Should all tubercular cavities be left alone? Lessons from a heart transplant

Abstract

Fungal infection after solid organ transplantation poses a diagnostic and therapeutic challenge. We present the case of a 50-year-old man who underwent orthotopic heart transplantation for dilated cardiomyopathy with a history of treated pulmonary tuberculosis 10 years pre-transplant. One year post-transplantation, he was admitted with recurrent productive cough and was evaluated to have intracavitory aspergillosis of the lung. He was started on medical therapy with reduction in immunosuppression, but succumbed later with allograft rejection and multiorgan failure. Management of invasive aspergillosis in immunocompromised host is a real challenge. Management protocol should be individualised.

Introduction

Organ transplantation has evolved as a successful therapy for many end-stage diseases in humans. This indeed has increased the immunosuppressed population in the community who are vulnerable to opportunistic infections. Aspergillosis in transplant recipients has a high mortality rate. In heart transplant recipients, reoperation, need for post-transplant dialysis, cytomegalovirus infections and presence of Aspergillus species in respiratory secretions have been proposed as high risk for getting an invasive Aspergillus infection [1]. Aspergillosis is detected to be one of the most common invasive fungal infections after heart transplantation (69.8% of all fungal infections) [2] and mostly occurs within 3 months post-transplantation. It may get delayed beyond 6 months until when ganciclovir prophylaxis is continued for cytomegalovirus infection [3]. The mortality of invasive aspergillosis in heart transplant recipients is proven to be more than 50% and even reaches 100% when it involves the central nervous system [3].

Case report

A 50-year-old man underwent orthotopic heart transplantation for dilated cardiomyopathy. He had history of pulmonary tuberculosis 10 years before which was treated with a complete course of antituberculous therapy. His pre-transplant evaluation with X ray and computed tomography (CT) of the chest showed right upper lobe lung fibrocavitory lesion, and since the patient was asymptomatic, was passed off as post-tuberculous sequelae. During transplantation, bilateral pleurae were kept intact and he had an uneventful postoperative recovery. An endomyocardial biopsy performed at 1 month post-transplantation showed no signs of allograft rejection. He received antifungal and cytomegalovirus prophylaxis for an initial period of 3 months. At 1 year, he was readmitted with recurrent productive cough and detailed evaluation with a chest X ray (Fig. 1), and a computed tomography of the chest (Fig. 2) showed evidence of dependant fragments in the pre-existing cavity which was a new onset compared to his pre-transplant radiology. Since the radiological appearance of fragments in the cavity could not be confirmed as Aspergillus ball, we proceeded to a CT-guided saline instillation to the cavity and aspiration of the contents. The microscopy of sample revealed growth of Aspergillus flavus (Fig. 3).

Fig. 1.

Plain chest X ray showing fibrocavitory lesion right upper lobe

Fig. 2.

High-resolution computed tomography (HRCT) chest with cavity right upper lobe with dependent fragments

Fig. 3.

Lactophenol cotton blue mount of Aspergillus flavus

Simultaneously, his serum was detected positive for Aspergillus-specific IgE and IgG antibodies. His sputum sample failed to grow Aspergillus, and hence a diagnosis of intracavitory aspergillosis was made. Considering the localised nature of infection, it was discussed whether to insert a pigtail catheter into the right upper lobe cavity for daily amphotericin instillation, but due to the high risk of catheter-related sepsis in immunosuppression we avoided inserting the same. As patient was clinically stable, he was started on oral voriconazole therapy, and immunosuppressants were modified to a minimum dose of tacrolimus to keep the 12 h trough level at 3–5 ng/ml. He was hospitalised for 2 weeks and discharged at request for further follow up. Three weeks later, he was admitted in a local hospital with severe vomiting and fatigue and was transferred to our centre. He was evaluated to have severe biventricular dysfunction in echocardiography with deranged organ functions and low cardiac output. He was transferred to the intensive care unit and started on inotropic support, pulse steroid therapy (suspecting allograft rejection), intravenous broad spectrum antibiotics and amphotericin B. His blood cultures did not grow any organism, but he deteriorated clinically over the next few days and succumbed to the illness.

Discussion

Invasive aspergillosis still continues to contribute to high mortality in transplant recipients. A delay in diagnosing the condition is the main cause attributed to the same. Aspergillus can be isolated in only less than one third of sputum sample in patients with invasive aspergillosis, even broncho alveolar lavage (BAL) cultures will be positive in only half of them [4]. Detection of specific antibodies cannot be considered reliable in immunosuppressed patients [5], and radiological evidence can be considered only supportive. Hence, histopathological evidence becomes necessary to establish the diagnosis in such cases. Identification of specific fungal antigens or metabolites can also be useful in confirming the diagnosis with high specificity.

Regarding management, amphotericin, voriconazole and caspofungin have been used to treat invasive aspergillosis. Considering the superiority of voriconazole over amphotericin in invasive aspergillosis [6], our patient was started on voriconazole. Since the sputum was negative for Aspergillus, we refrained from aerosolised amphotericin therapy. Surgical resection is recommended in those pulmonary focus that are contiguous with heart, pericardium, vascular structures, extension to chest wall, presence of osteomyelitis, endocarditis or haemoptysis [7].Many advocate early lobectomy [8] to eliminate the source in such a setting, and opinions based on descriptive studies and expert advice also recommend surgical resection as preferred treatment in such situations (B III recommendation) [7].

Although consensus guidelines have been set for tuberculous infections after solid organ transplantation, no definite guidelines are available for patients with a post-tubercular fibrocavitory lesion existing at the time of transplantation. It is still a dilemma as to how to manage this damaged lung segment as it potentiates future development of fungal balls while on immunosuppression.

Adjunctive immunotherapy should be kept to a minimum or even discontinued in such situations as significant drug interactions exist between antifungals and calcineurin inhibitors. Azole antifungals, being inhibitors of CYP34A isoenzymes, tend to increase the serum level of tacrolimus and hence potentiate their nephro- and neurotoxicity. Hence, we modified the regimen to tacrolimus monotherapy with dose adjusted to keep a minimum acceptable 12 h trough level of 3–5 ng/ml. Caspofungin on the other hand is found to decrease the serum tacrolimus level by 20% [8]. Although invasive aspergillosis has been proved to increase incidence of acute as well as chronic rejection and reduce the 5 year survival rate in lung transplant recipients, the same has not been validated after heart transplantation.

In our country, pulmonary tuberculosis is so frequent that it may be considered an endemic disease. In a patient with past history of tuberculosis and radiological evidence of a fibrocavitory lesion, it is a regular practice to ignore a post-tubercular sequelae. But in those patients who undergo a solid organ transplant, a much aggressive approach has to be taken. It is always better to consider to resect the damaged lung in the same setting in order to avoid the possibility of a future aspergilloma during immunosuppressive therapy.

Conclusion

Pulmonary Aspergillus infection after cardiac transplantation carries a high mortality. In the absence of consensus guidelines for patients with a pre-existing tubercular lesion, management strategy needs to be individualised, and a decision for surgical resection along with medical therapy must be made judiciously to get optimal outcome.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

An informed consent was obtained from the relatives to publish the case details and images.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.