Download Case Reports

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