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Case Reports An Atypical Subcutaneous Infection Associated with Acquired Immune Deficiency Syndrome MARK H. STOLER, M.D., THOMAS A. BONFIGLIO, M.D., ROY T. STEIGBIGEL, M.D., AND MARK PEREIRA, M.D. Cases of acquired immune deficiency syndrome (AIDS) continue to be reported at an alarming rate. As the numbers of cases increase, so too does the list of unusual manifestations associated with this syndrome. We report here a patient with AIDS who, during his clinical course, had a previously undescribed, histologically atypical, subcutaneous infection develop. Light microscopic, electron microscopic, and microbiologic data are presented. The cause and pathogenesis of this lesion are discussed. (Key words: AIDS; Immunologic deficiency syndrome) Am J Clin Pathol 1983; 80: 714-718 Departments of Pathology and Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York. cell-mediated immunity. 1,4 The defects in cellular immunity are associated with a profound susceptibility to multiple, often fatal, infections with opportunistic organisms. Whether some infectious agent induces the immunosuppressed state or whether some other factor primarily alters the immune system is unresolved as yet. This report describes a patient with AIDS who is interesting from two standpoints. First, he is one of the 5% of patients who are not epidemiological^ at risk for the disease.12 Second, during his clinical course he developed a unique lesion representing a new infectious manifestation of the acquired immune deficiency syndrome. ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) continues to be a serious public health problem with an ever-increasing list of unusual associated manifestations.5 AIDS originally was reported as affecting specific population subsets including homosexual males, Haitian immigrants, and intravenous drug abusers.3,6,7 The list of groups at risk recently has expanded to include hemophiliacs, female sexual partners of patients with AIDS, and infants. 2,8 " Although the cause of AIDS is unknown, epidemiologic observations such as these increasingly suggest the disease is caused by an infectious agent. The pathogenesis of this syndrome is also unclear. However, common to all these patients are characteristic abnormalities of immunoregulation affecting primarily Report of a Case On April 15, 1982, a previously healthy 32-year-old man presented to the Emergency Department with a two-week history of epigastric pain, heartburn, and odynophagia. He denied other gastrointestinal complaints, fever, or weight loss, and his medical history was unremarkable. The patient had worked as a bricklayer and four months earlier had immigrated to the United States from St. Vincent's in the Virgin Islands. The patient did not smoke and rarely drank ethanol. He had a wife and five healthy children and vehemently denied any homosexual experiences or drug abuse. The physical examination revealed that he was a slender black male in no distress. He was afebrile, and the physical examination was re- Received March 11, 1983; received revised manuscript and accepted for publication April 27, 1983. Address reprint requests to Dr. Stoler: Department of Pathology, Box 626, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642. FlG. 1 (upper, left). Representative field from a subcutaneous nodule. Capillary channels, histiocytes, and neutrophils impart a granulation tissue appearance. (Hematoxylin and eosin stain (original magnification, X50). FIG. 2 (upper, right). Prominent endothelial-liked vascular channels and stromal histiocytic elements are noted in this section of a nodular lesion. Hematoxylin and eosin stain (original magnification, X200). FIG. 3 (lower, left). In this plastic-embedded thin section, the histiocytic nature of some of the stromal cells is emphasized. Note lipid material and intracytoplasmic particles. Basic fuchsin-Methylene blue (original magnification, X200). FIG. 4 (lower, right). Small bacillary forms are identified singly and in clumps (arrows). Warthin-Starry stain (original magnification, X200). 0002-9173/83/1100/0714 $01.05 © American Society of Clinical Pathologists 714 Vol. 80 • No. 5 CASE 716 STOLER ET AL. markable only for white pharyngeal plaques and mild paronychia. Routine blood chemistry including SMA-6 and SMA-12 were normal. The hematocrit was 32, white cell count was 5,300/mm3, and absolute lymphocyte count was 1,060/mm3. Gastroscopy was performed, which revealed severe ulcerative esophagitis with pseudomembrane formation. Esophageal cultures grew Candida albicans as well as Herpes simplex. The patient was started on oral nystatin liquid. Immunologic evaluation including serum protein electrophoresis, immunoelectrophoresis, quantitative immunoglobulins, complement levels, ANA, rheumatoid factor, and direct antiglobulin tests had normal results. Because of the unusual occurrence of HSV-esophagitis in immunologically normal individuals, an analysis of the patient's peripheral blood T cells was done. The relative and absolute values of the T-cell subsets were as follows: sheep red cell rosettes, 22% and 292/mm3; Leu 3a (Thelper), 3% and 40/mm3; Leu 2a (T-suppressor) 17% and 225/mm3; helper/suppressor ratio 0.18. Normal ranges in our laboratory are 5590% (l,OOO-2,20O/mm3), 30-60% (500-1,340/mm3), 15^t0% (200-900/ mm3), and 0.9 to 3.0, respectively. Three weeks later, the patient's esophageal symptoms had improved, but he now complained of nonbloody diarrhea, weight loss, low-grade fever, and sweats. The patient was hospitalized. Physical examination was relevant for a temperature of 38°C and the new finding of