An infant with prolonged fever and chronic diarrhea

Prepared by...................Nuthapong Ukarapol, M.D.
Virat Sirisanthana, M.D.
Niruth Lertprasertsuk M.D.
Chiang Mai University , Thailand
Patient : 7-month-old male infant
CC: fever and diarrhea for 2 months
PI: 2 months PTA, he has been repeatedly hospitalized at a primary care hospital with a diagnosis of "infectious diarrhea". The stool examination revealed mucous appearance with WBC of 20-30/HPF, RBC of 3-5/HPF, and no parasites. Accordingly, he had been treated with multiple courses of antibiotics, including cefazidime, amikacin, metronidazole, co-trimoxazole, and norfloxacin. His symptom had not been improved, so he was refered to our hospital.
Past medical history:
>
 He was born to an HIV-infected mother who did not attend prenatal clinic. Zidovudine (AZT) was prescribed during the first 6 weeks of life for preventing perinatal HIV transmission. Unfortunately, his HIV-status was confirmed to be "INFECTED" by positive HIV-PCR at 2 and 4 months of age.
>
 Soon after birth he had clinical sepsis. Sepsis workup revealed negative result. He recieved intravenous antibiotics for 7 days.
>
 At 2 month old (5 months PTA) he had another episode of "sepsis" with pneumonia. He was treated as bacterial and pneumocystis carrinii pneumonia. Gastric washing and trachial suction secretion had no evidence of acid fast bacilli. He recoverd and went home on oral cotrimoxazole for PCP prophylasxis.
Physical exmination:
The patient has intermittent fever with peak-temperature of 38.5 C (axillary).
General appearance: cachexic and moderately dehydrated.
HEENT: mild pale with cervical lymphadenopathy and positive oral thrush
Heart and lungs: normal
Abdomen: moderate distension with generalized tenderness, hepatosplenomegaly

Basic laboratory:
CBC: Hb 9.2 g/dl, Hct 29.9%, WBC 24,200 /cumm, N80%, L18%, Mono2%, platelet 173,000 /cumm
PT 10.4 sec (12.1) PTT 29.9 sec (29.6)
U/A: normal
Stool examination: mucus stool (Fig 1A), WBC 20-30/HPF, RBC 0, stool pH 7, stool fat: negative, stool occult blood: postive, modified acid fast staining: negative
LFT: Alb/Glob 3.4/1.7 g/dl, AP 170 IU/L, cholesterol 146 mg/dl, AST/ALT 68/63 IU/L, TB/DB 0.59/0.22 mg/dl
CD4 : 11%, 740 cells/cumm, (normal value >25%, >1,000 cells/cumm)
HIV viral load: >750,000/mL.
Clinical course:
The patient was initially diagnosed as salmonella sepsis and was treated with intravenous cefotaxime for 1 week. He had no clinical improvement. On the 10th day after admission, he was more irritable and had bleeding per rectum (Fig 1B), in which packed red cell transfusion was given. Signs of peritoneal irritation was noted; however, there was no free-air on plain abdomen. An urgent careful colonoscopy revealed marked erythematous, friable, and edematous colonic mucosa. Multiple deep colonic ulcers, sized 2-20 mm in diameter, were seen throughout the colon, particularly in the rectosigmoid region. Biopsies were obtained for histopathologic study. On H&E stain, open ulceration with acute inflammatory cells infiltration were noted. Mulitple CMV-cytopathic cells containing both intranuclear and intracytoplasmic inclusions were observed (Fig 2-left). The diagnosis was confirmed using a special stain for polyclonal antibody to CMV (Fig 2-right). Ophthalmologic examination of the patient also showed retinitis of both eyes compatable with CMV-retinitis.

Figure 1. The mucus stool and bright red stool resulting from CMV infection are shown in Fig 1A and 1B, respectively.
Figure 2. The histopathology reveals open ulceration with positive CMV cytopathic cells (arrow). The diagnosis is confirmed by polyclonal antibody staining to CMV antigen (right).
Diagnosis: Disseminated cytomegalovirus infection in HIV-infected infant
Treatment and further course of illness
1. Due to the possibility of bowel perforation and massive lower GI bleeding, the patient was not allowed to take anything orally and the parenteral nutrition was administered.
2. Intravenous gangciclovir (10 mg/kg/day) was prescibed for 14 days. The maintenant dose of 5 mg/kg/day was then followed.
3. Supportive treatments including blood component transfusion and sucralfate rectal suppository were provided.

The bleeding gradually stopped and the fever subsided within the first week after the treatment. Enteral feeding was then started.
4. Antiretroviral therapy (ART)was added on day 12 of gangciclovir treatment.

