Distinguishing viruses responsible for influenza-like illness

Division Of Allergy And Immunology

Sosa AC, Kariuki B, Gan Q, Knutsen AP, Bellone CJ, Guzman MA, Tomatsu S, Barrera LA, Tomatsu S, Chauhan AK, Armbrecht E, Montaño AM. Induction of oral tolerance to improve enzyme replacement therapy in Morquio syndrome. J Clin Invest 130(3):1288-1300, 2020. PMID: 31743109 March

Knutsen AP. Allergic bronchopulmonary aspergillosis in asthma. Exp Rev of Clin Immunol 13(1):11-14, 2017. PMID 27599560 January

de la Morena MT, Leonard D, Torgerson T, Cabral-Marques O, MD, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla F, Kanariou M, Damrongwatanasuk R, Kuo C, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter, MD, DiGiovanni D, MD, Dhalla F, MD, Farmaki E, Speckmann DC, Espanol T, Shcherbina A, Hanson C, Litzman J, Routes J, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JDM, Chou J, Abbott J, van Montfrans J, Gonzalez-Granado LI, Bunin N, Kutukculer N, Gray P, Gisela S, Pasic S, Aquino V, Wysocki C, Abolhassani H, Gruebaum E, Dorsey M, Cunningham-Rundles C, Knutsen AP, Sleasman J, Chapel H, Ochs H, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo L, Roifman C. Long term outcomes of 176 patients with X-linked hyper IgM syndrome. J Allergy Clin Immunol 139:1282-1292, 2017. PMID 27697500 April

Borte M, Melamed I, Pulka G, Pyringer B, Knutsen AP, Ochs HD, Kobayashi RH, Kobayashi AL, Gupta S, Strach M, Smith W, Pituch-Noworolski A, Moy J. Efficacy and safety of human intravenous immunoglobulin 10% (Panzyga) in patients with primary immunodeficiency diseases: a two-stage multicentre, prospective, open-label study. J Clin Immunol 37:603-612, 2017 PMID 28755067 August

Dhandha MM, Siegfried EC, Knutsen AP. Treatment of selective antibody deficiency with IVIG resulting in decreased frequency of Streptococcal infection and improvement of guttate-psoriasis. Dermatol Online J 23(9):1-6, 2017. August

Caruthers C, Fernandes H, Shams A, Rodrigues J, Bhatla D, Knutsen AP. Outcomes for umbilical cord blood transplantation in severe combined immunodeficiency disorders: Ten-year experience. Pediatr Allergy Pulmol Immunol 30(3):171-180, 2017. September

Heimall J, Logan BR, Cowan MJ, Notarangelo L, Griffith LM, Puck JM, Kohn D, Pulsipher MA, Parikh S, Martinez C, Kapoor N, O'Reilly R, Boyer M, Pai SY, Goldman F, Burroughs L, Chandra S, Kletzel M, Thakar M, Connelly J, Cuvellier G, Davila B, S hereck E, Knutsen A, Sullivan K, DeSantes K, Gillio A, Haddad E, Petrovic A, Quigg T, Smith A, Stenger E, Yin Z, Shearer WT, Fleisher T, Buckley RH, Dvorak CC. Immune reconstitution and survival of 100 SCID patients post hematopoietic cell transplant: A Primary Immune Deficiency Treatment Consortium Natural History Study. Blood 130(25):2718-2727, 2017 PMID 29021228. December

Kelly BT, Knutsen AP, Routes JM. Difficult cases: bronchiectasis. J Allergy Clin Immunol In Pract 6(1):315-316, 2018. PMID 29310762 January-February

Melamed I, Borte M, Trawnicek L, Kobayashi A-L, Kobayashi RH, Knutsen A, Gupta S, Smits W, Pituch-Noworolska A, Strach M, Pulka G, Ochs H D, Moy JN. Pharmacokinetics of a novel high-yield human intravenous immunoglobulin 10% in patients with primary immunodeficiency diseases: analysis of a phase III, multicentre, prospective, open-label study. Eur J Pharm Sci 118:80-86, 2018. PMID 29522908 March

