Rhizopus microsporus (R. microsporus) lung infection is an invasive fungal disease with high mortality that is increasingly common in immunocompromised patients. However, it is very rare in immunocompetent patients. Here, we present the case of a 19-year-old girl who developed R. microsporus lung infection without any known immunodeficiency.

The patient presented to our hospital because of hemoptysis and irritative cough without expectoration. She was first treated for community-acquired pneumonia until the detection of R. microsporus in bronchoalveolar lavage fluid by metagenomics next-generation sequencing (mNGS). After a combination therapy of intravenous inhalation and local airway perfusion of amphotericin B, she eventually recovered, with significant absorption of lung infections.

Early diagnosis and treatment are very important for pulmonary mucormycosis. Compared to fungal culture, mNGS is a relatively precise and convenient method to obtain pathogenic results. A combination therapy of intravenous inhalation and local airway perfusion of amphotericin B may be a promising strategy for the treatment of pulmonary mucormycosis in the future.

Due to advancements in the diagnosis and treatment of immunosuppressed diseases, an increasing number of clinicians are aware of Rhizopus microsporus (R. microsporus) lung infection in immunocompromised patients. Rhizopus belongs to the zygomycotina and is also the most common species that causes pulmonary mucormycosis[1,2]. R. microsporus lung infection is more common in people with immunodeficiency diseases, especially in diabetic patients with poor blood sugar control and patients with hematological malignancies. It is also common in patients using immunosuppressive agents after transplantation to prevent transplant rejection. If not treated in time, the mortality rate is as high as 70%-100%[3]. A retrospective study in 2019 revealed 851 patients with mucormycosis from 2000 to 2017[4]. In that study, diabetes was the most common underlying disease (340/851, 40%), and pulmonary mucormycosis (172/851, 20%) was the third most common clinical manifestation. A total of 447 (53%) cases of certain Mucorales organisms were identified by culture, and R. microsporus (213/447, 48%) was the most common pathogen.

Mucormycosis in immunocompetent patients is rare and is easily ignored by clinicians. In the current study, we report a rare case of pulmonary R. microsporus infection in an immunocompetent young patient. Depending on the early pathological results via percutaneous lung puncture and pathogenic conclusions from metagenomics next-generation sequencing (mNGS), we avoid misdiagnosis and buy much time for the subsequent successful treatment of the patient.

Rhizopus microspore lung infection.

Surgical resection is indeed one of the important therapies to deal with Rhizopus infection. We made consultation with the thoracic experts. Considering that the operation may be traumatic, and the patient’s parents disagreed with the lobectomy. Therefore, we started medical treatment. According to the Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers (the 6^th revision), amphotericin B (AmB) for injection (5 mg intravenous daily, then gradually increased to 120 mg daily) was administered as antifungal treatment 5 d after admission, and intravenous antibiotics were stopped. As a result, after 12 d of antifungal treatment (intravenous AmB for 120 mg daily), the hemoptysis and cough of the patient were suspended, and the white blood cell count decreased to 8.26 × 10⁹/L (reference interval: 4.0-10.0 × 10⁹). Although lung symptoms seemed improved, the patient began to experience severe nausea and vomiting with hypokalemia. Considering both the effectiveness and safety, a treatment combining intravenous and inhaled AmB was performed. The intravenous dose of AmB was adjusted to 60 mg daily, combined with inhalation of AmB 10 mg twice a day. After administering antiemetic therapy and potassium supplementation at the same time, the patient's digestive symptoms gradually improved.

On March 3, 2021, after 30 d of antifungal treatment, chest CT showed a decrease in lung inflammation and an absorption of cavitation in the right lower lobe (Figure 3B). Perfusion with AmB (10 mg dissolved in 10 mL saline) on the basal segment of the right lower lobe was then tried three times through a microtube in an electronic bronchoscope on March 4, March 11, and March 21 (Figure 2B). A slight improvement of the swollen mucosa of the right lower lobe was observed after the treatment, and no secretions were found in the local airway.

Prior to discharge, the patient received an alternative therapy to posaconazole oral solution (400 mg twice daily) according to a Chinese expert consensus on the clinical use of posaconazole.

Significant absorption of lung infections was observed at the chest CT follow-up on April 15, 2021 (+ 80 d) (Figure 3C).