He gradually gained his body weight (4100 grams -> 5300 gram in 5 weeks after gancyclovir, 4 weeks after ART).
> At 3 weeks after ART, although he was gaining weight, he started having another episode of fever.
> At 4 weeks after ART (5+ weeks after gancyclovir) his body weight increased from 4100 grams -> 5300 gram. The repeated CD4 was 30% and 1310 cells/cu.mm. His Viral load dropped to 262/mL.
> Since then his clinical condition was complicated with convulsion, dystonia, myocarditis. Finally he expired on the 9th week of admission.
 
Gastrointestinal Cytomegalovirus Infection
Gastrointestinal involvement in disseminated CMV infection accounts for 20% of the AIDS patients. The colon is the most common affected part of the GI tract. The clinical spectrum varies from chronic diarrhea, abdominal pain, dysphagia, odynophagia, GI bleeding, bowel obstruction, perforation, and even death. In our study, prolonged fever and chronic diarrhea are the most common clinical presentation. Serologic tests, unfortunately, show low sensitivity in diagnosing of CMV infection. Therefore, the gastrointestinal endoscopy plays a crucial role to obtain tissue diagnosis. The most frequent endoscopic findings include colitis and multiple deep ulcers, locating predominantly in the recto-sigmoid region. Although the biopsies obtained from the ulcer base provide highly positive yield, the normal looking mucosa can also demonstrates the CMV cytopathic cells, containing typical intranuclear and intracytoplasmic eosinophilic inclusions. Despite resolution of the symptoms frequently noted after the ganciclovir therapy, relapses usually occur. Therefore, maintenance therapy and simultaneous treatment with antiretroviral agents may be a good option to improve the clinical outcome.
Cytomegalovirus Infection in HIV-infected Children
The most frequent problems related to CMV are retinitis, esophagitis, and colitis; infrequent complications include encephalitis, peripheral neuropathy, hepatitis, and pneumonitis.

It was shown that HIV-infected children have higher rates of CMV infection acquired during the first 4 y of life and that CMV infection is associated with an increased risk of HIV disease progression and CNS disease. However, the mechanism by which CMV co-infection leads to more rapid progression remains unclear. It is possible or even likely that CMV and HIV-1, two immunosuppressive viruses, may act synergistically to accelerate disease progression. (ref 1)

When to start HAART in symptomatic CMV infection in HIV-infected children?
There were several reports of successful treatment of CMV encephalitis in infants with perinatal HIV infection by giving highly active antiretroviral therapy (HAART) plus anti-CMV treatment (ganciclovir, foscarnet, or both) (ref 2-3). With the very poor prognosis of HIV-infected children who had gastrointestinal CMV infection (ref 4-5), we prefer adding HAART to anti-CMV treatment at a very early phase of therapy.

How long should anti-CMV therapy be given?
Treatment of CMV disease in AIDS patients essentially is palliative, requiring induction therapy with ganciclovir, foscarnet, or cidofovir to control the disease, followed by maintenance therapy with one of these drugs. The maintenance therapy is continued indefinitely or until the patient's immune function improves and stabilizes at a level that will allow discontinuation of anti-CMV treatment. Use of highly effective antiretroviral therapy has resulted in improved immunologic function in HIV-infected adults and children and has reduced the incidence of CMV disease dramatically (ref 6)
References:
1. Kovacs A, Schluchter M, Easley K, et al. Cytomegalovirus infection and HIV-1 disease progression in infants born to HIV-1-infected women. N Engl J Med 1999;341:77-84.
2. Rohrer T, Rinaldi D, Bubl R, Engelcke G, Di Gallo A, Rudin C. Combined treatment with zidovudine, lamivudine, nelfinavir and ganciclovir in an infant with human immunodeficiency virus type 1 infection and cytomegalovirus encephalitis: case report and review of the literature. Pediatr Infect Dis J 1999;18:382-6.
3. Zaknun D, Zangerle R, Kapelari K, Fischer H, Sailer M, McIntosh K. Concurrent ganciclovir and foscarnet treatment for cytomegalovirus encephalitis and retinitis in an infant with acquired immunodeficiency syndrome: case report and review. Pediatr Infect Dis J 1997;16:807-11.1.
4. Ukarapol N, Chartapisak W, Lertprasertsuk N, et al. Cytomegalovirus-associated manifestations involving the digestive tract in children with human immunodeficiency virus infection. J Pediatr Gastroenterol Nutr 2002;35:669-73.
5. Ukaraol N, Lertprasertsuk N, Fuchs GJ, Wongsawasdi L, Sirisanthana V. Impact of gastrointestinal endoscopy on HIV-infected children. Digest Endosc 2004;16:26-9.
6. Pass, RF.Cytomegalovirus Infection. Pediatr Rev 2002;23: 163-70.
Diagnosis : Disseminated CMV infection in an HIV-infected infant with gastrointestinal problem as a leading presentation.

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