Abstract
Patients on immunosuppression are at risk of unusual infections. We present a man diagnosed to have adult-onset Still's disease who, on high-dose oral steroid and tacrolimus, developed a cavitating pneumonia due to co-infection with Aspergillus flavus and Nocardia. Timely diagnosis and institution of appropriate therapy resulted in a favourable clinical outcome. Such co-infection in a patient receiving tacrolimus is rare in the published literature. This case serves to emphasise the need to be vigilant for unusual infections in patients who are immunosuppressed, either due to drugs or underlying disease condition.
Background
Patients on immunosuppressive medication are at risk of acquiring unusual infections. Nocardiosis usually occurs in the context of corticosteroid or other immunosuppressant use, haematological malignancies, HIV infection or transplant recipients; infection may be limited to lungs or it may undergo systemic dissemination involving brain, skin and soft tissues.1 Risk factors for Aspergillus infection include prolonged corticosteroid usage, T-lymphocyte immunosuppressants, neutropaenia and haematopoietic cell transplant recipients; it can be localised to the lungs or may disseminate to other organs such as the central nervous system.2 Co-infection with Nocardia and Aspergillus is, however, extremely rare; we present a case of a man with a diagnosis of adult-onset Still's disease on high-dose steroid and tacrolimus, who developed pulmonary infection with these pathogens as an adverse effect of immunosuppression.
Case presentation
A 37-year-old man presented to us in August 2013 with a history of quotidian fever, symmetric inflammatory polyarthritis affecting the large joints of upper and lower limbs, sore throat, weight loss of 20 kg over the past year, associated with neutrophilic leucocytosis and negative antinuclear antibodies, and rheumatoid factor. His serum ferritin was markedly elevated (7000 ng/mL), erythrocyte sedimentation rate measured by Westergren method was 110 mm/h and serum C reactive protein was also high (12.8 mg/dL). A diagnosis of adult-onset Still's disease was made as per the Yamaguchi criteria,3 after excluding other causes of fever (bone marrow, CT of the thorax and abdomen, and echocardiography were normal; blood and urine cultures showed no growth). The patient had already been treated with prednisolone, methotrexate, sulfasalazine and hydroxychloroquine in combination (table 1) for 9 months without adequate symptom relief. Use of biological agents was not feasible due to financial constraint. P-glycoprotein expression on peripheral blood lymphocytes was increased, accounting possibly for the steroid resistance,4 hence the patient had been started on prednisolone 1 mg/kg/day (60 mg) and tacrolimus 5 mg/day. In addition to blocking the calcineurin pathway, tacrolimus also decreases P-glycoprotein expression, thereby possibly resulting in improved steroid responsiveness; this was the reason behind the choice of this drug.5 The patient developed deranged glycaemic status due to the steroids, and so was started on insulin. Serum tacrolimus trough levels were in the therapeutic range. With this, over the next 2 months, his joint pains and fever almost completely subsided and he was able to resume his job as an electrician.
Table 1.
Details of medications prior to presenting to us
| Medication | November 2012 | December 2012 | February 2013 | May 2013 | July 2013 |
|---|---|---|---|---|---|
| Prednisolone (mg/day) | 15 | 20 | 10 | 20 | 20 |
| Methotrexate (mg/week) | 15 | 15 | 20 | 20 | 15 |
| Hydroxychloroquine (mg/day) | 200 | 200 | 200 | 200 | 200 |
| Sulfasalazine (mg/day) | – | – | 1000 | 2000 | 2000 |
Two months after the first admission, the patient presented to us with a history of loose stools for 16 days, small in amount, 7–8 times a day, initially watery, later admixed with blood and mucus. In addition, he reported a left-sided pleuritic chest pain for the past 6 days. He reported a decrease in urine output for the day prior to admission. He did not have fever or any other systemic symptoms. Examination revealed mild pallor and dehydration; he had no tachycardia (pulse 80/min), hypotension (blood pressure 130/80 mm Hg) or tachypnoea (respiratory rate 18 breaths/min). Respiratory system examination revealed diminished air entry in the left lower chest; otherwise systemic examination was unremarkable.
Investigations
Haemogram was normal except for mild anaemia (haemoglobin 11.9 g%, total leucocyte count 5900/mm3, platelet count 157 000/mm3). Serum chemistry was normal (serum creatinine 1.3 mg%, serum albumin 3.5 g%, serum bilirubin 0.3 mg%, aspartate transaminase 5 U/L and alanine transaminase 26 U/L). Chest X-ray showed a well-defined nodular shadow in the left lower lung zone (figure 1A).
Figure 1.
Chest X-ray (A) on the day of admission showing well-defined nodular shadow in the left lower lung zone and (B) on day 10 after admission showing increase in left lower zone shadows, with the left middle zone shadow in the parahilar region becoming prominent. (C) Chest X-ray 4 weeks after starting therapy for Nocardia and Aspergillus, showing resolving left lower zone shadows, with the left middle zone shadow having disappeared. (D) Chest X-ray 4 months after starting therapy for Nocardia and Aspergillus, showing almost complete resolution of previous shadows.
Differential diagnosis
The patient likely had bacterial dysentery in view of the blood in the stools. Keeping this in context with the findings of decreased breath sounds in the left lower lung and the well-defined nodular shadow in the lower lung field, a possibility of Gram-negative bacteraemia originating from the gut and seeding the lung was entertained. However, odd for this was lack of features of systemic inflammatory response on examination (no fever, tachycardia, tachypnoea, hypotension) or investigations (no leucocytosis or thrombocytosis) as well as subacute onset over a period of 16 days. A plausible explanation was that systemic symptoms were masked due to high-dose steroid intake.
