FHM fever 2009

PROLONGED FEVER IN HIV INFECTION : 

PROLONGED FEVER IN HIV INFECTION DEPARTMENT OF MEDICINE-I CMCH VELLORE

Session objectives : 

Session objectives At the end of the session, the participant should be able to discuss the approach to evaluation of fever in a PLHA order appropriate investigations in such situations plan treatment appropriately based on the diagnosis manage complications

Approach to fever : 

Approach to fever Acute febrile illness < 2 weeks Malaria Typhoid Scrub Typhus Bacterial Pneumonia Sinusitis Drug fever IRIS Prolonged fever > 2 weeks TB, Histoplasmosis Penicilliosis, Brucella Meliodosis, Nocardiosis Leishmaniasis Sarcoidosis Lymphomas Vasculitis

FEVER OF UNKNOWN ORIGIN : 

FEVER OF UNKNOWN ORIGIN DEFINITION: Petersdorf and Beeson in 1961 Fever higher than 101º F on several occasions, persisting without diagnosis for at least 3 weeks in spite of at least 1 week’s investigation in the hospital With the advent of AIDS,complex surgical & ICU protocols, and increased diagnostic investigations,this has been modified by Durack and Street et al into 4 categories: Classic, Nosocomial,Neutropenic and HIV related

Slide 5: 

FEVER OF UNKNOWN ORIGIN - SPECTRUM WORLD INDIA

DEFINITION OF FUO : 

DEFINITION OF FUO

Slide 7: 

FUO ETIOLOGY DEPENDS ON A FEW FACTORS GEOGRAPHIC LOCATION e.g.,Meliodosis (Northern Australia and South-East Asia) Kikuchi-Fujimoto disease(Japan) 2) AGE Infants- No cancers or connective tissue disease, predominantly infections Elderly- Infections, connective tissue diseases and cancers. 3) TYPE OF HOSPITAL 4) Occupation

Slide 8: 

COMMON CAUSES OF CLASSIC FUO INFECTIONS- Abscesses, endocarditis, tuberculosis, complicated Urinary tract infections CONNECTIVE TISSUE DISEASES- Still’s disease,systemic lupus erythematosus, variants of rheumatoid arthritis MALIGNANCIES- Lymphomas, Hypernephromas

PROLONGED FEVER : 

PROLONGED FEVER Is a common sign in HIV infection Usually caused by a treatable opportunistic infection.

DIAGNOSTIC EVALUATION OF HIV PATIENTS WITH FUO : 

DIAGNOSTIC EVALUATION OF HIV PATIENTS WITH FUO Comprehensive history Repeated physical examinations Complete blood counts, malarial parasites x 3 Urinanalysis Chest radiograph ANA Rheumatoid factor Blood cultures x 3 CT thorax, abdomen or ultrasound abdomen CD4 counts Tuberculin skin tests Venous duplex imaging Radionuclide scans

Slide 11: 

CAUSES OF FUO IN HIV-INFECTED PATIENTS CAUSE PERCENTAGE Tuberculosis 35.5 Mycobacterium avium complex 11.5 Visceral leishmaniasis 9.9 Pneumocystis carinii pneumonia 5.6 Mycobacteria other M.Tb and MAC 4.5 Non-Hodgkins lymphoma 4.2 Bacterial infections 3.9 Cytomegalovirus infection 2.5 Toxoplasmosis 2.4 Cryptococcosis 1.5 HIV associated fever 1.3 Histoplasmosis 0.5 Drug-induced fever 0.5

CAUSES OF PROLONGED FEVER IN INDIA : 

CAUSES OF PROLONGED FEVER IN INDIA DISS. TB 43% PULM. TB 16% EXTRAPULM. TB 10% PCP 7% CRYPTOCOCCOSIS 10% CER.TOXOPLASMA1% CA PNEUMONIA 2% AMOEB.L.ABSC 2% DISSEM HISTO 1% SINUSITIS 1% SBP 1% PYO.MENINGITIS 1% MALARIA 1%

