Immune restoration disease in HIV patient.We describe a severely immunosuppressed HIV-1-positive man in whom immune restoration disease associated with pulmonary infection caused by Mycobacterium microti developed after antiretroviral treatment. The diagnosis was made by using convenient spoligotyping techniques, but invasive investigations were required to exclude a tumor.
During the first few months of highly active antiretroviral treatment, immune restoration may be complicated by clinical events in which either previously subclinical infections are found or preexisting pre·ex·ist or pre-ex·ist
v. pre·ex·ist·ed, pre·ex·ist·ing, pre·ex·ists
To exist before (something); precede: Dinosaurs preexisted humans.
v.intr. partially treated opportunistic infections deteriorate. This condition, termed immune restoration disease (IRD), is thought to be caused by the improvement in the host's immune response to pathogens. We report what we believe is the first recorded case of IRD with confirmed Mycobacterium microti infection. M. microti is an unusual infection associated with small rodents. Novel genetic techniques have confirmed it as a human pathogen, but its true incidence remains unclear.
A 33-year-old man was admitted to the hospital in 2002 with a 3-month history of intermittent hemoptysis Hemoptysis Definition
Hemoptysis is the coughing up of blood or bloody sputum from the lungs or airway. It may be either self-limiting or recurrent. Massive hemoptysis is defined as 200-600 mL of blood coughed up within a period of 24 hours or less. . He had previously visited hematology outpatient clinics for many years for hemophilia A (3%-5% factor VIII) and HIV-1 had been diagnosed in 1996 (a stored sample from 1989 retrospectively tested HIV-1-antibody positive). CD4 cell counts had been recorded as 434 x [10.sup.6]/L in 1996 and 260 x [10.sup.6]/L in 1998. After this time, he failed to attend any further clinic appointments.
In addition to worsening hemoptysis, he had minor weight loss but no night sweats. He appeared moderately unhealthy, with oral thrush and mild splenomegaly splenomegaly /sple·no·meg·a·ly/ (-meg´ah-le) enlargement of the spleen.
congestive splenomegaly Banti's disease; splenomegaly secondary to portal hypertension. . A chest radiograph radiograph /ra·dio·graph/ (-graf?) the film produced by radiography.
n. showed left upper lobe shadowing (Figure 1, panel A), sputum smears contained numerous acid-fast bacilli, and sputum was sent for culture, speciation speciation
Formation of new and distinct species, whereby a single evolutionary line splits into two or more genetically independent ones. One of the fundamental processes of evolution, speciation may occur in many ways. , and sensitivity testing. Blood tests showed a CD4 cell count of 6 x [10.sup.6]/L and HIV viral load HIV viral load AIDS A measure of the amount of HIV RNA in blood, expressed as number of copies/mL of plasma. See AIDS, HIV. of 272,000 (log 5.4) copies/mL. His hemoglobin was 12.1 g/dL, leukocyte count 4.9 x [10.sup.-9]/L, and platelets 367 x [10.sup.9]/L. Renal and liver function test results were normal, apart from a 7-glutamyltransferase level of 200 U/L (normal <35 U/L). An ultrasound scan of his abdomen showed a diffuse increase in liver echogenicity and an enlarged (13.6-cm) spleen. He was naturally immune to hepatitis B, and tests for hepatitis C antibody and viremia were negative.
He was given broad-spectrum antimycobacterial therapy (rifampin, isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. , pyrazinamide, ethambutol ethambutol /etham·bu·tol/ (e-tham´bu-tol) an antibacterial, specifically effective against Mycobacterium; used with one or more other antituberculous drugs in the treatment of pulmonary tuberculosis, administered as the , and azithromycin) as treatment for both M. tuberculosis complex (MTB complex) and opportunistic mycobacteria. He improved throughout a 2-week hospital stay and highly active antiretroviral therapy Noun 1. highly active antiretroviral therapy - a combination of protease inhibitors taken with reverse transcriptase inhibitors; used in treating AIDS and HIV
drug cocktail, HAART (HAART HAART highly active antiretroviral therapy.
