected the development of complications such as microbial substitution , pneumomycosis and thus performed sputum culturing and serum fungal antigen tests .
the administration of taz / pipc was changed to meropenem ( 0.5 g / day ) . on day 16 ,
, cryptococcal bodies were identified in two sets of blood cultures and liposomal amphotericin b ( l - amb ) ( 3 mg / kg / day ) was administered . on day 23 ,
cryptococcal bodies were identified in the sputum , cerebrospinal fluid , and bilateral pleural effusion ( fig .
the administration of l - amb ( 3 mg / kg / day ) was continued . on day 31 ,
chest ct revealed a solitary nodule in the left lingular segment for the first time , which was suspected to be a pulmonary cryptococcus lesion ( fig .
after several days , all of the sputum , blood , bilateral pleural effusion , and cerebrospinal fluid cultures tested negative . on day 52
although l - amb was considered effective , the c - reactive protein level remained elevated and the bilateral pleural effusion continuously increased .
the patient lost consciousness because of decreased vital capacity with increasing bilateral pleural effusion and was diagnosed with co2 narcosis .
the patient 's general condition deteriorated . on day 87 , ventricular fibrillation occurred and the patient died .
a solitary nodule suspected to be a pulmonary cryptococcus lesion in the left lingular segment was revealed by chest computed tomography on day 31 .
b , c : another lung nodule in the right pulmonary apical region on day 52 .
the risk factors for this infection include hiv / acquired immune deficiency syndrome , connective tissue disease , diabetes mellitus , chronic kidney disease , liver cirrhosis , long - term steroid use , exogenous immunosuppression , and solid - organ transplant . c. neoformans and c. gattii are the main causative agents of cryptococcosis .
they are commonly associated with pigeon excreta and plant materials . c. neoformans is widespread in the environment , whereas c. gattii
almost all cases of cryptococcosis in japan are caused by c. neoformans ( 7 ) .
following inhalation , cryptococcus localizes to the lungs where it can be phagocytized by the alveolar macrophages .
cryptococcus is surrounded by a polysaccharide capsule that helps the fungus survive in vivo by interfering with phagocytosis .
ifn- which is secreted from th1 cells activate macrophages to increase the intracellular killing of cryptococcus ( 3 ) .
the efficient control of cryptococcus requires a delicate balance of both th1- and th2-type responses ( 8) . more cytokines are needed to control the th1/th2 balance and fungal infections , including il-12 , il-18 , il-13 , il-4 , il-23 , il-17 , upa , il-10 , tgf- ( 9 ) . dialysis and the uremic milieu cause the inability to produce selected cytokines for the immune cells ( 10 ) .
usually , the inhalation of cryptococcus causes focal pneumonitis , and the infection is generally detected as single or multiple pulmonary nodules ( 11,12 ) . in immunosuppressed patients , focal infection worsens and can cause life - threatening respiratory failure , fungemia , and meningoencephalitis .
disseminated cryptococcosis most frequently infects the lung and central nervous system but can also infect the skin , prostate , and bones .
the diagnostic tools that can be used to detect cryptococcosis include histology , fungal cultures , the serum cryptococcal antigen test , and radiography .
disseminated cryptococcosis is defined by either : 1 ) positive cultures of clinical samples taken from at least two different sites or 2 ) a positive blood culture ( 13 ) .
dissemination to extrapulmonary sites is associated with acute respiratory failure and a high rate of mortality ( 14 ) . in the present case ,
diabetes mellitus , uremia , hemodialysis , and mechanical ventilation were considered to be risk factors for the dissemination and activation of cryptococcosis , because they are closely related to disorders of both the innate and adaptive immune systems ( 15 - 17 ) .
furthermore , the patient lived in a buddhist temple that had garden with pigeons ; thus it was considered that he could have been infected with cryptococcus before admission .
we thought he was not infected with human t - cell leukemia virus type 1 ( htlv-1 ) , because of absence of atypical cells in his peripheral blood , splenohepatomegaly and skin symptoms ( 18 ) .
although cases of cryptococcosis have been reported in immunocompetent patients , cryptococcal pleurisy is rare ( 19,20 ) . in the present case ,
multiple nodules were detected in both lungs , and cryptococcal bodies were identified in blood and bilateral pulmonary effusion cultures . in the present case
, cryptococcus was therefore thought to have been disseminated through both the airway and the bloodstream .
induction therapy for disseminated cryptococcosis in non - hiv patients includes amphotericin b , flucytosine , and l - amb ( 21 ) .
flucytosine may cause drug - induced anemia ; thus , flucytosine was not administered to our patient because of his chronic renal anemia . on day 21
, we initiated the administration of l - amb , which was effective in shrinking the nodules and clearing the patient 's cultures .
however , on day 31 , we found that the pulmonary nodules had grown during treatment .
this paradoxical reaction is similar that observed in mycobacterial infection and is considered to be related to a state of relative immunosuppression mediated by a shift in t - helper cell responses to the th2 phenotype .
there is a previously reported case in which an hiv - seronegative patient with cryptococcus neoformans meningitis developed a severe inflammatory reaction during treatment ( 23 ) . to the best of our knowledge ,
however , we did not find any pathological or bacteriological evidence to suggest that his pulmonary nodules were pulmonary lesions of cryptococcus .
it is thought that the patient 's ventricular fibrillation , which was caused by cardiac ischemia , was associated with hypovolemia and severe arteriosclerosis .
disseminated cryptococcosis generally reflects immunosuppression and is rarely found in immunocompetent patients . in dialysis patients , growing pulmonary nodules can suggest disseminated cryptococcosis ; thus , appropriate testing and therapy should be immediately initiated .
a 73-year - old man with type 2 diabetes mellitus and end - stage renal disease was diagnosed with acute myocardial infarction . 
 he required continuous dialysis after percutaneous coronary intervention . 
 subsequently , multiple nodules were discovered in both lungs for the first time , and cryptococcus neoformans was isolated from the patient 's sputum , blood , bilateral pleural fluid , and cerebrospinal fluid cultures , resulting in a diagnosis of disseminated cryptococcosis . 
 this case represents an invaluable example of disseminated cryptococcosis with rapidly growing lung nodules in a dialysis patient , and illustrates that dialysis causes innate immune disorder and the reactivation of cryptococcosis .