Slide 13: 

Rupali P NMJI 2003

EVALUATION OF DIAGNOSTIC TESTS : 

EVALUATION OF DIAGNOSTIC TESTS U/S ABD 28/33= 85% BM TREPHINE 10/24= 42% LN FNAC 28/37= 75%

Correlation of infections causing fever with CD4 counts : 

Correlation of infections causing fever with CD4 counts CD4 CELL COUNT >500 / CU.MM 200-500 200 <50 COMPLICATIONS Acute retroviral synd. Bacterial Pneumonia Pulmonary Tb PC Pneumonia Extrapulmonary Tb Cryptococcosis Disseminated MAC/CMV

Slide 16: 

How useful is Absolute lymphocyte count ? Predictor of AIDS useful in identifying patients at risk of developing AIDS defining illnesses ALC < I000/mm3 predictive of CD4 count < 200 cells/mm3 ALC > 2000/mm3 predictive of CD4 count > 200 cells/mm3 [Shapiro NI, Karras DJ, Leech SH, Heilpern KL. Absolute lymphocyte count as a predictor of CD4 count. Ann Emerg Med 1998 Sep;32(3 Pt 1):323-8]

Absolute Lymphocyte Count : 

Absolute Lymphocyte Count ALC OF 1000 CORRELATES WITH A CD4 COUNT OF 200 [JAPI 1997 VOL45(6):455-6] ALC AIDS No AIDS Total <1000 45 6 51 >1000 36 7 43 81 13 94 The positive predictive value of ALC for AIDS was 45/51=88%

Slide 18: 

When the infamous bank robber Willie Sutton was asked why he robbed banks he reportedly replied, “That is where the money is.”

Case study : 

Case study Mr. V, 35 year old trucker from Namakkal, was diagnosed to have HIV infection two years ago. He presented with symptoms of fever and chills of two months duration. What are the specific questions you would like to ask in the history? Duration of HIV infection Associated symptoms – respiratory, CNS, urinary, abdominal and general symptoms like weight loss History of tuberculosis and TB treatment Other opportunistic infections Opportunistic Infections prophylaxis Highly active antiretroviral therapy Co-existent morbidity: Alcoholism, IVDU

Slide 20: 

What are the clinical findings that you would look for? Oral candida, oral hairy leukoplakia, hyperpigmentation Significant generalized lymphadenopathy Skin lesions - nodules, papules Hepatosplenomegaly, intra-abdominal glands Respiratory distress, lower respiratory signs Neck stiffness, limb weakness Fundal lesions – haemorrhages Elevated JVP, heart murmurs Genital examination - ulcers, glands Per Rectal examination - prostatic tenderness and fluctuation

GROUP ACTIVITY : 

GROUP ACTIVITY 6 groups and choose a leader who will explain the differential diagnoses

Case study I : 

Case study I 25 yr old male software consultant from Chittoor presents with fever for 1 week with chills and rigors. HIV infection diagnosed 6 months ago and he has been asymptomatic with no OIs. His WBC count done 2 months ago was TC 7000 cells/mm3 and differential count: neutrophils 55%, lymphocytes 40%, eosinophils 2%, basophils 2%. On examination: Weight 70 Kg, well built. No skin or mucous membrane findings, no lymph nodes enlarged. Spleen 2 cm. No cardiovascular, respiratory or neurological findings.

