Chronic granulomatous disease

Botryomycosis is an uncommon chronic suppurative and granulomatous lesion. On histologic examination, fungal stains are negative but there is the presence of eosinophilic fungus-like "clubbing material" containing the causative bacterium in a suppurative focus.[1] There have been over 57 documented cases of integumentary botryomycosis,[2] but only 20 case reports of the primary visceral form of the disease.[3] In only nine of these patients has there been primary lung involvement.[4] While it has been suggested that primary pulmonary botryomycosis is the result of inadequate antibiotic treatment of a bacterial infection,[1] its etiology is not known.

The following case report describes a patient with pathologically proven primary pulmonary botryomycosis and demonstrates chronic granulomatous disease to be the underlying cause of the disorder in this individual. This case emphasizes the need to consider CGD in any patient with botryomycosis regardless of age or gender.

Case Report

The patient was well until 12 years of age when she developed a left upper lobe cavitating pneumonia with fevers, leukocytosis,and negative sputum cultures. Bronchoscopy was performed because of progressive of cavitation on chest roentgenogram after three weeks of empiric penicillin therapy. Culture results were negative for bacteria, fungi, and acid-fast bacilli. The patient was followed off antibiotics with gradual resolution of the infiltrate over the next 1 1/2 years.

She did well until age 19 when she developed right upper lobe pneumonia. After failure to respond to erythromyin, bronchoscopy was performed. Lavage specimens were negative for bacteria, fungi, and mycobacteria. She had a mild anemia and leukocytosis, but other laboratory studies, including PPD, were negative. Exploratory thoracotomy with wedge resection of the right upper lobe was performed two weeks later. The patient was referred to the Johns Hopkins Hospital with persistent symptoms. Review of the lung biopsy showed a necrotizing granulomatous process without evidence of vasculitis.

Because of persistent weight loss, cough, and recurrence of low grade fever over the next five months, it was decided that a right upper lobectomy should be performed, since the lobe had never fully reexpanded to obliterate the pleural space, creating a potential area for infection. The specimen demonstrated obliterative fibrosis of the entire right upper lobe. Admixed with the fibrosis were microabscesses with associated granulomatous inflammation. Within the abscesses, rare granular clusters of bacteria were identified (Fig 1). The bacteria were best visualized with Dieterle and methylene blue staining (Fig 2) which showed the organisms to be curved rods morphologically suggestive of Pasteurella, Corynebacterium or Pseudomonas species. The bacteria showed variable staining with Gram-Weigert stain and were acid-fast negative. Special stains for fungi were negative. All cultures were negative. foreign material was not observed within the abscesses. This granulomatous and suppurative process with clusters of organisms was deemed to represent an unusual response to bacterial infection: primary pulmonary botryomycosis.

Since the etiology of this process was not known, a number of studies were performed including a negative sweat chloride test, normal total immunoglobulins and subclasses, normal T cell numbers and ratio, and antibody titer to tetanus, pneumococcal polysaccharide antibody and Hemophilus influenzae antibody. A cell-mediated immunity multiskin test revealed anergy. Neutrophil function was investigated with two methods. Flow cytometric evaluation of [H.sub.2 O.sub.2] -dependent oxidative product formation was performed using the method of Bass et al.[5] The patient's neutrophils were stimulated with PMA and demonstrated an absent oxidative burst compared to normal control subject. Her mother's neutrophils showed normal oxidative burst. Her father was not available for testing. Bacteria killing studies showed that the patients polymorphonuclear leukocytes killed only 51 percent of staphylococci 502A while normal polymorphonuclear leukocytes killed 99 percent.[6] The abnormal oxidative burst and neutrophil killing assay were consistent with the diagnosis of chronic granulomatous disease. Subsequent evaluation of the patient's neutrophils by electrophoresis and immunoblotting revealed that the 47-kd cytosolic protein required for oxidase activation was absent consistent with the diagnosus of autosomal recessive chronic granulomatous disease (patient 22).[7]

During this time, patient became acutely ill with fever and new right lower and left upper lobe infiltrates. Evaluation included percutaneous aspiration with negative cultures, a negative indium scan and bone scan and a gallium scan of the lung that was diffusely positive. She was started empirically on gentamicin and nafcillin with an excellent clinical response and resolution of her infiltrates over the next several weeks.

Discussion

While the characteristic fungus-like granules of botryomycosis were discovered in an equine pulmonary nodule over a century ago, the etiology had remained speculative.[8] The term botryomycosis (Greek: botrys, a bunch of grapes) was coined by Rivolta in 1887 because the etiologic agent was felt to be Actinomycetes.[9,10] Until 1913 when Opie[11] described the first human case occurring in a patient with hepatic involvement, it was thought that the disease was limited to animals. Shortly thereafter, Magrou experimentally demonstrated the bacterial etiology of the disorder by isolating Staphylococcus aureus from an equine lesion and reproducing the disease in guinea pigs. He proposed that botryomycosis was not due to a specific microorganism, but was the result of an unusual immune response resulting in a symbiotic relationship between the host and common bacteria.[8,10] Since then, a number of microorganisms have been identified as the etiologic agents. As in the described herein, there may be difficulty in isolating the organism unless the grains are smashed prior to inoculations.[10,12]

Histologically, within multiple abscesses are colonies of bacteria surrounded by eosinophillic hyaline "clubbing" material. Within the focus are characteristic grains which are composed of bacteria, cells, and debris.[1] The presence of clubbing material varies with animal species and may not be a universal characteristic of botryomycosis.[13] Surrounding this focus are chronic inflammatory cells composed of polymorphonuclear leukocytes, monocytes, and foreign body giant cells within a matrix of fibrous tissue. While the granules and clubbing material contain significant amounts of [IgG.sup.2] and may be the results of a host reaction,[10] their specific sources is unclear.

