INTRODUCTION
CASE IN DETAIL
SL has been experiencing progressive lethargy over the past 2 months. His lethargy is so severe that he feels exhausted even on minimal exertion. Over this period he has noticed weight loss of about 10 kg despite a well-preserved appetite, and watery diarrhoea without associated abdominal pain, vomiting or nausea. Over the past 2 months he has been suffering from occasional epistaxis that spontaneously resolves. This has gradually progressed in frequency and on presentation he was experiencing epistaxis about four times a week. Each episode settles spontaneously and he loses about 20 mL blood. He denies any bleeding from other mucosal surfaces and denies frequent bruising.
He started to develop high fevers up to 39°C and drenching night sweats 1 month ago. For the past week he has been experiencing night sweats almost every night. He denies any cough, headache or urinary symptoms. He did not seek medical help until 3 days ago, when he presented to the HIV outpatients clinic for his 3-monthly follow-up. On assessment, he was referred for hospital admission for further investigation and management. Since admission he has had multiple blood tests and imaging studies, including CT scans of the head, chest and abdomen, a gallium scan, testing of urine and stool samples and a bone marrow biopsy.
SL was diagnosed with HIV infection 5 years ago when he presented with progressive dyspnoea, significant weight loss and seborrhoeic dermatitis. He was diagnosed with Pneumocystis carinii pneumonia on this presentation, and treated with intravenous and oral trimethoprim and sulfamethoxazole together with oral prednisolone. Since his recovery from the acute episode he has been maintained on trimethoprim and sulfamethoxazole 160/800 mg, one tablet daily, for secondary prophylaxis. He claims good compliance with this treatment and denies any side effects. On recovery from the P. carinii pneumonia he was commenced on antiretroviral therapy with zidovudine. He tolerated this agent well. Three years ago zalcitabine and indinavir were added to the regimen due to viral count rebound.
He experienced severe ureteric colic due to nepholithiasis after the commencement of this combination. Indinavir was ceased immediately. He was maintained on zidovudine and zalcitabine until 1 year ago when saquinavir was added to the regimen after a progressive decline in the CD4 count was noted. He did not experience any distressing side effects with these medications. Six months ago he voluntarily stopped all antiretroviral therapy because he found consuming so many tablets a tremendous inconvenience.
When his HIV infection was first diagnosed, his CD4 count was 0 and the viral load 230000 HIV RNA copies/mL. His most recent CD4 count taken 3 days ago when he presented at hospital was 100/mL and the viral load was 20 000 HIV RNA copies/mL.
He was diagnosed with cytomegalovirus retinitis one year ago when he presented with blurred vision and occasional floaters in the left eye. He was treated with intravenous ganciclovir for a period of 3 weeks and then changed to oral ganciclovir. He is currently maintained on 2 g ganciclovir three times a day. He denies any side effects associated with this therapy. He has follow-up with the ophthalmologist every 3 months and claims that he is compliant with the therapy.
He has experienced oral candidiasis twice in the past, the first time 4 years ago and then again 5 months ago. He was treated with oral fluconazole on both occasions. He is maintained on 150 mg fluconazole daily. He has not experienced any side effects with this treatment.
He denies any other opportunistic infections in the past.
He was diagnosed with diabetes mellitus 10 years ago when he presented with polyuria and polydipsia. The diabetes was considered to be a complication of the haemochromatosis, which was diagnosed subsequently. His diabetes was treated with combination insulin initially and he is now on twice-daily rapid-acting insulin, 40 units in the morning and 25 units at night before meals. He monitors his blood sugar levels twice daily and the recent readings have been between 6 and 8 mmol/L. He is compliant with the diabetic diet. He has never experienced hypoglycaemic episodes or suffered from diabetic ketoacidosis.
His general practitioner has investigated him for diabetic nephropathy with spot urine tests. The last test was done about 6 months ago and he was informed that he had no protein in his urine. He has never performed a 24-hour urine collection for testing. He denies any symptoms of chronic renal insufficiency. He sees his ophthalmologist every 3 months and has not been told of any diabetic retinopathy or cataract formation. He denies any visual symptoms currently. He has never seen a podiatrist. He has experienced paraesthesias of the distal extremities in both the upper and lower limbs, but has never had formal nerve conduction studies performed. He denies postural dizziness or impotence.