Slide 23: 

What is his stage of HIV infection WHO clinical group 1. Clinically he is asymptomatic and has no clinical signs of immunodeficiency. His absolute lymphocyte count is 2800 cells/mm3 which approximately correlates to a CD4 count of >200 cells List the likely causes of fever in this patient Malaria, Typhoid, Hepatitis, Viral fever What tests will you order to evaluate the fever? Total and differential white cell count Malarial smear - thick and thin Blood culture (if available) Typhidot IgM LFT, Chest X-ray Urine microscopy – as part of a routine work up

Slide 24: 

His MP smear is found to be positive for P. vivax. What treatment would you start him on? Chloroquine 600 mg ( four 150 mg tablets) - Day 1 Chloroquine 600 mg (four 150 mg tablets) - Day 2 (300mg x 2) Chloroquine 300 mg (two 150mg tablets) - Day 3 Primaquine 15 mg OD for 14 days (NMEP regimen) Is there any role for prophylaxis for malaria for him? There is no increased risk for the development of malaria in HIV infection. Since he is residing in an endemic area, there is no role for malaria prophylaxis

Case study II : 

Case study II 32 yr old Ms C a female sex worker presented with a history of high grade fever with chills and rigors of 5 days duration and alteration of sensorium since this evening. On examination she is icteric, with a mild rash over her trunk, no neck stiffness and rest of the systems are within normal limits

What is your diagnosis ? : 

What is your diagnosis ? Scrub typhus If no eschar the DDx would have been Dengue fever Leptospirosis Viral hepatitis Malaria Typhoid fever

Slide 27: 

Mr. V a transgender was diagnosed to have HIV infection when he consulted his local GP for recurrent genital ulceration last year. Now he has 3 months history of fever with significant loss of weight and appetite. He had noticed darkening of skin and loose stools on and off. He also had occasional headache. On examination: An emaciated individual, temperature-38 0C, respiratory rate-24/min, Pulse rate-100/min. Darkening of palms and soles and generalized pruritic papular rash. Two 0.5 x 0.5 cm lymph nodes in the deep cervical region, a few small axillary nodes. Abdominal examination-mild hepatosplenomegaly. CNS examination-no signs of meningeal irritation, no papilloedema or focal deficits. CASE STUDY III

Slide 28: 

What is his clinical stage of HIV infection? WHO clinical stage 3 Based on his clinical stage what differential diagnosis would you consider in order of probability? Differential diagnoses 1. Disseminated tuberculosis 2. Lymphoma 3. Histoplasmosis 4. Cryptococcosis Tests BM trephine revealed AFB in tissue with ill formed granulomas and subsequently grew on culture

Case study IV : 

Case study IV 40 yr old Mr. R from Assam, IV drug abuser in the past, presented to us with fever, abdominal pain and cough of 2 months duration. Examination revealed a hepatosplenomegaly with a few lymph nodes in the cervical region. HIV ELISA was positive. Tests revealed elevated ESR, liver enzymes and alkaline phosphatase. Chest X-ray showed a mild hilar prominence. Ultrasound Abdomen showed a hepatosplenomegaly with adrenal enlargement. A CD4 count was done, which was found to be 102 cells/cu.mm. What are your differential diagnoses?

Slide 30: 

DDx Disseminated Histoplasmosis Disseminated Tuberculosis Lymphoma Management Itraconazole Amphotericin B

Case study V : 

Case study V 38 yr old male from Namakkal, diagnosed HIV positive in July 2002, on empirical ATT since July 2002, developed PCP in October 2002. His CD4 count was 110. He was started on Bactrim, and noted remarkable improvement. At discharge, he was started on HAART with Zidovudine /Lamivudine and Efavirenz. In Nov 2002 he presents with fever and cough of 9 days’ duration, with inspiratory crackles in right infra-scapular, left infra-axillary, and mammary areas. Chest X-ray shows bilateral patchy parenchymal opacities and CD 4 counts are 390 cells/cu.mm. What is your diagnosis?

Case study VI : 

Case study VI Ms. S a 35-year-old female, diagnosed HIV positive 2 months ago after an episode of multi-dermatomal herpes zoster presented with a 2-week history of high-grade intermittent fever with occasional chills and a dry cough. No BOE. Was never on HAART but is on Bactrim prophylaxis for 18 days. Tests revealed an eosinophilia, normal blood count, MPX3, Blood and Urine C/S, Chest X-ray, Induced Sputum for PCP, Ultrasound Abdomen, etc., were non-contributory. What are the possibilities?