HAART Highly active antiretroviral therapy, triple combination therapy AIDS The concurrent administration of 2 nucleoside reverse transcriptase inhibitors–eg, AZT and 3TC, and a protease ) was begun. It consisted of zidovudine and lamivudine and an increased dose of efavirenz efavirenz /ef·a·vi·renz/ (ef´ah-vi?renz) an antiretroviral, inhibiting reverse transcriptase; used in the treatment of HIV infection.
n. (800 mg daily) because of concomitant rifampicin therapy, together with cotrimoxazole for prophylaxis against Pneumocystisjirovecii.
At a 3-week follow-up appointment, the patient had continued to improve. No further hemoptysis had occurred, and he had gained 2 kg body weight. After that, by telephone, he complained of occasional fevers and malaise but declined to be seen. Nine weeks after his initial visit, he came to the ward and with symptoms of breathlessness, nausea, and diarrhea. He had fevers spiking to >38[degrees]C, and newly palpable lymph nodes were evident in the right axilla axilla /ax·il·la/ (ak-sil´ah) pl. axil´lae [L.] the armpit.ax´illary
n. pl. ax·il·lae
See armpit. and over the left parotid gland. A chest radiograph showed increased shadowing (Figure 1, panel B) and a computed tomographic (CT) scan of the chest showed a 6x3-cm solid mass in the upper left chest with visible air bronchograms and minor volume loss, reported as "almost certainly solid neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. " (Figure 2). A bronchoscopy Bronchoscopy Definition
Bronchoscopy is a procedure in which a cylindrical fiberoptic scope is inserted into the airways. This scope contains a viewing device that allows the visual examination of the lower airways. , before which the patient received factor VIII, showed an area of irregular nodular nodular
marked with, or resembling, nodules.
see nodular fasciitis (below).
a firm painless nodular swelling, 0. tissue in the posterior segment of the left upper lobe. His CD4 count was 26 x [10.sup.6]/L.
[FIGURE 1-2 OMITTED]
While we awaited histologic examination results, the patient's medication was withdrawn, and he improved within days. The lymph nodes reduced in size, and the spiking temperature resolved. Eight weeks after admission, the results of IS6110 polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is (PCR PCR polymerase chain reaction.
polymerase chain reaction
Polymerase chain reaction (PCR) ) testing on the slow-growing, positive mycobacterial culture confirmed the presence of MTB complex. The bronchial biopsy specimen showed necrotizing necrotizing /nec·ro·tiz·ing/ (nek´ro-tiz?ing) causing necrosis.
Causing the death of a specific area of tissue. Human bites frequently cause necrotizing infections. granulomatous granulomatous /gran·u·lom·a·tous/ (-lom´ah-tus) containing granulomas.
Resembling a tumor made of granular material. bronchitis; acid-fast bacilli were not visible, and this specimen did not grow any mycobacteria.
The Mycobacterium species was not growing well in the laboratory, but M. microti was identified in the culture with spoligotyping methods (1,2). On extension of culture, the isolate was confirmed as M. microti phenotypically and found to be sensitive in vitro to rifampin, isoniazid, ethambutol, and clarithromycin but resistant to pyrazinamide.
The antimycobacterial drugs were reintroduced without problems 4 weeks later, as was HAART after an additional 8 weeks. Thirty months after restarting antimycobacterial therapy, the patient remained well with a total weight gain of 19 kg, complete radiologic resolution of the pulmonary mass, undetectable HIV viral load (<50 copies/mL), and a progressive rise in his CD4 count to 249 x [10.sup.6]/L.
