The advent of pediatric AIDS has increased the clinician's awareness of many opportunistic infections and neoplasms. As the largest lymphoid organ in the body, the luminal gastrointestinal tract may be the first to manifest signs of immunodeficiency. Opportunistic infections include bacteria (Salmonella, Campylobacter, nontuberculous Mycobacterium), protozoa (Cryptosporidium, Microsporidium), fungi, viruses (rotavirus, herpes and hepatitis viruses) and worms (Strongyloides stercoralis).1, 2 In children symptoms may range from malabsorption with malnutrition and protein-losing enteropathy to chronic diarrhea and/or bloody stools.2
Processes associated with gastrointestinal blood loss in the pediatric AIDS patient include idiopathic thrombocytopenia, cytomegalovirus (CMV) colitis, candidal esophagitis and severe enteric bacterial infections.2 HIV-infected children have an increased incidence of tumors affecting the gastrointestinal tract, such as leiomyosarcoma, Kaposi's sarcoma and lymphoma.3
Disseminated Mycobacterium avium complex (DMAC) is rarely the presenting AIDS-defining illness in adults or children.4 We report a 4-month-old infant with vertically transmitted HIV and DMAC presenting with bloody stools. Unique aspects of this infant's presentation include DMAC as an AIDS-defining illness in a patient <1 year old, DMAC presenting with a CD4+ T cell count above 100 cells/mm3 and symptoms and endoscopic findings consistent with colitis.
Case report. A 4-month-old female infant with vertically transmitted HIV was admitted with a 5-day history of blood-streaked stools. Stools were increased in volume and frequency (5 to 8/day). The patient had low grade subjective fever but no emesis, irritability or change in eating habits and had no ill family contacts. Past medical history included a 36-week gestation and vaginal delivery (birth weight 2415 g (small for gestational age}) but an uncomplicated neonatal course. The mother was clinically asymptomatic duration the child's gestation and delivery, and the mother's CD4+ count was 453 cells/mm3 at the time of delivery. Neither the infant nor her mother received antepartum, peripartum or postpartum zidovudine prophylaxis. The patient's HIV status was based on three positive viral cultures (excluding cord blood) in the first 6 weeks of life. Her most recent CD4+ count was 478 cells/mm3 (severe immunosuppression).5 The patient was CMV-seropositive (CMV IgG enzyme-linked immunosorbent assay value, 2.82 (mid-positive); CMV IgM enzyme-linked immunosorbent assay value, 0.13 (negative)). Medications included zidovudine, trimethoprim/sulfamethoxazole and nystatin.
On examination the patient weighed 3400 g, and had a rectal temperature of 37.7°C, pulse 143 beats/min, respirations 40/min and blood pressure 88/43 mm Hg. Oral examination revealed easily removable white plaques. The patient's abdomen was soft with normoactive bowel sounds. No rectal fissures were appreciated. Stool was guaiac-positive. Initial fecal evaluation included bacterial and viral cultures, viral electron microscopy and Cryptosporidium stain. Peripheral blood cultures for mycobacteria, bacteria (aerobes and anaerobes), fungi and virus were also obtained. The patient was diagnosed with gastroenteritis and thrush and was treated with a 7-day course of oral fluconazole. Symptoms of blood-streaked stools persisted despite formula changes (Similac with Iron® to Pregestimil® and fluconazole therapy. Three weeks later blood cultures grew Mycobacterium spp. and the patient was admitted to the Texas Children's Hospital for drug therapy and further investigation of hematochezia. All other laboratory tests were negative.
At the time of admission vital signs were again normal and the patient's weight was 3880 g (<5th percentile; corrected to 50th percentile for a 1- month-old). Pertinent physical findings included hepatomegaly (previously noted 2 months before admission) and growth retardation. Admitting laboratory studies revealed a hematocrit of 28.1%, platelet count of 190 000, white blood cell count of 3510 cells/mm3 absolute neutrophil count of 1158 cells/mm3 and normal prothrombin and activated partial thromboplastin time of 11.5 and 37.3 s, respectively. Alanine aminotransferase was 243 IU/l, aspartate aminotransferase was 949 IU/l and gamma/glutamyl transferase was 1152 IU/l. The anemia and liver enzyme elevations were consistent with previously documented values 2 months earlier, when hepatitis A, B and C serologies, hepatitis B surface antigen and CMV IgM had been negative.
Chest radiographs of the patient and her mother were normal. Both mother and child had negative delayed hyper-sensitivity reactions to tuberculin agent. Repeat stool cultures/stains and blood cultures were negative with the exception of continued isolation of mycobacteria from peripheral blood. Both stool for Clostridium difficile toxin and peripheral blood for CMV PCR studies were negative. A funduscopic examination revealed no evidence of CMV retinitis or other pathology. Cerebrospinal fluid assessment revealed normal chemistry and cellular profile; routine bacterial/mycobacterial cerebrospinal fluid cultures were negative.
The mycobacterial isolate was identified as M. avium complex (MAC). Abdominal ultrasound revealed mild hepatomegaly without biliary obstruction or splenomegaly. To evaluate persistent hematochezia flexible sigmoidoscopy was performed 6 days after initiation of anti-mycobacterial therapy and revealed diffuse erythema, friability and superficial ulcers. Biopsies sent for mycobacteria, bacteria, virus and yeast culture and acid-fast and Fite stains for mycobacteria were negative. There was no reactivity to CMV antibody (DAKO® DD69/CCH2). Histology revealed normal architecture.