Slide 34: 

48-yr-old truck driver from Mizoram presented with a 3-month history of an ulcerative black lesion on the forehead. He developed fever with chills, cough, hemoptysis and weight loss in the last 2 months. There was no history of other skin lesions, underlying heart disease, past history of tuberculosis, surgery, blood transfusions or IV drug abuse. He denied any high-risk behaviour. Exam revealed a thin gentleman with small posterior cervical nodes, pallor, and a 5 x 4 cm blackish ulcerative lesion superior to his right orbit with peri-lesional oedema. He was febrile, and had no other skin lesions. RS : bilateral scattered crackles. PA: 2 cm non-tender hepatomegaly and a 1 cm splenomegaly. Cardiovascular and central nervous system examination was normal. Case Study VII

Slide 35: 

Investigations were as follows: Hemoglobin = 8.2 g%, Retics = 0.8%, MCV = 94 T. WBC count = 4,600/cm with N 77, E 1, L 20, and M 2. ALC was 920/cu.mm. ESR = 120 mm and platelets 1,85,000/cu.mm. Renal functions were normal, Liver function tests = 7.7/ 2.9 / 77 / 54 / 125 U/L. Chest x-ray : peribronchial inflammation, U/S abdomen: mild ascites, hepatomegaly and thickened mesentery. Sputum AFB negative. He was found to be ELISA reactive for HIV.

Case study VIII : 

Case study VIII 45 year old male from North India presented with high grade fever, fatigue and weight loss for 2 months. On examination he was pale, hyperpigmentation over his skin , oedematous, and had a splenomegaly. Tests revealed anemia, leukopenia, mild drop in platelets, hypergammaglobulinemia A test was done

Slide 38: 

MISCELLANEOUS CAUSES OF FEVER Drug fever Malaria Infective endocarditis Typhoid Bacterial pneumonia Disseminated salmonella infection Sinusitis MISCELLANEOUS CAUSES OF PULMONARY DISEASE IN THE HIV-INFECTED Lymphoid interstitial pneumonitis Non-specific interstitial pneumonitis

Unusual causes of PUO in India : 

Unusual causes of PUO in India Penicilliosis- North east Hepatosplenomegaly, skin and subcutaneous tissue Histoplasmosis- Eastern India GI involvement, hepato-splenomegaly, oral ulcers Kala-azar Classical features of disease, high relapse rate Meliodosis Fever with visceral abscesses (liver or splenic or cutaneous abscess Brucellosis Fever with joint or skeletal involvement

Slide 40: 

PCP IN THE HIV-INFECTED DIFFERENTIATED FROM BACTERIAL PNEUMONIA Duration of symptoms character of the sputum radiologic manifestations POOR PROGNOSTIC FACTORS FOR PCP Older age severity of pulmonary dysfunction at time of therapy PaO2 < 50 mmHg Alveolar-arterial gradient > 30 mmHg Abnormal chest X-ray Severe immunodeficency concomitant pathology large number of organisms on BAL or biopsy

Slide 44: 

ICU CARE IN PCP TIME YEARS SURVIVAL Era 1 1981-85 antimicrobials 14% Era 2 1986-88 adjunctive steroids 40% Era 3 1989-91 repeat episodes of PCP 24% Era 4 1992-95 antiretrovirals 63% Era 5 1996 onwards HAART 71% FAILURE OF PRIMARY THERAPY Switch to IV Trimetrexate with/without IV Co-trimoxazole IV Clindamycin with oral primaquine Use two specific therapies concurrently IV pentamidine

Slide 46: 

