Both disseminated cryptococcal infection and tuberculosis occur in hosts with impaired cell-mediated immunity, but there have been few reports about the concurrent infections in patients without human immunodeficiency virus infection. A 64-year-old man, who had been taking corticosteroids for interstitial pneumonia, was diagnosed with disseminated cryptococcal infection. While the patient was receiving anticryptococcal therapy, pulmonary tuberculosis also emerged. The patient developed acute exacerbation of interstitial pneumonia and passed away. Based on the patient’s clinical course, serial computed tomography images, and autopsy results, we believe that the preceding several months of corticosteroid treatment might have contributed to these coinfections in the lungs already vulnerable due to underlying fibrosis.
Disseminated cryptococcal infection and tuberculosis are both known to occur in immunocompromised hosts, such as patients with human immunodeficiency virus (HIV) infection and diabetes mellitus and patients taking immunosuppressants [
Reported cases of concurrent cryptococcosis and tuberculosis in patients without HIV infection.
Age/sex | Race | Region | Underlying disease | Pathological lesions ( |
Treatment ( |
Outcome | References | |
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1 | 61M | NA | United States | NA | CSF/lung | AMPH-B/INH, SM | Recovered | [ |
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2 | 69M | Caucasian | United States | NA | Both were detected in the same nodule in the lung | KCZ/INH, RFP | NA | [ |
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3 | 51M | NA | Spain | Chronic epididymitis | Both were detected in CSF at almost the same time | AMPH-B, 5-FC/EB, INH, RFP, PZA | NA | [ |
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4 | 61F | Caucasian | NA | Waldenstrom’s macroglobulinemia | CSF, blood/cerebral tissue | NA/EB, INH, RFP, SM | Lost to follow-up | [ |
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5 | 34F | Asian | Saudi Arabia | NA | L4-5 vertebral abscess/right axillary lymph node | FLCZ/EB, INH, RFP, PZA | Recovered | [ |
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6 | 25F | Asian | Italy | NA | Both were detected in CSF from the same sample | FLCZ, L-AMB/EB, INH, RFP, PZA, SM | NA | [ |
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7 | 62 (on average) | NA | Taiwan |
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AMPH-B, 5-FC/EB, INH, RFP, PZA | Two patients died due to either of the two primary infections | [ |
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8 | 18F | Asian | Canada | NA | Mediastinal lymph nodes and CSF/right upper lung lobe | AMPH-B, 5-FC/EB, INH, RFP, PZA | Recovered | [ |
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9 | 65M | Asian | NA | NA | Both were detected in a large endobronchial mass | AMPH-B, ITCZ/NA | Lost to follow-up | [ |
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10 | 58F | Asian | Taiwan | NA | Left upper and right lower lung lobe/neck lymph node | FLCZ/NA | NA | [ |
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11 | 45F | NA | Turkey | SLE | Both were detected in CSF at almost the same time | AMPH-B, FLCZ, L-AMB/EB, INH, RFP, PZA | Discharged with neurological impairment | [ |
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12 | 65F | Asian | Japan | Diabetes | CSF/left upper lung lobe | AMPH-B, FLCZ/EB, INH, RFP, PZA | Died due to aspiration pneumonia | [ |
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13 | 56M | Asian | Japan | Diabetes, liver cirrhosis | Lung/lung (multiple nodules) | NA/INH, RFP, PZA, LVFX | Died due to hepatocellular carcinoma | [ |
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14 | 83F | Asian | Japan | Rheumatoid arthritis, diabetes | Lung (revealed in autopsy)/lung, CSF, urine, and stool | No treatment/EB, INH, RFP, PZA | Died due to respiratory and heart failure | [ |
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15 | 64M | Asian | Japan | Interstitial pneumonia | Skin, CSF, lungs, pleural membranes, prostate gland/right lower lung lobe, and right pleural effusion | FLCZ, 5-FC, L-AMB, VRCZ/INH, LVFX, AMK | Died due to respiratory failure | Present case |
NA: not available, SLE: systemic lupus erythematosus, CSF: cerebrospinal fluid, L4-5: the 4th and 5th lumbar vertebrae, AMPH-B: amphotericin B, INH: isoniazid, SM: streptomycin, KCZ: ketoconazole, RFP: rifampicin, 5-FC: 5-fluorocytosine, EB: ethambutol, FLCZ: fluconazole, L-AMB: liposomal amphotericin B, PZA: pyrazinamide, ITCZ: itraconazole, VRCZ: voriconazole, LVFX: levofloxacin, and AMK: amikacin.
In April 2012, a 64-year-old man previously diagnosed with interstitial pneumonia presented to a local hospital, complaining of increasing dyspnea over the preceding 3 months. Because exacerbation of his interstitial pneumonia was considered, the patient was hospitalized and 60 mg/day oral prednisolone (PSL) was administered. As his dyspnea improved, the PSL dose was tapered by 5 mg every 4 weeks following discharge.
On September 2, almost three months after discharge, the patient suddenly developed a fever around 38°C and felt intermittent pain in his left lower leg. At that time, he was taking 25 mg of PSL daily. Although he developed steroid diabetes, his HbA1c levels were controlled within the normal range. When he presented to the emergency room of our hospital, his left lower leg had a localized reddish appearance and was slightly edematous without snowball crepitation. Although his consciousness was slightly impaired (Glasgow Coma Scale; E4V4M6), a cerebrospinal fluid (CSF) test without India ink staining was normal. Blood culture tests turned out to be negative. He was hospitalized with a diagnosis of acute bacterial cellulitis.