In their review of the literature, Brunken and co-workers[8] describes the age range of patients with botryomycosis from 9 months to 80 years. Of the 77 cases reported, the male to female ratio was 3:2 While a majority of cases have been integumentary, over 20 have involved the visceral organs including the liver, kidney, brain, prostate, intraabdominal space, and lungs. Of the ten cases reported in lung, seven were in children with cystic fibrosis.[4,10] In all cases with cystic fibrosis, cultures were positive foe either Staphycoccus aureus or Pseudomonas aeruginosa or both.[10] As with our patient, one of these cases had been misdiagnosed as having actinomycosis for one year until a second biopsy was performed. Other cases of primary pulmonary botryomycosis have included one patient with underlying diabetes mellitus[4] and two in which there was no underlying disease.[14,15]

Clinical symptoms are nonspecific and in a number of case reports described as mild, not unlike the patients described.[4] Respiratory complaints have included dyspnea, pleuritic chest pain, cough, and hemoptysis. On chest roentgenogram, upper lobe involvement is seen more frequently than lower lobe appearing as a diffuse infiltrate, discrete mass, or cavity lesion.[4] In a number of cases, there was secondary involvement of hilar lymph nodes, pleura, ribs, and vertebrae.[4,10] The diagnosis was made in all cases either at autopsy or on biopsy by histologic and bacterial examination.[10] There is no distinct clinical presentation of botryomycosis but clearly, the limited degree of constitutional symptoms in contrast to the extensive disease on chest roentgenogram biopsy suggest a host-parasite interaction that is not seen in acute pulmonary infections.

A number of case reports have identified patients with botryomycosis who have potential immunologic abnormalities. Four patients, including one with lung involvement were found to have diabetes mellitus.[4] In addition, other reported cases have included those associated with steroid treatment,[16] immunoglobulin deficiencies,[8] or the acquired immunodeficiency syndrome.[2]

Washburn and colleagues[3] recently described a 20-year-old male patient with a childhood history of recurrent pneumonias who underwent liver biopsy for persistent fevers, weight loss, hepatomegaly, and was found to have botryomycosis due to Neisseria mucosa. When his neutrophils were studied, they failed to reduce nitrotetrazolium blue dye or generate superoxide or hydrogen peroxide with appropriate stimuli consistent with the diagnosis of chronic granulomatous disease. Subsequent evaluation of this patient's neutrophils also demonstrated reduced cytosol activity consistent with autosomal recessive chronic granulomatous disease (patient 14].[7] Though the diagnosis of botryomycosis was made from liver in Washburn's case, both cases are similar in that each had autosomal recessive CGD. There is some evidence that patients with the autosomal recessive form of CGD may have a more benign clinical course.[3]

Our case and the case reported by Washburn and colleagues[3] suggest that visceral botryomycosis may be a clinical manifestation of CGD. Thus, the diagnosis of visceral botryomycosis should prompt an evaluation of the patient for CGD.

References

[1.] Spencer H. Pathology of the lung, 4th ed. Oxford: Pergamon Press, 1985; 267-68 [2.] Toth IR, Kazal HC. Botryomycosis in acquired immunodeficiency syndrome. Arch Path Lab Med 1987; 111:246-49 [3.] Washburn RG, Bryan CS, DiSalva AF, Macher AM, Gallin JI. Visceral botryomycosis caused by Neisseria mucosa in patient with chronic granulomatous disease. J Infect Dis 1985; 151:563-64 [4.] Speir WA, Mitchener JW, Galloway RF. Primary pulmonary botryomycosis. Chest 1971; 60:92-93 [5.] Bass DA, Olbrantz P, Szejda P, Seeds MC, McCall CE. Subpopulations of neutrophils with increased oxidative product formation in blood of patients with infection. J Immunol 1986; 136:860-66 [6.] Quie PG, White JG, Holmes B, Good RA, In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Invest 1967; 46:668-79 [7.] Clark RA, Malech HL, Gallin Jl, Nunoi H, Volpp BD, Pearson DW, et al. Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. Engl J Med 1989; 321:647-52 [8.] Brunken RC, Lichon-Chao N, van den Broek H. Immunologic abnormalities in botryomycosis. J Am Acad Dermatol 1983; 9:428-34 [9.] Wu WQ, Catteneu EA, Lapi A, Halde C. Botryomycosis: first report of human brain involvement. South Med J 1978; 71:1530-33 [10.] Katznelson D, Vawter GF, Foley GE, Shwachman H. Botryomycosis: a complication of cystic fibrosis. J Pediatr 1964; 65:525-39 [11.] Opie EL, Human botryomycosis of the liver. Arch Int Med 1913; 11:425-39 [12.] Harman RRM, English MP, Halford M, Saihan EM, Greenham LW. Botryomycosis: a complication of extensive follicular mucinosis. Br J Derm 1980; 102:215-21 [13.] Green EG, Schwartz JN. Bacterial pseudomycosis (botryomycosis) in an otherwise normal child. South Med J 1984; 77:296 [14.] Greenblat M, Heredia R, Rubenstein L, Alpert S. Bacterial pseudomycosis ("botryomycosis"). Am J Clin Path 1964; 41:188-93 [15.] Neuhauser EBD. Actinomycosis and Botryomycosis. Postgrad Med 1970; 48:59-91 [16.] Bishop GF, Green KE, Horwitz DA. Pseudomonas botryomycosis. Arch Dermatol 1976, 112:1568-70

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