MAC IN THE HIV-INFECTED Can colonize normal and immunodeficient hosts,occurs at CD4<100 cells/mm3 Always demonstrate invasive disease before treatment Diagnostic criteria for pulmonary MAC Radiographic evidence with either one of the following Positive sputum culture (2+) + AFB smear (2+) Positive culture + multiple positive AFB smears Or 2 positive cultures + 1 positive smear within 1 year Or 3 positive cultures within 1 year Or positive culture from a lung biopsy Or typical histologic features on biopsy +positive sputum culture Clinical features of pulmonary MAC:productive cough,fever Weight loss,hemoptysis

Slide 47: 

Radiographic appearance of pulmonary MAC Thin walled cavities Diffuse bilateral upper lobe infiltrates Localized bronchiectasis Clinical manifestations of disseminated MAC Fever,night sweats,anorexia,weight loss,hepatomegaly, Diarrhea,splenomegaly,abdominal pain Few reports of MAC in AIDS patients( proven by culture) in India Hence it is very rare,and diagnosis can only be made by Culture Therapy is lifelong unless patient is on HAART

Slide 51: 

CMV IN THE HIV-INFECTED Largest virus to infect man Disease is varied ranging from no disease in the normal host,congenital CMV disease in neonates, infectious mononucleosis in adults. In AIDS it is the commonest viral opportunistic pathogen Diagnosis is by typical cytopathic changes in tissue culture Or histopathology [ large,rounded,ground glass cytomegalic inclusions are seen in cytoplasm of infected cells]

Slide 52: 

Clinical manifestations include: Retinitis, pneumonia,polyradiculopathy,colitis,pancreatitis In autopsy series from India in AIDS patients CMV caused Pulmonary pathology 7%, GI path 27% CNS path 7% CMV retinitis occurs in 17% of ocular lesions in adults and 33% in children Biswas J, Madhavan HN, George AE, Kumarasamy N, Solomon S. Ocular lesions associated with HIV infection in India: a series of 100 consecutive patients evaluated at a referral center.Am J Ophthalmol 2000 Jan;129(1):9-15

Slide 56: 

HISTOPLASMOSIS IN THE HIV-INFECTED Discovered in December 1905 Fungus with 2 phases:mycelia and yeast.Transition occurs At high temperatures Pathogenesis:Macrophages are responsible for host resistance to this fungus. In HIV macrophages manifest defective activity Clinical manifestations:Acute pulmonary ,mediastinal granuloma,cavitary,progressive disseminated-acute,subacute Chronic. Acute PDH is seen in AIDS at CD4<200 cells/mm3 Fever,malaise,weight loss,cough,diarrhea Hepatosplenomegaly 100%,LNE 30%, Oropharyngeal ulcers <20%

Slide 57: 

Diagnosis is by histoplasma isolation from blood and body fluids.Histopathological section show caseating or non-caseating granulomas.Histochemical staining with PAS,GMS or Grocott silver stain. Treatment:Amphotericin B total dose=30-35mg/kg Itraconazole 200mg bid for 6 months About 50-60 cases of Histoplasmosis are reported in Indian literature. Commonest variety seems to be the oropharyngeal Followed by the disseminated variety A case series from our institution revealed that about 21% occurred in HIV positive patients. Risk factors: CD4 count <200 cells/mm3 History of exposure to a chicken coop

Slide 62: 

PENICILLIOSIS IN THE HIV-INFECTED Penicillium marneffei-thermally dimorphic fungus, occurs in a limited geographic area-South-East Asia and South China Before AIDS only 29 cases were reported worldwide but now numerous reports of disseminated infection Infection occurs during rainy season and during exposure to soil by inhalation of conidia Clinical features:Chronic illness fever,weight loss,skin and mucosal lesions, anemia,leukocytosis, LNE, hepato-splenomegaly, Radiological features:CXR:diffuse,reticulonodular,cavitary opacities

Slide 63: 

Diagnosis: Organism on smear,biopsy or culture. Intracellular yeast forms,extracellular sausage forms or as hyphae On biopsy appear as granulomas, suppurative or necrotizing reactions. Disseminated disease usually has skin /mucosal lesions Treatment:IV Amphotericin B for 2 weeks followed by itraconazole for 10 weeks. Lifelong prophylaxis A series of 50 cases of P.Marneffei in 202 HIV patients reported from Manipur in India.

