Immune Reconstitution Inflammatory Syndrome (IRIS) with Acute Tuberculous Osteomyelitis and Disseminated Mutilating Tuberculous Dactylitis in a Person Living with HIV and AIDS (PLHA)

Abstract

HIV infection changed the scenario of infectious diseases. The pre-HAART (highly active antiretroviral therapy) era had resulted in new opportunistic infections. HIV and tuberculosis together had high mortality in countries with high prevalence of tuberculosis. Disseminated and extra pulmonary tuberculosis is common in PLHA (People Living with HIV and AIDS). IRIS (Immune Reconstitution Inflammatory Syndrome) after HAART is common (10% to 25%) in PLHA. Pott's spine is the most common presentation in PLHA of bone and skeletal system. IRIS tuberculosis, especially extra pulmonary tuberculosis, is the most common. In this case, we are presenting an IRIS disseminated tuberculosis in the form of acute osteomyelitis and mutilating dactylitis involving many joints of the fingers. Of 37 cases (9 from India) reported worldwide multiple dactylitis was never presented in the medical journals. This might be the first multiple dactylitis with extensive mutilation to the dactyls due to IRIS in a patient on ART.

Mr M aged 27 years from a town in Villupuram district of Tamil Nadu, India, was admitted on January 20, 2011, with complaints of fever, multiple ulcers, breathlessness, joint pains, and loss of appetite for 7 days. On examination, the patient was found to be toxic, breathless, and febrile with tachycardia but had normal blood pressure. There were multiple ulcers of about 3× 3 cm with hemorrhagic tendencies, over the nose, left calcaneum, left thumb, and right second toe of the foot. He had deformities in the form of fusions of proximal interphalangeal joint, fixed flexion deformity in the ring and middle fingers of right hand with swelling, tenderness, and painful restricted movements, and warmth over these joints. There were swelling and deformity in the left wrist. His other systems were normal. He was diagnosed with multiple disseminated septic cellulitis and investigations were performed.

Patient was a known case of HIV since December 2010,  following up with Government Hospital of Thoracic Medicine, Tambaram. He showed positive for sputum smear acid-fast bacilli (AFB) pulmonary tuberculosis (TB) and was started on CAT I (2 months of isoniazid+rifampicin+ethambutol+pyrizinamide and 4 months of isoniazid+rifampicin thrice weekly) antituberculosis treatment (ATT) from December 6, 2010, and on antiretroviral therapy (ART) with stavudine (d4T) + lamivudine (3TC) + efavirenze(EFV), on December 22, 2010. His initial CD4 count was 17 cells/mm³, and all other investigations were within the normal limits. Cotrimoxazole prophylaxis was also given and he was discharged on January 5, 2011.

In the present admission, sputum AFB was also positive on 2 occasions, but all biochemical tests were normal. The repeat CD4 count taken on February 2, 2011, was 131 cells/mm³. Viral load test was not performed because of the cost and in a national program in India the follow-up is only for CD4 count. Viral load test will be done only when there is a immunological failure per the World Health Organization.

Figure 1 shows the x-ray of the left foot with calcaneum, showing osteolytic lesions with some new bone formation.

Figure 1.

Calcaneal ulcer and osteomyelitis

Figure 2 shows the x-ray of the right foot, showing osteolytic lesion in tarsals with soft tissue swelling.

Figure 2.

Foot ulcers and osteolytic lesions

Figure 3 shows the x-ray of the middle and ring fingers of the right hand, showing reactive osteoporosis with osteolytyic lesions in the lower end of the metacarpals.

Figure 3.

Hand lesions and osteolytic lesions

Swabs taken from pus from calcaneum for non-TB culture and sensitivity grew Klebsiella pneumoniae. The AFB swab from the wound was positive on 2 occasions. The swab was negative for fungi and gram staining, revealing the absence of other infections including nocardial filaments. Screening for Cryptococcus was also negative. Biopsy from the calcaneal lesions showed nongranulomatous lesion and did not show any evidence of malignancy.

The patient was treated for 14 days with cloxacillin (1 g intravenously [IV] twice daily) and ceftriaxone (2 g IV once daily) for septicemia and Klebsiella infection. The patient responded well, and the toxicity and fever subsided after 7 days. During this period, cotrimoxazole was also continued.

With these findings, diagnosis of HIV, acute tuberculous osteomyelitis of calcaneum, disseminated mutilating tuberculous dactylitis was made. Since there is a raise in CD4 count from 17 to 131 cells/mm³, the immune reconstitution inflammatory syndrome (IRIS) was considered.

After 2 months of inpatient treatment, he was discharged with his calcaneal ulcer unhealed. His lesions in the hand healed with fixed deformities with restricted movements of joints. The patient never returned to treatment. On inquiry, the patient was discovered to have died from the disease.

