:::: PEDIATRIC HIV/AIDS ::::

An HIV-infected child with prolonged fever and eye pain

Prepared by...
Aurmporn Oberdorfer, M.D., PhD.
Virat Sirisanthana, M.D.

Department of Pediatrics, Faculty of Medicine, Chiang Mai University

Patient: A 9-year-old HIV-infected girl

Address: Payoa province (Northern Thailand)

CC: Pain at both eyes for 4 weeks. Fever for 3 weeks.

Present Illness:

>	4 weeks PTA, after coming back from swimming in a river, she started having pain at her both eyes (more on the left side). The pain later accompanied with tearing, yellowish discharge and photophobia. The eye drop medicine from the local hospital could not relief her eye pain.
>	3 weeks PTA, she developed moderate grade fever and mild dry cough. Her eye pain persisted. She lost her appetite and was admitted to a hospital where she received ceftriaxone 70MKD, and ampicillin for 1 week without improvement.
>	1 week PTA, all symptoms persisted and she started having abdominal pain.

Past medical history:

>	Normal term labour, birth weight 3,500 gm.
>	At the age of 3 years she was diagnosed as having HIV infection.
>	Her mother has a history of pulmonary tuberculosis and has been on treatment for 7-8 months.
>	She has not gained weight for 1 year.

Physical examination:

GA: febrile, thin and fatigue. BW=18 kg (W/A < 3 percentile)
Vital signs: T: 40 celcius, RR: 36/min, PR: 122/min, BP: 110/72 mmHg
HEENT:

	EYES; pale and injected conjuctivae, with epiphora, left corneal ulcer(figure 1) and photophobia.
	Oral cavity; whitish patches (thrush)
	Ears; intact both tympanic membranes

Lymph nodes: Right supraclavicular lymphnode enlagement: 2 cm in diameter, firm, not tender (figure 2)
Heart: Tachycardia, S3 gallop, RV heaving, no murmur
Lungs: Medium creppitation both lungs
Abdomen: Distension, generalized mild tender, liver 4 cm below RCM, span 13 cm.
Extremities: no clubbing of fingers
Skin: hypo- and hyperpigmentation scars at extremities.
Neurological examination: no meningial sign, no neurological deficit


Figure 1 Corneal ulcer (courtesy of Winai Chaidaroon M.D.)	Figure 2 Left supraclavicular lymphadenopathy

Problem list:

1.	HIV-infected child with prolonged fever
2.	Corneal ulcers

Laboratory investigations:

CBC: Hb 6.1 g/dl, Hct 18%, WBC 3,600/mm3 (N=74%, L=22%, M=16%)

CD4 T-cell count: 4% (20 cells/mm3)

Tuberculin skin test : Negative

Gastric washing for AFB (x 3 days): Negative

CXR: Cardiomegaly, generalized reticulo-nodular infiltration both lungs suggesting miliary tuberculosis. (figure 3)

LP: WBC 13 celles/mm3 (lymphocyte 100%), protein 81mg%, sugar 35/129 mg%, gram stain and AFB: no organism seen

Echocardiogram:

Generalized cardiac dilatation, particularly left size was larger than right side. Mild depressed LV systolic function. Small amount of pericardial effusion. Most likely, the lesions are caused by tuberculous myopathy.

Opthalmology consultation:

	Left eye	Right eye
Visual Acuity	Decreased (6/9)	Decreased (6/9)
Conjunctiva	Diffuse injected	Diffuse injected
Pupil	3 mm	3 mm
Cornea	Dendritic lesion (figure 4)	Faint dendritic lesions


Figure 3 CXR :Cardiomegaly, generalized reticulo-nodular infiltration both lungs suggesting miliary tuberculosis.	Figure 4 Dendritic lesion (courtesy of Winai Chaidaroon M.D.)

