Unit 9 Fever and Lymphadenopathy

1. Unit 9 Fever and Lymphadenopathy

2. Learning Objectives • Describe the differential diagnosis and evaluation of an HIV positive adult with fever • Apply therapeutic options for HIV infected adults with fever • Describe evaluation and management of HIV infected persons with lymphadenopathy Training on Clinical Care of HIV, AIDS and Opportunistic Infections

3. Definitions: Persistent Fever • Applies to outpatient with HIV being seen by a nurse in a Level I primary care clinic • Temperature > 37.5°C • At least 2 weeks duration • Persistent or recurrent • No other significant signs/symptoms Republic of Namibia, MoHSS Guidelines for the Clinical Management of HIV and AIDS, 2001. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

4. Pyrexia of Unknown Origin (PUO) • Phrase created in the 1960’s to describe patients with fever lasting > 3 weeks and that remains unexplained despite > 1 week of investigation in hospital • Now 4 categories: • Classical • HIV-associated • Immunosuppression-associated • Nosocomial Training on Clinical Care of HIV, AIDS and Opportunistic Infections

5. Classic Pyrexia of Unknown Origin IMAGINE: Infections Medication Auto-immune disorders Granulomatous conditions Idiopathic Neoplasia Endocrine disorders Training on Clinical Care of HIV, AIDS and Opportunistic Infections

6. Definitions: HIV-Associated PUO • Applies to an HIV infected patient undergoing evaluation by a doctor for fever • Temperature > 38°C • Outpatients • ≥ 3 weeks duration • Inpatients • ≥ 3 days in hospital • No diagnosis made in this time Source: Mandell, G.L., J.E. Bennett, R. Dolin. Principles and Practice of Infectious Disease. Sixth Edition, 2004. Elseiver, Inc. www.elseiver.com Training on Clinical Care of HIV, AIDS and Opportunistic Infections

7. HIV-Associated PUO • Infections and malignancies are most common • Auto-immune (connective tissue) conditions are rare in patients with severe immunosuppression • Differential varies by CD4 cell count Training on Clinical Care of HIV, AIDS and Opportunistic Infections

8. PUO: Conditions Occurring in Namibia At Any CD4 Count • Bacterial Infection • TB • Bacterial pneumonia • Urinary tract infection • Sinusitis • Salmonella (enteric fever) • Borrelia • Brucella • Intra-abdominal, intra-hepatic or other hidden abscess Training on Clinical Care of HIV, AIDS and Opportunistic Infections

9. PUO: Conditions Occurring in Namibia At Any CD4 Count (2) • Parasitic Infection • Malaria • Trypanosomiasis • Viral Infection • Viral hepatitis, Primary HIV infection • Malignancy • Alcoholic hepatitis • Drug reactions Training on Clinical Care of HIV, AIDS and Opportunistic Infections

10. HIV-Associated PUO: Conditions in Southern Africa at Low CD4 Counts • CD4 < 200 • Pneumocystis pneumonia (PCP), Kaposi’s Sarcoma, Lymphoma • CD4 < 100 • Cryptococcus, Toxoplasma, Histoplasma, MOTT (M. kansasii) • CD4 < 50 • MOTT (M. avium complex), Cytomegalovirus (CMV) Training on Clinical Care of HIV, AIDS and Opportunistic Infections

11. HIV-Associated PUO (Study from New York City, USA) Source: Mandell, G.L., J.E. Bennett, R. Dolin. Principles and Practice of Infectious Disease. Sixth Edition,2004.Elseiver, Inc. www.elseiver.com Training on Clinical Care of HIV, AIDS and Opportunistic Infections

12. Principles in Managing HIV-Associated Fever • Confirm HIV infection if not already done • Perform clinical and laboratory staging • Consider local endemic infections • Look for focal organ involvement that can provide clues to the diagnosis • Provide empiric therapy if needed as the evaluation proceeds Training on Clinical Care of HIV, AIDS and Opportunistic Infections

13. Persistent Fever in Primary Care Setting • Perform a history and physical exam • Refer severely ill patients immediately • Antipyretic therapy • Assure proper hydration • If no cause is apparent. Do a rapid test and treat as indicated • For malaria: in an endemic area during malaria season Training on Clinical Care of HIV, AIDS and Opportunistic Infections

14. Empiric Therapy Options in Primary Care Setting • Blood smear negative and patient not on CTX prophylaxis • Cotrimoxazole 80/400 two tablets bd for 5 days. • Treats many bacterial causes • On CTX with respiratory symptoms • Amoxycillin 500 mg 8 hourly for 5 days • On CTX with GI symptoms or urinary tract symptoms • Nalidixic acid 1000 mg QID for 5 days Training on Clinical Care of HIV, AIDS and Opportunistic Infections

15. No Improvement with Empiric Antibiotics • Refer to medical doctor for history and physical exam • Examinations • FBC • CD4 cell count • Urine dipstick • Blood Culture • Sputums for AFB • Malaria/Borrelia smear • Consider chest x-ray now if seriously ill • Consider stool exams in case of diarrhea Training on Clinical Care of HIV, AIDS and Opportunistic Infections