M. microti is a slow-growing member of the MTB complex. It has most commonly been described in association with small rodents (2,3). Its role as a pathogen in humans has been proposed by a handful of case reports involving both immunocompetent im·mu·no·com·pe·tent
Having the normal bodily capacity to develop an immune response following exposure to an antigen.
im and immunodeficient persons (4-6). Because of the slow growth of the bacterium, confirmatory diagnosis is difficult, and cultures may be wrongly discarded as negative after a routine 8- to 12-week culture period. In such cases several commercial tests can identify the organism to the level of the MTB complex. The members of the tuberculosis complex are not reliably distinguished on biochemical grounds. Restriction fragment length polymorphism restriction fragment length polymorphism
n. Abbr. RFLP
Intraspecies variations in the length of DNA fragments generated by the action of restriction enzymes and caused by mutations that alter the sites at which these enzymes act, changing , DNA fingerprinting, is a time-consuming, slow, and expensive method of distinguishing members. Spoligotyping (spacer oligotyping) is a PCR-based test that can be quickly performed, even on the small amounts of DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. in poorly growing cultures. Strains differ in the size of spacer regions that intersperse direct repeat regions. These polymorphisms create differences in the PCR products produced, a process that allows strain identification (1, 7). Other PCR-based tests are being developed that may have advantages over spoligotyping for identifying some members of the complex (8). Culture remains the standard and allows drug sensitivity testing. We suggest that such cultures be extended for up to 6 months if acid-fast bacilli are noted in specimens from a patient with consistent pulmonary pathologic findings.
Severe immunosuppression associated with HIV-1 can allow coinfections to remain subclinical. After HAART is introduced, IRD can lead to the development of opportunistic infections with atypical and severe clinical signs and symptoms. In this case, necrotizing granulomatous inflammation occurred without isolation of mycobacteria, which is atypical in an immunodeficient HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. patient. These clinical manifestations have been described in many diseases, including MTB and other opportunistic mycobacterial infections (9), herpesvirus herpesvirus, any of the family (Herpesviridae) of common DNA-containing viruses, many of which are associated with human disease. See cytomegalovirus; Epstein-Barr virus; herpes simplex; herpes zoster. infections, and hepatitis B and C (10). Similar granulomatous endobrochial lesions have been described during immune restoration with M. avium complex in HIV-infected patients (11). IRD has been described as occurring in 30% to 40% of those with very low CD4 counts when they begin HAART, developing within the first few months of treatment as the CD4 count rises. IRD is a diagnosis of exclusion diagnosis of exclusion Decision-making A disease or clinical nosology that is extremely rare, and often unresponsive to therapy, the diagnosis of which is seriously considered only when all other possible–potentially treatable conditions–eg 'growing : other processes such as drug fever, resistance, treatment failure, or other infections must be excluded. IRD may be a life-threatening condition, and clinical interventions, such as stopping medications, steroids, or both, may be indicated. An associated increase in markers of immune activation occurs, which seems to vary depending on the pathogen involved (12,13).
In MTB, the major risk factor for IRD is beginning HAART within 2 months of antituberculosis treatment. This fact has led many experts to recommend delaying HAART for 2 months, a strategy that may also reduce the incidence of adverse events. However, a recent retrospective review suggested that delaying HAART would, particularly in those with CD4 cell counts<100 cells x [10.sup.6]/L, lead to significant increase in risk for death and new opportunistic infections (14). IRD should always be considered along with treatment failure if a patient's clinical condition deteriorates after HAART is introduced.
We thank Tony Hart, Malcolm Bennett, and Rachel Cavanagh for advice on M. microti and Ann Barrett and her colleagues in the Health Protection Agency Reference Laboratory, Newcastle, for confirming the identity and antimicrobial sensitivities of the isolate.
Dr Jenkins is a specialist registrar training in infectious diseases at Liverpool and Oxford, United Kingdom. He is also a Wellcome Clinical Training Fellow at the Liverpool School of Tropical Medicine The Liverpool School of Tropical Medicine (LSTM), England, was founded on 12 November 1898, by a donation from Sir Alfred Lewis Jones, a Liverpool Shipowner. The donation of £350 created the first school of its kind. , United Kingdom.