His haemochromatosis was diagnosed 10 years ago when his diabetes was investigated. He was initially treated with two 3-monthly desferrioxamine infusions followed by 6-monthly infusions for 2 years. He has not had any therapy for haemochromatosis for 8 years. His GP monitors his serum iron levels every 6 months. He denies any known hepatic involvement or any other complications of haemochromatosis.
In summary, his current medications are trimethoprim-sulfamethoxazole, ganciclovir, fluconazole and insulin.
He denies any allergies to medications.
He is an adopted child and therefore does not know whether there is any significant medical history in the family. He has never known his biological family.
He lives on the sixth floor of an apartment block with his partner. He has lived with two other partners previously and his first partner died of an AIDS-related illness. This was a traumatic experience for SL, even though he was separated from the man at the time of his demise. His second partner is also HIV-positive. He has been living with his current partner for the past 3 years and he is HIV-negative. Prior to meeting his first steady partner and after the two previous separations, he had unprotected sexual intercourse with multiple other partners on a casual basis. He has never suffered from any other sexually transmissible disease. He has been vaccinated against hepatitis B and hepatitis A in the past.
His current partner is very sympathetic and supportive. SL does not have any children.
He uses the lift to get to his apartment, and he has two steps inside his apartment that he negotiates without any difficulty.
He smokes 30 cigarettes a day and has a smoking history of 60 pack-years. He rarely, if ever, consumes alcohol. He smokes marijuana regularly at weekly intervals and rolls his own joints. He denies any other recreational drug use.
SL denies any sleep problems and has a satisfactory appetite. He has felt depressed at various times but has never sought medical help for this. He denies any current feeling of depression or suicidal ideation. He worked as a business consultant until 3 years ago when he decided to stop work due to lack of motivation. Currently he survives on sickness benefits, which he finds inadequate to support his lifestyle.
ON EXAMINATION
SL appeared cachectic. He had a depressive affect. His estimated body mass index was about 20. His pulse rate was 70 beats per minute, and it was regular in rhythm and normal in character. With the adoption of an upright posture his pulse rate rose to 90. His blood pressure was 110/70 mmHg without a postural drop and he was afebrile. His respiratory rate was 16 per minute at rest. He was alert and very cooperative. His cognitive function was intact, with a Mini-Mental State score of 30/30.
He had an intravenous cannula in his right forearm and the cannula site was not inflamed. He was not receiving any intravenous therapy at the time of examination. There was seborrhoeic dermatitis on the forehead and the nose as well as in the ventral aspect of the left forearm. No other cutaneous lesions were observed.
Gastrointestinal system examination showed no peripheral stigmata of chronic liver disease. There was oral candidiasis but there were no lesions in the perioral region. His abdomen was soft and non-tender. There was no palpable organomegaly or mass lesion. Bowel sounds were present. I was informed that the per rectum examination was unremarkable.
The respiratory system examination was unremarkable. Chest expansion was symmetrical with vesicular breath sounds.
Cardiovascular examination showed no elevation of the jugular venous pressure or peripheral oedema. He had two heart sounds, which were normal in character.
In the neurological examination his visual acuity in the left eye was 6/6 and in the right eye 8/6 without correction. Pupils were reactive and regular bilaterally. Fundoscopy showed a large cream-white patch immediately inferior to the macula in the left eye. Surprisingly, his visual fields were preserved, with intact extraocular movements. The remainder of the cranial nerve examination was unremarkable.
Upper limb examination showed generalised muscle wasting, with normal tone and reduced power of 4/5 at all levels bilaterally. Reflexes and coordination were normal. There was impaired pinprick sensation in a glove distribution bilaterally, with other modalities of sensation preserved. Sensory impairment extended to the level of the wrist bilaterally.
Lower limb examination showed generalised muscle wasting, with normal tone and impaired power of 4/5 at all levels bilaterally. Reflexes and coordination were preserved. Plantar response was flexor bilaterally. Pinprick sensation, joint position sensation and proprioception were impaired bilaterally to the level of the ankle in a stocking distribution. His gait was unremarkable.
There was no lymphadenopathy or bony tenderness.
His rheumatological examination was unremarkable.
In summary, this is a 44-year-old man with HIV infection presenting with constitutional symptoms on a background of poor compliance with antiretroviral therapy. He also suffers from haemochromatosis and diabetes mellitus.
The main problem with this man is non-compliance with antiretroviral therapy.
In addition I have identified four other medical problems and one social problem that need addressing.