Diagnosis: HIV-infected child (Category C3) with miliary tuberculosis, and herpes simplex keratitis


Treatment:
1.	Miliary tuberculosis and meningitis : INH (15MKD), RF (15MKD), PZA (25 MKD), S(25 MKD)
2.	Herpes simplex keratitis: Acyclovir ointment 5 times/day
3.	Cardiac dysfunction: Douzabox (1 tb tid), Enalapril (0.125MKD), Digoxin (6.25 microgramKD)
4.	Anemia: Ferrous Fumarate Co (1.5 tb OD)
5.	Suspeced bacteremia on admission: Cefotaxime 100 MKD IV x 7 days

Course of illness:

	After she received the anti-tuberculous drugs and cefotaxime for 4 days, the fever subsided as in figure 5. Her abdominal pain decreased. She gained appetite. Her eye pain and photophobia slowly recovered. Her cardiac condition gradually improved. The repeated chest radiography 1 month after antituberculous drugs and supportive treatment was shown in figure 6. The heart size was within normal limit. The previous mediastinal (hilar) lymphadenopathy partially subsided. Although each nodule of the "miliary" pattern was smaller in size, the pulmonary infiltration persisted.

	Figure 5

Figure 6 The heart size was within normal limit. The previous mediastinal (hilar) lymphadenopathy partially subsided. The "miliary" pattern persisted, although each nodule was smaller in size, .

DISCUSSION:
>	She is an AIDS case (category C3). She had 2 opportunistic infections, HSV keratitis and tuberculosis disease.
>	The prolonged fever, pulmonary "miliary" pattern, mediastinal (hilar) lymphadenopathy, cardiomegaly, pericardial effusion, a visible left supraclevicular node, hepatomegaly, anemia and slightly abnormal c.s.f. examination represent the clinical manifestations of disseminated tuberculosis. Transmission of M. tuberculosis was airborne, with inhalation of droplet nuclei produced by her mother who had contagious, cavitary, pulmonary tuberculosis. The initial pulmonary focus could be in the midlung zone which was the common site. Small numbers of bacilli might be ingested by alveolar macrophages. Infected macrophages were carried by lymphatics to regional (hilar, mediastinal, and supraclavicular) lymph nodes, and it spread hematogenously throughout the body as evidence by small nodules "military" in the lungs, pericardial effusion, hepatomegaly and abnormal c.s.f. findings.
>	Although the fever subsided in the first week of anti tuberculous drugs (plus cefotaxime), the pulmonary manifestations (increased RR 36-44/min, creppitation) gradually improved in 2-3 weeks. Cardiomegaly subsided and mediastinal (hilar) lymphadenopathy partially subsided on the repeated CXR 1 month after anti tuberculous drugs. It is not surprising that the "miliary" pattern persisted on this repeated CXR.

QUESTIONS & ANSWERS:

1. What is the hallmark of herpes simplex keratitis?(Ref 7-9)

	Clinical symptoms:
	> Pain > Photophobia > Blurred vision " > Tearing " > Redness

	Eye examination:
	> corneal vesicles > dendritic ulcers > geographic ulcers

2. How to diagnose the disseminated tuberculosis? (Ref 12)

>	Clinical signs: general deterioration, high fever, and dyspnea. Clinical signs that involve other organs such as plural effusion, digestive problems, hepatosplenomegaly and meningeal signs.
>	Chest radiography: a "Miliary" pattern on the chest radiography-extensive, tiny (1-2mm) nodules resembling millet seeds, all the same size and spread symmetrically over both lungs.
>	Smear microscopy of sputum from cases with disseminated (miliary) tuberculosis is usually negative.

3. What are the clinical characteristics suggesting of disseminated tuberculosis or tuberculous meningitis? (Ref 12)

>	Clinical signs: nonspecific, progressive deterioration of the states, mood, meningeal signs
>	The tuberculin test is usually negative
>	Fundoscopic examination shows the characteristic tuberculous lesions (choroidal tubercles)-round, slightly raised yellow or whitish lesions of 1-3mm in diameter.
>	Abnormal cerebrospinal fluid from lumbar puncture

4. What are the criteria of corticosteroid therapy in tuberculosis? (Ref 13)

In patients with:

> tuberculous meningitis with increased intracranial pressure

> acute pericardial effusion with tamponade

> pleural effusion with a shift of the mediastinum, and acute respiratory failure

> miliary tuberculosis with alveolocapillary block and cyanosis

> enlarged mediastinal lymphnodes that causing respiratory difficulties or severe collapse consolidation lesion

(The dosage of corticosteroids should be in the anti-inflammatory range-prednisolone, 1 to 2 mg/kg/day for 4-6 weeks with gradual withdrawal)

5. When to start HAART in patients with tuberculosis? (Ref 14)

In patient with HIV-related tuberculosis, the priority is to treat tuberculosis, especially smear-positive cases. However, with careful management, patients with HIV-related tuberculosis can have anti-retroviral therapy at the same times as tuberculosis treatment.