Lee J, Becker B, Kirby A, Knutsen AP. Chromosome 1q23.3q31.1 deletion associated with decreased newborn screening of T cell receptor rearrangement circles (TRECs). Ann Allergy Asthma Immunol 121(1): 125-126, 2018. PMID 29653236 July

Foster KJ, Rodrigues JM, Lee J, Powell S, Azmeh R, Knutsen AP. Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome at a single children's hospital. Inter J Allergy Medications 4(2):1-6, August 18, 2018. Doi./org 10.23937/2572-3308.1510034

Rodrigues J, Fernandes HD, Caruther C, Braddock SR, Knutsen AP. Cohen syndrome: review of literature. Cureus 10(9): e3330. Doi:10.7759/cureus.3330 September 18, 2018

Dvorak CC, Hadad E, Buckley RH, Cowan MJ, Logan B, Griffith LM, Kohn DB, Pai S-Y, Notarangelo L, Shearer W, O'Reilly R, Kapoor N, Heimall J, Chaudhury S, Shyr S, Chandra S, Cuvellier G, Moore T, Shenoy S, Goldman F, Smith A, Sunkersett G, Vander Lugt M, Caywood E, Quigg T, Burroughs L, Chandrakasan S, Craddock J, Saldana B, Gillio A, Shereck E, Aquino V, DeSantes K, Knutsen A, Thakar M, Yu L, Puck JM. The genetic landscape of SCID in the Current era. J Allergy Clin Immunol ePub September 5, 2018 PMID 30193840

Ochs HD Melamed I, Borte M, Moy JN, Pyringer B, Kobayashi AL, Knutsen AP, Smits W, Pituch-Noworolska A,. Kobayashi RH. Intravenous immunoglobulin 10% in children with primary immunodeficiency diseases. Immunotherapy 10(14):1193-1202, 2018. PMID 30088423 October

Hadad E, Logan BR, Griffith LM, Buckley RH, Parrott R, Prockop SE, Dvorak CC, Puck JM, Murnane M, Kapoor N, Pulsipher MA, Abdel-Azim H, Hanson IC, Martinez C, Bleesing JJ, Chandra S, Smith AR, Pai S-Y, Jyonouchi S, Sullivan KE, Burroughs L, Skoda-Smith A, Haight AE, Tumlin AG, Quigg TC, Taylor TC, Taylor C, Davila Saldana BJ, Keller MD, Seroogy CM, Desantes KB, Petrovic A, Leiding JW, Shyr DC, Decaluwe H, Teira P, Gillio AP, Knutsen A, Moore TB, Kohn DB, Kletzel M, Craddock JA, Aquino V, Davis JH, Yu LC, Cuvelier GDE, Bednarski JJ, Goldman FD, Kang EM, Shereck E, Porteus MH, Connelly JA, Fleisher TA, Maleck HL, Shearer WT, Szabolcs P, Thakar MS, Vander Lught MT, Heimall J, Yin Z, Cowan MJ, O'Reilly RJ, Notarangelo LD. Genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood 132(17):1737-1749, 2018. PMID 30154114 October

Lam JK, Braddock SR, Huddleston CB, Knutsen AP. Co-existent TBX1 mutation and chromosomal 20q13.13-q13.2 duplication in an infant with abnormal T cell receptor rearrangement excision circle (TREC) newborn screening. Ann Allergy Asthma Immunol 122(2):222-223, 2019. PMID 30712578 February

Knutsen AP, Kariuki B. Allergic bronchopulmonary aspergillosis and fungal allergy in severe asthma. Archives Applied Medicine 1(1):1-19, 2019. May

