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was withdrawn; urine volume was normal, and SCr was 133.9 μmol/L.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.