16. Initial Work-up Inconclusive • Repeat history and physical exam • Retinal exam • Chest X-ray if not yet done • Liver chemistry tests • Consider repeat malaria/borrelia smear • Consider repeat blood culture, with anaerobic and mycobacterial cultures • Consider CSF examination • Consider abdominal ultrasound Training on Clinical Care of HIV, AIDS and Opportunistic Infections

17. CMV Retinitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

18. Dry-Season Bacteremia in Malawi 70 (30%) of 233 adult patients with HIV admitted for fever during the dry season in Lilongwe had a positive blood culture. Source: Archibald L et al. J Infect Dis. 2000;181:1414. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

19. Wet-Season Bacteremia in Malawi 67 (36%) of 238 adult patients with HIV admitted for fever during the wet season in Lilongwe had a positive blood culture. Source: Bell M et al. Int J Infect Dis. 2001;5(2):63-9. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

20. Abdominal Ultrasound in AIDS Comparison of results among adults referred for U/S in Congo and Zambia Source: Tshibwabwa, ET et al. Abdominal Imaging. 2000 May-Jun;25(3):290-6. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

21. Do Not Miss Common Treatable Conditions • HIV-associated • Tuberculosis • Pneumocystis • Cryptococcosis • Toxoplasmosis • Other • Malaria • Borrelia • Typhoid • Brucellosis • Endocarditis, urinary tract infection, abdominal abscess Training on Clinical Care of HIV, AIDS and Opportunistic Infections

22. Tuberculosis • Most common cause of undiagnosed chronic fever among Namibians with HIV • Disseminated infection may not cause localised organ dysfunction • Over time, clues may emerge that can be further evaluated • Miliary pattern on CXR • Adenopathy • Pleural, pericardial disease • Meningitis • Infiltrative liver disease • Anaemia Training on Clinical Care of HIV, AIDS and Opportunistic Infections

23. Tuberculosis (2) • Typical abnormalities in body fluids are strongly suggestive of TB (CSF, pleural, peritoneal fluid) • Beware: CSF may be normal in TB meningitis occurring in HIV patients • Ziehl-Nielson stain and cytology or histology of aspirate or biopsy (including bone marrow) may provide evidence of TB Training on Clinical Care of HIV, AIDS and Opportunistic Infections

24. Tuberculosis (3) • A decision to give empiric treatment for TB • Is not just a therapeutic trial but a commitment to provide a course of therapy • Requires follow-up and patients who do not respond require further evaluation Training on Clinical Care of HIV, AIDS and Opportunistic Infections

25. Pneumocystis Pneumonia • Some patients may not complain of dyspnea • Count respiratory rate at rest and with exercise • Chest sounds may be normal • Interstitial, not alveolar, disease • Chest x-ray may initially be normal • The disease is progressive without therapy, so re-evaluation will lead you to suspect the diagnosis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

26. Cryptococcus • May present as an interstitial pneumonia before, or at the same time as, meningitis • Severely immunosuppressed persons often do not have meningismus • No stiff neck • May have only fever, headache, perhaps change in mental status or cranial nerve findings Training on Clinical Care of HIV, AIDS and Opportunistic Infections

27. Cryptococcus (2) • Have a low threshold for performing a lumbar puncture • Always perform India ink exam on CSF • Request lab to send for cryptococcal Ag if India ink negative • In Durban 17% of AIDS patients with Cryptococcal meningitis had CSF that was normal except for the presence of yeast cells • Effective therapy is widely available in Namibia and underused Training on Clinical Care of HIV, AIDS and Opportunistic Infections

28. Toxoplasmic Encephalitis • May or may not be associated with fever • Focal neurologic deficit may be subtle • Progression of focal neurologic findings over days to weeks suggestive • Clinical response to empiric therapy is usually evident within 2 weeks Training on Clinical Care of HIV, AIDS and Opportunistic Infections

29. Malaria and HIV • HIV-1 infection is associated with an increased frequency of clinical malaria and parasitaemia • Incidence rates of P. falciparum clinical disease increase as CD4 counts decrease • Genotyping shows the infections are new, and not recrudescence of previous infection Training on Clinical Care of HIV, AIDS and Opportunistic Infections

30. Malaria treatment • Coartem® • Combination tablet of • Artemether (20 mg) – fast acting and • Lumefantrine (120 mg) – slow prolonged action • Active against chloroquin resistant falciparum • Most common side effects • GI symptoms, headache, sleep disturbance, dizziness, myalgia or arthralgia, palpitations, cough Training on Clinical Care of HIV, AIDS and Opportunistic Infections

31. Coartem • Doses are weight-banded • 6 doses in 3 days: • First dose stat, repeat in 8 hours • Same dose bd on days 2 and 3 • ≥35 kg, 4 tablets/dose • Absorption improved if taken with food • Not currently approved for use in pregnant women and children < 6 months old Training on Clinical Care of HIV, AIDS and Opportunistic Infections