Marsh R, Leiding JW, Logan BR, Griffith LM, Arnold D, Haddad E, Falcone EL, Yin Z, Patel K, Arbuckle E, Bleesing JJ, Sullivan KE, Heimall J, Burroughs LM, Skoda-Smith S, Chandrakasan S, Yu L, Oshrine BR, Cuvelier G, Thakar M, Chen K, Teira P, Shenoy S, Rhelen R, Forbes L, Chellapandian D, Saldaña BD, Shah A, Weinacht K, Joshi A, Boulad F, Quigg T, Dvorak CC, Grossman D, Torgerson T, Graham P, Prasad V, Knutsen A, Chong H, Miller H, de la Morena MT, DeSantes K, Cowan MJ, Notarangelo LD, Kohn DB, Stenger E, Pai S-Y, Routes JM, Puck JM, Kapoor N, Pulsipher MA, Malech HL, Parikh S, Kang EM. Chronic granulomatous disease-associated IBD resolves and does not adversely impact survival following allogeneic HCT. J Clin Immunol 39(7):653-667, 2019. PMID 31376032 October

Sosa AC, Kariuki B, Gan Q, Knutsen AP, Bellone CJ, Guzman MA, Tomatsu S, Barrera LA, Tomatsu S, Chauhan AK, Armbrecht E, Montaño AM. Induction of oral tolerance to improve enzyme replacement therapy in Morquio syndrome. J Clin Invest 130(3):1288-1300, 2020. PMID: 31743109 March

Yakhmi N, Knutsen AP. Tumor necrosis factor associated periodic syndrome (TRAPS) in a pediatric patient. Ann Allergy Asthma Immunol 125(4):369-371, 2020. PMID 32376455 May

Dorsey M, Wright N, Chiamowitz N, Davila B, Miller H, Keller M, Thakar M, Shah A, Cowan MJ, Buckley RH, Dvorak CC, Griffith L, Haddad E, Kohn DB, Logan B, Notarangelo LD, Pai SY, Puck J, Pulsipher M, Heimall J, Survey Participants: Abu-Arja R, Andolina J, Aquino V, Barnum J, Bednarski JBhatia M, Bonilla F, Butte M, Chandra S, Chandrakasan S, Chaudhury S, Chen K, Chong H, Cuvelier G, Dalal J, DeFelice M. DeSantes K, Forbes L, Gillio A, Goldman F, Joshi A, Kapoor N, Knutsen AP, Kobrynski L, Lieberman J, Oshrine B, Patel K, Prockop S, Quigg T, Quinones R, Roncarolo MG, Schultz K, Seroogy C, Shyr D, Siegel S, Smith A, Torgerson TR, Vander Lugt M, Yu L. Infections in SCID Newborns: Isolation, Infection Screening and Prophylaxis in PIDTC Centers. J Clin Immunol 2020. PMID 33006109 October

Donegan R, Mathew S, Knutsen AP. Complement factor I deficiency in a 4 year old body with glomerulonephritis. Ann Allergy Asthma Immunol 125(5):613-614, 2020. PMID 32687990 November

Dixit C, Thatayatikom A, Pappa H, Knutsen AP. Treatment of severe atopic dermatitis and eosinophilic esophagitis with dupilumab in a 14-year-old boy with autosomal dominant hyper-IgE syndrome. J Allergy Clin Immunol In Practice 16:S2213-2198, 2021 PMID 34280586 July

Knutsen AP, Temprano J, Bhatla D, Slavin RG. Hypersensitivity pneumonitis and eosinophilic lung diseases. In: Wilmott R, Bush V, Deterding RR, Ratjen F, Sly P, Zar H, Li AP (editors), Kendig's Disorders of the Respiratory tract in Children, 9th Edition, Saunders Elsevier Inc, Philadelphia, Chapter 65 2018

Knutsen AP. IgG subclass deficiency. UpToDate (original June 2006) 14.2: 1-8, April 2021

Natural Isoprenoids Are Able To Reduce Inflammation In A Mouse Model Of Mevalonate Kinase Deficiency

Alendronate induced inflammation in BALB/c mice.