(1.) Goyal M, Saunders NA, van Embden JD, Young DB, Shaw RJ. Differentiation of Mycobacterium tuberculosis isolates by spoligotyping and IS6110 restriction fragment length polymorphism. J Clin Microbiol. 1997;35:647-51.
(2.) Cavanagh R, Begon M, Bennett M, Ergon T, Graham IM, de Haas PEW, et al. Mycobacterium microti infection (vole tuberculosis) in wild rodent populations. J Clin Microbiol. 2002;40:3281-5.
(3.) Wells AQ, Oxon DM. Tuberculosis in wild voles. Lancet. 1937;1:1221.
(4.) Horstkotte MA, Sobottka I, Schewe CK, Schafer P, Laufs R, Rusch-Gerged S, et al. Mycobacterium microti llama-type infection presenting as pulmonary tuberculosis in a human immunodeficiency virus-positive patient. J Clin Microbiol. 2001;39:406-7.
(5.) Niemann S, Richter E, Dalugge-Tamm H, Schlesinger H, Graupner D, Konigstein B, et al. Two cases of Mycobaeterium microti--derived tuberculosis in HIV-negative immunocompetent patients. Emerg Infect Dis. 2000;6:539-42.
(6.) Foudraine NA, van Soolingen D, Noordhoek GT, Reiss E Pulmonary tuberculosis due to Mycobacterium microti in a human immunodeficiency virus-infected patient. Clin Infect Dis. 1998;27:1543-4.
(7.) Van Soolingen D, van der Zanden AGM, de Haas PEW, Noordhoek GT, Kiers A, Foudraine NA, et al. Diagnosis of Mycobacterium microti infections among humans by using novel genetic markers. J Clin Microbiol. 1998;36:1840-5.
(8.) Huard RC, Oliveira Lazzarini LC, Butler WR, van Soolingen D, Ho JL. PCR-based method to differentiate the subspecies of the Mycobacterium tuberculosis complex on the basis of genomic deletions. J Clin Microbiol. 2003;41:1637-50.
(9.) Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis. 2005;5:361-73.
(10.) DeSimone JA, Pomerantz RJ, Babichak TJ. Inflammatory reactions in HIV-1 infected patients after initiation of highly active antiretroviral therapy. Ann Intern Med. 2000; 133:447-54.
(11.) Bartley PB, Allworth AM, Eisen DE Mycobacterium avium complex Mycobacterium avium complex (MAC) is a group of genetically-related bacteria belonging to the genus Mycobacterium. It includes Mycobacterium avium subspecies avium (MAA), Mycobacterium avium subspecies hominis (MAH), and causing endobronchial disease in AIDS patients after partial immune restoration. Int J Tuberc Lung Dis. 1999;3:1132-6.
(12.) Price P, Mathiot N, Krueger R, Stone S, Keane NM, French M. Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy. J Clin Virol. 2001 ;22:279-87.
(13.) French MA, Price P, Stone SF. Immune restoration disease after retroviral therapy. AIDS. 2004;18:1615-27.
(14.) Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV-associated tuberculosis in the era of highly active antiretroviral therapy. J Infect Dis. 2004;190:1670-6.
Neil E. Jenkins, * Mike B.J. Beadsworth, * James J. Anson, * Fred J. Nye, * Vanessa J. Martlew, * and Nick J. Beeching *
* Liverpool School of Tropical Medicine, Liverpool, United Kingdom
Address for correspondence: Neil E Jenkins, Tropical and Infectious Diseases Unit, Royal Liverpool University Hospital The Royal Liverpool University Hospital is a large teaching hospital in Liverpool, England. It is part of the Royal Liverpool and Broadgreen University Hospital NHS Trust and is associated with the University of Liverpool. , Liverpool, Merseyside L7 8XP, UK; fax: 44-151-706-5944; email: nejenkins@ doctors.net.uk
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