multiple subcutaneous nodules. These were firm indurated and nontender and varied in size from 2-6 cm in diameter. They were found in the left occipital area, right wrist, left forearm, right leg and knee, and dorsum of both feet. Over several days, new nodules appeared and older ones enlarged. Laboratory evaluation was now remarkable for a hematocrit of 29%, a white cell count of 4,900/mm3, and an absolute lymphocyte count of 735/mm3. The patient also had developed proteinuria and microscopic hematuria. Repeat endoscopy showed persistent esophagitis, and oral ketoconazole was added to his therapy. The patient was anergic to multiple skin tests, and repeat immunologic evaluation was unchanged. The nodules from the occipital area, right forearm, and left foot were used for biopsy, and the right knee lesion was aspirated. Tissue samples were cultured at 32°C and 37°C for aerobic and anaerobic bacteria, mycobacteria, Legionella, fungi, and viruses. None of the cultures grew any organisms. Histologic examination of the nodules revealed the tissue to be composed of a proliferation of histiocytic and endothelial cells within a framework of poorly formed capillary channels (Figs. 1 and 2). The vascular nature of the tissue was accentuated by the reticulin stain. The histiocytic cells had abundant granular occasionally vacuolated eosinophilic cytoplasm (Fig. 3). The nuclei were moderately enlarged with a vesicular chromatin pattern, and eosinophilic nucleoli usually were prominent. The tissue was infiltrated diffusely by polymorphonuclear leukocytes. Eosinophils were not noted. Special stains for organisms included periodic acid-Schiff, Gomori methenamine silver (GMS), Truant's, Ziehl-Nielson, Fite, Giemsa, Brown-Brenn. Warthin-Starry, and direct immunofluorescence against 10 of 12 available Legionella serotypes. All stains were negative with the exception of the WarthinStarry stain (Fig. 4). This stain revealed a diffuse infiltration of small bacillary forms measuring approximately 0.5 ^m X 1.5 tim. Transmission electron microscopy confirmed the presence of these forms (Fig. 5). They were diffusely present in the interstitium. The trilaminar structure of the cell wall was seen easily (Fig. 6). The internal structure consisted of electron dense granular material consistent with the nuclear material of a bacterial organism. A.J.C.P. • November 1983 Remainder of the Clinical Course The patient was started on empiric oral erythromycin and discharged. Over the next three weeks he did well. He gained 20 pounds of weight and denied fever or chills. The subcutaneous nodules disappeared. He continued to do well until late August, 1982, at which time he complained of painless hematuria. Urinalysis revealed an E. coli urinary tract infection, and oral trimethoprim-sulfamethoxazole was begun. On September 8, he presented to the Emergency Department with a several day history of progressive dyspnea, fever, and a nonproductive cough. Chest x-ray revealed diffuse bilateral alveolar and interstitial infiltrates and arterial blood gases showed profound hypoxemia with a p0 2 of 40 mmHg on room air. Blood, urine, and sputum were cultured, and the patient was treated with amikacin, erythromycin, and trimethoprimsulfamethoxazole. The patient continued to deteriorate, and cultures were negative. A transbronchial biopsy was inadequate. On the fifth hospital day an open-lung biopsy was performed. This revealed diffuse alveolar damage and interstitial fibrosis secondary to Pneumocystis carinii as well as cytomegalovirus pneumonia. No other organisms were identified by staining or eventual culture. Postoperatively the patient required continuous ventilatory support with increasing levels of positive and expiratory pressure. Pentamidine was added to his antibiotic regimen, and amikacin was stopped. On the seventh hospital day, the patient developed a paroxysmal cough. An endotracheal tube aspirate revealed cytologic evidence of herpetic infection, and cultures eventually grew Herpes simplex virus. On the eighth hospital day, a violent coughing spell caused the patient to extubate himself. He quickly suffered a respiratory arrest and could not be resuscitated. At postmortem examination the major findings included diffuse bilateral Pneumocystis carinii and cytomegalovirus pneumonitis, acute herpetic tracheobronchitis, ulcerative herpes esophagitis, and disseminated cytomegalovirus infection involving the esophagus, stomach, adrenal glands, and bladder. There was no evidence of Kaposi's sarcoma or any occult malignancy. There were no palpable subcutaneous nodules, and reexcision of previous nodule sites revealed complete healing without any residual microscopic evidence of the original lesion. Discussion The Center for Disease Control defines a case of AIDS as an illness associated with diseases seen in patients with defective cell-mediated immunity when no known cause for diminished resistance to these diseases is identified.12 Of the wide variety of organisms reported in AIDS, our patient was infected serially or concomitantly with Candida albicans, Herpes simplex virus, Cytomegalovirus, and Pneumocystis carinii. These opportunistic infections, together with the evidence for altered cellular immunity and the patient's fulminant course combine to establish this as a case of AIDS. Our patient's subcutaneous nodules represent a previously undescribed manifestation of AIDS. The clinical history including the growth and proliferation of these lesions as well as their eventual resolution would suggest FIG. 5 (upper). The presence of numerous extracellular bacillary forms as demonstrated by selection microscopy. Note