Saline solution or alendronate (40 μmol/kg) were given to BALB/c mice at the first day of our experimental plan (day 0). Evaluation of inflammatory markers, SAA and PEC, was done 3 d later (on day 3), considering that this was the time required to obtain the maximum increase of inflammation as reported elsewhere (15,16). Alendronate induced a marked increase in SAA mean level (53.2 μg/mL compared with 0.8 μg/mL with saline) (Fig. 1A) and PEC number (487.5 × 104 cells compared with 79.0 × 104 cells in controls) (Fig. 1B).

Figure 1

SAA levels (A) and PEC number (B) in controls (saline, n = 9), in mice treated with alendronate 40 μmol/kg on day 0 (ALD, n = 16), alendronate 40 μmol/kg on day 0, and MDP 100 μg/kg on day 3 (ALD/MDP, n = 16) or MDP 100 μg/kg alone on day 3 (MDP, n = 9). Data are reported as mean ± SE. Statistical significance was evaluated using a one-tailed t test for unpaired data. *p < 0.05; **p < 0.001.

The inflammatory response to MDP was studied in alendronate treated mice compared with controls. MDP showed a strong inflammatory effect in alendronate-treated mice, both as SAA levels (123.4 μg/mL compared with 53.2 μg/mL in ALD-treated mice) (Fig. 1A), and PEC number (777.5 × 104 cells compared with 487.5 × 104 cells in ALD-treated mice) (Fig. 1B). MDP alone induced only a mild, yet significant, increase in SAA (7.5 μg/mL compared with 0.8 μg/mL in controls) (Fig. 1A).

These data were consistent with the hypothesis that the inhibition of mevalonate pathway could overdraw the physiologic activation of inflammatory process.

GOH reduces the MDP-induced inflammatory response in alendronate/MDP-treated mice.

Hypothesizing that exogenous isoprenoids could rescue the deregulation of mevalonate pathway induced by amino-bisphosphonate, and the related inflammatory response, a natural monoterpene compound, GOH, was implied in our MKD mouse model.

GOH 250 mg/kg, given in two doses at day 0 and 1 significantly reduced SAA level and PEC number in alendronate-MDP-treated mice (SAA: 34.4 μg/mL in alendronate-MDP plus GOH compared with 100.0 μg/mL in alendronate-MDP; PEC: 115.2 × 104 cells in alendronate-MDP plus GOH compared with 744.9 × 104 cells in alendronate-MDP), but not in alendronate-treated ones (Fig. 2). In the same series of experiments, GOH was not able to significantly reduce MDP-induced inflammation.

Figure 2

SAA levels (A) and PEC number (B) in mice treated with alendronate 40 μmol/kg on day 0 (ALD, n = 11); alendronate 40 μmol/kg on day 0 plus geraniol 250 mg/kg on days 0 and 1 (ALD + GOH, n = 11); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (ALD/MDP, n = 8); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus geraniol 250 mg/kg on days 0 and 1 (ALD/MDP + GOH, n = 9); saline on day 0 and MDP 100 μg/kg on day 3 (MDP, n = 6); saline on day 0 and MDP 100 μg/kg on day 3, plus geraniol 250 mg/kg on days 0 and 1 (MDP + GOH, n = 3). Data are reported as mean ± SE. Statistical significance was evaluated using a one-tailed t test for unpaired data. *p < 0.05; **p < 0.001.

The anti-inflammatory effect of GOH in ALD/MDP-mice was also evident in histological analysis of the animal spleens (Fig. 3). The leukocyte infiltration was present in the spleen from alendronate-MDP-treated mice (Fig. 3B), while it was clearly reduced in animals treated with GOH (Fig. 3C).

