Aspergillosis and Oxalate Crystals

Association of crystals and disease: In 1973, Nime and Hutchins reported the presence of oxalate crystals associated with aspergillus in an acute, cavitating pneumonia [1]. The patient also had renal failure from tubular obstruction by the crystals. The authors reviewed 68 autopsied cases of aspergillus infection and found the crystals in 11 (16%). Although several aspergillus species were thought to be A. niger, based on the pigmented conidia, one of 6 cases with A. fumigatus cultured from the lesion also showed the crystals (but in lesser numbers). In 1975, in vitro studies showed that A. niger produced oxalate from citrate in the tricarboxylic acid cycle [2]. In the same year, the crystals were definitely identified as calcium oxalate by X-ray diffraction [3]. Now, identification is based on the rosette-like or wheat-sheaf-like appearance and bright birefringence with polarized light [4].

Diagnostic usefulness of oxalate crystals: Other reports have noted the usefulness of finding these crystals in sputum specimens, pleural fluid, bronchial washings, and lung biopsies, where they herald the finding of aspergillus [5]. Although most reports cite A. niger, which may cause black sputum, a black exudate on the bronchial mucosa [6], or black pleural fluid [7], as the cause, other species have also been implicated. Farley, et al. examined cytologic specimens from 65 patients with sputum cultures positive for aspergillus and found that 11 (17%) had oxalate crystals [4]. A. niger was cultured from 5, A. flavus from 4, and A. fumigatus from 1. Sixty control subjects, 29 with other fungal infections, showed no oxalate crystals. They noted that tissue sections from patients with fungus balls and crystals showed a foreign body reaction to the crystals. Also, crystals could be present for years before cultures became positive.

Hypocalcemia with acute oxalosis: In a recent report, a 63-year-old, non-immunocompromised man with emphysema was treated for a RUL pneumonia [8]. Multiple cavities developed in the opacified lung. The BUN and creatinine levels rose, and urine showed 1+ protein and a few RBCs. Serum calcium was 6.2 mg/dl. A sputum culture yielded aspergillus and candida. A c-ANCA, confirmed with a positive antibody to proteinase-3, suggested the diagnosis of Wegener's granulomatosis. The patient died on the third hospital day before any therapy was given. At autopsy, he had a cavitating, aspergillus pneumonia (A. niger was cultured), and the renal failure was caused by crystals of calcium oxalate. The authors speculated that the low serum calcium was caused by the formation of calcium oxalate from the aspergillus-produced oxalic acid and endogenous calcium. They also speculated that calcium oxalate-iron complexes (see below) may have been instrumental in causing the formation of the antineutrophil cytoplasmic antibodies.

Ghio, el al. noted a large number of oxalate crystals in a fungus ball from a patient with A. niger and wondered if the crystals contributed to inflammation [9]. They found that the crystals can form a coordination complex with ferric ion both in vivo and in vitro and speculated that with superoxide anion or H2O2 from the respiratory burst of macrophages, the complex could generate oxidants that cause inflammation:

The theory is intriguing, but in vivo effects have not been demonstrated. Our patient had many crystals in the walls of muscular arteries in and around the area of inflammation, but there was no evidence of destruction of the vascular walls. Furthermore, the crystals in our patient were found in sections of normal aortic wall, in normal lung adjacent to the gangrenous area, and in the kidney, where effects are believed to be mechanical. There was no inflammatory reaction to the crystals. Furthermore, the crystals are a frequent finding in normal thyoid gland colloid.

Figure: A section of kidney from the present patient (left) shows crystals in tubules (arrow) but not elsewhere. Polarized light (right) shows more crystals than are visible with ordinary light. The serum calcium level of our patient fell to 5.8 mg/dl 3 days before he died. It is possible that the oxalic acid was responsible for part of the hypocalcemia, but he also had a focus of pancreatitis with fat necrosis. The free fatty acids liberated in that process could also have bound calcium to cause the hypocalcemia. Although part of this man's terminal renal failure may have been caused by hypotension, oxalosis was a contributing factor. No aspergillus was present in the kidneys.

References

1. Nime F, Hutchins G. Oxalosis caused by aspergillus infection. Johns Hopkins Med J 1973; 133:183-194.

2. Müller H-M, Frosch S. Oxalate accumulation from citrate by Aspergillus niger. II. Involvement of the tricarboxylic acid cycle. Arch Microbiol 1975; 104:159-162.

3. Kurrein F, Green G, Rowles S. Localized deposition of calcium oxalate around a pulmonary Aspergillus niger fungus ball. Am J Clin Pathol 1975; 64:556-563.

4. Farley M, Mabry L, Muñoz L, Diserens H. Crystals occurring in pulmonary cytology specimens. Association with aspergillus infection. Acta Cytol 1985; 29:737-744.

5. Reyes C, Kathuria S, MacGlashan A. Diagnostic value of calcium oxalate crystals in respiratory and pleural fluid cytology. A case report. Acta Cytol 1979; 23:65-68.

6. Kimmerling E, Fedrick J, Tenholder M. Invasive Aspergillus niger with fatal pulmonary oxalosis in chronic obstructive pulmonary disease. Chest 1992; 101:870-872.

7. Metzger J, Garagusi V, Kerwin D. Pulmonary oxalosis caused by Aspergillus niger. Am Rev Respir Dis 1984; 129:501-502.

8. Cho C, Asuncion A, Tatum A. False-positive antineutrophil cytoplasmic antibody in aspergillosis with oxalosis. Arch Pathol Lab Med 1995; 119:558-561.

9. Ghio A, Peterseim D, Roggli V, Piantadosi C. Pulmonary oxalate deposition associated with Aspergillus niger infection. An oxidant hypothesis of toxicity. Am Rev Respir Dis 1992; 145:1499-1502.

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