The immediate medical problems are:
The possible differential diagnoses for his presenting picture include:
1. End-stage acquired immunodeficiency syndrome (HIV wasting syndrome)
2. An opportunistic infection such as disseminated Mycobacterium avium complex
3. Human immunodeficiency virus-associated non-Hodgkin’s lymphoma
4. Disseminated cytomegalovirus infection
5. Bacterial infection, such as Salmonella septicaemia
6. Cirrhosis with the development of a hepatoma.
The management objectives for this man are:
To start with, I would like to see the results of the following investigations:
1. Full blood count, looking for anaemia, leucocytosis, lymphopenia and thrombocytopenia
2. Blood cultures, including acid-fast cultures, that have been performed
3. Coagulation profile, looking for a coagulopathy
4. Current viral load and the CD4 lymphocyte subset count, to assess the activity of his HIV infection and the degree of CD4 subset lymphopenia
5. CT scan of the head, looking for ring-enhancing lesions, of the chest, looking for changes in the lung parenchyma and mediastinum for mass lesions, and of the abdomen, looking for organomegaly, lymphadenopathy and evidence of metastatic disease.
6. Gallium scan, looking for multiple foci of activity that may suggest lymphoma or disseminated sepsis.
7. Bone marrow biopsy, for the diagnosis of infiltrative lymphoma or infection with M. avium complex.
Questions and answers
Q: What is the antiretroviral therapy combination that you would recommend for this man?
A: The issues that need consideration in the recommencement of an antiretroviral regimen in this man are the need to overcome the viral resistance that may have developed to the formerly used agents, and formulation of a combination with a minimal side effect profile. Because he has been off antiretroviral therapy for almost 6 months it is likely that the virus will have reverted to wild type. I would consider commencing a new combination, comprising combivir and nevirapine. Combivir is a single tablet made with a combination of zidovudine and lamivudine, and can be given as two tablets twice daily. The combination of two agents in one tablet will reduce the number of tablets he has to take and thus improve compliance. This combination has a minimal side effect profile and, in particular, no neurotoxicity. I would not use any agent with the potential for neurotoxicity in this man due to his peripheral neuropathy.
Q: Would you exercise any caution in introducing nevirapine?
A: Yes, nevirapine can cause a severe rash. Therefore I would initially introduce it as two tablets once daily for about 2 weeks while observing for any rash. Then I would progress to the full dose of two tablets twice daily.
I chose nevirapine because it has been shown to have synergistic antiretroviral activity when combined with zidovudine and lamivudine.
Q: Interpret the following full blood count and tell us what you would do about it.
A: There is moderate anaemia and a significant thrombocytopenia. The anaemia is likely to be multifactorial. The likely contributors are chronic blood loss, anaemia of chronic disease, autoimmune haemolytic anaemia, M. avium complex sepsis and infiltrative lymphoma.
The other main abnormality in this blood picture is the profound thrombocytopenia, which may be the main contributing factor to his recurrent epistaxis. Thrombocytopenia may be due to bone marrow infiltration by lymphoma or M. avium complex or thrombocytopenia of the HIV infection itself.
To investigate his anaemia further, I would like to have a look at his blood film to ascertain the exact morphology of his red blood cells. In addition, I would like to know the results of the following investigations: serum creatinine and blood urea levels, looking for renal failure, reticulocyte count, serum iron studies, serum B12 and folate levels, and a haemolytic screen.
To treat this man I would transfuse him with two units of packed cells. Definitive management would depend on the results of the above investigations. But I believe diagnosis and treatment of his presenting condition and the recommencement of antiretroviral therapy would help improve both the anaemia and the thrombocytopenia.
Q: His liver function test results are as follows. What do you think is going on?
A: This man has a significant and dissociative elevation of serum alkaline phosphatase. AST and ALT are elevated only marginally. This picture fits disseminated M. avium complex (MAC) infection rather than hepatic infiltration with a lymphoma, hepatoma or cirrhosis due to haemochromatosis. I would pursue the diagnosis of disseminated M. avium complex infection.
Q: How would you diagnose M. avium complex infection?
A: I would perform multiple blood cultures taken at different times at least 12 hours apart. In total I would like to have four blood cultures done. I would request the cultures to be done using the BACTEC culture system, as this is the quickest and most reliable way of detecting MAC in the blood. I would also test bone marrow for acid-fast bacilli.
Q: Microscopic examination of the bone marrow aspiration biopsy showed acid-fast bacilli. How would you approach the management of this patient?