Figure 3

Hematoxylin and eosin-stained spleen from a control animal (A), a mouse treated with 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (B), and a mouse treated with alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus geraniol 250 mg/kg on days 0 and 1 (C). The infiltration of lymphomonocytic and polymorphonuclear cells is evident in panel B. Treatment of animals with geraniol almost completely prevented the alendronate-MDP-induced leukocyte infiltration. Light microscope magnification: ×40.

This effective dose schedule of administration of the GOH was chosen after some preliminary experiments. ALD/MDP-mice were treated with single dose of GOH at two concentrations (250 mg/kg or 500 mg/kg). It was administered together with (day 0), after (day 1), and before (day −1) alendronate. As described in Fig. 4A, no dose response was seen, whereas an inhibitory effect linked to the day of administration: GOH 250 mg/kg given at day −1 seems to have the best reducing effect on SAA level, but not in a statistical significant way. A second point was investigated: the administration of more than one dose of isoprenoid during the experimental plan. Established that 250 mg/Kg was the minor dose with maximum effect, GOH was given in different daily combination as reported in Fig. 4B. We obtained different inhibitory effect on SAA levels: day −1/0 > day −1/1 > day 0/1. As outlined above, the combination of daily doses seems to be important for the inhibitory effect of GOH. All these data were also reproduced with the other acute response marker, PEC number (data not shown).

Figure 4

(A) SAA levels in mice treated with alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (ALD/MDP, n = 14); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus geraniol 250 mg/kg on day −1 (250 d-1, n = 5), on day 0 (250 d0, n = 4), on day 1 (250 d1, n = 9); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus geraniol 500 mg/kg on day −1 (500 d−1, n = 4), on day 0 (500 d0, n = 4), on day 1 (500 d1, n = 4). (B) SAA levels in mice treated with alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (ALD/MDP, n = 12); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus geraniol 250 mg/kg on day −1 and 0 (250 d−1/0, n = 4), on day 0 and 1 (250 d0/1, n = 9), on day −1 and 1 (250 d−1/1, n = 6), and plus geraniol 500 mg/kg on day 0 and 1 (500 d0/1, n = 4). Data are reported as mean ± SE. Statistical significance was evaluated using a one-tailed t test for unpaired data. *p < 0.05; (3B) geraniol 250 d0/1 vs ALD/MDP p = 0.0046; geraniol d-1/1 vs ALD/MDP p = 0.0223.

Other isoprenoids are differently effective on alendronate-MDP-induced inflammation.

We studied the effect of two other isoprenoid compounds, GGOH and FOH, previously used to rescue the mevalonate pathway inhibition in cellular models (8,17). The compounds were first used in ALD/MDP-treated mice, at the same concentration (250 mg/kg) and timing (days 0 and 1) chosen for GOH (Fig. 5).

Figure 5

SAA levels (A) and PEC number (B) in mice treated with alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (ALD/MDP, n = 4); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus geranylgeraniol 250 mg/kg on days 0 and 1 (ALD/MDP + GGOH d0/1, n = 4). SAA levels (C) and PEC number (D) in mice treated with alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (ALD/MDP, n = 4); alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus farnesol 250 mg/kg on days 0 and 1 (ALD/MDP + FOH d0/1, n = 4). Data are reported as mean ± SE. Statistical significance was evaluated using a one-tailed t test for unpaired data. *p < 0.05.

GGOH significantly reduced both SAA (Fig. 5A) and PEC levels (Fig. 5B) (SAA: 57.3 μg/mL in alendronate-MDP plus GGOH compared with 165.6 μg/mL in alendronate-MDP; PEC: 270 × 104 cells in alendronate-MDP plus GGOH compared with 886.2 × 104 cells in alendronate-MDP).

On the other side, inflammation was not totally rescued by FOH, which was able only to significantly lower peritoneal infiltration (Fig. 5D) (PEC: 233.767 × 104 cells in alendronate-MDP plus FOH compared with 949.2 × 104 cells in alendronate-MDP) and not SAA (Fig. 5C).

