Complications of PAP include opportunistic infections, interstitial fibrosis, and rare instances of emphysematous bullae and pneumothorax . Infections associated with PAP may precede, follow or may also present in concurrence. PAP was reported as the initial presentation in 33% patients as seen in our patient . Majority of the infections were reported in adults with a mean age of 39 years and male predominance . Our patient was a 7-year-old female child.
First extensive review of infections in patients with PAP was done by Seymour et al. who reported that majority were by Nocardia followed by Mycobacteria, Cryptococcus, Histoplasma, Aspergillus, and others . Punatar et al. in 2012, reviewed a total of 75 cases from 1950 to July 2010 and identified Nocardia (43%) as the most common pathogen followed by mycobacteria (37%) and fungi (20%) . Of the 15 cases of fungal infections in their study, 5 were due to Cryptococcus and 4 each due to Aspergillus and Histoplasma. The most common site of infection was lung followed by the brain . CNS involvement was seen usually in disseminated cases . Our patient had cerebral Aspergillus abscess as the sole manifestation 7 months after the diagnosis of PAP.
Cryptococcosis is the most common infection reported in association with PAP; however, the other fungal infections include those due to Aspergillus, Histoplasma, Mucor, Blastomyces Coccidioides, and Pneumocystis [1, 2, 9, 11, 12]. They are all mycoses controlled by macrophages upon inhalation . Susceptibility to infections is found to be multi-factorial. Possible causes include impaired macrophage function and impaired host defense . When autoantibodies block the GM-CSF pathway, differentiation and function of alveolar macrophages are impaired and the ability to clear surfactants is diminished [2, 11, 12]. As a result, pulmonary alveoli accumulate periodic acid-Schiff (PAS)-positive proteinaceous surfactant components which act as a medium for infection [2, 11, 12]. Since autoantibodies to GM-CSF cause defects in chemotaxis, adhesion, phagocytosis, microbicidal activity, and phagolysosome fusion of alveolar macrophages, patients with PAP are at risk for infections from a variety of respiratory microorganisms including fungal species [2, 11, 12]. In our patient, screening for mutations of surfactant protein or assay for GM-CSF autoantibodies was not done. Corticosteroids were administered after the diagnosis of PAP and possibly it would have augmented the risk for opportunistic infection with Aspergillus.
The first case of CNS aspergillosis in a patient with PAP was described by Björkholm et al. . Kourkoumpetis et al. reported 14 cases of CNS aspergillosis and reviewed 123 reported cases from literature . In their report, CNS aspergillosis was associated with a wide variety of co-morbidities including diabetes mellitus, human immunodeficiency virus infection, hematological malignancies, transplant, etc., but none with PAP. Neutropenia was found to be a major contributor to the pathogenesis . However, in the present case, the patient did not have neutropenia. Qualitative rather than quantitative defect in neutrophilic function may be attributed to the opportunistic infections . Diagnosis of CNS aspergillosis is difficult as the clinical symptoms are non-specific . Our patient was initially diagnosed to have CNS tuberculoma on MRI and was treated with ATT before she underwent surgery. Aspergillus fumigatus was found to be the most common pathogen in CNS Aspergillosis as seen in our patient [14, 15]. Mortality rate was high in patients with CNS aspergillosis (28% in who underwent neurosurgery and 67% in who did not undergo neurosurgery) . However, Dotis et al. reported that there is a significant difference in mortality in cases reported before and after 1990 (82% and 39% respectively) which can be attributed to the introduction of amphotericin B and aspergillus sensitive azoles like voriconazole . Our patient underwent surgical excision and received voriconazole and stable at 1 year follow-up.