The patient was discharged to receive clarithromycin and ethambutol therapy. Colitis symptoms resolved within 2 weeks of starting the anti-DMAC regimen. Follow-up blood and cerebrospinal fluid cultures were documented to be sterile as early as 2 months after initiation of therapy. Anemia did not resolve throughout her life. The child had rapid CD4+ T cell count decline during the ensuing months with clinical diagnoses of HIV encephalopathy and HIV wasting documented (evaluations for Cryptosporidium, recurrent MAC and persistent Salmonella or other opportunistic bacterial infection were negative) (Fig. 1). The child died at 18 months of age from dehydration and likely renal failure (no autopsy was performed) despite her mother's attentiveness and timely access to care for her child.
Discussion. The unique features of this case include: (1) clinical presentation of DMAC-associated colitis not previously described; (2) presentation at <6 months of age with DMAC as her AIDS-defining illness; and (3) a CD4+ T cell count at DMAC presentation well above 100 cells/mm3. Clinicians have noted bimodal populations of children with vertically transmitted HIV (rapid and slow progressors to an AIDS-defining illness).6 Ongoing research seeks better to define these populations including clinical presentation, risk factors and differences in immunologic responses. This patient represents rapid HIV progression with early clinical disease (DMAC, HIV encephalopathy and wasting) and remarkable immunologic suppression (Fig. 1). At presentation the infant's CD4+ count (478 cells/mm3) was less than age-matched norms (> 1500 cells/mm3)5
MACs are ubiquitous organisms that are commonly found in soil and water.7 Because MAC in HIV-infected persons is thought to be acquired rather than reactivated disease, risk factors for acquisition are increasing age and declining CD4+ T cell count.7 Although gastrointestinal and respiratory colonization may occur earlier, DMAC is rare in adults with CD4+ T cell counts >100 cells/mm3.7 DMAC usually occurs relatively late in the course of adult HIV infection with a mean time to diagnosis of 7 to 15 months after the initial diagnosis of AIDS. DMAC was recently reported as the AIDS-defining illness in 25 of 84 (30%) HIV-infected children; however, the mean age at presentation was 5.4 years.4
Unlike adults development of DMAC in children may be associated with CD4+ T cell counts >100 cells/mm3. Rutstein et al.8 reported six HIV-infected children with DMAC, three of the six with CD4+ T cell counts from 108 to 282 cells/mm3. In this study age at presentation for patients with DMAC ranged from 36 to 126 months and 95% had met an AIDS criterion before their DMAC diagnosis.
Both adults and children with HIV infection usually succumb to opportunistic infections or other consequences of T cell depletion, and DMAC is usually associated with the end stages of AIDS.9 The median survival of 136 children with vertically acquired HIV and DMAC has been reported to be 5 months.4 We attribute this infant's unusually long survival time from the onset of DMAC to her mother's remarkable attentiveness and timeliness of accessing medical care.
Common gastrointestinal manifestations of DMAC in children are chronic diarrhea, abdominal pain and anorexia.8 Other features may include fever, malabsorption, failure to thrive, organomegaly, lymphadenopathy and anemia.1 In DMAC-associated diarrhea bloody stools are extremely rare and are less often associated with the lower intestinal tract. Failure to thrive and chronic bloody diarrhea were prominent features of this child's illness. Our patient's clinical presentation (bloody diarrhea), endoscopic findings (mucosal friability, superficial ulceration and diffuse erythema) and response to anti-DMAC drugs are consistent with DMAC-associated colitis. The sterility of biopsy cultures for MAC may have resulted from the ongoing anti-DMAC treatment.
The optimal regimen for treatment of DMAC in children has not been established. Combination clarithromycin and ethambutol therapy has been suggested based on reports in adults of rapid emergence of resistance to monotherapies.7,10 MAC prophylaxis guidelines for children <6 years of age are as yet undefined.
We report a 4-month-old infant with vertically transmitted HIV whose presenting AIDS-defining illness of DMAC occurred at a younger age and with a significantly more rapid course of disease progression than in previously reported pediatric DMAC cases.8 In addition, this infant's CD4+ T cell count was higher (410 cells/mm3) than those of other reported cases. This case serves to alert clinicians who care for HIV-infected infants that MAC can occur at very early ages (4 months in this infant) when the index of suspicion for MAC may be low and that prolonged survival on anti-DMAC therapy is possible with close medical follow-up. We believe that this is the first reported case of infantile DMAC-associated colitis.
Acknowledgments. This work was sponsored in part by Grants U01-AI34856 and U01-AI27759 from the National Institute of Allergy and Infectious Disease, Bethesda, MD. We thank Dr. David Wheeler and the staff of the Molecular Biology Computational Resource for the facilities made available for researching this report and Teri McCumber for technical administrative assistance.
Charles Keller, M.D; Suzanne Kirkpatrick, M.S.N.,P.N.P; Kenneth Lee, M.D.; Mary Paul, M.D.; I. Celine Hanson, M.D.; Mark Gilger, M.D.
Departments of Pediatrics (CK), Allergy and Immunology (SK, MP, ICH) and Nutrition and Gastroenterology (KL, MG)
Texas Children's Hospital
Baylor College of Medicine
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