However, in view of the above mentioned oddities, as well as the patient's immunosuppressed state, possibility of unusual infections (eg, fungal or tubercular) had to be considered. Hence it was imperative to get a microbiological diagnosis.
Treatment
The patient was given broad spectrum antibiotic coverage with piperacillin-tazobactam and teicoplanin. With rehydration, his urine output improved on the first day of admission. His blood sugars were controlled with insulin. A CT of the chest (figure 2) was performed to further characterise the lung nodule—to our surprise, it showed consolidation with cavitation in the left lingual and left upper lobe, along with small nodules in the right lung parenchyma as well. Bronchoalveolar lavage cultures initially grew Escherichia coli and Pseudomonas sensitive to piperacillin-tazobactam, hence the medication was continued. In view of the multifocal cavitating lung nodules, echocardiography was used to look for endocarditis, but no structural abnormalities or vegetations were detected. Blood cultures were sterile.
Figure 2.
CT of the chest showing consolidation with cavitation in the left lingual and left upper lobe, along with small nodules in the right lung parenchyma.
By day 10 of admission, fungal cultures grew Aspergillus flavus (septate branching hyphae at acute angles), and by day 13, growth of Nocardia was also confirmed from the bronchoalveolar lavage fluid. Infection with Nocardia and Aspergillus was more consistent with the clinical picture. Also, on piperacillin-tazobactam for more than a week, the lung shadows in the left lower zone continued to increase, with the left middle zone shadow in the parahilar region becoming prominent (figure 1B). Hence piperacillin-tazobactam was stopped, and the patient was started on injectable amphotericin B (for aspergillosis) and injectable ceftriaxone with oral cotrimoxazole (for nocardiosis). Amphotericin B was given for 6 weeks, and then changed over to oral voriconazole to complete 2 months of antifungal therapy. Injectable ceftriaxone was given for a month. Subsequently, oral cotrimoxazole alone was continued for nocardiosis, with a plan to give total duration of therapy for 1 year.
Outcome and follow-up
With the above treatment regimen, the lung shadows showed gradual improvement over the next month (figure 1C), and after 4 months of treatment, had almost completely resolved (figure 1D). The steroid dose was gradually tapered, and at his most recent hospital visit after 9 months of treatment, the patient was completely asymptomatic. The adult-onset Still's disease was also in remission on 5 mg daily prednisolone and the patient had resumed work as usual.
Discussion
Table 2 was derived from a search on PubMed regarding data on co-infection with Nocardia and Aspergillus. Information available was limited by accessibility to full text of these articles. Eight such cases could be identified6–13; most of them were on a background of solid organ transplantation. A common theme identified was risk attributable to steroid therapy. It is to be noted that our patient was receiving high-dose steroid therapy. Timely diagnosis and appropriate combination therapy to target both the microbes, wherever possible, resulted in a favourable outcome. Tacrolimus therapy had not been previously reported to predispose to this unusual co-infection; also none of these reports were on a background of autoinflammatory disease such as adult-onset Still's disease.
Table 2.
Co-infection with Nocardia and Aspergillus—a review of the literature
| Reference | Year of publication | Country | Underlying disease | Immunosuppressant | Outcome |
|---|---|---|---|---|---|
| 6 | 1984 | USA | Chronic granulomatous disease | None | Not available |
| 7 | 1990 | USA | Renal transplant | Azathioprine 50 mg/day, prednisolone 15 mg/day | Fatal (diagnosis made postmortem) |
| 8 | 1993 | USA | Cardiac transplantation | Not available | Successfully treated |
| 9 | 2000 | Spain | Not available | Glucocorticoid | Not available |
| 10 | 2005 | The Netherlands | Near-drowning | None | Full recovery with liposomal amphotericin B, amikacin, meropenem and cotrimoxazole |
| 11 | 2008 | USA | Chronic graft-versus-host disease following haematopoietic stem cell transplant | Not available | Not available |
| 12 | 2008 | Saudi Arabia | Angioimmunoblastic T-cell lymphoma | Prednisolone, mycophenolate mofetil, alemtuzumab | Successfully treated with liposomal amphotericin B, amikacin and cotrimoxazole |
| 13 | 2010 | USA | Lung transplant | Not available | Not available |
The present case serves to highlight the need to have an open mind when encountered with infection in the setting of immunosuppression. A clue to unusual infection in this patient was lack of significant systemic inflammatory response (no fever, leucocytosis or thrombocytosis) in spite of multiple pulmonary cavitary lesions; the high dose of steroids could also have masked any constitutional symptoms. Early diagnosis and appropriate therapy resulted in a favourable outcome. This case serves to emphasise that unusual infections such as these need prolonged therapy (1 year in the case of nocardiosis) to prevent recurrence.
Learning points.
Unusual infections are more likely in a setting of immunosuppression.
A high index of suspicion for such infections should be maintained in a patient with obvious infection but lacking a robust systemic inflammatory response.
Steroid therapy is an important risk factor for infections.
Prolonged therapy may be needed for such infections.
Footnotes
Contributors: All authors were involved in conception and design, acquisition of the data, and analysis and interpretation of the data. DPM and ACC drafted the article; JRP and VA revised it critically for important intellectual content. All authors gave final approval of the version published.
Competing interests: None.
Patient consent: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed.
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