To exclude a dose-dependent failure of FOH in reducing SAA levels, we repeated the experiments doubling the dose of the compound (500 mg/kg) and considering single dose administration (at days 0, 1, and −1), and 2 d combinations (at days 0/1, ×1/0, and ×1/1) on ALD/MDP-mice.

A substantial inhibition both of SAA (Fig. 6A) and PEC numbers (Fig. 6B) was obtained when FOH was given together (day 0) and the day after (day 1) or together (day 0) and the day before (day −1) the alendronate stimulus. A statistical significant decrease was observed for SAA at day −1/0 and for PEC at day 0/1. We hypothesized that increasing number of mice series could give significant values also for the other daily combination (day 0/1 for SAA, and day −1/0 for PEC).

Figure 6

SAA levels (A) and PEC (B) number in mice treated with alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3 (ALD/MDP, n = 7), alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus farnesol 500 mg/kg on day 0 (d0, n = 4), 1 (d1, n = 4) and −1 (d−1, n = 4). Alendronate 40 μmol/kg on day 0 and MDP 100 μg/kg on day 3, plus farnesol 500 mg/kg on days −1 and 0 (d−1/0, n = 4), 0 and 1 (d0/1, n = 4), −1 and 1 (d−1/1, n = 4). Data are reported as mean ± SE. Statistical significance was evaluated using a one-tailed t test for unpaired data. *p < 0.05.

Discussion and conclusions.

The pathogenesis of the inflammatory phenotype associated to MKD is still not known. It has been hypothesized that inflammatory disorder could be due to a defect in isoprenoid intermediates downstream MK (8). Many studies (1,18,19) were done to investigate the pathogenesis of the disease and to find out an etiologic treatment both for inflammatory symptoms, and especially for severe complications such as amyloidosis and neurological impairment.

Recent findings suggest a pro-inflammatory role of statins and aminobisphosphonates, two classes of molecules involved in the inhibition of cholesterol metabolism, respectively, upstream (HMGCoA reductase) (20) or downstream MK (geranylgeranyl-pyrophosphatase) (8–14).

Starting from these data, we treated BALB/c mice with the aminobisphosphonate alendronate. According to previous research (15,16), alendronate leads to a statistical significant increase of acute phase markers (Fig. 1). To optimize this MKD model and to reproduce, at least in some aspects, the typical periodic inflammatory episode, often induced in patients by mild stimuli, such as a vaccination (6), bacterial MDP was administered to mice as second boost. As expected, the coadministration alendronate plus MDP triggered an acute condition significantly higher than the alendronate alone (Fig. 1). Other authors (15,16) used LPS instead of MDP in alendronate-treated mice, with similar results. In our study, MDP was preferred because it was much better tolerated than LPS by the animals, and because it better represents the "mild stimulus" capable to induce a MKD episode.

Recently, the effect of some natural isoprenoid compounds was tested in vitro on peripheral blood cells of HIDS patients, and a partial rescue of inflammatory phenotype was obtained (21). We decided to test the anti-inflammatory effect of these compounds in our MKD-like mice, hypothesizing a possible future use in the human condition.

Exogenous isoprenoid intermediates, GOH, FOH, and GGOH, were administered in alendronate-MDP-treated mice with different results. GOH 250 mg/kg—given together and the day after alendronate—was able to reduce inflammation in alendronate-MDP-treated mice, counteracting the aminobisphosphonate effect (Fig. 2). These data were supported also by the diminished leukocyte infiltration in the spleen from alendronate-MDP mouse treated with GOH (Fig. 3).

These data were partially reproduced using the other two isoprenoids. GGOH—at the same dose and timing of GOH—reduced inflammation in alendronate/MDP-mice, as demonstrated by SAA and PEC levels (Fig. 5). FOH was able to inhibit both SAA levels and PEC values, but only where it was administered in a double dose (500 mg/kg) in two daily injections (Fig. 6).