Slide 66: 

NOCARDIOSIS IN THE HIV-INFECTED Aerobic actinomycete ubiquitous environmental saprophyte No data available on nocardiosis in HIV/AIDS in India.In the non-immunocompromised the prevalence varies from 1.4-1.9% Clinical manifestations:Cutaneous and lymphocutaneous Pulmonary-occurs when the CD4count is <200 cells/mm3 abscesses, pleural effusion,empyema or infiltrates. Spread to contiguous structures with soft tissue swelling common. Indolent or destructive Histopathologically :suppurative,occasionally granulomatous CXR –irregular cavitating nodules,diffuse or reticulonodular infiltrates and pleural effusions

Slide 69: 

CNS:abscesses and granulomas in brain and spinal cord Present with neurological deficits and psychiatric problems Diagnosis: Easily misdiagnosed . On gram stain seen as Gram positive beaded branching filaments which are acid fast Management:In localized disease cotrimoxazole TMP at a 5-10mg/kg and SMX at 25-30mg/kg. If immunocompromised , higher doses are required TMP15mg/kg and SMX 75mg/kg Pulmonary:treat for 6 months } followed by low dose Cerebral: Treat for 12 months } maintenance therapy

Slide 70: 

NON-HODGKINS LYMPHOMA IN HIV 200 fold higher rate in HIV infection and occurs in 8% of HIV-infected patients. 10% of the cases occur with CD4 count < 200 cells/mm3,otherwise a median cell count 100-180 reported In a study done in 35 HIV positive patients in India with lymphoid neoplasms- 24 were NHL, 7 were HL and 4 cases of plasmacytomas. Usually extranodal (95%)involvement with CNS ,bone Marrow,GI and liver. Poor Prognostic factors:Age > 35 yrs, CD4count <100 cells /mm3,IV drug abuse,tumor bulk(stage 3 or 4 disease)

Slide 71: 

OTHER MALIGNANCIES IN HIV Primary CNS lymphoma 1000 fold increase in HIV-positive patients,EBV positive in all these patients. Median CD4cell count <50 cells/mm3 Diagnosis: CT scan/MRI brain, toxoplasma serology –ve EBV PCR +ve in CSF,thallium scans Gold standard:BRAIN BIOPSY 2) Kaposi’s sarcoma –Low incidence in India.1 case of lung KS reported. cough,bronchospasm and dyspnea. CD4<100 cells/mm3 CXR:reticulonodular,interstitial,effusions,hilar LNE Usually skin and mucosal manifestations occur alongside Avoid bronchoscopic biopsy Treatment:chemotherapy

Slide 72: 

IMMUNE RECONSTITUTION IN THE HIV-INFECTED DEF: Acute symptomatic or paradoxical worsening of a pre-existing infection that is temporally related to the recovery of the immune function. Reversal of an immune process: HAART Till 2000, 46 cases of IRS reported in HIV +ve patients Median recovery of CD4counts:26 to 149 cells/mm3 Organisms isolated: M.Tuberculosis, MAC, Cryptococcus, CMV,HBV,HCV and lately Pneumocystis carinii. Median time to developing IRS for bacteria and fungi was 11 days(median), viruses was 42 days . Fever occurred in 75% of mycobacterial and fungal disease But not in viral disease. Features were otherwise similar to actual symptomatic disease

Slide 73: 

MISCELLANEOUS CAUSES OF FEVER Drug fever Malaria Infective endocarditis Typhoid Bacterial pneumonia Disseminated salmonella infection Sinusitis MISCELLANEOUS CAUSES OF PULMONARY DISEASE IN THE HIV-INFECTED Lymphoid interstitial pneumonitis Non-specific interstitial pneumonitis Rhodococcus equii