R. microsporus lung infection is rare in immunocompetent patients and seldom reported[5-11]. In a study in 2009, 24 patients with proven or probable pulmonary mucormycosis at Peking Union Medical College Hospital from January 2005 to December 2018 were retrospectively analyzed, and seven patients (29.2%) had no obvious predisposing risk factors[12]. Although some of these patients had normal immune function, they shared an environmental exposure history with mucor spores such as decaying food, soil, and animal excrement[1], which might be the diagnostic basis for pulmonary mucormycosis. In contrast, in the case that we reported, the patient was a 19-year-old young female student who usually lived on campus without any underlying diseases, weakened immune function, or mucor-related environmental exposure history. The patient was treated at another hospital for a period of time, accompanied by a prolonged course and nonabsorbable lung lesions. Invasive examinations, such as percutaneous lung puncture and electronic bronchoscopy, were tried promptly. The pathologic findings of mucor hyphae and the mNGS results both resulted in the conclusion of R. microsporus pulmonary infection. Commonly, pulmonary mucor infection lacks specificity in imaging and is variable. Techniques to determine infection by Aspergillus or Mucor based on the histopathological features of hyphae are not completely reliable[13]. Other clinical clues that suggest pulmonary mucormycosis rather than aspergillosis include concurrent sinus, previous voriconazole therapy, the presence of more than ten lesions, and the presence of pleural effusion for imaging findings[14]. None of the above abnormal manifestations were observed in this patient. On chest radiography, lobar and segmental consolidation is the most common imaging finding, and imaging in some patients shows a multilobar distribution[15], which is consistent with our case.

Prompt initiation of appropriate therapy is critical for patients with pulmonary mucomycosis[16]. A study also found that early intervention may lead to better outcomes[17]. Although histopathology will probably remain the gold standard for the diagnosis of mucormycosis[18,19], obtaining a biopsy specimen is not always feasible in most vulnerable populations. Moreover, the distinction between aspergillosis and scedosporiosis and between aspergillosis and fusariosis and certain mucormycosis from tissue sections may be difficult or impossible[20]. However, the clinical distinction between aspergillosis and mucormycosis is crucial since there is an increased incidence of mucormycosis in patients treated with voriconazole for suspected aspergillosis[21]. In recent years, mNGS methods have been used to try to improve the detection and identification of pathogens and have become a topic of concern as routine pathogen identification tools[22]. In our case, the identification of Rhizopus microspores in BALF by mNGS was achieved in the early stage. Considering that antibiotic treatment was ineffective in this patient and mNGS did not indicate other bacterial or viral infections, we made a final diagnosis of lung infection of Rhizopus microspores for the young immunocompetent patient. Unfortunately, we failed to obtain positive culture results from lung puncture specimens, which might be related to insufficient amounts or redundant necrotic contents of the specimens. However, early anti-mucor treatment was started immediately, which eventually led to an overall good therapeutic effect.

AmB is commonly used for the treatment of mucormycosis of the lung, and other optional drugs include posaconazole and isaconazole[17,23]. In addition to intravenous use of AmB, inhalation of AmB has been used in the clinic[24] and has the advantages of high local concentration and low systemic side effects. For the application of AmB in the local airway through bronchoscopy, there is still a lack of clinical reports. We initiated treatment with AmB in the early stage, with a combination therapeutic strategy of intravenous inhalation and local airway perfusion, followed by sequential posaconazole oral administration, which eventually brought about a satisfactory therapeutic effect with the absorption of lung lesions. However, there is not enough evidence for perfusion by AmB through the local airway. The advantage of this method is that it can be used for the precise treatment of local mucormycosis lesions. At the same time, the local drug concentration is higher compared with systemic use and less irritating to other nonfocal areas. The disadvantage is that it is limited by the patient's conditions and technical conditions of the medical team, and the patient is required to treat through bronchoscopy repeatedly, which means the requirement of a certain degree of compliance. To date, perfusion with AmB in the local airway might be safe and feasible, accompanied by small adverse effects. It can be used in combination, alternately or sequentially, with intravenous and inhalation therapy, although the prognostic efficacy needs further follow-up.

R. microsporus lung infection in immunocompetent patients is rare, which reminds clinicians to be alert to the potential risk of Rhizopus infection in these patients. Considering the high mortality rate of the disease, early diagnosis and treatment are very important for the prognosis of patients. In our clinical practice, a combination strategy of intravenous inhalation and local airway perfusion of AmB may be a new strategy for the treatment of pulmonary mucormycosis.