Our data strengthened previous observations about an important role of isoprenoids in inflammation (8,21–25), even if they do not explain how isoprenoids mediate this event. These compounds play an important role in different biological function, including protein prenylation and production of steroid hormones and biologically active terpenes. It seems unlikely that the alteration in prenylation might have a role in the inflammatory phenotype, as it was proven that prenylation of target proteins Ras and RhoA is normal in fibroblasts of MKD patients (10) and that proteins such as Rho have a positive role in inflammation (26). Thus, the inflammatory phenotype associated with the mevalonate pathway deficiency could be due to the lack of other biological actions of isoprenoids. It is of interest that presqualene-diphosphate has been shown to be an important counter-regulatory lipid in inflammatory activation of neutrophils (27).

Furthermore, farnesylation seems to play an important role in innate immune response. It was recently reported that a farnesyl-transferase inhibitor (Tipifarnib) was able to reduce the expression of many LPS-induced genes, probably targeting a protein of the TLR4 signaling pathway (28).

The different anti-inflammatory effective dose observed in this study for the three isoprenoids could be explained considering that FOH probably enters the pathway of farneslyation rather than geranylgeranylation, as we suppose for GOH and GGOH. Differences in intracellular concentration, phosphorylation to the pyrophosphate-form, interference with enzymatic activity, or still unknown collateral biochemical pathways, are more likely to account for the difference in anti-inflammatory effect observed between different compounds.

It will be interesting to use GOH and other isoprenoids in the recent published heterozygous MVK deficient mouse (29). MVK± mouse represent the first animal model of MKD. Even if, in this mouse, the enzyme activity is reduced to about a half compared with the 1 to 8% residual MK activity in MKD patients, the authors reported that the loss of a single MVK allele in the mouse results in an immunologic disorder very similar to the human MKD phenotype.

In conclusion, we hypothesize that the inflammatory phenotype observed in MKD and in aminobisphosphonate-treated mice is due to the lack of mevalonate-derived isoprenoids. Although further research will be necessary to identify which of these molecules is mainly involved in the observed anti-inflammatory activity, our data support the idea of developing and testing isoprenoid-based treatment for MKD.

Squeezed By The Dengue Fever Outbreak In Kendari

Lina recounted that her first child had been having a fever for the past two weeks. After Nasyah had a fever for several days, she took her to the Poasia Community Health Center, which is located near their residence. There, Nasyah was diagnosed with a common fever.

After a few days, the fever did not subside. She took her child back to the clinic, but was only given fever-reducing medication. In the second week, she couldn't stand seeing her child cry with a high fever and decided to take him to Kendari General Hospital.

Upon arrival, Nasyah was examined and given an IV drip. Nurses also take blood samples to find out the exact disease they are suffering from. Doctors and nurses said Nasyah was infected with DHF.

"I didn't expect the queue to be this long. I came at 10.00 Wita, but because the emergency room was full, I had to be treated in the lobby first," said Lina, exactly when the time showed 15.00 Wita.

Together, they sat in green plastic chairs, like seven other patients who were also being treated temporarily.

KOMPAS/SAIFUL RIJAL YUNUS

Patients are being infused on plastic chairs in the emergency room of the Kendari Regional Public Hospital in Southeast Sulawesi on Monday (25/3/2024). Some of them are infected with dengue fever, causing the hospital to be full. Ten people have died as a result of this outbreak in 2024.

Sitting impatiently three seats away, Ati (67) is frustrated. Along with four of her family members, she came from Konawe Utara to be referred to that hospital. She was diagnosed with dengue fever and needs further treatment.

"Yesterday he was treated at the North Konawe Regional Hospital, but was referred here," he said softly. He also hasn't received confirmation of the room.

