Clinical Meetings at RH Year 2008

2008 Clinical Meeting GH - A Man with Heart Failure

Drs Raymond FM LAM & PC WONG
TB and Chest Unit, Grantham Hospital

Introduction

Chronic necrotizing pulmonary aspergillosis CNPA is a chronic subacute, semi-invasive form of aspergillus lung infection. It most commonly affects diseased lungs and causes progressive parenchymal destruction with chronic cavitation.

The mainstay of treatment of this condition is antifungal drugs. Interventional therapy such as intracavitory amphotericin B and surgery can be used in selected cases. Itraconazole has been shown to be efficacious in the treatment of CNPA. However, the drug is also reported to cause various cardiovascular complications especially heart failure when it is used chronically for treatment of fungal infections 1.

We report a case of congestive heart failure without specific underlying cardiac illness that occurred during treatment of CNPA with itraconazole.

Case history

A 55-year-old male retired electrician presented with newly onset blood-stained sputum and occasional feverishness for 1 month. He also noticed subjective reduction in appetite, body weight and exercise capacity for 2 months. There was no chest pain, wheezing, ankle swelling, paroxysmal nocturnal dyspnoea or orthopnoea. Systemic enquiry was unremarkable.

He had history of diabetes mellitus and hypertension for 5 years. He was treated with metformin 1g BD, gliclazide 160mg BD and lisinopril 7.5mg QD. Both conditions were well-controlled. He had history of pulmonary tuberculosis in 2004 which was sputum culture positive with favourable drug susceptibility pattern. The main bulk of disease was at the right upper lobe. He was treated with 9 months of anti-TB treatment with good response except residual cavity and scarring at the right upper lobe (fig 1 and 2)

Sputum surveillance during follow up showed positive growth of Mycobacterium chelonae on 2 occasions after completion of anti-TB treatment. It was regarded as colonizer in view of no clinical symptom and no deterioration on chest radiograph.

He never smoked or abused alcohol or drugs. He had no specific contact or travel history.

Examination showed that he was not in distress. Jugular venous pressure was not elevated. There was no ankle edema. He weighed 60 kg. Vital signs were normal. There was no lymphadenopathy or clubbing. Chest examination revealed percussion dullness with bronchial breath sound at the right apex. Rest of the examination was unremarkable.

Complete blood counts were normal. Erythrocyte sedimentation rate 25 mm/hr. C-reactive protein less than 0.35 mg/dL. Urinalysis was normal. Serial chest radiographs showed parenchymal shadows over the right upper zone with some adjacent pleural thickening gradually worsening over a period of 1 month (Fig 3).

Fiberoptic bronchoscopy showed no endobronchial lesion. No abnormal secretion or bleeding was noted. Transbronchial biopsy of right upper lobe showed large aggregate of fungal hyphae in bronchial lumen associated with ulcerated and inflammed bronchial wall. On Grocott staining, the hyphae were septated and dichotomously branching, morphologically characteristic of Aspergillus species.

Sputum grew Aspergillus fumigatus persistently although bronchial aspirate for fungal culture was negative. CNPA was thus confirmed and he was started on itraconazole 400mgQD. His haemoptysis soon subsided.

Three weeks later, he complained of gradual worsening of shortness of breath on exertion. Exercise capacity had reduced to only 1 flight from 3 flights of stairs. Orthopnea, ankle and genitalia swelling were noted. There was no chest pain, cough, gastrointestinal upset or fever.

Physical examination revealed abnormally raised blood pressure up to 160/80 mmHg, raised jugular venous pressure, bilateral pitting ankle edema, and weight gain of 3 kg. Heart sounds were normal, no murmur was detected. Percussion dullness & inspiratory crackles were detected over both lung bases. ECG did not reveal any abnormality.

Routine blood tests were unremarkable. There was no renal function deterioration. Inflammatory markers had improved.

CXR showed bilateral pleural effusion, upper lobe diversion, Kerley’s lines [Fig 4]. The initial right upper zone changes had improved. A transudate was yield on tapping of the left pleural effusion. Echocardiography showed LVEF 55%, no focal hypokinesia, just mild mitral regurgitation and trivial tricuspid regurgitation. Coronary angiogram was normal.

He was treated as congestive cardiac failure (CHF) with diuretic. Repeated chest X-ray showed prompt resolution of the pulmonary congestion [Fig. 5]. In view of the temporal relationship of the CHF with itraconazole therapy, the drug was changed to voriconazole. After that, there was no recurrence of heart failure even without additional medications. The sputum for fungal culture showed persistent conversion from the 3rd months of therapy onwards.