Possible options for anti-retroviral therapy in the tuberculosis patients include:
>	defer anti-retroviral therapy until tuberculosis treatment is completed
>	defer anti-retroviral therapy until the end of the initial phase of tuberculosis treatment and use ethambutal and isoniazid in the continuation phase
>	treat tuberculosis with a rifampicin-containing regimen and use of efavirenz + 2NRTIs; then change to a maximally suppressive HAART regimen on completion of tuberculosis treatment.

6. Anti-retroviral therapy and anti-tuberculosis therapy: any drug interaction? (Ref 14)

Rifamipicin stimulates the activity of the cytochrome P450 liver enzyme system that metabolizes PIs and NNRTIs. This can lead to a reduction in the blood levels of PIs and NNRTIs. PIs and NNRTIs can also enhance or inhibit this same enzyme system, and lead to altered blood levels of rifampicin.

Isoniazid can produce peripheral neuropathy. The NRTIs (didanosine, zalcitabine, and stavudine) may produce peripheral neuropathy and there is a potential further toxicity if isoniazid is added. Isoniazid also has an interaction with abacavir

Follow up of the case : "Abdominal discomfort" 5 weeks later

References and suggested further reading:

American Thoracic Society, US Centers for Disease Control and Prevention: Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This stat. Am J Respir Crit Care Med 2000 Apr; 161(4 Pt 1): 1376-95.

Joint Tuberculosis Committee of the British Thoracic Society: Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax 1998 Jul; 53(7): 536-48.

Kim JH, Langston AA, Gallis HA: Miliary tuberculosis: epidemiology, clinical manifestations, diagnosis, and outcome. Rev Infect Dis 1990 Jul-Aug; 12(4): 583-90.

Klaus-Dieter, L., Cynthia L., Miliary tuberculosis In: http://www.emedicine.com/med/topic1476.htm, Last update February, 7 2003. Access: June, 30 2004

Gaynor BD, Margolis TP, Cunningham ET: Advances in diagnosis and management of herpetic uveitis. Int Ophthalmol Clin 2000 Spring; 40(2): 85-109.

Herpetic Eye Disease Study Group: Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol 2000 Aug; 118(8): 1030-6.

Herpetic Eye Disease Study Group: Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 1998 Jul 30; 339(5): 300-6.

Holland EJ, Schwartz GS: Classification of herpes simplex virus keratitis. Cornea 1999 Mar; 18(2): 144-54.

Jim CW, David CR. Keratitis, Herpes Simplex . In :
http://www.emedicine.com/oph/topic100.htm, Update: October 30, 2002, Access: 30 June, 2004

10.

Julka RK; Deb M; Patwari AK Tuberculous meningitis and miliary tuberculosis in children : a clinico-bacteriological profile. Indian Journal of Tuberculosis. 1998 Jan; 45(1): 19-22

11.

F. van den Bos, M. Terken, L. Ypma J. L. L. Kimpen, E. D. Nel, H. S. Schaaf, J. F. Schoemana and P. R. Donald Tuberculous meningitis and miliary tuberculosis in young children Tropical Medicine & International Health 2004; 9 (Issue 2): 309

12.

Ait-Khaled Nadia, Enarson Donald A. Tuberculosis a Manual for Medical Students.World Health Organization Geneva. 2003.

13.

Starke Jeffrey R., Smith Kimberly C. Tuberculosis. In: Feigin Ralph D., Cherry James D., Demmler Gail J., Kaplan Sheldon L., editors. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia : Saunders; 2004. p.1337-79.

14.

World Health Organization. Treatment of Tuberculosis:guidelines for national programmes. 3rd ed. World Health Organization Geneva 2003.

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