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NANASI 46: July 2006

NANASI 46: July 2006

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In this issue of NANASI:

  • Case Study: Sulfa allergy
  • Q & A: Why do CD4 cell counts fail to rise in some patients on ART including those with undetectable viral loads?
  • Very Sick Person: Mycobacterium Avium Complex Infection

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Case Study: Sulfa Allergy

A 24-year-old man, who is known to be HIV positive, comes to clinic with fever and cough, which he has had for two weeks. His condition has become progressively worse and he is severely dyspneic. Sputum examination for acid-fast bacilli (AFB) is negative. Chest X-ray shows a mottled, ground-glass appearance in both lungs. There is no consolidation, cavitation or effusion.

The doctor diagnoses pneumonia due to pneumocytis carinii (PCP) and the man is admitted to hospital and given oxygen by nasal cannula. He is prescribed cotrimoxazole 1920mg tid.

On the 5th day at the hospital, the man develops a generalized erythematous, morbilliform rash with areas of epidermal necrosis. He becomes nauseated, has abdominal pains and vomits frequently.

  • How would you assess this person?
  • What tests would you request?
  • What medicines would you prescribe?
  • What advice would you offer?

Discuss the case as a group, and then refer to the comments on another page of this newsletter.


Q & A: Why do CD4 cell counts fail to rise in some patients on ART including those with undetectable viral loads?

QUESTION: (From a Clinical Officer in a government hospital in Mwanza) Why do CD4 cell counts fail to rise in some people on ART including those with undetectable viral loads?

ANSWER:

Between 5 - 27% of people taking ART have persistently low CD4 cell counts despite maintaining their treatment and having undetectable viral loads for long periods. Since increases in CD4 cell count are believed to be important in preventing illness, there is concern that these people may be at risk of disease progression even while their antiretroviral treatment is keeping their viral load low.

Failure of CD4 cell counts to rise could occur due to either:

low-level production of new cells, or
excessive destruction of CD4 T-cells.

Production of new CD4 T-cells occurs through division of long-lived ‘memory‘ T-cells that have already been activated by a foreign substance, as well as a production of new ‘naïve' cells in the thymus. In contrast, destruction of CD4 T-cells can occur as a result of HIV infection, by being killed by ‘cytotoxic' T-cells, or through cell suicide / death (apoptosis).

Studies suggest that people living with HIV and AIDS who have low CD4 counts have several immunological abnormalities. This group of people has fewer naïve CD4 cells produced from the thymus, suggesting the thymus function is impaired and the increased T cell death may be due to persistent HIV replication within the body.

The most important things to do are to monitor the person closely clinically, ensure maximum adherence to ART, and ensure prophylaxis of opportunistic infections by appropriate use of cotrimoxazole. In case of a change in status, discuss within a multidisplinary team including an HIV expert.

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VERY SICK PERSON
Mycobacterium Avium Complex (MAC) Infection

Disseminated MAC infection is a common complication of HIV, affecting between 30% and 40% of people living with HIV and AIDS. With the advent of ART, however, the incidence of this complication has greatly decreased. MAC is composed of two related species: M avium and Mycobacterium intracellulare, both of which are found in the environment and pose virtually no threat of virulence to HIV negative people.

MAC can be found in aerosols as well as in standing water and food sources. It is thought that dissemination and symptomatic disease follow invasion of the bacilli from the environment into the human through the respiratory or gastrointestinal tracts. The time from invasion to colonization to dissemination varies.  Furthermore, not all invasions of MAC into HIV positive people results in dissemination. Dissemination likely occurs by hematogenous spread (eg. through the blood), and the organs most often affected are the bone marrow, liver, spleen, and the lymph nodes.

Clinical presentation and diagnosis

MAC infection occurs late in the course of AIDS, with onset at an average of 7 to 15 months after the diagnosis of AIDS. The major predictor of infection is the level of immune dysfunction or the CD4 lymphocyte count. Infection rarely occurs when the CD4 lymphocyte count is over 100/mm³. Clinical manifestations are nonspecific and vary according to the organ affected.

Fever, weight loss, night sweats, abdominal pain, and diarrhea are the most common symptoms. Laboratory findings suggestive of MAC infection include a CD4 count less than 50/mm³, anemia, and low serum albumin levels. In addition, elevated lactate dehydrogenase and alkaline phosphatase levels are often seen with MAC infection.

There are several approaches to the detection of MAC that will facilitate diagnosis. Peripheral blood cultures can be done. In general, two blood cultures are necessary to detect the organisms. Another diagnostic option is liver biopsy. Although acid-fast bacilli can be found in any affected organ, the liver may offer the highest yield. Bone marrow biopsy can also be used but it is more painful and technically demanding than liver biopsy.

Treatment

The preferred treatment regimens include:

Clarithromycin 500 mg bid PO + ethambutol 15 mg/kg/day PO
Consider adding a third medicine if the CD4 count <50/mm³, there is a high MAC load or there is absence of effective ART. The therapeutic alternatives include rifabutin 300 mg/day PO or amikacin IV 10-15 mg/kg/day or ciprofloxacin 500-750 mg PO bid or levofloxacin 500 mg daily PO

Start ART simultaneously or within 1-2 weeks

An alternative regimen is azithromycin 500-600 mg/day PO + ethambutol 15 mg/kg/day PO.

A decrease in fever and improvement in blood culture results are expected in 2-4 weeks. New blood cultures should be obtained if there is no clinical improvement within 4-8 weeks, and treatment failure is defined by positive blood cultures at 4 to 8 weeks.

Sensitivity tests should be done at that time, and treatment should include the use of at least two new medicines showing in vitro activity.


Answer to the case study:

This person with PCP requires cotrimoxazole therapy (trimethoprim + sulfamethoxazole), but most likely he is severely allergic to this medicine. The most offending agent in this combination medicine is sulfamethoxazole.  There are a few effective alternative treatment options available, so in cases of a severe reaction (like this one), one of the alternative regimens should be used.  However, in mild allergic reactions, desensitization to cotrimoxazole often works and should be attempted.

An alternative regimen is:

- Dapsone 100 mg per day

As outlined above, in mild cases rapid desensitization may be attempted as follows:

Use a paediatric suspension (40 mg trimethoprim / 200 mg sulfamethoxazole per 5 mL)

- Hour 0 - put 1 ml suspension into 1000 ml water - give 0.5 ml
- Hour 1 - put 1 ml susp. into 1000 ml water - give 5 ml
- Hour 2 - put 1 ml susp. into 100 ml water - give 5 ml
- Hour 3 - put 1 ml susp. into 10 ml water - give 5 ml
- Hour 4 - give 5 ml susp. without dilution
- Hour 5 - give two cotrimoxazole tablets - total 960 mg
- Then begin the prescribed therapeutic dose

Do not use corticosteroids or antihistamines during this desensitization process.  If a mild reaction occurs during the process, desensitization may be attempted again from the beginning (eg. restart at "Hour 0" as above) but if the reaction is severe or is worsening, then the desensitization should be abandoned and one of the alternative PCP therapies used.

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