the histiocyte at the upper right of the figure (XI 1,700). FIG. 6 (lower). Note trilaminar structure of bacterial cell wall (arrows) and electron dense granular central structures (X28.600). Vol. 80 • No. 5 CASE REPORTS 717 718 STOLER ET AL. a reactive process. From a microbiologic standpoint, the finding of bacterial forms by histochemistry and electron microscopy would imply an infectious cause for these lesions. The resolution of the nodules also was related temporally to the administration of antibiotics, and this again would support a bacterial cause. Clinically, the distribution and natural history of the nodules was consistent with hematogenous dissemination of an organism. The absence of clinical evidence of deep organ involvement and consistent localization in the subcutaneous tissue would seem to suggest an organismal tropism for this location. This could be perhaps temperature related or perhaps related to other undefined factors. It is noteworthy that if the patient did indeed experience bacteremia(s), he did not exhibit signs of overt sepsis. Repeated blood cultures had negative results, as did all nodule cultures. An unusual subcutaneous infection with an atypical mycobacterium was initially a diagnostic consideration. Relatively new pathogens such as M. haemophilum have been reported to cause subcutaneous infections in immunocompromised patients.10 However, these organisms are usually acid-fast, are culturable when, as in this case, they are specifically sought, and are almost always highly resistant to antibiotic therapy. As stated above, this organism apparently responded to antibiotics, in our hands could not be cultured, and clearly was not acid-fast. Organisms that are Warthin-Starry positive but fail to stain with other routine histochemical stains are few in number and include Legionella, spirochetes, some species of Nocardia, and Whipple's bacillus. Of these, this patient's organism most resembles a small bacillus. The inability to culture the organism and the negative Legionella immunofluorescence would seem to rule out the species of Legionella. Like Whipple's bacillus, this organism was highly resistant to culture, could be visualized by electron microscopy and the Warthin-Starry stain, and apparently responded to treatment with antibiotics. However, Whipple's disease, to our knowledge, has not been reported to involve the skin, and there was no clinical or autopsy evidence to support this diagnosis. From the standpoint of tissue pathology, the morphology is consistent with an exuberant tissue reaction quite reminiscent of an exaggerated granulation tissue response. The atypical appearance of many of the cells and the development of multiple "metastatic" nodules could suggest a malignant neoplasm. Focally there was some resemblance to a low-grade malignant fibrous histiocytoma. The inflammatory infiltrate and angioprolif- A.J.C.P. • November 1983 erative appearance was also reminiscent of lesions described by Rosai and associates within the spectrum of the histiocytoid hemangiomas.9 The clinical history, location of the lesions, their multiplicity, and the absence of eosinophiles would not support either of these diagnoses. More importantly, the presence of bacterial forms and the rapid resolution of these nodules associated with antibiotic therapy is further evidence favoring a reactive (infectious) process. In summary, these nodules represent an atypical granulation tissuelike process with neutrophilic infiltration associated with a culturally undefined bacterial infection in a victim of AIDS. As awareness and diagnosis of AIDS increases, the list of manifestations associated with the syndrome continues to expand. Because the cause is as yet unknown, continued detailed documentation of the spectrum of changes seen in these patients is of obvious importance. Hopefully, this eventually will lead to a better understanding of this fascinating yet frightening new syndrome. References 1. Gottlieb MS, Schroff R, Schanker HM, et al: Pneumocystic carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: Evidence of a new acquired cellular immune deficiency. N Engl J Med 1981; 305:1425-1431 2. Immune Deficiency Among Female Sexual Partners of Males with Acquired Immune Deficiency Syndrome—New York. Morbidity and Mortality Weekly Report 1983; 31:697-698 3. Kaposi's Sarcoma and Pneumocystis Pneumonia Amoung Homosexual Men—New York City and California. Morbidity and Mortality Weekly Report 1981; 30: 305-307 4. Kornfield H, VandeStowe RA, Lange M, et al: T-lymphocyte subpopulations in homosexual men. N Engl J Med 1982; 307:729731 5. Marx JL: New disease baffles medical community. Science 1982; 217:618-621 6. Masur H, Michelis MA, Greene JB, et al: An outbreak of communityacquired Pneumocystis carinii pneumonia: Initial manifestations of cellular immune dysfunction. N Engl J Med 1981; 305:14311438 7. Opportunistic infections and Kaposi's sarcoma among haitians in the United States. Morbidity and Mortality Weekly Report 1982; 31:353-361 8. Pneumocystis carinii among persons with hemophilia A. Morbidity and Mortality Weekly Report 1982; 31:365-367 9. Rosai J, Gold J, Landy R: The histiocytoid hemangiomas. Hum Pathol 1979; 10:707-730 10. Sompolinski D, Lazziel A, Naveh D, et al: Mycobacterium haemophilum sp nov, a new pathogen in humans. Int J System Bact 1978; 28:67-75 11. Unexplained immunodeficiency and opportunistic infections in infants—New York, New Jersey, California. Morbidity and Mortality Weekly Report 1982; 31:665-667 12. Update on Acquired Immune Deficiency Syndrome (AIDS)—United States. Morbidity and Mortality Weekly Report 1982; 31:507514