32. Borrelia • Tick borne relapsing fever caused by many species of Borrelia • 3-day long episodes of high fever with rigors and severe headache recur at 7 day intervals with splenomegaly (41%), hepatomegaly (17%) and rash (28%) • Spirochetes seen on blood smear • Tetracycline or erythromycin 500 mg 4x daily for 5-10 days • Doxycyline 100 mg bd for 5-10 days • IV penicillin/ceftriaxone for meningitis Training on Clinical Care of HIV, AIDS and Opportunistic Infections

33. Typhoid and Other Salmonella Bacteremia • More common in rainy season in neighboring countries; maybe infrequent in Namibia • Fever without or with GI symptoms, transient rash, splenomegaly • Leucopaenia common, blood cultures confirm diagnosis • Treatment: flouroquinolones, chloramphenicol • Local salmonella species resistant to ampicillin and amoxycillin • ceftriaxone is active but rarely used for this in Namibia Training on Clinical Care of HIV, AIDS and Opportunistic Infections

34. Brucellosis • Acquired from infected cattle and dairy products • Chronic fever, sweats, fatigue, pain, adenopathy (20%), hepatosplenomegaly (20-30%), epididymitis (20%), mild pancytopenia • Diagnosed with blood or bone marrow culture and antibody tests • Treatment • Doxycyline 200mg/d with rifampicin 600mg/d for 6 weeks • Doxycycline for 6 weeks with streptomycin IM daily for 2-3 wks Training on Clinical Care of HIV, AIDS and Opportunistic Infections

35. Empiric Therapy of Bacterial Infections • Respiratory tract & Pneumonia • Not very sick: high dose amoxycillin, azithromycin, erythromycin, tetracycline • Very sick: high dose penicillin with gentamicin or cefuroxime with azithromycin • Meningitis • Ceftriaxone or high dose penicillin + chloramphenicol Training on Clinical Care of HIV, AIDS and Opportunistic Infections

36. Empiric Therapy of Bacterial Infections (2) • Skin and soft tissue (suspected S. aureus) • Cloxacillin, erythromycin, cephalothin • Bone and joint (suspected S. aureus) • Clindamycin or cloxacillin, • Urinary tract infection • Nitrofurantoin • Nalidixic acid • Not improving or very sick: ciprofloxacin +/- gentamicin Training on Clinical Care of HIV, AIDS and Opportunistic Infections

37. Empiric Therapy of Bacterial Infections (3) • Bacillary dysentery • Nalidixic acid, ciprofloxacin • Metronidazole if amebiasis or C. difficile suspected • Intra-abdominal abdominal abscess or peritonitis • Ampicillin, gentamicin, metronidazole Training on Clinical Care of HIV, AIDS and Opportunistic Infections

38. Empiric Therapy of Bacterial Infections (4) • Endocarditis • Native valve: penicillin and gentamicin • Drug injector: ciprofloxacin or cephalothin + gentamicin • Sepsis or bacteremia • Ampicillin and gentamicin OR • Cefuroxime and gentamicin • Neutropenic fever • Pipiracillin/tazobactam with gentamicin Training on Clinical Care of HIV, AIDS and Opportunistic Infections

39. Generalised Lymphadenopathy: Differential Diagnosis • Acute Retroviral Syndrome • HIV associated Persistent Generalised Lymphadenopathy • not a febrile illness • Secondary syphilis • EBV or CMV viral infection • Autoimmune disease • Unusual in immunosuppressed patients Training on Clinical Care of HIV, AIDS and Opportunistic Infections

40. Localised Lymphadenopathy: Differential Diagnosis • Acute Bacterial Infection • Nodes draining a localised bacterial infection • Sexually Transmitted Infection • Chancroid • Lymphogranuloma venereum • Chronic Infection • Tuberculosis, MOTT • Histoplasma • Immune Response Inflammatory Syndrome • Cancer • Lymphoma • Kaposi’s Sarcoma • Metastases Training on Clinical Care of HIV, AIDS and Opportunistic Infections

41. Localised Adenopathy • Evaluation of localised adenopathy not due to a local draining infection (pharynx, skin, limb), STI, or obvious KS • Needle aspiration of suppurating node for drainage and diagnosis • Rarely surgical drainage is needed • Needle aspiration for cytology and AFB smear • Biopsy Training on Clinical Care of HIV, AIDS and Opportunistic Infections

42. Yield of Needle Aspiration for Diagnosis: HIV-Related Lymphadenopathy - Zambia Source: Patil and Bern. Journal of Clinical Pathology 1993;46:806-9. Training on Clinical Care of HIV, AIDS and Opportunistic Infections

43. Key Points: Fever • First rule-out malaria • Attempt antibacterial empiric therapy • Tuberculosis is the most common cause (but not the only cause) of pyrexia of unknown origin in HIV+ patients in Southern Africa Training on Clinical Care of HIV, AIDS and Opportunistic Infections

44. Key Points: Adenopathy • Generalised adenopathy may be Primary HIV, PGL, another viral infection, secondary syphilis, or an auto-immune disease • Localised adenopathy usually has a specific cause and needs to be fully evaluated Training on Clinical Care of HIV, AIDS and Opportunistic Infections