Discussion

CNPA was first described in early1980’s by Gefter and Binder [2,3]. In both series, mortality was high despite drug treatment. The diagnosis is based on demonstration of septated hyphae typical of Aspergillus species invading lung parenchyma on biopsy specimens and positive Aspergillus culture. This usually means positive culture from a bronchopulmonary sample, eg. Lung biopsy, BAL, percutaneous lung aspirate, or sputum. Exclusion of other significant bacterial , fungal, or mycobacterial pathogens is also important. There is absence of, or presence of very little, vascular invasion, granulomatous reaction, and a low tendency for metastatic infection. Histological proof can usually be obtained in about 49% of the cases. When histology is not available, clinical diagnosis is based on compatible chest imaging findings and positive results or serologic tests for Aspergillus. Documented response to anti-fungal therapy is also important [3-5].

CNPA is usually associated with some specific risk factors eg, alcohol abuse, poor nutrition or DM, or an underlying lung disease eg, tubersolosis, bronchiectasis, lung fibrosis, thoracic irradiation or COPD, which is responsible for the presence of a residual cavity. These lead to deterioration in systemic or local immunity [6]. The greater the number of risk factors especially accompanied with hypoalbuminaemia and history of dual pulmonary mycobacteriosis, the higher the probability of a fatal outcome [7].

Treatment with amphotericin B (AMB) was unfavourable. Target dose is difficult to reach due to toxicity. Various successes have been reported for the use of high dose itraconazole in the treatment of this condition since late 1980’s [8,9].

Animal studies and early clinical studies indicate that itraconazole may exert negative inotropic effect, mechanism of this effect is not known. No published data on a possible association with heart failure exists for other related anti-fungal drugs such as ketoconazole & fluconazole.

Despite the presence of confounders, potential cases of CHF associated with itraconazole therapy have been noted [1,10]. Therefore, it is recommended that, for systemic fungal infections, the risks & benefits of using itraconazole should be reassessed if signs or symptoms of CHF develop.

Other cardiovascular adverse effects of itraconazole reported include hypertension, hypokalaemia, cardiac arrhythmia, pleural & pericardial effusions [11-15].

Our experience has alerted us that the cardiovascular adverse events associated with itraconazole are not an uncommon occurrence. Among 8 patients treated in our unit during January, 2005 to March, 2008, three developed congestive heart failure and 1 had hypertension while receiving itraconazole at 400mg daily. Patients with underlying cardiovascular risk factors like diabetes and hypertension are probably more vulnerable to the cardiovascular adverse effects of itraconazole. Therefore, thorough cardiac assessment should be considered in all patients started on itraconazole therapy. Baseline echocardiogram might be indicated in patients with underlying diabetes or hypertension and close monitoring of blood pressure is mandatory during therapy.

Like many studies on the complications of a treatment, our small patient numbers and presence of confounder are main problems. Exhaustive investigations to rule out other causes are important but may not be possible for every patient. Yet our observation serves to remind us the importance of close monitoring in the setting of itraconazole therapy for CNPA which usually lasts for months.

In the latest editions of the drug information, it is stated that itraconazole has been shown to have a negative inotropic effect and associated with heart failure. In healthy volunteers, a transient asymptomatic decrease of the left ventricular ejection fraction was observed after intravenous infusion. The clinical relevance of the finding to the oral formulation is unknown.

Therefore, itraconazole should be avoided in patients with in heart failure or history of heart failure unless benefit clearly outweighs its risk. An accurate diagnosis is very important to avoid overuse of the drug. When it is used, attention should be paid for detail baseline assessment, careful dosing and close monitoring during therapy. Other risk factors such as renal impairment, oedematous states, pulmonary disease, use of negative inotropic drugs [eg beta-blockers, calcium channel blockers] may also increase the risk of development of congestive heart failure during treatment. Benefit of using high dose should be balanced against its risk. The duration of high dose therapy should always be limited according to the clinical response.

Prompt treatment of heart failure and its contributory causes should be instituted when symptoms of heart failure are noted. Dosage reduction and changing itraconazole to other alternatives are appropriate options.

Voriconazole is a newer triazole which has good activity against aspergillus infections [4,16,17]. It has been shown to be effective in treatment of invasive aspergillosis and CNPA. It is also useful for patient who had treatment failure or intolerance to itraconazole. Common side effects include visual disturbance, gastrointestinal upset, and liver function derangement.

The echinocandins belong to a new class of anti-fungal agent. Only limited data are available for use of micafungin in combination with other agents [18,19].

There is no study addressing the role of surgery in CNPA despite being a possible option for patients who failed medical therapy. Due to significant risk, surgery is only contemplated in a small subset of patients with local infection with adequate cardiopulmonary reserve.

In conclusion, antifungal drugs remain the mainstay of treatment of CNPA and experience with high dose itraconazole treatment has been accumulated over years. It is not surprising to encounter some of the side effects that have not been emphasized previously. There may be a number of strategies in dealing with heart failure or other cardiovascular problems complicating itraconazole therapy. The diagnosis of CNPA and the response to treatment should be reviewed. Treatment cessation can be considered in those with high risk-benefit ratio. If continuation of treatment is more advisable, changing to alternative anti-fungal agent or reducing the dosage of itraconazole should be considered.

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