According to the Health Department of Kendari, since January 2024, the total number of dengue fever cases has reached 1,505 cases. Out of these, 1,452 cases have been reported to have recovered, while 10 patients have died.

Also read: Dengue Fever Cases in Kendari Continue to Increase, 10 People Die

The Director of Kendari Regional Hospital, Sukirman, on Tuesday (26/3/2024), conveyed that a number of patients had to be temporarily treated in the hallway due to the full ward. Based on coordination with BPJS Health and other parties, residents who came were eventually treated with limited conditions.

For more than the past two months, he explained, the number of patients coming in has continued to increase. Most of them are cases of dengue fever. In the hallways, patients wait for empty rooms or spaces to become available.

"We cannot refuse patients, especially when their condition requires medical attention. Moreover, we know that other hospitals in Kendari are also full," he said.

Kendari Regional Hospital can accommodate 215 patients. However, the current condition is estimated to number 250 patients.

KEMENTERIAN KESEHATAN

Data on the death rate due to dengue fever in Indonesia in 2022.

Not only at Kendari Regional Public Hospital, but several other hospitals are also full. Ahmad (27), another resident of Kendari, revealed that three of his family members are now infected with dengue fever. They were fortunate enough to be helped as one of them is a police personnel who can be treated at Bhayangkara Hospital.

"It was full too. Now the difficult thing is fogging. "We have asked, but we can't because we are limited," he said.

Also read: Trend of Death Rate due to Dengue is Increasing

Acting Head of the Kendari Health Department, Dr. Fauziah, stated that since January 2024, cases of dengue fever have indeed continued to increase. As many as 10 patients have died in several hospitals in this region.

"To be frank, the cases have continued to increase. Since the beginning, there have been several joint efforts in various layers of society," said Fauziah in Kendari on Monday (25/3/2024).

According to Fauziah, several steps have been taken by her team in handling the issue. Prevention measures have been implemented since earlier times, ranging from socialization to education, especially for environmental cleaning activities. Not only that, her team also recommends residents with dengue fever symptoms to immediately seek treatment.

KOMPAS/SAIFUL RIJAL YUNUS

A nurse is administering medication via an IV drip in the emergency room lobby of Kendari Regional General Hospital in Southeast Sulawesi on Monday (3/25/2024). Dengue fever patients are overflowing and filling up the hospital. A total of 16 patients have died in Southeast Sulawesi due to the illness transmitted by mosquitoes.

Additionally, environmental spraying efforts are also continuously being carried out. However, for some time, these efforts have been limited due to resource constraints. Personnel have finally been added from the BPBD and Satpol PP Kendari.

Based on records from the Sultra Provincial Government, the number of dengue fever cases in this province reached 3,287 cases. The total number of patients who died reached 16 people.

In addition to Kendari, several other regions also experience a high increase in cases. In South Konawe, for example, there are a total of 607 cases with four deaths. Meanwhile, in Konawe there are a total of 266 cases with one death.

The Ministry of Health has placed Sultra as the province with the highest number of dengue fever cases until the third week of March 2024. Above Sultra, there are West Java and East Java which have tens of millions of inhabitants, a far cry compared to Sultra's only 2.7 million population.

The epidemiologist from Halu Oleo University, Ramadhan Tosepu, explained that cases of dengue fever are an annual occurrence and have a periodic cycle. An increase in cases always occurs at the beginning of the year, especially from January to March.

Early anticipation should have been carried out since October to December. Socialization and environmental clean-up should be promoted so that when the rainy season comes, the community's preparations are already complete.

"This looks like indifference and delay in handling," he said.

On the other hand, he hopes that currently all parties are expected to focus on handling it. Especially preventing the disease from spreading further into the environment and infecting the community.

SAIFUL RIJAL YUNUS

Officials from the Kendari Health Department in Southeast Sulawesi conducted fumigation in areas where dengue fever cases were identified on Thursday (4/11/2021). The number of cases continues to increase, with a total of four fatalities.

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