The Third Stage
On May 29, the patient suddenly developed purulent and blood-tinged sputum without fever or dyspnea. Urine volume reached 1500 ml with diuretics, urine color was normal, and SCr before dialysis was 211 μmol/L. ESR and serum CRP were normal. Although p-ANCA was still positive with an immunofluorescent technique, MPO antibody concentration was already below 20 units/ml. Plasma C3 and C4 concentrations were unchanged, and both serum procalcitonin and the T-SPOT.TB test were negative. Chest X-rays revealed no specific findings (Fig. 3). One day later, sputum culture revealed growth of Mucor species, and the serum (1-3)-β-D-glucan concentration had increased to 504.2 pg/ml. Chest CT was repeated and showed a solid nodule with cavitation in the dorsal segment of the left lower lobe (Fig. 4). In light of the improvement in the other activity indicators, pulmonary mucormycosis was believed to be present rather than contamination, although the sputum sample was not obtained using bronchoscopy. According to the drug sensitivity testing results, amphotericin B liposomes (LAMB) were administrated intravenously. The initial dosage was 10 mg per day (May 30), and the dose was increased by 5 mg every other day to 50 mg per day. The cumulative dosage was 2.0 g, with 2 months’ treatment duration. In the first 3 days, cetirizine and acetaminophen were used to prevent allergic reactions. The treatment protocol was well tolerated, and the patient expressed no discomfort, such as shivering, fever, or arthralgia. By June 4 (5 days later), the expectoration had resolved. Two weeks later (June 12), chest CT revealed that the cavitary wall had thinned significantly although the lesion’s extent appeared wider (Fig. 5). Four weeks later (June 27), the lung lesion and its internal cavity had shrunk (Fig. 6). At the end of treatment, sputum culture was negative, the nodular lesion had disappeared, and only a cystic air space remained (Fig. 7). No LAMB-related nephrotoxicity was seen. On July 28, dialysis was withdrawn; urine volume was normal, and SCr was 133.9 μmol/L. However, plasma C3 and C4 concentrations remained low (32.6 mg/dl and 1.56 mg/dl, respectively). The patient was discharged from hospital with 20 mg prednisone per day and 75 mg CsA twice a day.
Discussion and Conclusion
Mucormycosis is a rare, highly aggressive, and usually fatal infection[4], which in humans is mainly limited to hosts with risk factors, such as hematologic diseases, organ transplantation, severe immunosuppression, diabetes mellitus, renal failure, solid tumors, and malnutrition[5-6]. The clinical forms may be cutaneous, rhinocerebral, pulmonary, and disseminated infections[5,7]. Our patient had several risk factors (diabetes mellitus, progressive renal dysfunction, and immunosuppressive treatment); however, few patients with AAV have been reported with acquired Mucor species infections. Treatment-related factors might have played an important role in our patient’s clinical course. First, given her age, we hoped to use lower doses of corticosteroids to control disease activity, initially[8]. Her symptoms improved after 80 mg/d methylprednisolone for 3 days, and the dosage was decreased by half with intravenous CTX. This tapering regimen was hasty, which might have contributed to her disease relapse, resulting in a larger cumulative dose and longer exposure time. Second, the CTX dosage was higher than the recommended guidelines. The latest kidney disease improving global outcomes (KDIGO) guideline draft suggests an intravenous dose of CTX of 10 mg/kg for 70-year-old patients at weeks 0, 2, 4, 7, 10, and 13. Therefore, 600 mg CTX may be more appropriate than 400 mg for 2 consecutive days. On May 27, leukopenia occurred (peripheral blood leukocyte count: 3.26 × 109/L), and the lymphocyte absolute value was 0.34 × 109/L, in which the cluster of differentiation 4 (CD4) cell count was less than 50/μl. These findings were associated with the Mucor species infection. Garcia-Vives, et al.[9] retrospectively analyzed 132 AAV patients and found that leukopenia was the only factor independently related to opportunistic infections. Third, broad-spectrum antibiotic use also increased the risk of fungal infection. Although trimethoprim-sulfamethoxazole and acyclovir can be used to preventPneumocystis carinii pneumonia and cytomegalovirus infection, respectively, in immunocompromised patients, there are no effective preventive measures for deep fungal infections. Our patient received nystatin gargling twice a day, which failed to prevent fungal infection.Mucor species are widely distributed in nature; intensive air purification might be helpful.
Lin et al.[10] retrospectively reviewed the clinical data of 35 patients with pulmonary mucormycosis. The authors reported that common presenting clinical findings were fever, neutropenia, dyspnea, and cough, and that the radiologic findings were pleural effusion and nodules. Our patient had an emerging pulmonary nodule, but no fever or dyspnea, which might have resulted from the use of CsA.
Calcineurin plays essential roles in the virulence and growth of pathogenic fungi[11]. Calcineurin mutation or inhibition confers a yeast-locked phenotype that is vulnerable to control by host macrophages. Additionally, concurrent bacteremia is the sole reported independent predictor of mortality[10]. Owing to antibiotic use, our patient did not develop bacterial infections; and in this sense, antibiotics may have been a double-edged sword.
Hemoptysis is related to the invasion of vessel walls by Mucorspecies[5]. One study reported that mucormycosis could cause arterial thrombosis and thrombotic microangiopathy[12]. Vasculitis can also lead to pulmonary nodules and hemoptysis; hence, distinguishing between infection and disease activity is essential. However, the early diagnosis of pulmonary mucormycosis is difficult[13]. With a high level of suspicion, chest CT is more useful than plain X-rays. Monitoring galactomannoglycan (GM), and polymerase chain reaction (PCR) and antibody testing may also be helpful[5]. Finally, clinicians should remain vigilant in high-risk patients.
Initially, with our patient, the paradoxical subjective symptoms and objective indicators were confusing. On the first day of hospitalization, the patient’s Birmingham vasculitis activity score (BVAS)[14] was 16 compared with 10 after the CTX infusion, which suggested that AAV disease activity had decreased. However, the patient’s later condition revealed that this was not the case. BVAS may be more often used to assess the disease activity at diagnosis [2]. In our patient, SCr increase fell behind symptom deterioration for several days. Therefore, the combined dynamic assessments of symptoms, signs, and additional examinations are more important than individual indices, especially during immunosuppressive treatment. Indeed, it was a limitation that kidney biopsy was not obtained, in this case.
This patient had significant hypocomplementemia. In the past decade, several studies have suggested that the complement system is involved in the pathogenesis of AAV[15]. However, nearly all evidence suggests an alternative pathway[15-16]. Plasma C3 and C4 concentrations were both obviously decreased in this patient. Although the role of C4 remains to be researched, a retrospective cohort study has shown that patients with low C3 or C4 experienced increased renal damage[17]. Hypocomplementemia may be involved in our patient’s protracted disease course and in developing the opportunistic infection.
Disease activity and treatment-related toxicity are the most important prognostic factors for patients with AAV. However, their clinical manifestations are often very confusing, and it is a great challenge for physicians to distinguish uncontrolled disease from treatment-related complications. Constant alertness and vigilance are needed during the entire treatment course.