A: The diagnosis of M. avium complex is very likely, according to the clinical picture and also the investigational markers. I would commence treating him with a combination of clarithromycin 500 mg twice daily, rifabutin 300 mg daily and ethambutol 15 mg/kg daily. I would observe the patient for 2–6 weeks for any improvement in the clinical picture.
I am conscious of the fact that rifabutin is an inducer of the hepatic microsomal enzyme system and may decrease the serum levels of other drugs that this man takes. Therefore some of those drugs may need a dose increment.
Q: How long would you treat this man for the MAC infection?
A: I would treat him with this initial regimen for 12 weeks. Thereafter I would commence him on a suppressive regimen made up of the two agents azithromycin given at weekly intervals and rifabutin given daily. This therapy is given lifelong. Prior to the commencement of ethambutol therapy I would obtain an ophthalmology review for the patient and follow him up with ophthalmology reviews at regular intervals.
Q: What do you think is the cause of his thrombocytopenia and how would you manage it?
A: This is highly likely to be thrombocytopenia of HIV infection, which is an autoimmune phenomenon akin to idiopathic thrombocytopenic purpura. In addition, the infiltration of megakaryocytes by the virus can lead to a thrombocytopenia. The best treatment for the thrombocytopenia is to recommence antiretroviral therapy.
Q: What do you think is his likely prognosis?
A: His prognosis is extremely poor, but I would still actively treat his MAC infection and continue antiretroviral therapy, given his young age and previously good functional state.
Q: Could he have a lymphoma?
A: Non-Hodgkin’s lymphoma can occur at any stage of HIV infection. Given his significant immunosuppression, he is highly susceptible to the development of lymphoma.
His initial clinical presentation is consistent with the usual presentation ofHIV-associated non-Hodgkin’s lymphoma, but he did not have any lymphadenopathy, mass lesions or organomegaly, which are the expected signs in lymphoma. I would like to see the results of bone marrow biopsy, looking for lymphoma cells; results of the CT scans of head, chest, abdomen and pelvis, looking for lymphadenopathy and organ involvement; serum lactate dehydrogenase level, for an elevation; and a gallium scan, looking for ‘hot spots’.
Q: What else would you want to do for this man?
A: Another major cluster of problems that this man suffers from is weight loss, lethargy and anorexia. I believe these problems may resolve to a large extent with the treatment of his MAC infection and the HIV infection. It can be addressed further by treating him with agents such as megestrol acetate, dronabinol or the anabolic steroid nandrolone decanoate. Further to this I would recommend a high-protein, high-energy diet in consultation with a dietitian with expertise in dealing with patients with HIV.
His persistent diarrhoea should be investigated and treated appropriately. The likely contributing factors include MAC infection, HIV wasting disease, salmonellosis and infestation with parasites such as Cryptosporidium, Microsporidium and Isospora belli. I would test his stool samples for parasites, parasitic ova and cysts.
This man has significant social and psychological problems, warranting specialised care. Depression or dysthymia may contribute to his non-compliance with the antiretroviral therapy. To cope with his current physical debility, he may need psychological support. I would organise a review of his situation by a psychologist for evaluation and therapy. He also needs specialised counselling and further education, stressing the importance of antiretroviral therapy and compliance with it. He should be reassured that HIV is a chronic disorder that needs ongoing suppressive therapy and that modern medications are very successful in improving overall prognosis and quality of life. I would organise the hospital social worker to assess his financial status and the level of support available for him in the community.
Q: How would you manage his neuropathy?
A: His neuropathy is multifactorial. The main differential diagnoses are antiretroviral therapy toxicity and diabetic peripheral neuropathy. Antiretroviral drugs such as stavudine, didanosine and zalcitabine can cause a peripheral neuropathy, and this man was on zalcitabine previously. His neuropathy seems to persist despite stopping zalcitabine 6 months ago, and therefore the chance of its contributing significantly is low. A change of antiretroviral therapy to agents with no known neurotoxicity and strict blood sugar control are the remedies I would consider.
Q: How would you manage his haemochromatosis?
A: I would like to see the results of his recent iron studies. The parameters I want are: 1) serum ferritin, 2) transferrin saturations, and 3) serum iron. Any evidence of iron overload would warrant therapy with desferrioxamine rather than phlebotomy, given his anaemia on presentation.
The previously shown liver function profile does not exclude hepatic involvement of haemochromatosis and cirrhosis. Therefore I would follow him up with an MRI of the liver.