Discussion

Prevalence of HIV among patients with TB is estimated at 4.8% (95% CI: 4.1%-5.7%). ¹ Tuberculosis is common in patients living with HIV/AIDS (PLHA). It is estimated that annually 3% to 8% of PLHA develop TB. Almost 50% to 60% of PLHA develop TB in their life time. Disseminated tuberculous lesions are more common in PLHA than in immunocompetent patients. Involving the extra pulmonary sites is more common in PLHA than in immunocompetent patients. Musculoskeletal TB forms 1% to 3 % of all tuberculous cases. Mycobacterium tuberculosis takes 1 to 5 years to manifest as skeletal disease. ²

In a pediatric hospital in Melbourne, Australia, 37 cases of dactylitis in immune-competent patients, ³ in the past 17 years, were reviewed. In this analysis, only 9 cases are reported in children from India. In most of the cases in this series, only single joint of the distal phalanges was involved and all were non-PLHA patients.

This patient was discharged 2 weeks before this admission as a case of PLHA/PT/sputum positive with ATT and ART without any bone or skin lesions or pain or bone and joint deformity. He had developed these mutilating lesions within 2 weeks; but in healthy children and in adults, it takes months to years before the bone and joints are affected with TB. So a tuberculous lesion from lungs getting disseminated so acutely and causing mutilations is seen very rarely. Involvement of dactylitis is more common in children than in adults. ³ So far all the cases reported are only in immunocompetent patients. This must be the first case to be involved in PLHA. Most of the cases, both in children and adults, presented with a single dactyl as one form of extra-pulmonary dissemination of TB. The involvement of calcaneal bone and multiple dactyls with severe deformity and swelling is very uncommon as seen in this patient. It may be due to the low CD4 count in this patient.

Multidrug resistent tuberculosis (MDRTB) and atypical tuberculous infections were not thought of as deferential diagnosis because the sputum turned negative for AFB after 1 month of antituberculous treatment and all the dactyl lesions healed with some fixed deformities. The smear from calcaneum also turned negative after 1 month of ATT.

Another aspect of adding highly active antiretroviral therapy resulted in CD4 count increase and precipitating immune reconstitution inflammatory syndrome must also be considered which is also very common in PLHA. The incidence of IRIS is between 10% and 25% in various studies, tuberculous IRIS being the most common. ⁴

The minimum criteria required to diagnose IRIS are (a) temporal association between initiation of ART and subsequent development of symptoms (usually within 3 months), (b) evidence of immune restoration (decrease in plasma HIV RNA level by more than 1 log₁₀ copies/mL and an increase in CD4 count from baseline), and (c) clinical symptoms and signs consistent with an inflammatory process.

Colebunders et al ⁵ reported that in resource-limited settings, a confirmed case of tuberculous IRIS must have the following 3 criteria (a) new/worsening radiological signs, (b) good virological response and/or increase in CD4 count and/or conversion of tuberculin skin testing from negative to positive, and/or adequate adherence to ART and TB treatment, and (c) exclusion of treatment failure or other opportunistic infections (OIs), tumors, or allergic reactions. In this patient all 3 criteria were found and hence it is IRIS.

International Network for the Study of HIV-associated IRIS (INSHI) case ⁵ definition for paradoxical TB-IRIS says that 1 major criterion or 2 minor clinical criteria are required after 3 months of ART initiation, reinitiation, or regimen change. Its major criteria are (a) new or enlarging lymph nodes, cold abscesses, or other focal tissue involvement and (b) new or worsening serositis, central nervous system TB, radiological features of TB. The minor criteria are new or worsening constitutional symptoms, respiratory symptoms, abdominal pain accompanied by peritonitis, hepatomegaly, splenomegaly, or abdominal adenopathy after excluding TB drug resistance, poor adherence to treatment, drug toxicity, and another opportunistic infection. Here the required clinical criteria suggested by INSHI is IRIS.

French et al^5,6 suggested 2 major criteria or 1 major and 2 minor criteria for IRIS diagnosis. The major criteria are the OI presenting with atypical presentation like (a) localized disease, (b) exaggerated inflammatory response, (c) atypical inflammatory response, and (d) organ dysfunction and enlargement after initial response to treatment and ART. The next major criterion HIV RNA levels falling to >1 log copies/mL. The minor criteria are (a) increase in CD4 count, (b) increased immune response, and (c) spontaneous response to ART. In this case, one of the major criteria namely exacerbated inflammatory response, atypical response and organ dysfunction, or enlargement was present. One minor criterion of increase in CD4 was also present indicating it is IRIS.

According to Robertson et al, ⁶ IRIS can be diagnosed with the required criteria and supportive criteria. Required criteria are (a) worsening symptoms of inflammation or infection, (b) temporal relationship with ART, (c) symptoms not explained by new OI or course of OI or old OI, and (d) HIV viral load falling to  > 1 log copied/mL. In this case, all the suggested required criteria for IRIS diagnosis were present, except for viral load suppression. Here the viral load testing is not done as it is not possible in a programmatic set up due to its high cost. They also suggest supportive criteria of (a) increases in CD4 count and (b) well-formed granuloma or exuberant inflammation. Only 1 supportive criterion of increased CD4 count is seen in this case.

The biopsy did not show any granuloma in the lesion when tested with AFB. The reasons may be due to the low CD4 count, and it could have been in the stage of acute tuberculous lesion before the graunuloma is formed. Although Robertson et al reported that the presence of granuloma is a supportive criterion, they have not studied any mean duration of time for it to develop. In this case, it may be very early to form a granuloma as only 15 days had passed since the IRIS occurred and the biopsy was taken. There are studies that show the biopsy without granuloma in proved TB lesions.