After admission, the patient received intravenous meropenem. His fever subsided and his mental status returned to normal within days. On day 23 after admission, his leg was no longer swollen or reddish, but the localized pain had not completely disappeared. In order to rule out malignancy and collagen vascular diseases, a skin biopsy of his left ankle was done, and it revealed
Major test results of CSF, blood, and sputum.
Day 1 | Day 30 | Day 49 | Day 70 | ||
---|---|---|---|---|---|
CSF | Pressure (cmH2O) | 13 | 5 | 6 | 10 |
Cell numbers/ |
7 | 12 | 9 | 3 | |
(mono) | 5 | 12 | 9 | 3 | |
|
2 | 0 | 0 | 0 | |
Cryptococcal antigen | N/A | N/A |
|
256 | |
India ink stain | N/A |
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N/A | N/A | |
Cryptococcal culture | N/A |
|
N/A | N/A |
Day 23 | Day 30 | Day 38 | Day 72 | Day 78 | Day 91 | ||
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Blood | QFT | Negative |
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Cryptococcal antigen |
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CMV antigenemia | Negative | Negative | Negative | ||||
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Sputum | Acid-fast staining | Negative | Negative | Negative |
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Negative | |
TB culture | Negative | Positive |
Positive |
|
Negative | ||
TB PCR | Negative | Negative |
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Negative | ||
Cryptococcal antigen |
|
Bold parts: the results became positive while the patient was alive.
QFT: QuantiFERON TB-2G test; NA: not available.
A chest computed tomography (CT) scan taken on day 20 showed that a consolidation in the right upper lung lobe had increased from approximately 25 mm to approximately 40 mm in size (Figures
Serial changes in chest computed tomography findings. (a) Computed tomography (CT) scan taken 3 months before admission, showing reticular opacities and small cystic airspaces predominantly in subpleural regions. Mediastinal emphysema is also visible. (b) CT scan taken at admission, showing minimal mediastinal emphysema without major signs of pneumonia. Small centrilobular nodules are visible in the right upper lobe (arrowhead). (c) CT scan taken on the 20th day of hospitalization, showing consolidation in the right upper lobe (arrowheads). (d) CT scan taken on the 77th day of hospitalization, showing increased consolidation size with emergence of diffuse ground-glass opacities in both lungs.
Nevertheless, the patient developed acute kidney failure and watery diarrhea possibly due to the L-AMB and 5-FC treatments, respectively. On day 50, we discontinued L-AMB and 5-FC and started the patient on 400 mg/day of oral fluconazole (FLCZ). When we confirmed that the side effects had abated, we added L-AMB again (Figure
Clinical course. PSL: prednisolone, mPSL: methylprednisolone, L-AMB: liposomal amphotericin B, 5-FC: 5-fluorocytosine, FLCZ: fluconazole, VRCZ: voriconazole, DRPM: doripenem, PIPC/TAZ: piperacillin/tazobactam, INH: isoniazid, LVFX: levofloxacin, AMK: amikacin, BT: body temperature, KL-6: sialylated carbohydrate antigen KL-6, and CRP: C-reactive protein.
On November 20 (day 77), the patient had a fever over 40°C and severe oxygen desaturation. A CT scan revealed diffuse ground-glass opacities in both lungs, which suggested acute exacerbation of interstitial pneumonia (Figure
The autopsy results were as follows. The lungs had developed significant fibrosis with honeycombing, particularly in the lower lobes. There were areas with diffuse alveolar damage characterized by dense infiltration of inflammatory cells and hyaline membranes. These findings were consistent with the clinical diagnosis of exacerbation of interstitial pneumonia.
Because the patient had no known factors for immunosuppression other than prolonged steroid treatment, serum levels of autoantibodies against interferon-
We present a case of disseminated cryptococcal infection in a non-HIV patient who had received systemic corticosteroids for several months prior to admission. Consolidation in the right upper lung lobe, which was first considered to be a primary focus of cryptococcal infection, grew in spite of antifungal treatment and was revealed to be tuberculosis during pathological examination. Although combination therapies targeting both cryptococcosis and tuberculosis seemed effective, the patient developed fatal multiple organ failure following acute exacerbation of interstitial pneumonia. The present case indicates that multiple pathogens should be considered for opportunistic infections in patients undergoing prolonged steroid therapy.
Serial changes in the CT appearance and laboratory tests as well as the autopsy findings indicated that this patient might have developed pulmonary infection within only three months due to three different pathogens:
Although cryptococcosis and tuberculosis are both known to occur in immunocompromised hosts, there have been limited reports regarding concurrent cryptococcosis and tuberculosis infections [
The present case also involved steroid-induced diabetes, which might have contributed to the development of the infection. We considered that, in addition to the prolonged corticosteroid treatment for interstitial pneumonia, there might have been a host factor that increased susceptibility to infection. It has been reported that neutralizing anti-IFN-
In this case, the tuberculosis diagnosis was delayed because a newly developed lung consolidation was presumed to be focal pneumonitis due to
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Dr. Takuro Sakagami of the Department of Medicine II and Dr. Koh Nakata of the Bioscience Medical Research Center, Niigata University Graduate School of Medical and Dental Sciences, for measuring serum levels of autoantibodies against IFN-